Publisher Health

Vitamin B12 is a well-known micronutrient that has long been acknowledged for its essential role in maintaining nerve function, supporting red blood cell production, and facilitating DNA synthesis, all vital processes for overall health. Researchers led by Dr. Manuel Serrano at IRB Barcelona have now revealed that vitamin B12 also plays a pivotal role in cellular reprogramming and tissue regeneration. The findings have been published in the journal Nature Metabolism.
The research was focused on an experimental process known as cellular reprogramming which is thought to mimic the early phases of tissue repair. The IRB team found that cellular reprogramming in mice consumes large amounts of vitamin B12. Indeed, the depletion of vitamin B12 becomes a limiting factor that delays and impairs some aspects of the reprogramming process. Considering the abundance of vitamin B12 in the normal diet of mice, the investigators were surprised to observe that the simple supplementation of vitamin B12 significantly enhanced the efficiency of reprogramming.
Therapeutic potential in ulcerative colitis
The researchers validated their findings in a model of ulcerative colitis, demonstrating that the intestinal cells initiating repair undergo a process similar to cellular reprogramming and also benefit from vitamin B12 supplementation. Patients with intestinal bowel disease could potentially benefit from vitamin B12 supplementation.
“Our research uncovers a critical role of vitamin B12 in cellular reprogramming and tissue repair. These findings hold promise for regenerative medicine, with the potential to benefit patients through an improved nutrition,” says Dr. Manuel Serrano.
Understanding the role of vitamin B12 in cellular reprogramming
In this study, the researchers delved into the metabolic requirements of cellular reprogramming and found that vitamin B12 is a limiting factor for a particular branch of metabolism involved in a reaction known as methylation. Precisely, the DNA of the cells initiating reprogramming or tissue repair require very high levels of this methylation reaction and therefore of vitamin B12. The researchers discovered that vitamin B12 insufficiency during reprogramming or tissue repair resulted in significant epigenetic changes, leading to errors in the function of multiple genes.

“Supplementation with vitamin B12 corrected this imbalance, resulting in enhanced gene function fidelity and overall improved reprogramming efficiency,” confirms Dr. Marta Kovatcheva, first author of the study and a postdoctoral researcher in the same laboratory. Dr. Kovatcheva will open a new laboratory in 2024 at the Istituto Fondazione di Oncologia Molecolare ETS (IFOM) in Milan, Italy, which will be focused on the study of partially reprogrammed cells in vivo.
Separate study links vitamin B12 to lower inflammation
The group led by Dr. Serrano has recently published another study, in collaboration with the laboratory of Dr. Rosa Lamuela-Raventós at the University of Barcelona (UB), and Dr. Ramon Estruch at the Hospital Clínic of Barcelona, in which they concluded that people with higher levels of vitamin B12 in blood had lower levels of inflammatory markers (IL-6 and CRP). The researchers also observed a similar relationship in aged mice. These observations suggest that vitamin B12 exerts anti-inflammatory action by reducing these markers in the body and they provide valuable insights into the potential health benefits of vitamin B12.
This research project was conducted in collaboration with the groups of Dr. Guido Kroemer at the Institut Gustave Roussy (in France), the laboratory led by Dr. Oscar Yanes at the Universitat Rovira i Virgili (Spain), IRB Barcelona’s Bioinformatics and Biostatistics Core Facility, led by Dr. Camille Stephan-Otto Attolini and the Histopathology Core Facility, led by Dr. Neus prats both at IRB Barcelona and the University of Barcelona.
Dr. Manuel Serrano is presently working at Altos Labs, Cambridge, UK.
The project has received funding from the following agencies: the Barcelona Institute of Science and Technology (BIST); the Asociación Española Contra el Cáncer (AECC); the European Molecular Biology Organization (EMBO); the Karolinska Institute, the Swedish Research Council; the Ligue contre le Cancer; the Agence National de la Recherche (ANR); the Association pour la recherche sur le cancer (ARC); the Fondation pour la Recherche Médicale (FRM); the European Joint Programme on Rare Diseases (EJPRD); the European Research Council (ERC); the Institut National du Cancer (INCa); the Institut Universitaire de France; the Mark Foundation; the Seerave Foundation; “la Caixa” Foundation; the Milky Way Research Foundation; the Spanish Ministry of Science, the European Regional Development Fund (ERDF); and the Secretaria d’Universitats i Recerca del Departament d’Empresa i Coneixment of Catalonia.

