The study’s findings, published October 26 in the journal PLOS ONE, substantiate and help validate that memory, and other cognitive difficulties experienced long-term by individuals with post-treatment Lyme disease, are linked to functional and structural changes in the brain.

Lyme disease, whose early symptoms may include a characteristic rash, flu-like aches and fever, joint pain, and fatigue, is treated using a rigorous course of antibiotics, which usually clears the illness.

However, in those considered long-haul patients for whom Lyme symptoms continue after completion of antibiotics, the condition is a chronic illness that can be marked by fatigue, muscular pain, insomnia, depression and cognitive difficulties, such as trouble with concentration and memory. Such individuals generally have no obvious clinical or laboratory evidence of ongoing issues.

In a bid to identify what they suspect are long-term changes in brain function that may be causing certain persistent Lyme disease symptoms, researchers from Johns Hopkins Medicine’s departments of neurology and psychiatry and behavioral sciences, in collaboration with the Lyme Disease Research Center, used functional MRI (fMRI) scans of the brain, a technology that detects changes in brain blood flow. These scans allow investigators to track changes in the brain in real time.

“Objective biologic measures of post-treatment Lyme symptoms typically can’t be identified using regular MRIs, CT scans, or blood tests,” says researcher John Aucott, M.D., director of the Johns Hopkins Lyme Disease Clinical Research Center and associate professor of medicine at the Johns Hopkins University School of Medicine. “We needed to expand our methods of evaluation,” he adds.

Spearheaded by lead author Cherie Marvel, Ph.D., the team recruited 12 male and female post-treatment Lyme disease patients, and 18 participants without a history of Lyme, to undergo fMRI scans while performing a short-term memory task.

The imaging tests revealed unusual activity in the frontal lobe, an area of the brain responsible for cognitive tasks such as memory recall and concentration. Participants were asked to memorize and recall capital and lowercase letters, as well as the alphabetical order of multiple letters.

Notably, the researchers say, the images showed differences in their frontal lobe activity between the two groups in the white matter of the brain, which normally does not show up in fMRI scans, as this tissue operates with less blood flow than gray matter. White matter is crucial for moving information around the brain, acting like train tracks that help deliver information to the train depot, or gray matter.

“We saw certain areas in the frontal lobe under-activating and others that were over-activating, which was somewhat expected,” says Marvel, an associate professor of neurology. “However, we didn’t see this same white matter activity in the group without post-treatment Lyme.”

To confirm this finding, researchers used a second form of imaging called diffusion tensor imaging (DTI) on all 12 participants with Lyme and 12 of the 18 non-Lyme participants. DTI detects the direction of water movement within brain tissue. This unique approach corroborated their fMRI findings and revealed new findings: Water was diffusing, or leaking, along the patients’ axons — the extensions of neurons that carry electrical signals to other neurons — within the same white matter regions identified in the fMRI.

Surprisingly researchers also found that axonal leakage in white matter correlated with fewer cognitive deficits and better outcomes among the post-treatment Lyme disease patients they studied.

The researchers believe the increased activity they saw in white matter may reflect a helpful immune response in the post-treatment Lyme patients, as it correlated with better disease outcomes. However, this finding was also correlated to the patients with post-treatment Lyme needing longer periods of time to complete the memory task. The researchers say this is indicative that the white matter response could be an adaptive one, but that the white matter’s physiology and function have been changed, which could come at a cost.

“Approaching this problem collaboratively with experts in different fields is what gave us these novel findings, and will hopefully answer our remaining questions, specifically about the role of axonal leakage and white matter activation in post-treatment Lyme disease,” she says.

Marvel and Aucott say this research may help illuminate underlying mechanisms and potential therapeutic targets for neurologic Lyme disease. Their findings may also have relevance to other kinds of infection-associated chronic illnesses, including long COVID and chronic fatigue syndrome.

Funding for the project was provided by an anonymous donor to John Aucott.

