Publisher Health

Scientists at Oregon Health & Science University have identified a naturally occurring mutation in nonhuman primates that closely resembles a rare neurodegenerative disease in people.
The discovery could lead to the development of new therapies to treat Pelizaeus-Merzbacher disease and is the latest in a trove of discoveries made possible by a massive genomic database established at OHSU’s Oregon National Primate Research Center.
The latest study was published today in the journal Neurobiology of Disease.
“This is a condition that is caused by a single mutation in a single gene,” said senior author Larry Sherman, Ph.D., professor in the Division of Neuroscience at the primate center. “This really sets us up for the possibility of doing gene therapies, or neural stem cell-based therapies in the developing brain.”
Sherman said scientists at OHSU are already looking forward to collaborating with scientists who have developed experimental gene therapies in mice. The discovery of the genetic mutation in three young rhesus macaques provides the opportunity to apply therapies to an animal model that’s much closer to humans.
The study also included new findings revealing how Pelizaeus-Merzbacher and related diseases develop.

A gene called DOT1L appears to play a role in progression and severity of ovarian cancer, and inhibitors of the DOT1L enzyme may offer a new therapeutic approach for the disease, University of Alabama at Birmingham researchers say in a study published in the journal Oncogenesis.
The need is clear — despite decades of work to develop new treatment modalities, the five-year survival of patients with advanced ovarian cancer is between 10 and 30 percent.
Others have found that DOT1L is overexpressed in several cancer types, and recent clinical work has shown synergistic antiproliferative activity for a DOT1L inhibitor against MLL-rearranged leukemia.
The UAB researchers, led by Romi Gupta, Ph.D., assistant professor of biochemistry and molecular genetics, now show that DOT1L promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking the programmed cell death called apoptosis.
Gupta and colleagues first looked at data sets from patients. They found that DOT1L expression was significantly higher in tissues from ovarian cancer patients compared with tissues from healthy patients. Furthermore, patients with ovarian tumors that had high DOT1L expression showed shorter progression-free survival and shorter overall survival rates compared with patients whose ovarian tumors had lower DOT1L expression.
DOT1L is a histone methyltransferase that epigenetically methylates the histone H3 lysine 79 in chromatin, and this alters gene expression in cells. The UAB researchers found that EPZ-5676 — a DOT1L inhibitor that has been used in several clinical trials to treat MLL-rearranged leukemia — was able to block the growth of ovarian cancer cells in culture. EPZ-5676 also significantly blocked subcutaneous ovarian cancer tumor growth in a mouse xenograft model.
Mechanistically, DOT1L inhibition downregulated the expression of various genes that are required for biosynthetic pathways and reduced the levels of essential biosynthetic metabolites in the ovarian cancer cells. DOT1L inhibition also upregulated genes involved in programmed cell death, which increased apoptotic cell death for ovarian cancer cells in culture. The pharmacologic inhibition of DOT1L also upregulated expression of ligands for natural killer cells in some of the ovarian cancer cell lines tested.
These gene expression changes seen in DOT1L inhibitor-treated cells thus suggest that DOT1L overexpression in ovarian cancer leads to plentiful supplies of the metabolites needed for rapid tumor growth and also protects against tumor cell death caused by apoptosis or natural killer cell attack.
“Our results suggest that DOT1L might be a pharmacologically tractable drug target for ovarian cancer therapy,” Gupta said. “It will also be useful in combination with other immunotherapeutic agents to further enhance their effectiveness in treating ovarian cancer.”
Co-authors with Gupta for the study, “Disruptor of telomeric silencing 1-like promotes ovarian cancer tumor growth by stimulating pro-tumorigenic metabolic pathways and blocking apoptosis,” are Suresh Chava, Suresh Bugide and Yvonne J.K. Edwards, UAB Department of Biochemistry and Molecular Genetics.
Support came from National Institutes of Health grants CA230815-02 and CA248913-01.