Common oral infections, periodontal diseases and caries, are associated with inflammatory metabolic profiles related to an increased risk of cardiometabolic diseases, a new study by an international team of researchers suggests. Oral infections also predicted future adverse changes in metabolic profiles.
The association between oral infections and adverse metabolic profiles was observed in the Finnish Health 2000/2011 and Parogene study cohorts.
“The observation is novel, since there are only few studies connecting extensive metabolic measures with oral infections, and no earlier prospective studies exist,” says Professor Pirkko Pussinen from the University of Eastern Finland.
Published in Journal of Dental Research, the study also involved researchers from the University of Helsinki, Karolinska Institutet and Medical University of Graz.
Progressed oral infections and inflammations — endodontic lesions and periodontitis — are known to be associated with an increased risk of cardiometabolic diseases. Although the mechanisms behind these associations are partially unclear, poor oral health is probably sustaining systemic inflammation.
The present study comprised 452 middle-aged and elderly Parogene patients and 6,229 participants of the population-based Health-2000 survey. In 2011, 4,116 Health-2000 participants provided a follow-up serum sample. Serum concentrations of 157 metabolites reflecting the risk of chronic diseases, such as lipid and glucose metabolites, ketone bodies and amino acids, were determined with an NMR spectroscopy method.
Parameters describing the oral health status were collected at baseline in clinical and radiographic examinations. They included those describing the periodontal status, such as bleeding on probing, periodontal probing depth and alveolar bone loss. Caries-related parameters included root canal fillings, apical rarefactions and caries lesions. The study composed of a cross-sectional part analysing the association between the metabolic measures with prevalent oral health, and of a prospective part examining whether oral infections predict the levels of metabolic measures in the follow-up.

Periodontitis especially linked to prevalent inflammatory metabolic profile, caries to future adverse metabolites
Among 157 metabolic measures, increased periodontal probing depth associated with 93, bleeding on probing with 88, and periodontal inflammation burden with 77 measures. Among the caries-related parameters, root canal fillings were associated with 47, inadequate root canal fillings with 27, and caries lesions with 8 metabolic measures. In the prospective analyses, caries was associated with 30 and bleeding on probing with 8 metabolites. These metabolic measures were typical of inflammation, thus showing positive associations with fatty acid saturation degree and very low density lipoprotein (VLDL) parameters, and negative associations with high density lipoprotein (HDL) parameters.
“Oral infections may partially explain unhealthy lipid profiles,” says Adjunct Professor Aino Salminen from the University of Helsinki.
Adjunct Professor Kåre Buhlin from Karolinska Institutet concludes: “Oral infections represent a significant risk factor for systemic health. Importantly, they are modifiable through early prevention and treatment.”

Investigators from the UCLA Health Jonsson Comprehensive Cancer Center have developed an artificial intelligence (AI) model based on epigenetic factors that is able to predict patient outcomes successfully across multiple cancer types.
The researchers found that by examining the gene expression patterns of epigenetic factors — factors that influence how genes are turned on or off — in tumors, they could categorize them into distinct groups to predict patient outcomes across various cancer types better than traditional measures like cancer grade and stage.
These findings, described in Communications Biology, also lay the groundwork for developing targeted therapies aimed at regulating epigenetic factors in cancer therapy, such as histone acetyltransferases and SWI/SNF chromatin remodelers.
“Traditionally, cancer has been viewed as primarily a result of genetic mutations within oncogenes or tumor suppressors,” said co-senior author Hilary Coller, professor of molecular, cell, and developmental biology and a member of the UCLA Health Jonsson Comprehensive Cancer Center and the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. “However, the emergence of advanced next-generation sequencing technologies has made more people realize that the state of the chromatin and the levels of epigenetic factors that maintain this state are important for cancer and cancer progression. There are different aspects of the state of the chromatin — like whether the histone proteins are modified, or whether the nucleic acid bases of the DNA contain extra methyl groups — that can affect cancer outcomes. Understanding these differences between tumors could help us learn more about why some patients respond differently to treatments and why their outcomes vary.”
While previous studies have shown that mutations in the genes that encode epigenetic factors can affect an individual’s cancer susceptibility, little is known about how the levels of these factors impact cancer progression. This knowledge gap is crucial in fully understanding how epigenetics affects patient outcomes, noted Coller.
To see if there was a relationship between epigenetic patterns and clinical outcomes, the researchers analyzed the expression patterns of 720 epigenetic factors to classify tumors from 24 different cancer types into distinct clusters.
Out of the 24 adult cancer types, the team found that for 10 of the cancers, the clusters were associated with significant differences in patient outcomes, including progression-free survival, disease-specific survival, and overall survival.

