Publisher Health

A form of gene therapy currently used to treat Parkinson’s disease may dramatically reduce alcohol use among chronic heavy drinkers, researchers at Oregon Health & Science University and institutions across the country have found.
The study in nonhuman primates showed that implanting a specific type of molecule that induces cell growth effectively resets the brain’s dopamine reward pathway in animals predisposed to heavy drinking. The gene therapy procedure involves brain surgery, and may be useful in the most severe cases of alcohol use disorder.
“This was incredibly effective,” said co-senior author Kathleen Grant, Ph.D., professor and chief of the Division of Neuroscience at OHSU’s Oregon Primate National Research Center, or ONPRC.
The study published today in the journal Nature Medicine.
The implanted virus is not harmful and carries a gene that codes for the protein known as glial-derived neurotrophic factor, or GDNF. It was injected in a specific area of the brain of a group of rhesus macaque monkeys that voluntarily and heavily drink ethanol diluted in water. After four macaques underwent the procedure, researchers found their consumption dropped by more than 90% compared with a control group.
“Drinking went down to almost zero,” Grant said. “For months on end, these animals would choose to drink water and just avoid drinking alcohol altogether. They decreased their drinking to the point that it was so low we didn’t record a blood-alcohol level.”
GDNF is known as a growth factor — meaning it stimulates cells to rapidly increase in number — which enhances the function of neurons in the brain that synthesize dopamine, a feel-good chemical released in the brain. In the case of alcohol use disorder, chronic drinking decreases the release of dopamine.

A breakthrough project mapping brain changes in nearly 1,300 people diagnosed with six different types of mental illness has revealed the extraordinary diversity of brain changes found in people with conditions like major depression and schizophrenia.
The study, published in Nature Neuroscience and led by researchers at Monash University’s Turner Institute for Brain and Mental Health and School of Psychological Sciences, used brain imaging to measure the size, or volume, of over 1000 different brain regions.
“Over the past few decades, researchers have mapped brain areas showing reduced volume in people diagnosed with a wide variety of mental illness, but this work has largely focused on group averages, which makes it difficult to understand what is happening in the brains of individual people” said PhD student Ms Ashlea Segal, who led the research. “For example, knowing that the average height of the Australian population is about 1.7 m tells me very little about the height of my next-door neighbour” she added.
The team used new statistical techniques developed Prof Andre Marquand at the Donders Institute, Netherlands, who co-led the project, to map regions in the brain showing unusually small or large volumes in people diagnosed with either schizophrenia, depression, bipolar disorder, obsessive-compulsive disorder, attention-deficit hyperactivity disorder, or autism spectrum disorder.
“We used a statistical model to establish expectations about brain size given someone’s age and sex. We can then quantify how much an individual person’s brain volume deviates from these expectations, much like the growth charts commonly used for height and weight in paediatrics” said Professor Alex Fornito, who led the research team.
“We confirmed earlier findings that the specific brain regions showing large deviations in brain volume vary a lot across individuals, with no more than 7% of people with the same diagnosis showing a major deviation in the same brain area” said Professor Fornito. “This result means that it is difficult to pinpoint treatment targets or causal mechanisms by focusing on group averages alone. It may also explain why people with the same diagnosis show wide variability in their symptom profiles and treatment outcomes” he added.
The team then investigated the connectivity of the areas showing large volume deviations. “Because the brain is a network, dysfunction in one area can spread to affect other, connected sites. We found that, while deviations occurred in distinct brain regions across different people, they were often connected to common upstream or downstream areas, meaning they aggregated within the same brain circuits” said Ms Segal. “It’s possible that this circuit-level overlap explains commonalities between people with the same diagnosis, such as, for example, why two people with schizophrenia generally have more symptoms in common than a person with schizophrenia and one with depression.”
The team leveraged their new approach to identify potential treatment targets for different disorders. “We found that certain specific brain circuits were preferentially involved in some disorders, suggesting that they are potential treatment targets” explained Ms Segal. “However, our findings suggest that these targets will only be appropriate for a subset of people. For instance, we found evidence that brain circuits linked to frontal areas were preferentially involved in depression. These circuits are commonly used as targets for non-invasive brain stimulation therapies, but our data suggest that they may only effective targets for around 1/3 of people.”
The approach developed by the team opens new opportunities for mapping brain changes in mental illness. “The framework we have developed allows us to understand the diversity of brain changes in people with mental illness at different levels, from individual regions through to more widespread brain circuits and networks, offering a deeper insight into how the brain is affected in individual people” said Professor Fornito.

