Researchers identify 10 pesticides toxic to neurons involved in Parkinson’s

Photo Credit: Rosyid Arifin

Researchers at UCLA Health and Harvard have identified 10 pesticides that significantly damaged neurons implicated in the development of Parkinson’s disease, providing new clues about environmental toxins’ role in the disease.

While environmental factors such as pesticide exposure have long been linked to Parkinson’s, it has been harder to pinpoint which pesticides may raise risk for the neurodegenerative disorder. Just in California, the nation’s largest agricultural producer and exporter, there are nearly 14,000 pesticide products with over 1,000 active ingredients registered for use.

Through a novel pairing of epidemiology and toxicity screening that leveraged California’s extensive pesticide use database, UCLA and Harvard researchers were able to identify 10 pesticides that were directly toxic to dopaminergic neurons. The neurons play a key role in voluntary movement, and the death of these neurons is a hallmark of Parkinson’s.

Further, the researchers found that co-exposure of pesticides that are typically used in combinations in cotton farming were more toxic than any single pesticide in that group.

How Breast Cancer Arises

Breast cancer: polyploid giant cancer cell (PGCC)
Image Credit: National Cancer Institute

In what may turn out to be a long-missing piece in the puzzle of breast cancer, Harvard Medical School researchers have identified the molecular sparkplug that ignites cases of the disease currently unexplained by the classical model of breast-cancer development.

A report on the team’s work is published May 17 in Nature.

“We have identified what we believe is the original molecular trigger that initiates a cascade culminating in breast tumor development in a subset of breast cancers that are driven by estrogen,” said study senior investigator Peter Park, professor of Biomedical Informatics in the Blavatnik Institute at HMS.

The researchers said as many as one-third of breast cancer cases may arise through the newly identified mechanism.

The study also shows that the sex hormone estrogen is the culprit behind this molecular dysfunction because it directly alters a cell’s DNA.

Most, though not all, breast cancers are fueled by hormonal fluctuations. The prevailing view of estrogen’s role in breast cancer is that it acts as a catalyst for cancer growth because it stimulates the division and proliferation of breast tissue, a process that carries the risk for cancer-causing mutations. The new work, however, shows that estrogen causes mischief in a far more direct manner.

Mystery of important blood pressure drugs solved

Prof. Daniel Fuster, M.D. Department for BioMedical Research (DBMR) of the University of Bern and Department of Nephrology and Hypertension, Inselspital, Bern University Hospital.
Photo Credit: Courtesy of Daniel Fuster

Diuretic drugs from the thiazide group have been used for 60 years to treat high blood pressure. But they also increase the risk of developing diabetes. Researchers at the University of Bern and Inselspital have now pinpointed the cause of this side effect and in the process also gained new insights into the development of diabetes.

High blood pressure is a global health problem. In Switzerland, one in two people over the age of 65 has high blood pressure. This has been shown to increase the risk of serious secondary diseases such as dementia, stroke, cerebral hemorrhage, heart attack, and kidney failure. According to estimates by the World Health Organization, for example, around 54 percent of strokes are a direct result of high blood pressure. "Accordingly, there is a great need for effective, and also inexpensive and widely available antihypertensive drugs - particularly in light of our aging society," explains Prof. Daniel Fuster, M.D., from the Department for BioMedical Research at the University of Bern (DBMR) and Head Physician at the Department of Nephrology and Hypertension at Inselspital, Bern University Hospital.

Insight into brain’s waste clearing system may shed light on brain diseases

The image shows a microscopic image revealing the enhanced glymphatic transport of an intranasally delivered tracer (red), achieved using ultrasound combined with microbubbles.
Image Credit: Chen lab

Like the lymphatic system in the body, the glymphatic system in the brain clears metabolic waste and distributes nutrients and other important compounds. Impairments in this system may contribute to brain diseases, such as neurodegenerative diseases and stroke.