This was especially true for adrenocortical carcinoma, kidney renal clear cell carcinoma, brain lower grade glioma, liver hepatocellular carcinoma and lung adenocarcinoma, where the differences were significant for all the survival measurements.
The clusters with poor outcomes tended to have higher cancer stage, larger tumor size, or more severe spread indicators.
“We saw that the prognostic efficacy of an epigenetic factor was dependent on the tissue-of-origin of the cancer type,” said Mithun Mitra, co-senior author of the study and an associate project scientist in the Coller laboratory. “We even saw this link in the few pediatric cancer types we analyzed. This may be helpful in deciding the cancer-specific relevance of therapeutically targeting these factors.”
The team then used epigenetic factor gene expression levels to train and test an AI model to predict patient outcomes. This model was specifically designed to predict what might happen for the five cancer types that had significant differences in survival measurements.
The scientists found the model could successfully divide patients with these five cancer types into two groups: one with a significantly higher chance of better outcomes and another with a higher chance of poorer outcomes.
They also saw that the genes that were most crucial for the AI model had a significant overlap with the cluster-defining signature genes.
“The pan-cancer AI model is trained and tested on the adult patients from the TCGA cohort and it would be good to test this on other independent datasets to explore its broad applicability,” said Mitra. “Similar epigenetic factor-based models could be generated for pediatric cancers to see what factors influence the decision-making process compared to the models built on adult cancers.”
“Our research helps provide a roadmap for similar AI models that can be generated through publicly-available lists of prognostic epigenetic factors,” said the study’s first author, Michael Cheng, a graduate student in the Bioinformatics Interdepartmental Program at UCLA. “The roadmap demonstrates how to identify certain influential factors in different types of cancer and contains exciting potential for predicting specific targets for cancer treatment.”
The study was funded in part by grants from the National Cancer Institute, Cancer Research Institute, Melanoma Research Alliance, Melanoma Research Foundation, National Institutes of Health and the UCLA Spore in Prostate Cancer.

People who drink more than three liters of fluid a day may be suffering from a rare hormone deficiency. For many, however, it is just a harmless habit. Failing to differentiate the two correctly can be fatal, so researchers have been investigating what kind of test delivers a reliable diagnosis.
In most cases, drinking excessive amounts of fluid, known as polyuria-polydipsia syndrome, either arises out of habit over time or is concomitant with a psychological illness. In rare cases, however, it can be caused by vasopressin deficiency. This hormone, released by the pituitary gland, regulates the body’s water and salt content. People with vasopressin deficiency cannot concentrate their urine, causing them to lose large quantities of fluid and to feel very thirsty.
It is extremely important to differentiate between a “harmless” form of excessive fluid ingestion and vasopressin deficiency: in the first case, those affected receive behavioral therapy to help them reduce their fluid intake gradually. People with vasopressin deficiency, however, are given the hormone vasopressin. If a patient is mistakenly treated with vasopressin, it can lead to water intoxication, which can be life-threatening.
Should we test with salt or arginine?
Over the past few years, the two research group leaders Professor Mirjam Christ-Crain and PD Dr. Julie Refardt, together with a number of national and international centers, have been working intensively on testing methods to distinguish between these two disorders. They have found that a test that stimulates vasopressin release via a highly concentrated salt infusion is very reliable. “However, due to the resulting increase in salt concentration, constant monitoring is necessary, including half-hourly measurements of the salt levels in the patients’ blood,” explains Professor Christ-Crain.
A simplified and more easily tolerated test uses an infusion of arginine. Arginine, an essential amino acid, also stimulates the release of vasopressin and was shown to deliver a reliable diagnosis.
Clarity in diagnostics
With an international team, Christ-Crain and Refardt have now performed a direct comparison between the two tests and have published the results in the New England Journal of Medicine. The study, involving 158 participants, shows that the salt infusion resulted in a correct diagnosis for over 95 percent of patients. The test that uses arginine infusion, however, only led to a correct diagnosis in just under 75 percent of cases. Dr. Refardt sums up: “In view of these results, we recommend the salt infusion test as the gold standard for reliable differentiation between polydipsia and vasopressin deficiency.”