The research team also includes Kylie Alm, Deeya Bhattacharya, Alison Rebman, Arnold Bakker, Jason Creighton, Erica Kozero, Arun Venkatesan, and Prianca Nadkarni of Johns Hopkins Medicine; as well as Owen Morgan who is now at Cornell University.

The authors declare no competing interests.

Led by Simone Schürle, Professor of Responsive Biomedical Systems, the ETH Zurich researchers chose to work with bacteria that are naturally magnetic due to iron oxide particles they contain. These bacteria of the genus Magnetospirillum respond to magnetic fields and can be controlled by magnets from outside the body.

Exploiting temporary gaps

In cell cultures and in mice, Schürle and her team have now shown that a rotating magnetic field applied at the tumour improves the bacteria’s ability to cross the vascular wall near the cancerous growth. At the vascular wall, the rotating magnetic field propels the bacteria forward in a circular motion.

To better understand the mechanism to cross the vessel wall works, a detailed look is necessary: The blood vessel wall consists of a layer of cells and serves as a barrier between the bloodstream and the tumour tissue, which is permeated by many small blood vessels. Narrow spaces between these cells allow certain molecules from the to pass through the vessel wall. How large these intercellular spaces are is regulated by the cells of the vessel wall, and they can be temporarily wide enough to allow even bacteria to pass through the vessel wall.

Strong propulsion and high probability

With the help of experiments and computer simulations, the ETH Zurich researchers were able to show that propelling the bacteria using a rotating magnetic field is effective for three reasons. First, propulsion via a rotating magnetic field is ten times more powerful than propulsion via a static magnetic field. The latter merely sets the direction and the bacteria have to move under their own power.

The second and most critical reason is that bacteria driven by the rotating magnetic field are constantly in motion, travelling along the vascular wall. This makes them more likely to encounter the gaps that briefly open between vessel wall cells compared to other propulsion types, in which the bacteria’s motion is less explorative. And third, unlike other methods, the bacteria do not need to be tracked via imaging. Once the magnetic field is positioned over the tumour, it does not need to be readjusted.

“Cargo” accumulates in tumour tissue

“We make use of the bacteria’s natural and autonomous locomotion as well,” Schürle explains. “Once the bacteria have passed through the blood vessel wall and are in the tumour, they can independently migrate deep into its interior.” For this reason, the scientists use the propulsion via the external magnetic field for just one hour — long enough for the bacteria to efficiently pass through the vascular wall and reach the tumour.

Such bacteria could carry anti-cancer drugs in the future. In their cell culture studies, the ETH Zurich researchers simulated this application by attaching liposomes (nanospheres of fat-like substances) to the bacteria. They tagged these liposomes with a fluorescent dye, which allowed them to demonstrate in the Petri dish that the bacteria had indeed delivered their “cargo” inside the cancerous tissue, where it accumulated. In a future medical application, the liposomes would be filled with a drug.

Bacterial cancer therapy

Using bacteria as ferries for drugs is one of two ways that bacteria can help in the fight against cancer. The other approach is over a hundred years old and currently experiencing a revival: using the natural propensity of certain species of bacteria to damage tumour cells. This may involve several mechanisms. In any case, it is known that the bacteria stimulate certain cells of the immune system, which then eliminate the tumour.

Multiple research projects are currently investigating the efficacy of E. coli bacteria against tumours. Today, it is possible to modify bacteria using synthetic biology to optimise their therapeutic effect, reduce side effects and make them safer.

Making non-magnetic bacteria magnetic

Yet to use the inherent properties of bacteria in cancer therapy, the question of how these bacteria can reach the tumour efficiently still remains. While it is possible to inject the bacteria directly into tumours near the surface of the body, this is not possible for tumours deep inside the body. That is where Professor Schürle’s microrobotic control comes in. “We believe we can use our engineering approach to increase the efficacy of bacterial cancer therapy,” she says.

E. coli used in the cancer studies is not magnetic and thus cannot be propelled and controlled by a magnetic field. In general, magnetic responsiveness is a very rare phenomenon among bacteria. Magnetospirillum is one of the few genera of bacteria that have this property.