Story Source:
Materials provided by University of Alabama at Birmingham. Original written by Jeff Hansen. Note: Content may be edited for style and length.

Modern portable devices are the result of great progress in miniaturization and wireless communications. Now that these devices can be made even smaller and lighter without loss of functionality, it’s likely that a great part of next-generation electronics will revolve around wearable technology. However, for wearables to truly transcend portables, we will need to rethink the way in which devices communicate with each other as “wireless body area networks” (or WBANs). The usual approach of using an antenna to radiate signals into the surrounding area while hoping to reach a receiver won’t cut it for wearables. But, this method of transmission not only demands a lot of energy but can also be unsafe from a cybersecurity standpoint. Moreover, the human body itself also constitutes a large obstacle because it absorbs electromagnetic radiation and blocks signals.
But what alternatives do we have for wearable technology? One promising approach is “human body communication” (HBC), which involves using the body itself as a medium to transmit signals. The main idea is that some electric fields can propagate inside the body very efficiently without leaking to the surrounding area. By interfacing skin-worn devices with electrodes, we can enable them to communicate with each other using relatively lower frequencies than those used in conventional wireless protocols like Bluetooth. However, even research on HBC began over two decades, this technology hasn’t been put to use on a large scale.
To explore the full potential of HBC, researchers from Japan, including Dr. Dairoku Muramatsu from Tokyo University of Science and Professor Ken Sasaki from The University of Tokyo focused on using HBC for a yet unexplored use: binaural hearing aids. Such hearing aid devices come in pairs — one for each ear — and greatly improve intelligibility and sound localization for the wearer by communicating with each other to adapt to the sound field. Because these hearing aids are in direct contact with the skin, they made for a perfect candidate application for HBC. In a recent study, which was published in the journal Electronics, the researchers investigated, through detailed numerical simulations, how electric fields emitted from an electrode in one ear distribute themselves in the human head and reach a receiving electrode on the opposite ear, and whether it could be leveraged in a digital communication system. In fact, the researchers had previously conducted an experimental study on HBC with real human subjects, the results of which were also published in Electronics.
Using human-body models of different degrees of complexity, the researchers first determined the best representation to ensure accurate results in their simulations and then Once this was settled, they proceeded to explore the effects of various system parameters and characteristics, as Dr. Muramatsu puts it, “We calculated the input impedance characteristics of the transceiver electrodes, the transmission characteristics between transceivers, and the electric field distributions in and around the head. In this way, we clarified the transmission mechanisms of the proposed HBC system.” Finally, with these results, they determined the best electrode structure out of the ones they tested. They also calculated the levels of electromagnetic exposure caused by their system and found that it would be completely safe for humans, according to modern safety standards.
Overall, this study showcases the potential of HBC and extends the applicability of this promising technology. After all, hearing aids are but one of all modern head-worn wireless devices. For example, HBC could be implemented in wireless earphones to enable them to communicate with each other using far less power. Moreover, because the radio waves used in HBC attenuate quickly outside of the body, HBC-based devices on separate people could operate at similar frequencies in the same space without causing noise or interference. “With our results, we have made great progress towards reliable, low-power communication systems that are not limited to hearing aids but also applicable to other head-mounted wearable devices. Not just this, accessories such as earrings and piercings could also be used to create new communication systems,” concludes Dr. Muramatsu.
Story Source:
Materials provided by Tokyo University of Science. Note: Content may be edited for style and length.

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.

A new study by the University of Eastern Finland and Kuopio University Hospital shows that wearable sensor technology can be used to reliably assess the occurrence of myoclonic jerks in patients with epilepsy also in the home environment. The method used in the study was based on the measurement of electrical neuromuscular function and movement, and it corresponded well to an assessment performed by an experienced physician. The findings were recently published in Clinical Neurophysiology.