Hormone therapy may be associated with menopause and fertility treatment, but now an SDU-led research team reports that certain intestinal hormones seem to have a beneficial effect on the processes behind the formation of scar tissue in the liver (liver fibrosis).
Liver fibrosis may occur as a result of liver diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and currently, there is no medical treatment to cure liver fibrosis.
Doctors often try to address the underlying causes of the diseases, such as obesity and diabetes, and these treatments may lead to improved liver function over several years but they do not eliminate fibrosis.
The processes that initiate the formation of scar tissue in the liver, i.e., fibrosis, are cellular. In their new study published in the Journal of Hepatology, a Danish/American research team, led by Associate Professor Kim Ravnskjaer from the Department of Biochemistry and Molecular Biology and the ATLAS center of excellence, reports that they have found previously unknown changes in the cell types responsible for fibrosis formation.
These are the liver’s so-called stellate cells, named for their star-like appearance.
“We have found a way to inactivate these cells and thus halt the fibrogenic process. This may offer a real opportunity for halting the formation of scar tissue,” explains Kim Ravnskjaer.
One way to deactivate stellate cells is to expose them to certain intestinal hormones, the team discovered.

“We have focused mainly on the intestinal hormone called vasoactive intestinal polypeptide (VIP), which is naturally present in the intestine and neurons, from where it is released when we eat. The liver’s stellate cells, in particular, have a high expression of specific VIP receptors on their surface. VIP stimulates the liver’s blood supply but also appears to keep the stellate cells inactive,” says Kim Ravnskjaer.
The researchers believe that their work could provide the basis for the treatment of liver fibrosis.
“This could result in new ways to treat patients. For example, one could develop synthetic hormones designed to target the receptors on specific cells,” Ravnskjaer adds.
Research on liver fibrosis is ongoing worldwide, with many efforts focused on developing effective drugs. Unfortunately, these often come with serious side effects and for this reason, they are not approved.
“If we target these drugs more towards the cell changes we have discovered, we might be able to avoid many of the side effects,” says Kim Ravnskjaer.
The results of the research team were initially seen in mice that for a year were fed what the scientist refers to as “a pretty bad western diet”; high in fat and sugar.

“When we discovered these cell changes in diseased liver tissue from mice, we went on to look for them in diseased liver tissue from humans. We examined tissue from liver patients from two hospitals in Denmark, and we found the same cell changes in all tissue samples,” Ravnskjaer says.
The researchers will now continue studying stellate cells and their surface receptors in patient samples.
“The more precisely we can target the right cells, the fewer side effects and the better for the patient,” says Kim Ravnskjaer, emphasizing that a new drug based on these discoveries are still years away.
The work was supported by the Danish National Research Foundation, the Novo Nordisk Foundation-funded Danish Diabetes and Endocrine Academy, and the U.S. National Institutes of Health.
About liver fibrosis: Liver fibrosis is the formation of scar tissue in the liver. It may occur after prolonged harmful effects on the liver and liver inflammation resulting from factors such as alcohol, obesity, diabetes, or viral infection. Fibrosis is the initial stage of cirrhosis, which leads to progressive liver failure, and 80-90 percent of patients with cirrhosis also develop liver cancer.

