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Medicine

Researchers Discover New Factor in Preventing Phenylketonuria, Offering New Treatment Strategy (Medicine)

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Study first to discover long noncoding RNA regulates phenylalanine metabolizing enzyme

Researchers at The University of Texas MD Anderson Cancer Center have discovered a critical new factor in regulating phenylalanine metabolism and, therefore, in preventing the inherited metabolic disorder phenylketonuria (PKU). The research also suggests a possible avenue for new treatments that may be effective for certain patients with PKU.

The study, published today in Science, demonstrates that the long noncoding RNA (lncRNA) HULC directly regulates the metabolic enzyme phenylalanine hydroxylase (PAH). Loss of the lncRNA resulted in excess phenylalanine and symptoms consist with PKU in model systems, whereas applying synthetic mimics of HULC restored PAH activity and lowered phenylalanine levels.

“There is a growing appreciation for the role of long noncoding RNAs in a variety of human diseases, but this is the first discovery of any long noncoding RNA involved with PKU,” said co-senior author Liuqing Yang, Ph.D., associate professor of Molecular & Cellular Oncology. “Our research not only shows that HULC plays a very important role in PKU, but that we may be able to apply this discovery toward developing new treatments for patients who desperately need them.”

Long noncoding RNAs are a form of RNA that do not encode a protein, but instead perform a variety of regulatory roles within the cell. Interested in identifying lncRNA with important biological functions, the researchers began this study by profiling lncRNAs expressed in various organs, both in early life and adulthood.

They discovered HULC, and its murine equivalent Pair, were highly expressed in the adult liver. Hypothesizing this lncRNA may act as a tumor suppressor, the researchers genetically deleted Pair in mouse models. However, rather than developing liver cancer, the Pair knockouts instead developed metabolic symptoms consistent with PKU.

Phenylketonuria and its milder variant hyperphenylalaninemia (HPA) are inherited metabolic disorders marked by an inability to convert the amino acid phenylalanine into tyrosine. These conditions affect roughly 1 in every 10,000 infants, most of whom have mutations in the PAH gene. Untreated PKU can lead to brain damage, intellectual disabilities, seizures and behavioral or psychiatric disorders. However, the only treatments available are a protein-restricted diet and/or supplementation with BH4 – a PAH cofactor.

Upon further examination, the researchers confirmed that Pair knockouts had excessive levels of phenylalanine. Biochemical studies demonstrated that both Pair and HULC bind directly to the PAH enzyme, enhancing its ability to convert phenylalanine into tyrosine.

“Phenylalanine hydroxylase has long been known to be regulated by allosteric factors, but we didn’t know what those factors were until now. This represents the first identification of a non-substrate factor regulating PAH,” said co-senior author Chunru Lin, M.D., Ph.D., associate professor of Molecular & Cellular Oncology. “Synthetic mimics of HULC were able to partially restore enzymatic activity in 13 of 17 different PAH mutants in vitro, representing some of the most frequent mutations seen in PKU.”

The lncRNA mimics used in the study are synthetic nucleotides designed to be more stable and home to the liver for targeting PAH. To further investigate this approach as a possible treatment strategy, the researchers created a mouse model of PKU, carrying the most commonly found mutation in PAH. The HULC mimic improved phenylalanine metabolism as evidenced by a sustained reduction in phenylalanine levels.

Based on these results, the researchers anticipate that HULC mimics may be a useful strategy in treating patients with mutations in both the lncRNA as well as the PAH enzyme. In collaboration with experts at the University Hospital of Nancy Reference Center for Inborn Errors of Metabolism (Nancy, France), the team is working to determine the prevalence of HULC mutations in patients with PKU as a possible alternate cause of the disease.

The team also is pursuing additional laboratory studies to advance HULC mimics toward future clinical studies to evaluate safety and efficacy.

The study was led by Yajuan Li, Ph.D., and Yaohua Zhang, Ph.D., both postdoctoral fellows in Molecular & Cellular Oncology, and Zhi Tan, M.D., Ph.D., now at the Baylor College of Medicine.  A complete list of collaborating authors and their disclosures can be found with the full study here.

Reference: Yajuan Li et al., “A noncoding RNA modulator potentiates phenylalanine metabolism in mice” , Science  06 Aug 2021: Vol. 373, Issue 6555, pp. 662-673. DOI: 10.1126/science.aba4991

Provided by University of Texas M. D. Anderson Cancer Center

Biology

Fasting May Help Ward Off Infections (Biology)

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Fasting before and during exposure to Salmonella enterica bacteria protects mice from developing a full-blown infection, in part due to changes in the animals’ gut microbiomes, according to new research published in PLOS Pathogens by Bruce Vallance and colleagues at University of British Columbia, Canada.