Patients with progressive myoclonic epilepsy (EPM1) suffer from myoclonus, i.e., sudden muscle jerks that are activated by movement and other stimuli. The severity of these myoclonic jerks varies during the day, and myoclonus can be either positive or negative. A positive myoclonus refers to a sudden contraction of a muscle, while a negative myoclonus refers to loss of muscle activation, which in a worst-case scenario may lead to the fall of a patient, for example. A method for long-term, at-home assessment of myoclonus would facilitate a comprehensive understanding of its occurrence. Objective measurement data on the occurrence of myoclonic symptoms and on the effect of treatment over hours and days would also support the development of new drug therapies. Myoclonus also occurs in other epileptic syndromes and neurological disorders.
The aim of the recently published study was to develop and test a wearable technology-based method for assessing myoclonus symptoms in the home environment. Patients wore a small, wearable sensor on their arm for 48 hours, which measured their muscle function and movement. They also wrote down their own assessment of the severity of the myoclonus symptom. An algorithm that picks up the occurrence and variation of muscle jerks from the measurement data was developed to evaluate myoclonus symptoms, describing them as a myoclonus index.
In current clinical practice, the Unified Myoclonus Rating Scale, UMRS, is used to assess myoclonus symptoms. When using the UMRS, an experienced physician views a video recording and scores the patient’s symptoms according to their severity. This UMRS assessment provides information on the occurrence of myoclonus at one point in time. The measurement-based myoclonus index developed in the study correlated well with the UMRS assessment performed by the physician. Patients’ at-home measurements showed that the measurement-based myoclonus index was able to detect variation in the occurrence of myoclonus symptoms during the day and night. The reliability of the measurement results was also supported by patients’ own, at-home assessment and reporting of their myoclonus symptoms.
According to the study, the myoclonus index can be used to reliably assess positive and negative myoclonus in patients with EPM1. This assessment correlates well with the assessment performed by an experienced physician, and also makes it possible to assess patients’ symptoms in the home environment.
The study was carried out as part of the larger New Modalities ecosystem funded by Business Finland, involving three universities and eight companies in Finland. The ecosystem is coordinated by Orion Corporation. The research group working with patients included researchers from the Department of Applied Physics and the Institute of Clinical Medicine at the University of Eastern Finland, as well as from the Epilepsy Centre at Kuopio University Hospital. The ecosystem also collaborates with Adamant Health Ltd., which is a spin-off company of the University of Eastern Finland focusing on software development.
Story Source:
Materials provided by University of Eastern Finland. Note: Content may be edited for style and length.

For a cell to grow and divide, it needs to produce new proteins. This also applies to cancer cells. In a new study published today in Science Advances, researchers at Karolinska Institutet in Sweden have investigated the protein eIF4A3 and its role in the growth of cancer cells. The study shows that by blocking or reducing the production of this protein, other processes arise that cause the growth and cell division of cancer cells to cease and eventually die.
The body’s normal cell division is carefully controlled, where genes in the cell regulate when it is time to start and stop cell division. Sometimes this balance is disturbed and the cell continues to divide uninhibitedly. After some time, a small collection of cells develops — cancer may be about to form.
“When a cell grows, new proteins are produced, among other things, through the translation of the cell’s DNA information into mRNA, which forms the basis for the creation of proteins. The cell also needs to manufacture rRNA for the cell’s small factories, the ribosomes, which are responsible for producing proteins,” says Associate Professor Mikael Lindström, co-author and part of Professor Jiri Bartek’s research group at the Department of Medical Biochemistry and Biophysics who conducted the study.
In the study, the research group investigated cultured cancer cells and cancer tissue where the eIF4A3 protein’s expression was high compared to normal tissue. By adding synthetically produced small molecules that can later be further developed into finished drugs, the production of eIF4A3 can be checked. The researchers then discovered two distinct changes in the cancer cells.
“Firstly, we saw that the blocking of eIF4A3 activated the protein p53, a protein that has an important role to play in fighting cancer cells,” says Dimitris Kanellis, a postdoctoral fellow at the Department of Medical Biochemistry and Biophysics, and the first author of the study.