The advent of whole genome sequencing technology has prompted an explosion in research into how genetics are associated with disease risk. But the vast majority of genetics research has been done on people of European ancestry, and genetics researchers have realized that in order to address health disparities, more needs to be done.
In a new study, Georgia Tech researchers investigated whether 25 rare gene variants known to be associated with inflammatory bowel disease (IBD) play a role in risk for African Americans. While the rare variant associations were recently discovered in individuals of European ancestry, contributing to about 15% of cases, it was unknown if and how those same rare gene variants might affect risk for African Americans.
Led by Greg Gibson, Regents’ Professor and Tom and Marie Patton Chair in the School of Biological Sciences, the study highlights the importance of considering genetic diversity and the mixing of ancestry in genetics research. The findings were published in the journal Genome Medicine.
“Because of major advancements in the last decade, we now know that most diseases are far more complex than we originally thought, in terms of genetics,” said Gibson, who is also director of the Center for Integrative Genomics at Georgia Tech. “Understanding whether genetic differences contribute to health disparities is a major point of focus for current genetics research, and we had an opportunity to test one idea with this study.”
Today, African Americans have a similar prevalence of various types of IBD as European Americans. But progression is often much worse: African Americans are more likely to progress to severe disease requiring colectomies and other major interventions.
Courtney Astore, a Ph.D. student in Gibson’s lab and first author on the paper, wanted to assess whether those same rare variants would have a similar effect on IBD risk in African Americans. In a collaboration with Subra Kugathasan from Emory University and the NIH’s IBD Genetics Consortium, Gibson’s lab had analyzed the complete genome sequences of over 3,000 genomes of African Americans, half with IBD. Astore used that database to conduct her analysis.
She started by plotting the difference in frequency of the rare variants, and quickly realized that there was a significant reduction in prevalence of the variants in African Americans. Through further computations, she estimated that European ancestry variants actually only made a very small contribution to IBD in African Americans (around 44 additional cases per 100,000 people), fourfold less than Americans of European ancestry.

“Prior to our analysis, we suspected that admixture may play a role in the presence of IBD-associated rare variants in African Americans,” Astore said. “When I saw the differences, that was when I realized that there was something important there that we needed to discover.”
Astore then used a method known as chromosome painting, which is a tool for visualizing where each segment of the genome comes from. She showed that the rare variants found in African Americans were almost always located on segments of European ancestry genomes.
In simple terms, the location of the variants indicated that the genes resulted from admixture — a scientific term for mixing of genetic backgrounds throughout ancestry — which enabled Astore to show that the mutations had arisen outside of Africa, and only began to appear in people of African ancestry over the last dozen generations.
To conclude the study, Gibson and Astore assessed the presence of other rare variants associated with a dozen other diseases, which similarly confirmed that the presence of the variants contributes to African Americans generally through admixture.
The findings are important for several reasons. First, they highlight the value of considering genetic diversity and admixture in all genetics research, and especially when investigating rare variants and their associations with complex disease. While they showed that the European variants were rare in African Americans, there are almost certainly rare variants that contribute to IBD in African Americans that have yet to be discovered and may point to biological mechanisms.
“Doing more genetic studies on diverse populations, and especially those that have admixture, is going to be pivotal for therapeutic discovery,” Astore said.
Precision medicine will eventually be tailored to a person’s genome, which means that in some cases knowing the identity of rare variants will help guide therapy. If that is the case, knowing the context of ancestry will be beneficial. It also means that if more research on diverse ancestry groups isn’t done, then new treatments might not be effective for all people. The team also emphasizes that genetics is not the only factor contributing to risk for complex diseases like IBD, and their study simply highlights that it cannot be assumed that genetic discoveries are risk factors for all people.
“Our study emphasizes that in order to move in the direction of greater health equity, it is absolutely crucial to do large-scale genetic sequencing for African Americans and all ancestry groups,” Gibson said. “We hope our work will encourage more research on both social determinants of health and the genetics of IBD across ancestries.”