A team of researchers in the McKelvey School of Engineering at Washington University in St. Louis has found a noninvasive and nonpharmaceutical method to influence glymphatic transport using focused ultrasound, opening the opportunity to use the method to further study brain diseases and brain function. Results of the work are published in Proceedings of the National Academy of Sciences May 15, 2023.

Hong Chen, associate professor of biomedical engineering in McKelvey Engineering and of neurological surgery in the School of Medicine, and her team, including Dezhuang (Summer) Ye, a postdoctoral research associate, and Si (Stacie) Chen, a former postdoctoral research associate, found the first direct evidence that focused ultrasound, combined with circulating microbubbles — a technique they call FUSMB — could mechanically enhance glymphatic transport in the mouse brain. 

Focused ultrasound can penetrate the scalp and skull to reach the brain and precisely target a defined region within the brain. In previous work, Chen’s team found that microbubbles injected into the bloodstream amplify the effects of the ultrasound waves on the blood vessels and generate a pumping effect, which helps with the accumulation of intranasally-delivered agents in the brain, such as drugs or gene therapy treatments.

Mast cells have an important impact on the development of chronic myeloid leukemia

Microscopic image of bone marrow from a mouse with CML showing an unusually high number of mast cells (purple).
Image Source / Credit: Sebastian Halbach

Research team at the University of Freiburg traces the origin of proinflammatory cytokines

Chronic myeloid leukemia (CML) is a type of blood cancer that arises from malignant changes in blood-forming cells of the bone marrow. It mainly occurs in older individuals and represents about 20 percent of all adult leukemia cases. A research team led by Dr. Sebastian Halbach, Melanie Langhammer and Dr. Julia Schöpf from the Institute of Molecular Medicine and Cell Research at the University of Freiburg has now demonstrated for the first time that mast cells play a crucial role in the development of CML.  Mast cells could therefore serve as an additional therapeutic target in the clinic. “It was really impressive to see that mice lacking mast cells no longer developed severe CML,” says study leader Halbach. The results were recently published in the journal Leukemia.

Significantly elevated cytokine levels

Mast cells are cells of the immune system that play a decisive role in the defense against pathogens, but also in allergies. In this context, mast cells release inflammation inducing messenger molecules, so-called proinflammatory cytokines, which are crucial for the immune response. However, proinflammatory cytokines are also frequently found in the microenvironment of tumors and are suspected of decisively promoting cancer development. Using a mouse model for CML, the scientists were able to demonstrate for the first time that cytokines in CML could indeed originate from mast cells.

Deficiency causes appetite for meat

A carnivorous leaf of Triphyophyllum peltatum with glands excreting a sticky liquid to capture insect prey.
Photo Credit: Traud Winkelmann / Universität Hannover

Under certain circumstances, a rare tropical plant develops into a carnivore. A research team from the universities of Hannover and Würzburg has now deciphered the mechanism responsible for this.

Triphyophyllum peltatum is a unique plant. Native to the tropics of West Africa, the liana species is of great interest for medical and pharmaceutical research due to its constituents: In the laboratory, this show promising medically useful activities against pancreatic cancer and leukemia cells, among others, as well as against the pathogens that cause malaria and other diseases.

However, the plant species is also interesting from a botanical perspective: Triphyophyllum peltatum is the only known plant in the world that can become a carnivore under certain circumstances. Its menu then includes small insects, which it captures with the help of adhesive traps in the form of secretion drops and digests with synthesized lytic enzymes.

Heat is the Top Cause of Exertion-Related Injuries and Fatalities for Laborers

This study is one of the first of its kind to evaluate exertion-related injuries and fatalities from word-related activities
Photo Credit: Jeriden Villegas

Dangers like working high above the ground or with heavy machinery are common hazards for laborers in industries like construction or excavation. But there’s another near-universal hazard for laborers – heat.

Margaret Morrissey, a postdoctoral fellow within UConn’s College of Agriculture, Health and Natural Resources and president of occupational safety for the Korey Stringer Institute, led a recently published study that found heat is the number one cause of exertion-related injuries and fatalities on U.S. work sites.

This work was recently published in the International Journal of Environmental Research and Public Health.