However, one challenge with many types of tumours is that the positive functions of the p53 protein are counteracted by another protein, MDM2.
“Interestingly, we noted that the blocking eIF4A3 also meant that the MDM2 protein changed. This change helps to maintain and strengthen p53 and can be beneficial when we want to inhibit the growth of cancer cells,” continues Dimitris Kanellis.
The main conclusions of the study indicate that depletion or inhibition of eIF4A3 activates p53, alters the manufacturing process of proteins by disrupting ribosome biogenesis, and thereby inhibits the growth of cancer cells. Knowledge of the importance of the eIF4A3 protein opens up new opportunities for better and more effective treatment of cancer patients.
“The discovery is very relevant as this type of targeted treatment may represent a new possible approach in chemotherapy, for example in colon cancer where cancer cells often have a high level of ribosomes and rapid growth. Another example is a sarcoma, cancer of the body’s support tissues, where we know that sometimes there is an overproduction of MDM2. This increases the chances of more effective treatment,” says Associate Professor Mikael Lindström and Professor Jiri Bartek, corresponding authors in the study.
These findings provide an important foundation for further studies. However, since the study has mainly been carried out in cultured cancer cells and clinical tumour material, it remains to be seen how the blocking of eIF4A3 will affect the growth of cancer in vivo.
“There may also be synergies between the chemical compounds that block eIF4A3 and drugs that are already used to treat cancer that we will now research further,” concludes Mikael Lindström.
The research was funded by the Swedish Research Council, the Cancer Foundation, the Swedish Childhood Cancer Foundation, ERC, and Karolinska Institutet.
Story Source:
Materials provided by Karolinska Institutet. Note: Content may be edited for style and length.

Cambridge scientists have grown beating heart cells in the lab and shown how they are vulnerable to SARS-CoV-2 infection. In a study published in Communications Biology, they used this system to show that an experimental peptide drug called DX600 can prevent the virus entering the heart cells.
The heart is one the major organs damaged by infection with SARS-CoV-2, particularly the heart cells, or ‘cardiomyocytes’, which contract and circulate blood. It is also thought that damage to heart cells may contribute to the symptoms of long COVID.
Patients with underlying heart problems are more than four times as likely to die from COVID-19, the disease caused by SARS-CoV-2 infection. The case fatality rate in patients with COVID-19 rises from 2.3% to 10.5% in these individuals.
To gain entry into our cells, SARS-CoV-2 hijacks a protein on the surface of the cells, a receptor known as ACE2. Spike proteins on the surface of SARS-CoV-2 — which give it its characteristic ‘corona’-like appearance — bind to ACE2. Both the spike protein and ACE2 are then cleaved, allowing genetic material from the virus to enter the host cell. The virus manipulates the host cell’s machinery to allow itself to replicate and spread.
A team of scientists at the University of Cambridge has used human embryonic stem cells to grow clusters of heart cells in the lab and shown that these cells mimic the behaviour of the cells in the body, beating as if to pump blood. Crucially, these model heart cells also contained the key components necessary for SARS-CoV-2 infection — in particular, the ACE2 receptor.
Working in special biosafety laboratories and using a safer, modified synthetic (‘pseudotyped’) virus decorated with the SARS-CoV-2 spike protein, the team mimicked how the virus infects the heart cells. They then used this model to screen for potential drugs to block infection.

Two new molecules that generate minute amounts of the gas hydrogen sulfide have been found to prevent skin from ageing after being exposed to ultraviolet light found in sunlight.
Sunburn is a major cause of premature ageing in skin, and a primary risk factor for skin cancer, and other skin problems associated with ageing. Now, an international research team has made inroads towards being able to reverse or delay this damage for the first time.