Researchers at Colorado State University and the University of St. Andrews in Scotland have developed an effective and flexible antimicrobial material that could be used to coat medical devices placed inside the body.
The work combines previous research from both universities into metal-organic frameworks — three-dimensional crystalline materials made of metals and linkers that are porous and remain stable in water. Working together, the teams combined their two frameworks into a single thin- film membrane to slowly release nitric oxide. A well-known antimicrobial agent that occurs naturally in the body, nitric oxide not only kills bacteria and fungus on contact but continues to do so over an extended period of time.
The study was published in the November issue of ACS Applied Materials & Interfaces.
Chemistry Professor Melissa Reynolds, who led the work at CSU, said that coating implanted devices with the material may provide a non-drug-based route to preventing infections in common surgical procedures such as hip replacements or shunts that are in constant contact with skin. About 1% of patients undergoing hip or knee replacements may develop an infection after the operation according to the American Academy of Orthopaedic Surgeons.
“Non-elective surgery is a key area for this work because they are increasingly common and many people getting them have underlying medical issues that increase the chances for infection. Additionally, many patients may not realize they have developed an infection from the surgery until much later,” she said. “Using this material could help keep those devices running smoothly inside the body and prevent the need for additional surgeries.”
Many medical devices currently use silver coatings to prevent infection. However, there is a potential for high doses of that element to leach into the body over time. Additionally, silver cannot be used for some types of implanted devices that are load-bearing or require support. Reynolds also noted that while drugs can treat infections, they have a limited life span of effectiveness and may bring side effects.
To develop the thin-film material, the team studied three membranes with different combinations of the metal-organic frameworks using a new cryogenic imaging technique. Reynolds said that helped the team identify the best ratios and methods to release the nitric oxide.
“The preliminary data shows the material is effective at eliminating common bacteria such as staph or E. coli,” she said. “We also found that a very small amount of this material by weight percentage is still very effective at killing bacteria. That is promising for future applications and for feasibility in use outside of a university test setting.”
Reynolds said the team will continue to research the delivery methods and how to take the material from its current thin-film form to something that can be applied across devices like pacemakers.
“Any implantable device is a candidate for this technology, and we think it will actually be inexpensive to manufacture,” she said. “We haven’t found any limitations yet and are looking forward to working with companies to develop this approach.”

Macrophages, a type of white blood cell that can destroy invading pathogens, have an innate ability to infiltrate tumor cells, making them a potentially important tool in treatments that use transplanted cells to fight disease, known as cell therapy. In the lab, macrophages show a lot of promise in treating cancer but so far, clinical trials have been a disappointment and biologists are trying to figure out why.
But what if it’s not a biological problem?
In a recent paper, researchers from the Harvard John A. Paulson School of Engineering and Applied Sciences (SEAS) approached the failure of macrophages in clinical trials from an engineering perspective.
The research team, led by Samir Mitragotri, the Hiller Professor of Bioengineering and Hansjorg Wyss Professor of Biologically Inspired Engineering at SEAS, looked at the physical barriers that might be preventing macrophages from reaching their target in the first place.
By combining microscopy with machine learning, the team found that a specific phenotype of macrophage was better at traveling to the tumor than others — and it’s not the one that researchers commonly use in the clinic for cancer therapies.
The research was published Applied Physics Reviews.
“Our engineering approach led us to question whether the poor therapeutic outcome of macrophages in cell therapies can in part originate from their inability to get into the tumor in the first place,” said Mitragotri. “And indeed, our results show that different phenotypes exhibit different penetration into the tumor. This provides an interesting physics-based hypothesis for the poor clinical outcome of previously reported macrophage therapies and provides a counter- and complementary hypothesis to the classical biology-based paradigm.”
There are multiple types of macrophages, simplified as M0, M1, and M2. Of the three, M1 macrophages have the best tumor-fighting capacities and therefore have been used the most for cell therapies. But they have yielded disappointing results in clinical trials.