Using data reported to OSHA (Occupational Safety and Health Administration), the team found that of all injuries and fatalities, about 3% were exertion related. Of that 3%, a staggering 89% were related to heat stress.

Combined delivery of engineered virus with immunotherapy is safe and improves outcomes in subset of patients with glioblastoma

From left to right: Frederick Lang, M.D., Juan Fueyo, M.D., and Candelaria Gomez-Manzano, M.D.
Image Credit: Courtesy of MD Anderson Cancer Center

Intratumoral delivery of an engineered oncolytic virus (DNX-2401) targeting glioblastoma (GBM) cells combined with subsequent immunotherapy was safe and improved survival outcomes in a subset of patients with recurrent GBM, according to results from a multi-institutional Phase I/II clinical trial co-led by researchers at The University of Texas MD Anderson Cancer Center and the University of Toronto.

The study, published today in Nature Medicine, met its primary safety endpoint and demonstrated the combination was well tolerated overall with no dose-limiting toxicities. The study did not meet its primary efficacy endpoint of objective response rate, but the combination achieved a 12-month overall survival (OS) rate of 52.7%, which is greater than the prespecified efficacy threshold of 20%. Three patients remained alive at 45, 48 and 60 months after treatment.

“This viral therapy is a different approach to the current standard of care,” said co-corresponding author Frederick Lang, M.D., chair of Neurosurgery. “Our previous trial demonstrated that not only does the virus act by killing cancer cells directly, it also effectively activates the innate immune system to convert these immunologically cold tumors into hot tumors. This led us to evaluate a combination with checkpoint inhibitors, which we now see can improve survival outcomes in a subset of patients.”

Clinically relevant deficiency of the “bonding hormone” oxytocin demonstrated

The hormones oxytocin and vasopressin are produced in the same area of the brain and are also very similar in structure. This is why disorders that cause vasopressin deficiency could also affect the neurons that produce oxytocin
Image Credit: Colin Behrens

The hormone oxytocin is important for social interaction and to control emotions. A deficiency of this hormone has previously been assumed, for example, in people with autism, but has never been proven. Now, for the first time, researchers from the University of Basel and the University Hospital of Basel have succeeded in demonstrating a deficiency of oxytocin in patients with a deficiency of vasopressin caused by a disease of the pituitary gland. This finding could be key to developing new therapeutic approaches.

The hormones oxytocin and vasopressin are produced in the same area of the brain and are also very similar in structure. Patients with a rare deficiency of vasopressin cannot concentrate their urine and lose liters of water as a result. In order to compensate for this loss, they are obliged to drink up to 10 liters or more per day.

With a nasal spray or a tablet containing synthetically produced vasopressin, these symptoms can usually be treated without any problems. However, even with this treatment, many patients report anxiety, have trouble with social interactions or demonstrate impaired emotional awareness.

Putting the STING into cancer immunotherapy

Belcher and Hammond Lab researchers developed a cancer vaccine that could make checkpoint blockade therapies more effective for more patients.
Illustration Credit: Bendta Schroeder

Immune checkpoint blockade therapies have been revolutionary in the treatment of some cancer types, emerging as one of the most promising treatments for diseases such as melanoma, colon cancer, and non-small cell lung cancer.  

While in some cases checkpoint blockade therapies elicit a strong immune response that clears tumors, checkpoint inhibitors do not work for all tumor types or all patients. Moreover, some patients who do experience an initial benefit from these therapies see their cancers recur. Only a small minority of patients treated with checkpoint blockade therapies see lasting benefits. Researchers have developed various combination therapy strategies to overcome resistance to checkpoint blockade therapies, with the STING pathway emerging as one of the most attractive lines of inquiry.  

In a study appearing in Advanced Healthcare Materials, a team of MIT researchers engineered a therapeutic cancer vaccine capable of restoring STING signaling and eliminating the majority of tumors in mouse models of colon cancer and melanoma, with minimal side effects. The vaccine also inhibited metastasis in a breast cancer mouse model and prevented the recurrence of tumors in cured mice. 

