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Chimeric antigen receptor T-cell therapy, or CAR T, has made a big impact on the treatment of certain blood cancers, allowing patients with relapsed/refractory disease to live longer, healthier lives. But in clinical study, the cellular therapy has not been as successful for patients with solid tumors, due in part to the lack of tumor targets not expressed in vital tissues. In a new study published in Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research, Moffitt Cancer Center researchers share the identification of a new potential target for CAR T cells called OR2H1 that they have demonstrated inhibits growth in lung and ovarian tumors.
The key to CAR T-cell therapy is the genetic modification made to the patient’s T cells. Their cells are collected through a process called apheresis, and then shipped to a laboratory where the cells are modified to contain a gene for the T cell receptor that recognizes a specific marker on cancer cells. Those modified T cells, now CAR T cells, are stimulated to grow and multiply before being sent back to the hospital to be infused back into the patients. The receptor on the CAR T cells acts as a GPS, seeking out their specific marker on the surface of the cancer cells. Currently there are CAR T therapies approved to treat patients with lymphoma, leukemia and multiple myeloma, but there are no approved CAR T therapies for solid tumors.
Moffitt researchers are working to identify tumor markers that can make CAR T an effective therapy for patient with solid tumors. The goal is to find a marker that is expressed on tumor cells but not on normal cells, to reduce the potential for unwanted toxicities. The team, led by Dr. Jose Conejo-Garcia, focused the search on a family of proteins called olfactory receptors that are expressed in the nose and contribute to the perception of smell. During lab experiments, they discovered that the protein OR2H1 is expressed in a variety of solid tumors, ranging from 4% of colon cancer samples to 69% of cancers of the gall bladder. Importantly, of all normal tissues examined, OR2H1 was found only in the testis, suggesting that therapies that target OR2H1 would have minimal effects on normal cells.
The researchers then created CAR T cells that were specific to the OR2H1 protein. The OR2H1 CAR T cells were able to kill lung and ovarian cancer cells that expressed OR2H1 but had no effect on healthy cells. The OR2H1 CAR T cells also had anti-tumor effects in vivo in immunodeficient mice challenged with human tumors. Tumor inhibition was observed in lung and ovarian cancer mice models with varying levels of OR2H1, including ovarian cancer cells that were resistant to chemotherapy.
These combined data suggest that OR2H1 may be an effective target for CAR T therapies in solid tumors. The researchers hope these initial studies will lead to the development of OR2H1 CAR T cells for a wide variety of patients with solid tumors.
“Our work demonstrates the applicability of this therapy to a wide variety of patients, given the expression of OR2H1 in a subset of solid tumors across multiple histologies, including high-grade serous ovarian cancers, lung carcinoma, cholangiocarcinoma, prostate cancer and ovarian cancers of multiple other histologies. Targeting a molecule that is not expressed in vital tissues would allow us to further engineer T cells to overcome immunosuppression at tumor beds, if needed,” said Conejo-Garcia, chair of Moffitt’s Department of Immunology.
This work was supported by the National Cancer Institute (P30CA076292, R01CA157664, R01CA124515, R01CA178687, R01CA211913, U01CA232758, T32CA009140, K99CA266947), the Moffitt Foundation, Moffitt’s Junior Scientist Research Partnership Award and the American Cancer Society Postdoctoral Fellowship.
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Materials provided by H. Lee Moffitt Cancer Center & Research Institute. Note: Content may be edited for style and length.