When people or animals develop an infection, they often lose their appetite. However it remains controversial whether fasting protects a host from infection, or increases their susceptibility. In the new study, mice were fasted for 48 hours before and during oral infection with the bacteria Salmonella enterica serovar Typhimurium, a common cause of foodborne illness in people.

Fasting decreased the signs of bacterial infection compared to fed mice, including nearly eliminating all intestinal tissue damage and inflammation. When fasted animals were re-fed for a day after their fast, there was a dramatic increase in Salmonella numbers and invasion into the intestinal walls, although the associated inflammation was still attenuated compared to normal. The results did not hold true when mice were exposed to Salmonella intravenously instead of orally, and analyses of the microbiomes of mice showed significant changes associated with fasting and protection against infection. Moreover, fasting did not fully protect germ-free mice—bred to lack a normal microbiome—from Salmonella, suggesting that some of the protection was due to fasting’s effect on the microbiome. Experiments using the bacteria Campylobacter jejuni confirmed that the effect of fasting was not limited to Salmonella, with similar results seen.

“These data suggest that therapeutic fasting or calorie restriction has the potential to beneficially modulate infectious and potentially non-infectious gastrointestinal diseases,” the researchers conclude.

The researchers add, “Our research highlights the important role that food plays in regulating interactions between the host, enteric pathogens and the gut microbiome. When food is limited, the microbiome appears to sequester the nutrients that remain, preventing pathogens from acquiring the energy they need to infect the host. While more research is needed, fasting or otherwise adjusting food intake could be exploited therapeutically to modulate infectious diseases in the future.”

Reference: Graef FA, Celiberto LS, Allaire JM, Kuan MTY, Bosman ES, Crowley SM, et al. (2021) Fasting increases microbiome-based colonization resistance and reduces host inflammatory responses during an enteric bacterial infection. PLoS Pathog 17(8): e1009719. doi.org/10.1371/journal.ppat.1009719

Provided by Public Library of Science

Biology

Cytokine Increases Production of ‘Beige Fat’ to Burn More Cellular Energy (Biology)

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An immune signal promotes the production of energy-burning “beige fat,” according to a new study publishing August 5th in the open-access journal PLOS Biology by Zhonghan Yang of Sun Yat-Sen University, Guangzhou, China, and colleagues. The finding may lead to new ways to reduce obesity and treat metabolic disorders.

The beige color in beige fat comes from its high concentration of mitochondria, the cell’s powerhouses. Mitochondria burn high-energy molecules like fats and sugars with oxygen, releasing energy. Normally, that energy is stored as ATP, the energy currency that the cell uses for almost all its activities. But in beige fat, mitochondria accumulate a protein called “uncoupling protein-1” that limits ATP production, generating heat instead.

Babies are born with “brown fat,” a similar tissue concentrated in the shoulder region, which helps them stay warm, but brown fat is gradually lost with age. Not so beige fat, which is more widely distributed and which can be generated throughout life in response to both cold and neuronal or hormonal stimulation.

Recent work, including by the authors of the new study, has revealed that cytokines—immune system signaling molecules—play a role in regulation of beige fat. To explore that regulation further, the authors manipulated levels of the cytokine interleukin-25, and showed that an increase in the cytokine could mimic the effects of both cold and stimulation of a hormone receptor in increasing the production of beige fat in mice. They traced the signaling chain further, showing that IL-25 exerted its effects through two other cytokines, which in turn regulated immune cells called macrophages. Those cells acted on neurons that terminate in the beige fat tissue, promoting an increase in production of the neurotransmitter norepinephrine, which was already known to promote beige fat production. Thus, the authors’ work revealed the sequence of regulatory signals that begins with IL-25 and ends with release of norepinephrine and an increase in beige fat.

Finally, the authors showed that administering IL-25 to mice that were eating a high-fat diet prevented them from becoming obese and improved their ability to maintain their responsiveness to insulin, which is impaired in chronic obesity.

“Our results show that interleukin-25 plays a key role in production of beige fat,” Yang said, “and point toward increasing interleukin-25 signaling as a potential treatment for obesity.”

Reference: Li L, Ma L, Zhao Z, Luo S, Gong B, Li J, et al. (2021) IL-25–induced shifts in macrophage polarization promote development of beige fat and improve metabolic homeostasis in mice. PLoS Biol 19(8): e3001348. doi.org/10.1371/journal.pbio.3001348

Provided by Public Library of Science

Medicine

A COVID-19 Biomarker: Low Blood Levels of Sphingosine Predict Symptomatic Infections (Medicine)

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Researchers remain perplexed as to why some patients infected with SARS-CoV-2, the virus responsible for COVID-19, remain asymptomatic while other patients develop severe disease symptoms. This question is once again at the front of mind as the Delta variant spreads across the country. In a new retrospective study, researchers at the Medical University of South Carolina (MUSC) discovered a specific and sensitive biomarker in blood samples that predicts which patients will develop COVID-19 symptoms. Their results, published online on July 9 in Scientific Reports, show that reduced levels of a specific lipid, sphingosine, are significantly associated with developing COVID-19 symptoms. Conversely, elevated levels of sphingosine, as well as a protein involved in its production, acid ceramidase (AC), are associated with asymptomatic infections.