Schürle therefore wants to make E. coli bacteria magnetic as well. This could one day make it possible to use a magnetic field to control clinically used therapeutic bacteria that have no natural magnetism.

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Materials provided by ETH Zurich. Original written by Fabio Bergamin. Note: Content may be edited for style and length.

Americans die younger than people in most other high-income countries and within the United States life expectancy differs markedly across geographic areas. In 2019, it ranged from 74.4 years in Mississippi to 80.9 years in Hawaii.

In the new work, the researchers used data from the 1999-2019 National Vital Statistics System to calculate state-level age-adjusted mortality rates for deaths from all causes and from cardiovascular disease (CVD), alcohol, suicide and drug poisoning among adults ages 25 to 64. They merged that data with annual state-level data on eight policy domains, where each state’s policies were scored on a 0-to-1 conservative-to-liberal continuum.

The analysis revealed that more liberal policies on the environment, gun safety, labor, economic taxes and tobacco taxes were associated with lower mortality in each state. However, for marijuana, more conservative policies were associated with lower mortality. Particularly strong associations were found between gun safety policies and suicide mortality among men; between labor policies and alcohol-induced mortality; and between economic and tobacco tax policies and cardiovascular disease mortality. Simulations suggested that changing all policies in all states to a fully liberal orientation could have saved 171,030 lives in 2019, while changing them to a fully conservative orientation may have cost 217,635 lives.

The authors conclude that the emergence of more conservative state policies in several domains and shifts in the share of the population living in states with these policies provide a partial explanation for the high and rising mortality among working-age Americans and the overall mortality disadvantage of the US compared to other high-income countries.

The authors add: “U.S. state policies in recent decades may have contributed to the high and rising mortality rates of working-age adults. Changing state policies could prevent thousands of deaths every year from cardiovascular disease, suicide, alcohol, and drug poisoning.”

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Materials provided by PLOS. Note: Content may be edited for style and length.

The researchers have developed a drug compound that appears to stop cancer cell growth in what’s known as triple-negative breast cancer. The drug, which has not yet been tested in humans, has been shown to eliminate tumors in mice, with little to no effect on normal healthy cells, making it potentially nontoxic for patients.

The therapy is based on a newly discovered way that a gene known as epidermal growth factor receptor, or EGFR, leads to cancer. EGFR is a long-investigated oncogene — a gene that in certain circumstances can transform a cell into a tumor cell.

The researchers’ findings are published in the journal Cancer Gene Therapy, and the team is working to get Food and Drug Administration approval to test the compound in phase 1 clinical trials in humans.

Triple-negative breast cancer accounts for about 10 to 15% of all breast cancers. Triple-negative refers to the fact that the cancer cells test negative for the three other types of breast cancer — those driven by too much estrogen, too much progesterone or too much of a protein called HER2, according to the American Cancer Society. Triple-negative breast cancer is more common in women under 40 who are Black or who have a specific mutation in a gene called BRCA1. About half of all cases of triple-negative breast cancer overexpress the EGFR oncogene, according to the National Institutes for Health.

The UArizona researchers devised a compound that blocks EGFR from going to a part of the cell that drives survival of the cancer. The compound shuts down functioning of the EGFR protein that acts in cancer cells but not normal cells.

Often, drugs aren’t targeted enough in their attack and so they will attack parts of other, healthy cells, resulting in unwanted side effects. The researchers wanted to prevent that.

“EGFR has been known to be an oncogene for six decades, and there’s a lot of drugs out there trying to target it, but they all had limitations that didn’t make them workable as drugs for breast cancer,” said Joyce Schroeder, who co-wrote the paper with lead author Benjamin Atwell, a postdoctoral student in the Department of Molecular and Cellular Biology.

Schroeder heads the university’s Department of Molecular and Cellular Biology and leads the lab where the research for the paper was conducted. She is also a member of the university’s BIO5 Institute and Cancer Center.