New therapy helps immune system eradicate brain tumors

Professor Anna Dimberg.
Photo Credit: Mikael Wallerstedt

Researchers from Uppsala University have developed a method that helps immune cells exit from blood vessels into the tumor and kill cancer cells. The aim is to improve the treatment of aggressive brain tumors. The study has been published in the journal Cancer Cell.

Glioblastoma is an aggressive brain tumor that lacks efficient treatment. This is in part due to the ability of the tumor to suppress or evade the body´s natural anti-cancer immune response. Immunotherapy, using checkpoint inhibitors, aims to reactivate our immune system against cancer. However, for this type of treatment to be effective, specific immune cells known as killer T cells are required to be present within the tumor.

Unfortunately, blood vessels in brain cancer are dysfunctional and act as a barrier, preventing killer T cells from reaching the tumor. As a result, this form of immunotherapy, which is effective against many forms of cancer, is ineffective against brain cancers.

Help the killer T cells

In the new study, the Uppsala researchers have developed a method to help the killer T cells reach the tumors and fight cancer cells. They used a viral vector that specifically infected the blood vessels in the brain and enabled them to produce a factor called LIGHT. This altered the function of the tumor vessels, increasing their ability to transport T cells from the blood into the tumor tissue.

12 Months of Treatment with EPIT Superior to Placebo in Desensitizing Children to Peanuts

Wesley Burks, MD, and Edwin Kim, MD
Photo Credit: Courtesy UNC School of Medicine

The study, called EPITOPE, led by senior author A. Wesley Burks, MD, CEO of UNC Health and dean of the UNC School of Medicine, and contributing author Edwin Kim, MD, MS, associate professor of pediatrics in the Division of Pediatric Allergy and Immunology at the UNC School of Medicine, shows superior results in desensitizing children to peanuts. Results were recently published in the New England Journal of Medicine.

Peanut allergy affects approximately two percent of children in the United States, Canada, and other westernized countries, with a rapidly rising prevalence over the past 20 years. Currently there are no FDA approved treatment options for peanut-allergic children under the age of 4 years, but further research into the safety, efficacy, and tolerability of epicutaneous immunotherapy (EPIT) could play a significant role in novel options for immunotherapy. The EPITOPE trial, led by senior author A. Wesley Burks, MD, CEO of UNC Health and dean of the UNC School of Medicine, evaluating the safety profile of Viaskin, a novel form of EPIT, among peanut-allergic toddlers shows that after 12 months of treatment in children aged 1-3 years, the treatment was found to be statistically superior to placebo in desensitizing participants to peanuts, increasing the peanut dose triggering allergic symptoms. Edwin Kim, MD, MS, associate professor of pediatrics in the Division of Pediatric Allergy and Immunology at the UNC School of Medicine is also a contributing author to the paper.

Cancer may lurk in ‘normal looking’ skin

Researchers say reducing skin mutations in 'normal looking' skin could reduce the risk of skin cancers.
Photo Credit: Anna Nekrashevich

A University of Queensland study has found skin with few visible freckles or blemishes may still carry sun-damaged DNA mutations that can trigger cancer.

Researchers from UQ’s Frazer Institute Dermatology Research Centre investigated the relationship between the number of mutations found in ‘normal looking’ skin and the number of a person’s past skin cancers.

Lead author and PhD candidate Ms. Ho Yi Wong said the findings show Australians can still have a high number of mutations in skin they think looks normal.

“We took skin samples from the forearms of 37 skin cancer patients which were frequently sun exposed,” Ms. Wong said.

“They had an average of 4-5 times more mutations in normal looking skin compared to similar studies overseas.

Delivery of antioxidants to liver mitochondria

Damage to the liver induced by acetaminophen (dotted blue outlines) is almost completely mitigated by CoQ10-MITO-Porter (right), compared to the effect of phosphate buffered saline (left) and direct administration of CoQ10(center).
Image Credit: Mitsue Hibino, et al. Scientific Reports. May 10, 2023

A new drug delivery system delivers an antioxidant directly to mitochondria in the liver, mitigating the effects of oxidative stress.