Organoids have now been created from stem cells to secrete the proteins that form dental enamel, the substance that protects teeth from damage and decay. A multi-disciplinary team of scientists from the University of Washington in Seattle led this effort.
“This is a critical first step to our long-term goal to develop stem cell-based treatments to repair damaged teeth and regenerate those that are lost,” said Hai Zhang, professor of restorative dentistry at the UW School of Dentistry and one of the co-authors of the paper describing the research.
The findings are published today in the journal Developmental Cell. Ammar Alghadeer, a graduate student in Hannele Ruohola-Baker’s laboratory in the Department of Biochemistry at the UW School of Medicine was the lead author on the paper. The lab is affiliated with the UW Medicine Institute for Stem Cell and Regenerative Medicine.
The researchers explained that tooth enamel protects teeth from the mechanical stresses incurred by chewing and helps them resist decay. It is the hardest tissue in the human body.
Enamel is made during tooth formation by specialized cells called amelobasts. When tooth formation is complete, these cells die off. Consequently, the body has no way to repair or regenerate damaged enamel, and teeth can become prone to fractures or subject to loss.
To create ameloblasts in the laboratory, the researchers first had to understand the genetic program that drives fetal stem cells to develop into these highly specialized enamel-producing cells.
To do this they used a technique called single-cell combinatorial indexing RNA sequencing (sci-RNA-seq), which reveals which genes are active at different stages of a cell’s development.

A new study from clinicians and researchers at the University of Michigan Rogel Cancer Center, U-M Department of Pathology and the Michigan Center for Translational Pathology reveals findings from over 800 clinical assays performed for kidney patients with MiTF family gene mutations. This study, published in the American Journal of Clinical Pathology¸ is the largest series of its kind in kidney cancer and carries deep clinical and diagnostics implications.
The team, led by Rohit Mehra, M.D., performed over 800 clinical assays on the MiTF family genes TFE3 and TFEB in renal tumors with morphologic and biomarker alterations considered suspicious for MiTF family genetic mutations.
The findings show that the patients who had renal tumors with TFEB amplification were significantly older than patients with renal tumors housing TFE3 or TFEB translocation.
Further, renal tumors with TFEB amplification, known to be associated with poor prognosis, were seen to be at least three times as common as those with TFEB translocation. Mehra says these assays are the gold standard for diagnosing MiTF mutated renal cell carcinoma.
“These findings give us a comprehensive picture of the molecular landscape of renal tumors with MiTF family aberrations,” said Mehra. “Renal cell carcinoma prognosis and personalized therapy can be heavily influenced by renal tumor subtyping, and these FISH assays are crucial towards identifying such genomic aberrations.”
These assays help accurately categorize patients with the MiTF mutation into three genomic categories: TFE3 translocation, TFEB translocation and TFEB amplification. This knowledge adds further understanding to the complexities in kidney cancer disease, and can help provide researchers and clinical teams with deeper diagnostic, prognostic and clinical insight.