More than 60 million magnetic resonance imaging (MRI) scans are performed worldwide each year, but imaging for the millions of patients with cardiac implantable electronic devices (CIEDs) such as pacemakers is a logistical challenge, because of concerns with how the magnetic field affects the implants. Now, a newly published study from the University of Missouri School of Medicine reveals safe and effective reprogramming of these devices is possible, even from a remote location.
Researchers conducted an observational study of 209 patients at MU Health Care’s University Hospital who underwent remote programming of their device for MRI using Medtronic RM CareLink technology. Of those scans, 51 were performed urgently. An MRI technician started each session by contacting an off-site operator and placing a programming wand on the patient’s CIED, enabling the programmer to access the device remotely and switch to an MRI-safe mode. After completing the scan, the remote programmer returned the device to the patient’s baseline settings.
“During this study, none of the patients experienced any symptoms during the scan, no one needed any changes to the baseline settings afterward, and there were no technology issues,” said senior author Sandeep Gautam, MD, associate professor of clinical medicine. “The estimated time saved per scan was 18 to 38 minutes per patient, calculated by measuring the device representative’s travel time to the MRI suite.”
Remote programming could reduce the need to reschedule MRI scans and other procedures that require device programming in case there is no device representative or other qualified personnel present on-site to perform the task.
“We believe this technology will reduce unnecessary use of health care resources and manpower,” Gautam said. “This will eventually lead to reduction in health care costs, as it will require a smaller number of personnel for device programming, eliminate travel cost and may be especially helpful in rural areas where access to health care is limited.”
Gautam said future studies are needed to evaluate the safety and efficacy of remote programming in larger patient populations, with different vendors and more diverse settings.
Gautam’s co-authors include principal investigator Sisir Siddamsetti, MD, cardiology fellow; and Alexander Shinn, DO, medical resident.
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Materials provided by University of Missouri-Columbia. Note: Content may be edited for style and length.

Clusters of microscopic bacteria exist all around us. These invisible communities, known as biofilms, are found in habitats ranging from our skin surface to sewer pipes and play integral roles in environments spanning healthcare to agriculture.
Molecular biologists and physicists at the University of California San Diego have joined forces to develop a novel method of using electrical shocks to control the development of communities of bacteria. Their findings, obtained with a newly developed technology, are significant from a medical perspective. In areas where bacteria growth is a concern, biofilms can lead to chronic infections, especially in locations such as hospitals where antibiotic resistance is a major health threat.
Much like other multi-cellular organisms, biofilms are composed of various cell types that carry out specialized roles. For example, matrix-producing cells provide the structural “glue” that holds the bacterial community together while motile cells play a role in the formation and spread of biofilms. The balance of these two cell types defines the physical and biological properties of the biofilm and is also important for its development. If there are too many matrix-producing cells, the biofilm becomes too rigid and cannot grow efficiently. If there are too many motile cells, the biofilm disintegrates as the cells swim away. Thus, changing the ratio of these two cell types offers a precise method for controlling biofilms.
As described May 4, 2022 in the journal Cell Systems, a team at UC San Diego with postdoctoral scholar Colin Comerci and fellow researchers in the laboratory of Professor Gürol Süel in the Department of Molecular Biology, along with colleagues in the Department of Physics, developed a novel microfluidic device and combined it with a multi-electrode array, which allowed them to apply localized electric shocks to a growing biofilm.
To the researchers’ surprise, electrical stimulation caused motile cells to multiply, even though all cells in the biofilm are genetically identical.
“While it is known that electrical shocks can kill cells, here we show that they can cause growth of a specific sub-type of cells,” said Süel, a Biological Sciences professor with affiliations in the San Diego Center for Systems Biology, BioCircuits Institute and Center for Microbiome Innovation. “How a second-long stimulation can promote growth for hours and only of one type of cells is a great puzzle that we are eager to solve.”
“Being able to modulate cell types in this way is not just important for understanding biofilms,” said Comerci. “The electrochemical signals we used are similar to signals used during development in more complicated organisms like frogs, fish or even humans. Thus, our findings may offer analogies to other biological systems.”
Why electrical stimulation boosts the population of one cell type rather than another remains a mystery and continues to be studied at the Süel laboratory. Such influence, the researchers say, provides control of the biofilm’s composition and development, and may offer a new tool to destabilize biofilms in healthcare and agriculture settings.
The paper’s full author list includes: Colin Comerci, Alan Gillman, Leticia Galera-Laporta, Edgar Gutierrez, Alex Groisman, Joseph Larkin, Jordi Garcia-Ojalvo and Gürol Süel.
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Materials provided by University of California – San Diego. Original written by Mario Aguilera. Note: Content may be edited for style and length.