Mitochondria are microscopic organelles found within cells, and are well-known as the “powerhouse of the cell.” They are by far the largest producer of the molecule adenosine triphosphate (ATP), which provides energy to many processes in living cells. The process by which mitochondria synthesize ATP generates a large amount of reactive oxygen species (ROS), chemical groups that are highly reactive. 

In a healthy cell, the ROS is controlled by the mitochondria; however, when this balance is lost, the excess ROS damages the mitochondria and subsequently cells and tissues. This phenomenon, known as oxidative stress, can cause premature aging and disease. The ROS that causes oxidative stress can be controlled by antioxidants.

A research team led by Professor Yuma Yamada, Distinguished Professor Hideyoshi Harashima and Assistant Professor Mitsue Hibino at Hokkaido University have developed a system to deliver antioxidants to mitochondria to mitigate the effects of excess ROS. Their findings were published in Scientific Reports.

A New Cancer Mechanism: Failed Cell Housekeeping

Illustration of single-stranded RNA
Illustration Credit: National Institute of General Medical Sciences

New research pinpoints a gene that, when mutated, causes cancer through a mechanism scientists haven’t seen before: cells lose the ability to dispose of their trash, namely defective strands of RNA.

This mechanism appears to cut across many different malignancies and could present a whole new set of molecules for cancer drugs to target, as reported in the journal Science by a team from Harvard Medical School, Boston Children’s Hospital, and Dana-Farber Cancer Institute.

While studying zebrafish, Megan Insco, HMS instructor in medicine who was a research fellow in the lab of Leonard Zon at HMS and Boston Children’s at the time, identified a tumor-suppressing gene called CDK13. When mutated, it expedited the development of melanoma. 

The same gene was also mutated in many human melanomas, she found.

But what was really surprising was how the CDK13 mutation causes cancer.

Investigating the RNAs made by melanoma cells, Insco saw multiple short, defective RNAs. She immediately shared this odd finding with Zon.

AI Predicts Future Pancreatic Cancer

Pancreatic cancer cells
Image Credit: National Cancer Institute

An artificial intelligence tool has successfully identified people at the highest risk for pancreatic cancer up to three years before diagnosis using solely the patients’ medical records, according to new research led by investigators at Harvard Medical School and the University of Copenhagen, in collaboration with VA Boston Healthcare System, Dana-Farber Cancer Institute, and the Harvard T.H. Chan School of Public Health.

The findings, published May 8 in Nature Medicine, suggest that AI-based population screening could be valuable in finding those at elevated risk for the disease and could expedite the diagnosis of a condition found all too often at advanced stages when treatment is less effective and outcomes are dismal, the researchers said. Pancreatic cancer is one of the deadliest cancers in the world, and its toll projected to increase.

Currently, there are no population-based tools to screen broadly for pancreatic cancer. Those with a family history and certain genetic mutations that predispose them to pancreatic cancer are screened in a targeted fashion. But such targeted screenings can miss other cases that fall outside of those categories, the researchers said.

“One of the most important decisions clinicians face day to day is who is at high risk for a disease, and who would benefit from further testing, which can also mean more invasive and more expensive procedures that carry their own risks,” said study co-senior investigator Chris Sander, faculty member in the Department of Systems Biology in the Blavatnik Institute at HMS. “An AI tool that can zero in on those at highest risk for pancreatic cancer who stand to benefit most from further tests could go a long way toward improving clinical decision-making.”

T Cells Can Activate Themselves to Fight Tumors

T cells are a type of white blood cell and play a central role in the immune response.
Photo Credit: NIAID.

When you need a bit of motivation, it often has to come from within. New research suggests cancer-fighting immune cells have found a way to do just that.

Scientists at University of California San Diego have discovered a property of T cells that could inspire new anti-tumor therapeutics. Through a previously undescribed form of cell auto-signaling, T cells were shown to activate themselves in peripheral tissues, fueling their ability to attack tumors.