“We developed this project at a time when there wasn’t a successful vaccine,” said Besim Ogretmen, Ph.D., director of the Lipidomics Shared Resource at Hollings Cancer Center and leader of the Hollings Developmental Cancer Therapeutics Research Program. “We wanted to contribute to the field and know which patients who were exposed to this virus would be symptomatic versus asymptomatic.”

Over the past 16 months several waves of SARS-CoV-2 infections in the U.S. have resulted in more than 35 million cases and almost 630,000 deaths. Despite the development of multiple safe and effective vaccines, we are currently experiencing another wave of infections.

The mortality of COVID-19 is thought to result from an overactive immune response to the virus in the lungs of infected patients that causes severe respiratory distress. However, symptoms vary widely, and scientists and clinicians don’t understand why some patients develop severe symptoms while others remain asymptomatic.

“If we can separate asymptomatic patients from symptomatic patients, we can use limited remedies and resources for patients who are more vulnerable.”, said Dr. Besim Ogretmen.

It is known that sphingolipids, a class of molecules that are important for the integrity of the cell membrane and communication between cells, can regulate inflammation and the immune system in response to various infections. The Ogretmen laboratory has decades of expertise in analyzing the production and processing of different lipids, including sphingolipids, using a global measurement method called lipidomics.

Using this expertise, the Ogretmen lab undertook an unbiased analysis of COVID-19 patient serum samples from the MUSC COVID-19 Biorepository to look for changes in sphingolipid levels.

The results were striking.

“Just by looking at the data, you can clearly separate the different patient groups, even without doing technical statistical analyses,” said Alhaji Janneh, lead author and graduate student in the Department of Biochemistry and Molecular Biology.

In asymptomatic patients who tested positive for a SARS-CoV-2 antibody, the researchers found a slight increase in serum sphingosine levels – and only sphingosine – compared to patients who tested negative. Remarkably, in patients who developed COVID-19 symptoms, there was a 15-fold reduction in sphingosine levels. Conversely, almost 75% of asymptomatic patients had elevated AC levels while most symptomatic patients had no detectable AC. The presence of serum AC correlates with the increased levels of sphingosine.

“Can this be an alternative way to predict which patients are the most vulnerable to severe disease?” asked Ogretmen, who is also a professor in the Department of Biochemistry and Molecular Biology and the SmartState Endowed Chair in Lipidomics and Drug Discovery. “If we can separate asymptomatic patients from symptomatic patients, we can use limited remedies and resources for patients who are more vulnerable.”

Overall, there is a 99% probability of correctly determining which patients, who have tested positive for SARS-CoV-2 antibodies, will develop disease symptoms versus remain asymptomatic, using blood levels of sphingosine.

These striking results would not have been possible without the MUSC COVID-19 Biorepository and collaboration with the South Carolina Clinical & Translational Research Institute (SCTR). SCTR set up the biorepository to serve as a resource for COVID-19 research, and SCTR co-principal investigator Patrick Flume, M.D. is its director and one of the authors of the article.

Analyzing levels of various lipids from patient samples is expensive and requires sophisticated equipment, making this type of analysis prohibitive under most circumstances. However, the development of an ELISA-based assay – like those used to diagnose HIV infection – to detect levels of AC could provide a cost-effective alternative that could be widely implemented.

There are several outstanding questions remaining. How does vaccination impact sphingosine levels? How do sphingosine levels change with the introduction of more variants? Nevertheless, the ability to identify at-risk patients quickly could vastly improve treatment of COVID-19 and allow for effective distribution of scarce resources.

Featured image: Dr. Besim Ogretmen (left) and graduate student Alhaji Janneh (right) in the laboratory. © MUSC

Reference: Alhaji H. Janneh et al, Alterations of lipid metabolism provide serologic biomarkers for the detection of asymptomatic versus symptomatic COVID-19 patients, Scientific Reports (2021). DOI: 10.1038/s41598-021-93857-7

Provided by MUSC

Paleontology

A Shocking Discovery in Excavations in Israel: A New Type of Ancient Man Unfamiliar With Science Has Been Discovered (Paleontology)

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The bones of an ancient man who lived in our area until about 130,000 years ago were discovered in excavations at the prehistoric site “Nesher Ramla”

Researchers from Tel Aviv University and the Hebrew University have identified a new type of ancient man at the Nesher Ramla site, who lived in Israel until 130,000 years ago. According to the researchers, the morphology of the human type “Eagle Ramla” is a general morphology, and it shares features both with the Neanderthals (mainly in the teeth and jaw) and with older humans such as Homo erectus (mainly in the skull). At the same time, it is very different from modern man – the structure of the skull is completely different, it has no chin and the teeth are very large. Following the findings of the study, the researchers believe that the ancient human group “Nesher Ramla” is the origin population from which most human populations in the Middle Pleistocene evolved, including the Neanderthals from Europe, and they mated with Homo sapiens who arrived in the area 200,000 years ago. .