Mitragotri and his team looked at how each of the three different phenotypes could move through a complex hydrogel and into a tumor in a petri dish.
“We basically wanted to measure how well the transport mechanics and GPS of these different macrophages worked in a complex environment,” said Kolade Adebowale, a postdoctoral fellow at SEAS and first author of the paper. “We found that the M1 phenotype, anti-tumor microphage, seem to have trouble finding their targets, almost like their GPS wasn’t working. But the M0 phenotype seemed to have a really good map.”
The big question is why.
It’s well known that macrophages exist in various shapes and some phenotypes are really good at changing their shape. Adebowale and the team found a correlation between shape-shifting abilities and transport efficiency — meaning the better the macrophage was at shape shifting, the better able they were to get to the tumor.
And, as it turned out, M1 macrophages are the worst of the three when it comes to shapeshifting.
“Our study demonstrates that the reduced transport of M1 macrophages compared to M0 macrophages is correlated with their reduced ability to undergo shape transformations,” said Adebowale. “We hope that these findings shed new light on the biophysics of macrophage migration and delivery of macrophage cell therapies.”
“There is tremendous potential in utilizing macrophages to mediate anti-tumor immune responses in human tumors and clinical trials are ongoing to treat patients with macrophages,” said Jennifer Guerriero, Assistant Professor at Harvard Medical School, lead investigator of Brigham and Women’s Hospital Breast Oncology Program and co-author of the study. “We learned in this study that, surprisingly, macrophages that resemble an M0 phenotype were most efficient at getting to their target. These data will have an immediate impact on clinical trials are likely to transform the next generation of macrophage-mediated therapies.”
The research was supported by the National Science Foundation under Award No. 2138064.

Pancreatic cancer is tricky to manage because it spreads easily and early, and the tumors have a unique biological makeup. But, researchers made a breakthrough by learning about the genetic changes that occur during tumor migration — and also found a drug that can obstruct the process.
The next step is a groundbreaking clinical trial at the University of Rochester’s Wilmot Cancer Institute, planned for early in 2024, to test the drug from their laboratory discovery, said senior investigator Darren Carpizo, MD, PhD, co-leader of Wilmot’s Genetics, Epigenetics and Metabolism research program, and chief of Surgical Oncology at the University of Rochester Medical Center.
“We will be the first institution in the U.S. to study the safety and effectiveness of the experimental drug, known as NP137, on pancreatic cancer that has spread to the liver,” Carpizo said.
Carpizo and several collaborators recently published the results of their bench science investigation in the journal Cell Reports, and Carpizo will lead the Wilmot clinical trial with Aram Hezel, MD, chief of Hematology/Oncology at Wilmot, and Nabeel Badri, MBChB, a medical oncologist at Wilmot.
The five-year survival rate for pancreatic cancer is only 12 percent, which is a slight increase in 2023 compared to previous years. The number of cases is rising worldwide, however, and by 2030, pancreatic cancer is predicted to be the second leading cause of cancer deaths.
Why is pancreatic cancer deadly?
First, because it spreads (metastasizes) very early during its development. In 85 percent of patients, the cancer has already spread outside of the pancreas at diagnosis. Even when the cancer is localized to the pancreas and surgical removal is possible, the majority of patients face a recurrence of their cancer. The metastasis causes these patients to eventually succumb to the disease, which is why researchers are focused on understanding the biology of metastatic pancreatic cancer.

Second, although pancreatic cancer cells do not have to travel far to reach the liver, along the way they genetically reprogram themselves and become stronger. The result: newly seeded cancer cells in the liver have a distinctly different biology from the primary tumor in the pancreas, and are able to resist standard treatment, Carpizo said.
In their latest work, Wilmot researchers built on what was already known about a key gene, Netrin-1, involved in pancreas, breast and colon cancers. They discovered, for the first time, the complex mechanisms that allow Netrin-1 to drive the lethal, genetic changes as pancreatic cancer cells migrate to the liver. They also showed how Netrin-1 activates hepatic stellate cells, which are involved in liver fibrosis, a serious chronic disease, priming the liver as a host for cancer.
In mice and in tissue studies, when researchers suppressed Netrin-1 with the anti-cancer drug (NP137), cancer was less likely to spread and cancer cell death occurred. The team includes scientists from Rutgers University, where Carpizo worked as a surgeon-scientist before joining Wilmot in 2020, Fox Chase Cancer Center in Philadelphia, and a laboratory in France.
The Wilmot clinical trial will likely require eligible patients to take two cycles of NP137 before surgery, undergo surgery to remove the cancer, and then take more of the experimental medication along with chemotherapy after surgery for up to six months, Carpizo said. He noted that NP137 is made by Netris Pharma, of Lyon, France, and is currently being tested in clinical trials in that country.
The Pancreatic Cancer Action Network (PanCAN) funded much of the work through a grant to Carpizo; Wilmot also provided pilot funding. PanCAN has emphasized that the recent, small uptick in survivorship rates for pancreatic cancer is due to transformative research and clinical trials, and strongly recommends that patients talk to their oncologists about clinical trials at every stage of their disease.
Carpizo’s study is part of a larger collaborative effort at Wilmot aimed at pancreatic cancer. Others, including URMC Surgery Chair David Linehan, MD., and Wilmot investigator Scott Gerber, PhD., and members of the Cancer Microenvironment research program, are also conducting studies on new, targeted treatments. The goal is to use newly discovered drugs in combination with immunotherapy, radiation therapy, and chemotherapy to attack pancreatic cancer.