Scientists at City of Hope, one of the largest cancer research and treatment organizations in the United States and a leading research center for diabetes and other life-threatening illnesses, have uncovered new molecular targets on a cell receptor that play a major role in cardiovascular regulation. The findings could lead to improved drugs for heart disease, an unfortunate side effect of some cancer therapies. Science Signaling published the study this week.
The City of Hope researchers led by Nagarajan Vaidehi, Ph.D., professor and chair of the Department of Computational and Quantitative Medicine within Beckman Research Institute of City of Hope, collaborating with a team at McGill University led by Stephane Laporte, Ph.D., revealed mechanisms on a receptor called Angiotensin II type 1, or AT1R, that allow hormones and drugs to transfer information on the cell surface. Unraveling these communication pathways enable scientists to take the next step in designing targeted therapies for cardiovascular disease.
The study used a combination of computational methods and experiments to identify newer drug binding sites in the receptor AT1R that significantly expands the scope of potential targets for drug development, particularly new therapeutics that influence the activity of the receptor in heart disease.
“We identified previously unknown domains and mechanisms within AT1R that enable the receptor to bind with molecules and transmit specific signals. Our work strongly suggests these regions offer promising targets for new treatments for cardiovascular diseases,” Vaidehi said. “Equally exciting, is the finding that multiple drug binding sites exist on these proteins that bind to AT1R, paving the way for us to develop a new class of medicines with less side effects for patients.”
Current medicines act on the AT1R receptor to elicit specific cellular responses, but, until now, scientists have not decoded the mechanisms behind them. In this study, the team blended computational modeling with leading-edge approaches in structural biology and pharmacology to detect signaling within AT1R that dictates the receptor’s responses to key intracellular pathways. Understanding the nuances behind this interaction will lay the foundation for researchers to design effective targeted therapies for cardiovascular diseases.
Grants from the National Institutes of Health (R01-GM117923) and the Canadian Institutes of Health Research (PJT-162368 and PJT-173504) supported the research.

A study from the University of Michigan Rogel Cancer Center uncovers a new mechanism to explain why some prostate tumors switch from a common, treatable form to a more rare and aggressive form of prostate cancer.
Using tissue samples and cell models from patients, Joshi Alumkal, M.D., Wicha Family Professor of Oncology and leader of the genitourinary medical oncology section at Rogel, and his team zeroed in on the lysine specific demethylase 1 (LSD1), a protein involved in turning genes off and on in normal and cancer cells that appears particularly important in certain aggressive forms of prostate cancer. Further, they outlined a promising path to overcome this deadly form of treatment-resistance: LSD1 inhibitors.
The findings are published in JCI Insight.
Most prostate tumors remain adenocarcinomas, or glandular tumors, after male-hormone lowering treatments — the principal treatment for metastatic prostate cancers. But many undergo a deadly switch called lineage plasticity, where the tumor shifts from a glandular tumor to one with a nerve, or brain-like, make-up.
Researchers have a limited understanding of how prostate tumors undergo lineage plasticity, but once it happens, few treatment options exist.
“Aggressive forms of prostate cancer are on the rise as a work-around to some of our newer, more potent hormonal treatments,” said Alumkal. “Our prior work demonstrated that approximately 15-20% of patients whose tumors start growing despite newer hormonal treatments will lose the adenocarcinoma program and take on other identities, including one called neuroendocrine prostate cancer.”
Patients with neuroendocrine prostate cancer fare much worse than patients whose tumors remain adenocarcinomas, and there are currently limited treatment options for these patients.