Behind the exciting discovery, published in the prestigious journal Science, are two research teams: an anthropological team led by Prof. Israel Hershkovitz, Dr. Hila May and Dr. Rachel Sarig of the Sackler Faculty of Medicine , Dan David Center for Human History Research and the Shmonis Institute of Anthropology, Sitting at the Steinhardt Museum of Nature at Tel Aviv University, and an archeological team led by Dr. Yossi Zeidner of the Institute of Archeology at the Hebrew University of Jerusalem. The excavations at the site were conducted by the Zinman Institute of Archeology, University of Haifa.

The “new” ancient man

“The scientific importance of finding a new type of human allows us to put the fossil world in order, put together another piece in the puzzle of ancient human evolution and understand the journeys he went through around the old world,” says Prof. Hershkovitz. “The” Nesher Ramla “human type is the bridge between the Asian and European populations in the Middle Pleistocene and shows that some of the fossils of the time classified into different species are in fact local geographical orientations of the same group – the Nesher Ramla group.”   

The human fossil was discovered by Dr. Zeidner of the Hebrew University in rescue excavations conducted at the prehistoric site “Nesher Ramla”. This site is located in the mining area of ​​the Nesher cement plant (owned by Len Belvatnik) near the city of Ramla. Many animals such as horses, donkeys and wild bulls, stone tools as well as human bones. Among the bones were also the bones of the “new” ancient man. Was known to science.This is the first type of person defined in the country, and as is customary, the new person was named based on the place of his discovery – “person type Nesher Ramla”.

Dr. Zeidner further noted that “the discovery is extraordinary, we did not imagine that alongside the ancient Homo sapiens, another group of people roamed here who survived to such a late stage in human history. If so far there have not been enough findings regarding this type of person, now a window is opened for us to know more about his lifestyle and culture that were very close to those of Homo spines. “Findings regarding his lifestyle, culture and cultural connections between” Adam Nesher Ramla ” They too are today in the scientific journal Science in a parallel article.

Prof. Hershkovitz adds that the discovery of the ancient man “Nesher Ramla” challenges the accepted view that Neanderthal man originated in Europe. “Until the new findings were revealed, most researchers believed that the Neanderthals were a ‘European story’, with small groups of them having to migrate south with the spread of glaciers in Europe and even arriving in Israel about 70,000 years ago. The man from Nesher Ramla challenges this theory. “Neanderthals in Europe lived in Israel about 400,000 years ago, and from here they migrated (in repeated migrations) west to Europe and east to Asia. The famous Neanderthals of Western Europe are nothing but the remnants of a much larger population living here in the Levant – and not the other way around.”

The research team © Tel Aviv University

According to Dr. May, although unfortunately no DNA has been preserved in the Ramla fossil fossil, the findings could offer a solution to a very big question in human history: how Homo sapiens genes entered the Neanderthal population living in Europe long before Homo sapiens arrived there. In previous studies geneticists studying the DNA of Neanderthals in Europe assumed the existence of a Neanderthal-like population, which they called the “missing population” or “X population”, which mated with the Homo sapiens population at least 100,000 years ago, and its descendants migrated to Europe. -Science, the researchers claim that the person from “Nesher Ramla” represents the same population that is missing in the human fossil evidence. Moreover, the researchers claim that the person from “Nesher Ramla” is not a single find in our area, Like the human fossils from the Tabun Cave that are about 160,000 years old,

The Land of Israel as a melting pot in the old world

“People think in paradigms,” explains Dr. Sarig, “so to this day attempts have been made to associate these fossils with known human groups such as Homo sapiens, Homo erectus, Homo heidelbergensis or Neanderthals, and now we come and say: No – they are a group in themselves with characteristics And special markers. At a later stage small groups of the Nesher Ramle human type also migrated to Europe (in interglacial periods) – where they are known as pre-Neanderthals, and evolved, over time, to become the ‘classic Neanderthals’ we know. Similarly, the archaic Asian populations that carry Neanderthal characteristics (and were considered an evolution from the local Homo erectus) are probably the descendants of populations that migrated from our region (human type Nesher Ramla) eastward towards Asia. Being a crossroads between Africa, Europe and Asia, the Land of Israel was a melting pot in which the various human populations mingled with each other and spread throughout the Old World.

Dr. Sarig believes that this discovery of a new type of man with primordial (archaic) and Neanderthal features, with similarities to fossils from both Europe and East Asia, will lead to the history of Neanderthals being studied differently. More, European-Asian, where the Levant is the starting point or connection point between the two continents.