The study, published May 8, 2023 in Immunity, was led by study first author and postdoctoral fellow Yunlong Zhao, PhD, and co-senior authors Enfu Hui, PhD, professor in the School of Biological Sciences at UC San Diego and Jack D. Bui, MD, PhD, professor of pathology at UC San Diego School of Medicine.

T cells are a type of white blood cell that protect against infection and help fight cancer. In the lymph organs, T cells are trained by antigen-presenting cells, which, as their name suggests, present an antigen (a piece of tumor or pathogen) to T cells, stimulating an immune response. 

Researchers develop model for how the brain acquires essential omega-3 fatty acids

Step-by-step process of lipid transport across blood-brain barrier.
Illustration Credit: Ethan Tyler from NIH Medical Arts

Researchers at the UCLA David Geffen School of Medicine, the Howard Hughes Medical Institute at UCLA and the National Institutes of Health have developed a zebrafish model that provides new insight into how the brain acquires essential omega-3 fatty acids, including docosahexaenoic acid (DHA) and linolenic acid (ALA). Their findings, published in Nature Communications, have the potential to improve understanding of lipid transport across the blood-brain barrier and of disruptions in this process that can lead to birth defects or neurological conditions. The model may also enable researchers to design drug molecules that are capable of directly reaching the brain.

Omega-3 fatty acids are considered essential because the body cannot make them and must obtain them through foods, such as fish, nuts and seeds. DHA levels are especially high in the brain and important for a healthy nervous system. Infants obtain DHA from breastmilk or formula, and deficiencies of this fatty acid have been linked to problems with learning and memory. To get to the brain, omega-3 fatty acids must pass through the blood-brain barrier via the lipid transporter Mfsd2a, which is essential for normal brain development. Despite its importance, scientists did not know precisely how Mfsd2a transports DHA and other omega-3 fatty acids.

Study sheds light on how the immune system protects the body

Photo Credit: RDNE Stock project

Researchers explore how patients with a rare and severe immunodeficiency were still able to defend themselves normally against viruses, including COVID-19

The first study of humans with a rare immunodeficiency reveals how the immune system protects the body against pathogens known to cause serious diseases, such as tuberculosis and COVID-19. The research involving McGill University, paves the way for new therapies to treat autoimmune diseases, chronic inflammatory diseases, and new approaches to vaccine development.

The immune system responds differently to various types of pathogens, like bacteria, parasites, and viruses. However, scientists are still trying to uncover how this complex network functions together and the processes that can go wrong with immunodeficiencies.

“The immune system plays a vital role in protecting the body from harmful germs that make people ill. It’s made up of a complex network of organs, cells, and proteins – like IRF1 or regulatory factor 1, which is key in the regulation of an early immune response to pathogens,” says co-author of the study David Langlais, an Assistant Professor in the Departments of Human Genetics and Microbiology and Immunology at McGill University.

Prolonging the survival of patients with gastric cancer

Zolbetuximab is given as an intravenous infusion to patients with advanced gastric cancer in combination with chemotherapy.
Photo Credit: Hiroshi Tsubono

Gastric cancer is the fifth most commonly diagnosed malignancy worldwide. It ranks a sad third in cancer-related causes of death. The reason for this is late diagnosis coupled with rapid spread of tumor cells in the body. In an international clinical study co-chaired by investigators from Leipzig University’s Faculty of Medicine, researchers investigated a substance that is expected to prolong the survival of patients and also established a new clinically relevant biomarker. The results have been published in the renowned journal “The Lancet”.

“The results of the study are important for cancer research. They show that patients with gastric cancer who have been treated with zolbetuximab live longer. The progression of the tumor disease is delayed and overall survival of patients is improved. We expect that the study will lead to the approval of this drug in Europe and as a result also in Germany. This is an important step for those affected by this serious and often fatal cancer,” said Professor Florian Lordick, director of the University Cancer Center Leipzig. The experienced oncologist helped to design the recently published study at the international level and ensured that German patients were able to participate.