A first-in-human trial of deep brain stimulation (DBS) for post-stroke rehabilitation patients by Cleveland Clinic researchers has shown that using DBS to target the dentate nucleus — which regulates fine-control of voluntary movements, cognition, language, and sensory functions in the brain — is safe and feasible.
The EDEN trial (Electrical Stimulation of the Dentate Nucleus for Upper Extremity Hemiparesis Due to Ischemic Stroke) also shows that the majority of participants (nine out of 12) demonstrated improvements in both motor impairment and function. Importantly, the study found that participants with at least minimal preservation of distal motor function at enrollment showed gains that almost tripled their initial scores.
Published in Nature Medicine, these findings build on more than a decade of preclinical work led by principal investigators Andre Machado, M.D., Ph.D., and Kenneth Baker, Ph.D., at Cleveland Clinic.
“These are reassuring for patients as the participants in the study had been disabled for more than a year and, in some cases, three years after stroke. This gives us a potential opportunity for much needed improvements in rehabilitation in the chronic phases of stroke recovery,” said Dr. Machado, chair of Cleveland Clinic’s Neurological Institute. “The quality-of-life implications for study participants who responded to therapy have been significant.”
Dr. Machado patented the DBS method in stroke recovery. Boston Scientific owns a license to those patents and provided the Vercise DBS systems used in the trial. In 2010, Cleveland Clinic Innovations established Enspire DBS Therapy, Inc., a Cleveland Clinic portfolio company and is commercializing technology developed at Cleveland Clinic to commercialize the method and it co-funded the study. Dr. Machado holds stock options and equity ownership rights with Enspire and serves as the chief scientific officer.
“We saw patients in the study regain levels of function and independence they did not have before enrolling in the research,” Dr. Machado said. “This was a smaller study and we look forward to expanding as we have begun the next phase.”
The completed EDEN trial enrolled 12 individuals with chronic, moderate-to-severe hemiparesis of the upper extremity as a result of a unilateral middle cerebral artery stroke 12-to-36 months prior. There were no major complications throughout the study. Nine of the 12 participants improved to a degree that is considered meaningful in stroke rehabilitation.

In the refrigerated grocery store aisle, meat alternatives greatly outnumber plant-based seafoods. But more mock seafood options are needed because of unsustainable fishing and aquaculture practices, which can deplete the supply and harm the environment. Today, researchers present a new approach for creating desirable vegan seafood mimics that taste good, while maintaining the healthful profile of real fish. They 3D-printed an ink made from microalgae protein and mung bean protein, and their proof-of-concept calamari rings can even be air-fried for a quick, tasty snack.
The researchers will present their results at the fall meeting of the American Chemical Society (ACS).
“I think it’s imminent that the seafood supply could be very limited in the future,” adds Poornima Vijayan, a graduate student who is presenting the work at the meeting. “We need to be prepared from an alternative protein point of view, especially here in Singapore, where over 90% of the fish is imported.”
People around the world eat a lot of seafood, but the oceans are not an infinite resource. Overfishing has depleted many wild fish populations. That lack of sustainability, combined with heavy-metal and microplastic contamination, as well as ethical concerns, have pushed some consumers toward plant-based mimics. But such alternatives are still difficult for seafood lovers to find.
While some mock seafood products — such as imitation crabmeat made from minced and reshaped pollock or other white fish — are already on the market, making mimics from plants has been a challenge. It’s hard to achieve the nutritional content, unique textures and mild flavors of cooked fish meat using vegetables or fungi. “Plant-based seafood mimics are out there, but the ingredients don’t usually include protein. We wanted to make protein-based products that are nutritionally equivalent to or better than real seafood and address food sustainability,” says Dejian Huang, Ph.D., the principal investigator of this research.
Recently, Huang and his research group at the National University of Singapore used legume protein to develop better seafood mimics. And they replicated the flakiness and mouth feel of real fish by 3D printing a protein-based ink with a food-grade 3D printer. Depositing the edible ink layer by layer created different textures, some fatty and smooth and others fibrous and chewy, in a single product.
“We printed salmon filets with protein from red lentils because of the protein’s color, and we’ve printed shrimp,” says Huang. “Now, we wanted to print something else interesting with the potential for commercialization — calamari rings.”
In this work, the team tested two sustainable, high-protein plant sources: microalgae and mung beans. Some microalgae already have a “fishy” taste, which Vijayan says made them a good candidate to use in the squid-ring analogue. And mung bean protein is an underutilized waste product from manufacturing starch noodles, also called cellophane or glass noodles, which are a popular ingredient in many Asian dishes.