“The discovery from the Nesher Ramla site writes a new and fascinating chapter in the story of human evolution,” says Dr. Sarig. “A common perception among anthropologists,” says Prof. Hershkovitz, is that “the past changes (according to the findings), only the future is certain.”

Provided by Tel Aviv University

Medicine

The Diagnosis That Will Save Millions Of Lives From Breast Cancer (Medicine)

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Detection of changes in lung tissue, indicating possible development of cancerous metastases, will allow diagnosis and preventive treatment

A new study from Tel Aviv University has revealed changes in healthy lung tissue, which are a preliminary sign of the possible development of cancer cell metastases. The changes were detected in an area known as the ‘microenvironment’ of the tumor, and found in connective tissue cells called fibroblasts. According to the researchers, understanding the metastatic process and diagnosing it at such an early stage may lead to life-saving preventive treatment.

Decipher the ‘black box’ of breast cancer

The study was led by Prof. Neta Erez, Head of the Department of Pathology at the Sackler Faculty of Medicine , along with a team of researchers in her laboratory, Dr. Ofir Shani and Dr. Yael Raz, as well as other researchers from Tel Aviv University, Tel Aviv Medical Center (Ichilov) , From the Sheba Medical Center and the Weizmann Institute The article was published in the journal eLife .

According to the researchers, in many cancers, including breast cancer, patients do not necessarily die from the primary tumor. The deadly cause, in the end, is the metastases, which reach vital organs and thrive there. Even in a patient who has undergone all the proposed treatments, including surgery to remove the primary tumor, followed by chemotherapy treatments and radiation designed to eliminate its remnants, metastases may appear several years later. In the follow-up methods used today, the metastases are detected when the disease is in an advanced stage, and medicine has no effective solutions.

For this reason, Prof. Erez’s group is researching the ‘black box’ – the same period of time between the apparent recovery and the appearance of the metastases, in order to understand the metastatic process and identify it already in the initial stages. The group’s research in recent years has shown that the target tissues in the organs to which the metastases are destined to reach ‘prepare the area’ for their absorption, and create a ‘friendly environment’ for them long before the metastases themselves appear. In the present study, the team looked for signs of these changes, which may be used in the future to identify the process at an early stage. They focused on connective tissue cells (fiber cells), called fibroblasts and found in, among other things, health.

What happens in the microenvironment of the metastases?

“In normal condition, fibroblasts play a key role in healing wounds and tissue damage, but recent studies have shown that cancer manages to recruit them and cause them to produce a supportive environment for it,” explains Prof. Erez.

The researchers performed sequencing of all expressed genes (transcriptomic sequencing) in fibroblast cells taken from the lungs of mice in a breast cancer model. They compared the results of the flooring in cells sampled from healthy lungs, lungs with micro-metastases (tiny metastases that cannot be detected by conventional clinical trials), and lungs with large metastases, in a state of advanced disease. Based on the changes identified from stage to stage, the researchers were able to characterize for the first time the process that takes place in the microenvironment of the cancer metastases, already in the early stages of preparing the surface for their absorption.

In addition, they specifically identified the proteins that drive the ‘rewiring’ processes in fibroblasts, and found that one of the key proteins in the process is Myc  , which is known as a driving factor in accelerating the division of cancer cells. It now turns out that this protein also plays an important role in the change that occurs in fibroblasts towards the absorption of metastases.

“We have been able to characterize processes that occur in seemingly healthy tissues in preparation for the absorption of cancerous metastases. We believe that in the future our findings could help identify the metastatic process before the metastases themselves reach and take root in the target organ. Of millions of people all over the world, “concludes Prof. Erez.

Featured image: Prof. Neta Erez © Tel Aviv University

Reference: Ophir Shani et al, Evolution of fibroblasts in the lung metastatic microenvironment is driven by stage-specific transcriptional plasticity, eLife (2021). DOI: 10.7554/eLife.60745

Provided by Tel Aviv University

Medicine

New Drug Combo Shows Early Potential For Treating Pancreatic Cancer (Medicine)

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Researchers find three immunotherapy drugs given together can eliminate pancreatic tumors in mice.

Pancreatic cancer, which affects about 60,000 Americans every year, is one of the deadliest forms of cancer. After diagnosis, fewer than 10 percent of patients survive for five years. 

While some chemotherapies are initially effective, pancreatic tumors often become resistant to them. The disease has also proven difficult to treat with newer approaches such as immunotherapy. However, a team of MIT researchers has now developed an immunotherapy strategy and shown that it can eliminate pancreatic tumors in mice.

The new therapy, which is a combination of three drugs that help boost the body’s own immune defenses against tumors, is expected to enter clinical trials later this year.

“We don’t have a lot of good options for treating pancreatic cancer. It’s a devastating disease clinically,” says William Freed-Pastor, a senior postdoc at MIT’s Koch Institute for Integrative Cancer Research. “If this approach led to durable responses in patients, it would make a big impact in at least a subset of patients’ lives, but we need to see how it will actually perform in trials.”