The research was led by Professor Matt Whiteman at the University of Exeter Medical School, and Professor Uraiwan Panich at the Faculty of Medicine Siriraj Hospital, Mahidol University, in Thailand. In the study published in Antioxidant and Redox Signaling, the team exposed adult human skin cells and the skin of mice to ultraviolet radiation (UVA). UVA is the part of natural sunlight which damages unprotected skin and can penetrate through windows, and even through some clothes. It causes skin to age prematurely by turning on skin digesting enzymes called collagenases. These enzymes eat away at the natural collagen, causing the skin to lose elasticity and sag, resulting in wrinkles. UVA also penetrates deeper into skin than the UV radiation that causes sunburns (UVB)-, and it damages cellular DNA, leading to mutations that can contribute to some skin cancers. Classic sun creams people use on holiday sit on top of the skin and absorb UV radiation, but they do not penetrate the skin where the long-lasting damage occurs.
However, the team’s research paves the way for a new way to protect the deeper layers of skin using two compounds invented at the University of Exeter: AP39 and AP123. In the experiments, the compounds did not protect the skin in the same way traditional sun creams prevent sunburn, but instead penetrated the skin to correct how skin cells’ energy production and usage was turned off by UVA exposure. This then prevented the activation of skin-degrading collagenase enzymes and subsequent skin damage.
The compounds used in this study were previously shown to have impressive effects in reducing skin inflammation and skin damage after burn injury and atopic dermatitis (eczema). In an anti-ageing context, they prevented human skin cells in test tube experiments from ageing, but this is the first time the effects of photo-ageing have been seen in animals.
Professor Uraiwan Panich, of the Faculty of Medicine Siriraj Hospital, Mahidol University, in Bangkok, a co-senior author on the paper, said: “The compounds AP39 and AP123 specifically target the energy generating machinery inside our cells, the mitochondria, and supply them with minute quantities of alternative fuel, hydrogen sulfide, to use when skin cells are stressed by UVA. The direct result of this was the activation of two protective mechanisms. One is a protein call PGC-1α, which controls mitochondria number inside cells and regulates energy balance. The other is Nrf2, which turns on a set of protective genes that mitigate UVA damage to skin and turn off the production of collagenase, the main enzyme that breaks down collagen in damaged skin tissue and causes skin to look significantly more “aged” .”
Professor Matt Whiteman, of the University of Exeter Medical School, a co-senior author on the paper added: “Some skin sun creams and cosmetics contain ingredients thought to protect mitochondria from UV radiation. However, it isn’t clear that these cosmetic skin-applied substances get inside skin cells at all, whereas we found that our molecules penetrate cells and specifically target mitochondria where they are needed. By protecting mitochondria, we also preserve and upregulate the protective mechanisms by which mitochondria control inflammation, protect cells and prevent tissue destruction. Currently, we have no way of reversing or delaying skin ageing caused by sunlight exposure. Our results are a really exciting step towards that goal, and could one day help reduce age-related skin conditions, as well as be useful in other conditions resulting from the ageing process.”
The important observation noted was the compounds only regulated energy production, PGC-1α and Nrf2 in skin that was exposed to UVA. This suggests a novel approach to treating skin that has already been damaged by UV radiation, and could potentially reverse, as well as limit, that damage.
While more research is now needed, long term implications of this work could be medical as well as cosmetic, where protecting skin from UV light is important. For example, not only premature skin ageing and skin cancers, but UV light allergies, solar urticaria (hives) and rare hereditary skin diseases such as xeroderma pigmentosum, although further work is needed. The Exeter team are currently mid-way through testing newer and more potent molecules able to do the same task using newer approaches via the University of Exeter spin-out company MitoRx Therapeutics; a company developing highly potent mitochondrial drugs for clinical use.

Patients with vitamin D deficiency who received vitamin D supplements had a reduced need for pain relief and lower levels of fatigue in palliative cancer treatment, a randomized and placebo-controlled study by researchers at Karolinska Institutet shows. The study is published in the scientific journal Cancers.