Hearing loss due to aging, noise and certain cancer therapy drugs and antibiotics has been irreversible because scientists have not been able to reprogram existing cells to develop into the outer and inner ear sensory cells — essential for hearing — once they die.
But Northwestern Medicine scientists have discovered a single master gene that programs ear hair cells into either outer or inner ones, overcoming a major hurdle that had prevented the development of these cells to restore hearing.
The study will be published in Nature May 4.
“Our finding gives us the us the first clear cell switch to make one type versus the other,” said lead study author Jaime Garcia-Anoveros, professor of anesthesia, neurology and neuroscience at Northwestern University Feinberg School of Medicine. “It will provide a previously unavailable tool to make an inner or outer hair cell. We have overcome a major hurdle.”
About 8.5 percent of adults aged 55 to 64 in the U.S. have disabling hearing loss. That increases to nearly 25 percent of those aged 65 to 74 and 50 percent of those who are 75 and older, reports the Centers for Disease Control.
Currently, scientists can produce an artificial hair cell, but it does not differentiate into an inner or outer cell, which provide different essential functions to produce hearing. The discovery is a major step towards developing these specific cells.

It’s not often that a failed clinical trial leads to a scientific breakthrough.
When patients in the UK started showing adverse side effects during a cancer immunotherapy trial, researchers at La Jolla Institute for Immunology (LJI) Center for Cancer Immunotherapy and University of Liverpool went back through the data and worked with patient samples to see what went wrong.
Their findings, published recently in Nature, provide critical clues to why many immunotherapies trigger dangerous side effects — and point to a better strategy for treating patients with solid tumors.
“This work shows the importance of learning from early stage clinical trials,” says La Jolla Institute for Immunology (LJI) Professor Pandurangan Vijayanand, M.D., Ph.D., who co-led the new research with Christian H. Ottensmeier, M.D., Ph.D., FRCP, a professor with the University of Liverpool, The Clatterbridge Cancer Centre NHS Foundation Trust, and adjunct professor at LJI.
Limited success with immunotherapies
Both Vijayanand and Ottensmeier are physician scientists, and Ottensmeier is an attending oncologist who treats solid tumor patients. In just the last decade, he has seen more and more patients thrive thanks to advances in immunotherapies, which work with the immune system to kill cancers.

Eight different herpes viruses are known to date in humans. They all settle down permanently in the body after acute infection. Under certain circumstances, they wake up from this dormant phase, multiply and attack other cells. This reactivation is often associated with symptoms, such as itchy cold sores or shingles.
In the course of evolution, most herpesviruses have learned to use small RNA molecules, so-called microRNAs, to reprogram their host cells to their advantage. A research team led by Bhupesh Prusty and Lars Dölken from Julius-Maximilians-Universität (JMU) Würzburg in Bavaria, Germany, has now been able to show for the first time that a viral microRNA acts as a master regulator to induce the reactivation of the virus. In the journal Nature, the researchers present the previously unknown cellular mechanism by which human herpesvirus 6 (HHV-6) triggers its own awakening.
Problems after reactivation of the virus
More than 90 percent of all people are infected with HHV-6 without noticing it. The virus probably only causes problems when it wakes up repeatedly.
HHV-6 reactivation is suspected of impairing heart function, causing the rejection of transplanted organs and triggering diseases such as multiple sclerosis or chronic fatigue syndrome (ME/CFS). In addition, recent studies suggest that this herpesvirus may be involved in the development of schizophrenia, bipolar disorder and other diseases of the nervous system.
“How herpesviruses reactivate from a dormant state is the central question in herpesvirus research,” says JMU virologist Lars Dölken. “If we understand this, we know how to intervene therapeutically.” A previously unknown key to this is a viral microRNA called miR-aU14. It is the central switch that initiates the reactivation of HHV-6.