Freed-Pastor, who is also a medical oncologist at Dana-Farber Cancer Institute, is the lead author of the new study, which appears today in Cancer Cell. Tyler Jacks, the David H. Koch Professor of Biology and a member of the Koch Institute, is the paper’s senior author.

Immune attack

The body’s immune system contains T cells that can recognize and destroy cells that express cancerous proteins, but most tumors create a highly immunosuppressive environment that disables these T cells, helping the tumor to survive.

Immune checkpoint therapy (the most common form of immunotherapy currently being used clinically) works by removing the brakes on these T cells, rejuvenating them so they can destroy tumors. One class of immunotherapy drug that has shown success in treating many types of cancer targets the interactions between PD-L1, a cancer-linked protein that turns off T cells, and PD-1, the T cell protein that PD-L1 binds to. Drugs that block PD-L1 or PD-1, also called checkpoint inhibitors, have been approved to treat cancers such as melanoma and lung cancer, but they have very little effect on pancreatic tumors.

Some researchers had hypothesized that this failure could be due to the possibility that pancreatic tumors don’t express as many cancerous proteins, known as neoantigens. This would give T cells fewer targets to attack, so that even when T cells were stimulated by checkpoint inhibitors, they wouldn’t be able to identify and destroy tumor cells.

However, some recent studies had shown, and the new MIT study confirmed, that many pancreatic tumors do in fact express cancer-specific neoantigens. This finding led the researchers to suspect that perhaps a different type of brake, other than the PD-1/PD-L1 system, was disabling T cells in pancreatic cancer patients.

In a study using mouse models of pancreatic cancer, the researchers found that in fact, PD-L1 is not highly expressed on pancreatic cancer cells. Instead, most pancreatic cancer cells express a protein called CD155, which activates a receptor on T cells known as TIGIT.

When TIGIT is activated, the T cells enter a state known as “T cell exhaustion,” in which they are unable to mount an attack on pancreatic tumor cells. In an analysis of tumors removed from pancreatic cancer patients, the researchers observed TIGIT expression and T cell exhaustion from about 60 percent of patients, and they also found high levels of CD155 on tumor cells from patients.

“The CD155/TIGIT axis functions in a very similar way to the more established PD-L1/PD-1 axis. TIGIT is expressed on T cells and serves as a brake to those T cells,” Freed-Pastor says. “When a TIGIT-positive T cell encounters any cell expressing high levels of CD155, it can essentially shut that T cell down.”

Drug combination

The researchers then set out to see if they could use this knowledge to rejuvenate exhausted T cells and stimulate them to attack pancreatic tumor cells. They tested a variety of combinations of experimental drugs that inhibit PD-1 and TIGIT, along with another type of drug called a CD40 agonist antibody.

CD40 agonist antibodies, some of which are currently being clinically evaluated to treat pancreatic cancer, are drugs that activate T cells and drive them into tumors. In tests in mice, the MIT team found that drugs against PD-1 had little effect on their own, as has previously been shown for pancreatic cancer. They also found that a CD40 agonist antibody combined with either a PD-1 inhibitor or a TIGIT inhibitor was able to halt tumor growth in some animals, but did not substantially shrink tumors.

However, when they combined CD40 agonist antibodies with both a PD-1 inhibitor and a TIGIT inhibitor, they found a dramatic effect. Pancreatic tumors shrank in about half of the animals given this treatment, and in 25 percent of the mice, the tumors disappeared completely. Furthermore, the tumors did not regrow after the treatment was stopped. “We were obviously quite excited about that,” Freed-Pastor says.

Working with the Lustgarten Foundation for Pancreatic Cancer Research, which helped to fund this study, the MIT team sought out two pharmaceutical companies who between them have a PD-1 inhibitor, TIGIT inhibitor, and CD40 agonist antibody in development. None of these drugs are FDA-approved yet, but they have each reached phase 2 clinical trials. A clinical trial on the triple combination is expected to begin later this year.

“This work uses highly sophisticated, genetically engineered mouse models to investigate the details of immune suppression in pancreas cancer, and the results have pointed to potential new therapies for this devastating disease,” Jacks says. “We are pushing as quickly as possible to test these therapies in patients and are grateful for the Lustgarten Foundation and Stand Up to Cancer for their help in supporting the research.”

Alongside the clinical trial, the MIT team plans to analyze which types of pancreatic tumors might respond best to this drug combination. They are also doing further animal studies to see if they can boost the treatment’s effectiveness beyond the 50 percent that they saw in this study.

In addition to the Lustgarten Foundation, the research was funded by Stand Up To Cancer, the Howard Hughes Medical Institute, Dana-Farber/Harvard Cancer Center, the Damon Runyon Cancer Research Foundation, and the National Institutes of Health.