The first two drug technologies that she and her team created worked to kill the cancer cells, but they had problems.

In their first attempt, the researchers targeted what Schroeder called an “unstructured” part of the EGFR protein, and as a result, the compound couldn’t act consistently and reliably.

The second attempt resulted in a compound that was too generalized and hit a part of the protein that also drove normal activities in healthy cells, making the drug toxic.

To be effective, Schroeder and her team knew that they had to develop a compound that could enter a cancer cell and target the exact right part of the proteins created by the EGFR gene to stop cancer from spreading. They succeeded on their third attempt.

“It was like the Goldilocks effect,” Schroeder said.

She and her team knew they had to find a solution that would not impact a normal cell and that would remain active inside the body.

“When we tested the drug in animal models, we got this fabulous result where it actually didn’t just stop the tumors from going, it caused them to regress and go away, and we’re seeing no toxic side effects,” she said. “We are so excited about this because it’s very tumor specific.”

Like designing a key to fit a very specific lock, molecular and cellular biologists ideally design drug chemistry that will interact with the target protein in the exact right way and nothing else.

“Targeting triple-negative breast cancer has been difficult because it doesn’t have one of these obvious things to target,” Schroeder said. “People have known for a long time that triple-negative breast cancer cells express EGFR, but when the known EGFR drugs were thrown at it, it didn’t respond.”

Many researchers thought that maybe EGFR shouldn’t be the target, so they looked for new ones. Schroeder, on the other hand, thinks EGFR is just working in a way that researchers don’t yet understand. She and her team attempted to target it in a novel way, with success.

The next step, besides human trials, is to test the drug’s ability to suppress metastasis, which occurs when cancer cells spread to other parts of the body, Schroeder said.

The researchers have been working to protect the intellectual property and further invest in licensing the asset with Tech Launch Arizona, the university office that commercializes university innovations.

Funding for the work was provided by the Department of Defense, as well as donations from Ginny L. Clements Breast Cancer Fund and philanthropist Susan Greendorfer.

You no doubt know that water, H₂O, is composed of two molecules of hydrogen and one of oxygen. What you may not know is that there are a few different varieties of both hydrogen and oxygen. The “normal” hydrogen, for example, has a nucleus with only one proton, but there’s another version: “heavy hydrogen,” or deuterium, which has both a proton and a neutron in its nucleus. This deuterium is comparatively rarer, and it can be used both to track rainfall amounts over time as well as to understand evaporation and seasonal changes in climate. The same is true for oxygen, which has both a common light version and a rare heavy version.

“Deuterium excess,” or when the ratio of heavy hydrogen to heavy oxygen increases, is a fingerprint that is widely used in climate and hydrological modeling and for reconstructing past climates to understand the history of a raindrop. But the processes that lead to the excess of deuterium aren’t entirely understood. “Our paper is the first to look at seasonal variations of deuterium excess in rainfall across the globe to better understand what affects these chemical tracers at regional scales,” says Matthew Winnick, professor of geosciences at UMass Amherst, and the paper’s senior author.

Winnick and his team, led by Zhengyu Xia, who completed this study as part of his postdoctoral research at UMass Amherst and is now a faculty member in the School of Geographical Sciences at Northeast Normal University, China, have shed new light on how and where different processes combine to impact deuterium excess. For instance, in the tropics, deuterium excess most clearly reflects seasonal changes in humidity and the evaporation of raindrops as they fall through the air. In the mid-latitudes, deuterium excess is primarily tied to climate conditions over the oceans where clouds first form, though these ocean signals are modified as clouds move inland over continents.

“There are multiple processes that can affect the deuterium excess of rain and these have been well recognized, but perhaps, have also puzzled the research community,” says Xia. “Our study combined data analysis and simple modeling to tease apart these complex controls at global scales, filling an important knowledge gap.”

“My hope,” says Winnick, “is that our findings will be used to better track the entire history of a raindrop, from when it first evaporates from the ocean to when it falls on land, trickles into a river and then flows back to the ocean.”