Electroconvulsive therapy (ECT), formerly known as electroshock therapy, involves inducing a brief seizure in the brain using controlled doses of electricity. While ECT is highly effective for certain mental illnesses, particularly depression, the reasons for its efficacy have long puzzled the fields of psychiatry and neuroscience.
Now, researchers from University of California San Diego may have an answer. In two new studies published November 16, 2023 in Translational Psychiatry, they propose a new hypothesis that ECT alleviates depression symptoms by increasing aperiodic activity, a type of electrical activity in the brain that doesn’t follow a consistent pattern and is generally considered to be the brain’s background noise.
“We’re solving a puzzle that’s stumped scientists and doctors since electroconvulsive therapy was first developed nearly a century ago,” said first author Sydney Smith, a PhD candidate in the Voytek Lab at UC San Diego. “On top of that, we’re also helping to demystify one of the most effective, yet stigmatized treatments for severe depression.”
Electroconvulsive therapy has a great track record, but a bad reputation. The therapy is effective in up to 80% of patients who receive the treatment, most often for depression but occasionally for bipolar disorder or schizophrenia. However, despite this high success rate, electroconvulsive therapy is frequently associated with frightening images of people receiving painful, high voltage shocks.
“A lot of people are surprised to learn that we still use electroconvulsive therapy, but the modern procedure uses highly controlled dosages of electricity and is done under anesthesia,” said Smith. “It really doesn’t look like what you see in movies or television.”
While generally safe and effective, ECT does have drawbacks, including temporary confusion and cognitive impairment. It also requires multiple outpatient visits, which can present a barrier to some people who might otherwise benefit from the treatment.
“One of the reasons ECT isn’t more popular is that for a lot of people, it’s easier and more convenient to just take a pill,” said senior author Bradley Voytek, PhD, professor of cognitive science at UC San Diego. “However, in people for whom medications don’t work, electroconvulsive therapy can be life-saving. Understanding how it works will help us discover ways to increase the benefits while minimizing side effects.”
The researchers used electroencephalography (EEG) scans to study the brain activity of patients who received ECT therapy for depression. They also looked at another similar form of treatment called magnetic seizure therapy, which induces a seizure with magnets instead of electrodes. Both therapies showed increased aperiodic activity levels in patients’ brains post-treatment.

“Aperiodic activity is like the brain’s background noise, and for years scientists treated it that way and didn’t pay much attention to it,” said Smith. “However, we’re now seeing that this activity actually has an important role in the brain, and we think electroconvulsive therapy helps restore this function in people with depression.”
One of the functions of aperiodic activity in the brain is helping control how neurons turn on and off. Our neurons are constantly going through cycles of excitation and inhibition that correspond with different mental states. Aperiodic activity helps boost inhibitory activity in the brain, effectively slowing it down.
“Something we see regularly in the EEG scans of people who receive electroconvulsive or magnetic seizure therapy is a slowing pattern in the brain’s electrical activity,” said Smith. “This pattern has gone unexplained for many years, but accounting for the inhibitory effects of aperiodic activity helps explain it. It also suggests that these two forms of therapy are causing similar effects in the brain.”
While these findings establish a link between aperiodic activity and ECT benefits, the researchers stress the need for further investigation to leverage these insights in clinical applications. They are currently exploring the possibility of using aperiodic activity as a metric of treatment effectiveness in other depression treatments, such as medications.
“At the end of the day, what’s most important to patients and to doctors is that the treatment works, which in the case of ECT, it does,” said Voytek. “However, it’s our job as scientists to dig into what’s really going on in the brain during these treatments, and continuing to answer those questions will help us find ways to make these treatments even more effective while reducing negative effects.”