The market-ready meat alternative is very similar in taste and texture, but is a biotech product which — by replacing beef — involves much less land resources and greenhouse gas emissions from agriculture and land-use change. This goes under the assumption of a growing world population’s increasing appetite for beefy bites, and it is the first time researchers have projected the development of these market-ready meat substitutes into the future, assessing their potential impact on the environment.
“The food system is at the root of a third of global greenhouse gas emissions, with ruminant meat production being the single largest source,” says Florian Humpenöder, researcher at PIK and lead author of the study. That is because more and more forests that store a lot of carbon are cleared for cattle grazing or growing its feed, and because of further greenhouse-gas emissions from animal agriculture. Part of the solution could be existing biotechnology: Nutritious protein-rich biomass with meat-like texture produced from microbes like fungi via fermentation, what scientists call “microbial protein.”
“The substitution of ruminant meat with microbial protein in the future could considerably reduce the greenhouse gas footprint of the food system,” says Humpenöder. “The good news is that people do not need to be afraid they can eat only greens in the future. They can continue eating burgers and the like, it’s just that those burger patties will be produced in a different way.”
Sustainable burgers: replacing minced red meat with microbial protein
The team of researchers from Germany and Sweden included microbial protein in a computer simulation model to detect the environmental effects in the context of the whole food and agriculture system, as opposed to previous studies at the level of single products. Their forward-looking scenarios run until 2050 and account for future population growth, food demand, dietary patterns as well as dynamics in land use and agriculture. As meat consumption will likely continue to rise in the future, more and more forests and non-forest natural vegetation may be doomed to extinction for pastures and cropland.
“We found that if we substituted 20 per cent of ruminant meat per capita by 2050, annual deforestation and CO2 emissions from land-use change would be halved compared to a business-as-usual scenario. The reduced numbers of cattle do not only reduce the pressure on land but also reduce methane emissions from the rumen of cattle and nitrous oxide emissions from fertilizing feed or manure management,” says Humpenöder “So replacing minced red meat with microbial protein would be a great start to reduce the detrimental impacts of present-day beef production.”
Microbial protein can be decoupled from agricultural production
“There are broadly three groups of meat analogues,” Isabelle Weindl, co-author and also researcher at PIK, explains. “There are plant-based ones like soybean burger patties, and animal cells grown in a petri dish also known as cultured meat, which is so far very expensive but got a lot of public attention recently. And there’s fermentation-derived microbial protein, which we consider most interesting. It is available in a large variety already today in supermarkets, for example in the UK or in Switzerland, and, importantly, it can be largely decoupled from agricultural production. Our results show that even accounting for the sugar as feedstock, microbial protein requires much less agricultural land compared to ruminant meat for the same protein supply.”
Microbial protein is made in specific cultures, just like beer or bread. The microbes are living on sugar and a steady temperature, and getting out a very protein-rich product that can taste like, feel like and be as nutritious as red meat. Based on the centuries-old method of fermentation, it was developed in the 1980s. The US Food and Drug Administration (FDA) greenlighted a microbial protein meat alternative (mycoprotein) as safe in 2002.
Green biotechnology needs to be fuelled by green energy
“Biotechnology offers a promising toolbox for a number of land-related challenges from ecosystems preservation through improving food security,” says co-author Alexander Popp, leader of the Land Use Management group at PIK. “Alternatives to animal proteins, including substitutes for dairy products, can massively benefit animal welfare, save water and avert pressure from carbon-rich and biodiverse ecosystems.” However, there are crucial questions attached to shifting more and more production from livestock to fermentation tanks — most importantly the energy supply for the production process.
“A large-scale transformation towards biotech food requires a large-scale decarbonisation of electricity generation so that the climate protection potential can be fully developed,” Popp adds. “Yet if we do this properly, microbial protein can help meat-lovers embrace the change. It can really make a difference.”

Prescriptions for multiple drugs, or polypharmacy, is often recommended for the treatment of complex diseases. However, upon ingestion, multiple drugs may interact in an undesirable manner, resulting in severe adverse effects or decreased clinical efficacy. Early detection of such drug-drug interactions (DDIs) is therefore essential to prevent patients from experiencing adverse effects.
Currently, computational models and neural network-based algorithms examine prior records of known drug interactions and identify the structures and side effects they are associated with. These approaches assume that similar drugs have similar interactions and identify drug combinations associated with similar adverse effects.
Although understanding the mechanisms of DDIs at a molecular level is essential to predict their undesirable effects, current models rely on structures and properties of drugs, with predictive range limited to previously observed interactions. They do not consider the effect of DDIs on genes and cell functionality.
To address these limitations, Associate Professor Hojung Nam and Ph.D. candidate Eunyoung Kim from the Gwangju Institute of Science and Technology in South Korea developed a deep learning-based model to predict DDIs based on drug-induced gene expression signatures. These findings were published in the Journal of Cheminformatics on March 4, 2022.
The DeSIDE-DDI model consists of two parts: a feature generation model and a DDI prediction model. The feature generation model predicts a drug’s effect on gene expression by considering both the structure and properties of the drug while the DDI prediction model predicts various side effects resulting from drug combinations.
To explain the key features of this model, Prof. Nam explains, “Our model considers the effects of drugs on genes by utilizing gene expression data, providing an explanation for why a certain pair of drugs cause DDIs. It can predict DDIs for currently approved drugs as well as for novel compounds. This way, the threats of polypharmacy can be resolved before new drugs are made available to the public.”
What’s more, since all compounds do not have drug-treated gene expression signatures, this model uses a pre-trained compound generation model to generate expected drug-treated gene expressions.
Discussing its real-life applications, Prof. Nam remarks, “This model can discern potentially dangerous drug pairs, acting as a drug safety monitoring system. It can help researchers define the correct usage of the drug in the drug development phase.”
A model with such potential will truly revolutionize how the safety of novel drugs is established in the future.
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Materials provided by GIST (Gwangju Institute of Science and Technology). Note: Content may be edited for style and length.