Among patients with cancer in the palliative phase, vitamin D deficiency is common. Previous studies have shown that low levels of vitamin D in the blood may be associated with pain, sensitivity to infection, fatigue, depression, and lower self-rated quality of life.
A previous smaller study, which was not randomized or placebo-controlled, suggested that vitamin D supplementation could reduce opioid doses, reduce antibiotic use, and improve the quality of life in patients with advanced cancer.
244 cancer patients with palliative cancer, enrolled in ASIH, (advanced medical home care), took part in the current study in Stockholm during the years 2017-2020.
All study participants had a vitamin D deficiency at the start of the study. They received either 12 weeks of treatment with vitamin D at a relatively high dose (4000 IE/day) or a placebo.
The researchers then measured the change in opioid doses (as a measurement of pain) at 0, 4, 8, and 12 weeks after the start of the study.
“The results showed that vitamin D treatment was well tolerated and that the vitamin D-treated patients had a significantly slower increase in opioid doses than the placebo group during the study period. In addition, they experienced less cancer-related fatigue compared to the placebo group,” says Linda Björkhem-Bergman, senior physician at Stockholms Sjukhem and associate professor at the Department of Neurobiology, Healthcare Sciences, and Society, Karolinska Institutet.
On the other hand, there was no difference between the groups in terms of self-rated quality of life or antibiotic use.
“The effects were quite small, but statistically significant and may have clinical significance for patients with vitamin D deficiency who have cancer in the palliative phase. This is the first time it has been shown that vitamin D treatment for palliative cancer patients can have an effect on both opioid-sensitive pain and fatigue,” says first author of the study Maria Helde Frankling, senior physician at ASIH and postdoc at the Department of Neurobiology, Healthcare Science and Society, Karolinska Institutet.
The study is one of the largest drug studies conducted within ASIH in Sweden. One weakness of the study is the large drop-out rate. Only 150 out of 244 patients were able to complete the 12-week study because many patients died of their cancer during the study.
The study was funded by Region Stockholm (ALF), the Swedish Cancer Society, Stockholms Sjukhems Foundation and was carried out with the support of ASIH Stockholm Södra and ASIH Stockholm Norr.
Story Source:
Materials provided by Karolinska Institutet. Note: Content may be edited for style and length.

Scientists at St. Jude Children’s Research Hospital have created a laboratory model for studying retinoblastoma driven by inherited mutations in the RB1 gene.Retinoblastoma is a rare cancer of the retina, the thin tissue inside the back of the eye. The researchers created retinoblastoma organoid models that closely mimic the biology of tumors in patients. These models provide an important resource for studying the earliest stages of the disease as well as screening new therapies. The findings were published recently in Nature Communications.
Retinoblastoma occurs in very young children, and in some cases children are born with the disease. Inherited mutations in RB1 are one reason why this happens, but how these tumors form and what other factors underlie their development remains difficult to study.
Retinoblastoma is also unusual because it is one of the only types of cancer that is not diagnosed by taking a biopsy of a tissue sample. This is because the process might help the tumor cells spread outside of the eye. That means the tumor samples researchers have access to are from cancers that progressed beyond their earliest stages, requiring eye removal.
“What we have developed with these retinoblastoma organoids is, for the first time ever, a laboratory model where it’s possible to study the processes that go on when retinoblastoma is starting to form,” said co-corresponding author Michael Dyer, Ph.D., St. Jude Department of Developmental Neurobiology chair. “We can follow the process from the beginning to the early stages of tumor development, which is really exciting and opens up new avenues for research.”
The need for a new model
Models provide a way for scientists to study disease in the lab, both its biologic underpinnings as well as the way it responds to potential therapies. Creating models that reflect the reality of disease in human patients is a tremendous challenge. For rare diseases such as retinoblastoma, there are additional hurdles due to the limited number of patients. Retinoblastoma models, including cell lines, genetically engineered mouse models and patient-derived xenografts, have been useful for research. However, these models have also fallen short of replicating the disease as it occurs in patients.