Featured image: In this pancreatic tumor, T cells (pink) have infiltrated tumor cells (labeled green) following treatment with a novel combination immunotherapy developed by MIT researchers.Credits:Credit: William Freed-Pastor

Reference: William A. Freed-Pastor, Laurens J. Lambert, Zackery A. Ely, Nimisha B. Pattada, Arjun Bhutkar, George Eng, Kim L. Mercer, Ana P. Garcia, Lin Lin, William M. Rideout, William L. Hwang, Jason M. Schenkel, Alex M. Jaeger, Roderick T. Bronson, Peter M.K. Westcott, Tyler D. Hether, Prajan Divakar, Jason W. Reeves, Vikram Deshpande, Toni Delorey, Devan Phillips, Omer H. Yilmaz, Aviv Regev, Tyler Jacks, The CD155/TIGIT axis promotes and maintains immune evasion in neoantigen-expressing pancreatic cancer, Cancer Cell, 2021, , ISSN 1535-6108, https://doi.org/10.1016/j.ccell.2021.07.007. (https://www.sciencedirect.com/science/article/pii/S1535610821003846)

Provided by MIT

Planetary Science

Solving Solar Puzzle Could Help Save Earth From Planet-wide Blackouts (Planetary Science)

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New solar modelling could help predict space weather

Could solar storms knock out the global internet? Yes, but we don’t know when or how it could happen. Mathematician Dr Geoffrey Vasil has proposed a new understanding of the Sun’s convection zone to help.

Lead author of the study Dr Geoffrey Vasil.
Lead author of the study Dr Geoffrey Vasil. Photo: Louise Cooper

Scientists at the University of Sydney and in the USA have solved a long-standing mystery about the Sun that could help astronomers predict space weather and help us prepare for potentially devastating geomagnetic storms if they were to hit Earth.

The Sun’s internal magnetic field is directly responsible for space weather – streams of high-energy particles from the Sun that can be triggered by solar flares, sunspots or coronal mass ejections that produce geomagnetic storms. Yet it is unclear how these happen and it has been impossible to predict when these events will occur.

Now, a new study led by Dr Geoffrey Vasil from the School of Mathematics & Statistics at the University of Sydney could provide a strong theoretical framework to help improve our understanding of the Sun’s internal magnetic dynamo that helps drive near-Earth space weather.

The Sun is made up of several distinct regions. The convection zone is one of the most important – a 200,000-kilometre-deep ocean of super-hot rolling, turbulent fluid plasma taking up the outer 30 percent of the star’s diameter.

Existing solar theory suggests the largest swirls and eddies take up the convection zone, imagined as giant circular convection cells as pictured here by NASA (and published below).

However, these cells have never been found, a long-standing problem known as the ‘Convective Conundrum’.

Dr Vasil said there is a reason for this. Rather than circular cells, the flow breaks up into tall spinning cigar-shaped columns ‘just’ 30,000 kilometres across. This, he said, is caused by a much stronger influence of the Sun’s rotation than previously thought.

“You can balance a skinny pencil on its point if you spin it fast enough,” said Dr Vasil, an expert in fluid dynamics. “Skinny cells of solar fluid spinning in the convection zone can behave similarly.”

The findings have been published in the Proceedings of the National Academy of Sciences of the United States of America.

“We don’t know very much about the inside of the Sun, but it is hugely important if we want to understand solar weather that can directly impact Earth,” Dr Vasil said.

“Strong rotation is known to completely change the properties of magnetic dynamos, of which the Sun is one.”

Artist's image of the internal structure of the Sun. NASA
Diagram showing the internal structure of the Sun based on existing theory that assumes circular convection cells near the solar surface. Dr Vasil’s new model suggests thinner, spinning ‘cigar-shaped’ convection cells driving the Sun’s magnetic dynamo. Image: NASA

Dr Vasil and collaborators Professor Keith Julien of the University of Colorado and Dr Nicholas Featherstone at Southwest Research Institute in Boulder, say that this predicted rapid rotation inside the Sun suppresses what otherwise would be larger-scale flows, creating more variegated dynamics for the outer third of the solar depth.

“By properly accounting for rotation, our new model of the Sun fits observed data and could dramatically improve our understanding of the Sun’s electromagnetic behaviour,” said Dr Vasil, who is the lead author of the study.

In the most extreme cases, solar geomagnetic storms can shower the Earth with pulses of radiation capable of frying our sophisticated global electronics and communication infrastructure.

A huge geomagnetic storm of this type hit Earth in 1859, known as the Carrington Event, but this was before our global reliance on electronics. The fledgling telegraph system from Melbourne to New York was affected.

“A similar event today could destroy trillions of dollars’ worth of global infrastructure and take months, if not years, to repair,” Dr Vasil said.