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Materials provided by University of Massachusetts Amherst. Note: Content may be edited for style and length.

Breast cancer is the second most common cancer in U.S. women, and triple-negative breast cancer (TNBC) is a more aggressive and deadly form of disease that accounts for 10-15% of all breast tumors.

TNBC grows and spreads more quickly than other breast tumors and is associated with worse patient outcomes, accounting for nearly one-third of all breast cancer-related deaths.

Additionally, TNBC affects Black women disproportionately: Black women die from TNBC at a significantly higher rate than white women despite being diagnosed at a younger age. Finding an effective therapy that works well in all patients would be an important step in addressing this disparity.

Through a comprehensive and cutting-edge genomic screening method known as CRISPR/CAS9 screening, Massey scientists — led by Anthony Faber, Ph.D., and Jennifer Koblinski, Ph.D. — were able to identify a specific enzyme called UBA1 that revealed itself as an ideal therapeutic target. Using a novel UBA-inhibiting drug called TAK-243, they blocked the cellular function of UBA1 and effectively killed cancer cells in patient-derived breast tumors in mice.

Previous research has shown that UBA1 inhibitors can have a positive impact in hematological cancers such as acute myeloid leukemia (AML) and chronic myelogenous leukemia (CML). This study — recently published in PNAS Nexus — is the first to suggest that UBA1 inhibitors could be effective in TNBC. TAK-243 has been tested recently in early phase trials, paving the way for potential testing in TNBC patients.

“We found that the majority of TNBC cells in our study were uniformly susceptible to the antitumor effects of TAK-243,” said Koblinski, director of the Cancer Mouse Models Core and member of the Cancer Biology research program at Massey, as well as an associate professor of pathology at the VCU School of Medicine. “In addition to demonstrating this drug’s success at the local site of the primary breast cancer, our findings demonstrate that TAK-243 can also shrink tumors in various organs after the disease has spread.”

The researchers also determined that the c-MYC gene — an important and infamously difficult drug target in TNBC — can be harnessed to cooperate with TAK-243 to initiate a cellular stress response and enhance the drug’s ability to fight TNBC. This supports the notion that TAK-243 may be effective in high-cMYC-expressing TNBC, where c-MYC may serve as a biomarker for response to the drug.

Chemotherapy remains one of the few routinely utilized treatment options for TNBC, with variable patient responses and little efficacy.

“The implementation of targeted therapies — drugs that target a specific genetic defect — has been revolutionary in treating different cancers, including breast cancer,” said Faber, co-leader of the Developmental Therapeutics research program and Natalie N. and John R. Congdon, Sr. Endowed Chair in Cancer Research at Massey, as well as an associate professor in the Philips Institute for Oral Health Research at the VCU School of Dentistry.

However, the hormone receptors, estrogen receptors or human epidermal growth factor receptor 2 (HER2) that can be effectively targeted in breast cancer treatment are missing in TNBC, hence the name “triple-negative breast cancer.”

“Genomic and clinical evidence suggests that the implementation of targeted therapies in the treatment of TNBC will require an expansion of potential targets,” Faber said. “Our study may have identified a key and novel target for the development of new therapies.”

Faber added, “Importantly, as TNBC is a major disease of disparate outcomes between Black patients and white patients, we were able to harness the power of new breast cancer mouse models from Black TNBC patients that were developed by Dr. Koblinski’s group. Traditionally, these models have been underrepresented and are important new tools to identify effective therapies for Black patients. The most exciting part of the study was that we found TAK-243 was effective across these models, suggesting TAK-243 or other UBA1 inhibitors could be equally effective in all TNBC patients.”

The next steps of this research include exploring the use of TAK-243 in TNBC with the drug company that is developing it, and evaluating other targets in the UBA1 pathway that may also demonstrate efficacy.

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Materials provided by Virginia Commonwealth University. Original written by Blake Belden. Note: Content may be edited for style and length.