Overwhelming evidence shows that infection with severe acute respiratory syndrome (SARS-CoV-2) causes dysfunction of multiple organ systems, including the nervous system. Neurologic symptoms are frequently reported even in patients with mild illness and for some, these neurologic symptoms may persist as part of long-haul COVID.
To describe the prevalence, associated risk factors and outcomes of serious neurologic manifestations among patients hospitalized with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, researchers from Boston University School of Medicine (BUSM) studied 16,225 patients from 179 hospitals in 24 countries as part of the Society for Critical Care Medicine’s Viral Infection and Respiratory Illness University Study.
The researchers found nearly 13 percent of patients admitted for COVID-19 in the first year of the pandemic developed serious neurologic manifestations. Specifically, 1,656 (10.2 percent) had encephalopathy (any diffuse disease of the brain that alters brain function or structure) at admission, 331 (2.0 percent) had a stroke, 243 (1.5 percent) had a seizure, and 73 (0.5 percent) had meningitis or encephalitis at admission or during hospitalization.
“Our findings show that encephalopathy at hospital admission is present in at least one in 10 patients with SARS-CoV-2 infection, while stroke, seizures and meningitis/encephalitis were much less common at admission or during hospitalization,” explains corresponding author Anna Cervantes-Arslanian, MD, associate professor of neurology, neurosurgery and medicine at BUSM.
Additionally, they discovered all serious neurologic manifestations were associated with increased disease severity, greater need for ICU interventions, longer length of stay, ventilator use and higher mortality.
According to the researchers, patients with neurologic manifestations were more likely to have medical comorbidities. Most notably, a history of stroke or neurologic disorder increased the odds of developing a neurologic manifestation.
Moreover, they found neurologic manifestations differed by race. Black patients had an increased frequency of stroke, seizure and encephalopathy when compared with white patients. “Given the association of neurologic manifestations with poorer outcomes, further study is desperately needed to understand why these differences occur and what can be done to intervene,” added Cervantes, who also is a neurologist at Boston Medical Center.
These findings appear online in the journal Critical Care Explorations.
Funding for this study was provided by NIH/NCRR/NCATS CTSA grant number UL1 TR002377. The registry is funded in part by the Gordon and Betty Moore Foundation and Janssen Research & Development, LLC. Research Electronic Data Capture support provided by the Mayo Clinic.
Parts of these results were presented at the American Academy of Neurology annual meeting (on April 5, 2022), as an oral abstract.
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Materials provided by Boston University School of Medicine. Note: Content may be edited for style and length.

In the search for eternal youth, fecal transplants may seem like an unlikely way to reverse the ageing process.
However, scientists at the Quadram Institute and the University of East Anglia have provided evidence, from research in mice, that transplanting faecal microbiota from young into old mice can reverse hallmarks of ageing in the gut, eyes, and brain.
In the reverse experiment, microbes from aged mice induced inflammation in the brain of young recipients and depleted a key protein required for normal vision.
These findings show that gut microbes play a role in the regulating some of the detrimental effects of ageing and open up the possibility of gut microbe-based therapies to combat decline in later life.
Prof Simon Carding, from UEA’s Norwich Medical School and head of the Gut Microbes and Health Research Programme at the Quadram Institute, said: “This ground-breaking study provides tantalising evidence for the direct involvement of gut microbes in ageing and the functional decline of brain function and vision and offers a potential solution in the form of gut microbe replacement therapy.”
It has been known for some time that the population of microbes that we carry around in our gut, collectively called the gut microbiota, is linked to health. Most diseases are associated with changes in the types and behaviour of bacteria, viruses, fungi and other microbes in an individual’s gut.