Patients with localised prostate cancer have a good chance of survival, but mortality rates among those with advanced, metastatic forms of the condition remain high. Until now, the precise mechanism behind the spread of the tumour has not been fully explained. But an international research team headed by MedUni Vienna has succeeded in decoding the underlying cellular signal pathway and has carried out research using a common diabetes medication that could provide a new treatment option. The study has just been published in the journal Molecular Cancer.
Using a complex mouse model, the research team under Lukas Kenner (MedUni Vienna Department of Pathology, Department of Laboratory Animal Pathology at Vetmeduni Vienna) examined prostate cancer cells and identified the key factors in the regulation of tumour cell growth and the way they interact with each other. The protein signal transducer and activator of transcription 3 (STAT3) plays the leading role — its activation by another protein called interleukin 6 (IL6) has been a focus for cancer researchers in connection with tumour progression for some time now.
“Interestingly, our study showed for the first time that permanent activation of STAT3 prevents the development of prostate cancer as well as the development and spread of metastases. Conversely, we discovered that the loss of the signal pathway between STAT3 and IL6 in the prostate can lead to massive tumour growth and metastasis, which significantly increases the aggressiveness of the cancer and the mortality rate,” explained principal investigator Lukas Kenner, summarising the core findings.
Potential medication already available
In the course of the study, the researchers also found that activation of STAT3 in the prostate leads to increased levels of cell components (LKB1/pAMPK) that are responsible for the regulation of glucose metabolism and are linked to type 2 diabetes mellitus. The proteins LKB1/pAMPK block certain cancer molecules (mTOR and CREB) and as a result also stop the tumour growing. “In light of this finding, we used a common diabetes drug in our research,” said Kenner. Kenner and his team discovered that the active ingredient metformin, which is used in the treatment of type 2 diabetes to regulate glucose levels, can significantly slow the progression of STAT3-positive prostate cancer, a condition with a metabolism that is very similar to type 2 diabetes. “As metformin is already available, our research findings could be useful in developing new treatment options for patients with STAT3-positive prostate cancer in the foreseeable future,” Kenner pointed out, looking ahead to further research into the newly discovered approach.
Most common form of cancer in men
Prostate cancer has been the most common type of cancer in men in Austria since 1994, followed by lung cancer (Statistics Austria, 2022). In 2019, 6,039 new cases and 1,352 deaths due to prostate cancer were recorded. In the vast majority of cases, tumours in the prostate gland remain localised, meaning that they can be treated effectively. However, about 20% of patients develop metastatic prostate cancer, which is still incurable. Malignant prostate tumours are the second most common cause of cancer-related death in men worldwide (after lung cancer).

No amount of air pollution is good for the brain, but wildfires and the emissions resulting from agriculture and farming in particular may pose especially toxic threats to cognitive health, according to new research from the University of Michigan.
Increasingly, evidence shows exposure to air pollution makes the brain susceptible to dementia. And now the findings of Boya Zhang and Sara Adar, environmental epidemiology researchers in U-M’s School of Public Health, point to a strong likelihood that agriculture and wildfires, with their release of a range of harmful emissions at high concentrations, need to be more closely studied and monitored for their risks to public health, specifically dementia.
“We saw in our research that all airborne particles increased the risk of dementia but those generated by agricultural settings and wildfires seemed to be especially toxic for the brain,” said Adar, associate chair of the Department of Epidemiology in the School of Public Health. She currently leads several large cohort studies on the impacts of exposures on cognitive aging and dementia.
“Our findings indicate that lowering levels of particulate matter air pollution, even in a relatively clean country like the United States, may reduce the number of people developing dementia in late life,” Adar said.
Adar and Zhang’s paper, “Comparison of Particulate Air Pollution From Different Emission Sources and Incident Dementia in the U.S.,” appears today in the Journal of the American Medical Association’s Internal Medicine.
Zhang, a research fellow who focuses on the effects of air pollution on cardiopulmonary disease and cognitive aging, said: “This work suggests that particulate matter air pollution from agriculture and wildfires might be more neurotoxic compared with other sources. However, more research is needed to confirm these effects, especially for these two sources which have received less attention in prior research.”
“Given that the development of dementia could take a long time, this study mainly aimed to provide evidence for policymakers to reduce exposures to these sources of emissions,” Zhang said.