A solar coronal mass ejection in August 2012

A small-scale event in 1989 caused massive blackouts in Canada in what some initially thought might have been a nuclear attack. In 2012 a solar storm similar in scale to the Carrington Event passed by Earth without impacting, missing our orbit around the Sun by just nine days.

“The next solar max is in the middle of this decade, yet we still don’t know enough about the Sun to predict if these cyclical events will produce a dangerous storm,” Dr Vasil said. 

“While a solar storm hitting Earth is very unlikely, like an earthquake, it will eventually happen and we need to be prepared.”

Solar storms emerging from within the Sun can take from several hours to days to reach Earth. Dr Vasil said that better knowledge of the internal dynamism of our home star could help planners avoid disaster if they have enough warning to shut down equipment before a blast of energetic particles does the job instead.

“We cannot explain how sunspots form. Nor can we discern what sunspot groups are most prone to violent rupture. Policymakers need to know how often it might be necessary to endure a days-long emergency shutdown to avoid a severe catastrophe,” he said.

Dr Vasil and his colleagues’ theoretical model will now need to be tested through observation to further improve the modelling of the Sun’s internal processes. To do this, scientists will use a technique known as helioseismology, to listen inside the beating heart of the star.

“We hope our findings will inspire further observation and research into the driving forces of the Sun,” he said.

This could involve the unprecedented launch of polar orbiter observational satellites outside the elliptical plane of the Solar System.

Declaration

Dr Geoffrey Vasil received no additional funding for this paper. Professor Keith Julien acknowledges support from NASA and the US National Science Foundation. Dr Nicholas Featherstone also acknowledges support from NASA.

Reference: Geoffrey M. Vasil, Keith Julien, Nicholas A. Featherstone. Rotation suppresses giant-scale solar convection. Proceedings of the National Academy of Sciences, 2021; 118 (31): e2022518118 DOI: 10.1073/pnas.2022518118

Provided by University of Sydney

Planetary Science

What Lies Beneath The Far Side of the Moon? (Planetary Science)

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Researchers have discovered multiple layers of soil that lie directly beneath an area on the far side of the Moon’s surface, overturning an existing theory of a single deep layer in the same area.

A new technique for processing lunar radar data has allowed scientists to see what lies beneath the surface of the Moon in the clearest ever detail.

In a study led by the University of Aberdeen, a team of researchers discovered multiple layers of soil that lie directly beneath an area on the far side of the Moon’s surface, overturning an existing theory of a single deep layer in the same area.

The area studied was the landing site of the Chang’E-4 spacecraft mission – the first to the far side of the Moon.

Analysis of radar data captured by the mission’s rover, Yutu-2, had suggested the existence of a single soil layer in the Moon’s regolith (subsurface).  However, the data did not indicate the existence of different layers of soil, which were transparent to electromagnetic waves due to the smooth boundaries between them.

By developing a new method of processing the data captured by Yutu-2, which uses the shape of radar signatures of buried rocks and boulders to infer the properties of surrounding lunar soil and detect previously unseen layers with smooth boundaries, scientists were able to detect four distinct layers of soil, stacked to a depth of 12 metres.

Dr Iraklis Giannakis, from the University of Aberdeen’s School of Geosciences, led the research in collaboration with counterparts from the University of Edinburgh, Northumbria University and Chinese University of Geosciences Wuhan.  The results have been published in the journal Geophysical Research Letters.

Dr Giannakis said: “The novel radar processing method that we have developed has allowed us to study the radar data from the Chang’E-4 landing site in much greater detail.

This will be of great importance in terms of increasing our understanding of planetary soils, as we can now see what lies beneath the surface in more detail than ever before”

Dr Iraklis Giannakis

“By doing so, we have discovered that, rather than a homogenous 12 metre deep regolith whose material source was thought to be a nearby crater called Finsen, there is a more complicated structure where the first 12 metres consist of four distinct layers that were previously unseen using conventional radar processing.”

Dr Giannakis said that the development of a new method of interpreting lunar radar data is a significant development in planetary exploration.

He said: “We are experiencing the new golden era of space exploration with numerous successful planetary missions and many more planned for the future.

“Tianwen-1 and Perseverance are two successful Mars missions that include radar in their scientific payloads, as well as the Chang’E-3, E-4, E-5 and the planned Chang’E-7 mission.

“The methodology we have developed can be used to infer the properties of the subsurface using radar and detect previously unseen layered structures within the first 10-20 meters of planetary soils.  

“This will be of great importance in terms of increasing our understanding of planetary soils, as we can now see what lies beneath the surface in more detail than ever before.”

Reference: Giannakis, I., Zhou, F., Warren, C., & Giannopoulos, A. (2021). Inferring the Shallow Layered Structure at the Chang’E-4 Landing Site: A Novel Interpretation Approach Using Lunar Penetrating Radar. Geophysical Research Letters, 48, e2021GL092866. https://doi.org/10.1029/2021GL092866

Provided by University of Aberdeen