Posts Tagged ‘science’


Case Western Reserve researchers cure drug-resistant infections without antibiotics

Biochemists, microbiologists, drug discovery experts and infectious disease doctors have teamed up in a new study that shows antibiotics are not always necessary to cure sepsis in mice. Instead of killing causative bacteria with antibiotics, researchers treated infected mice with molecules that block toxin formation in bacteria. Every treated mouse survived. The breakthrough study, published in Scientific Reports, suggests infections in humans might be cured the same way.

The molecules cling to a toxin-making protein found across Gram-positive bacterial species, called AgrA, rendering it ineffective. Treating mice with the therapeutic molecules effectively cured infections caused by methicillin-resistant Staphylococcus aureus (MRSA). S. aureus is notorious for its ability to overcome even the most potent antibiotics. Its resistance arsenal is broad, limiting therapeutic options to treat infections.

In a mouse model of S. aureus sepsis, treatment with small molecules alone resulted in 100 percent survival, while 70 percent of untreated animals died. The small molecules were as effective in promoting survival as antibiotics currently used to treat S. aureus infections. The molecules also appear to give antibiotics a boost. Septic mice treated with a combination of the small molecules and antibiotics had 10x fewer bacteria in their bloodstream than mice treated with antibiotic alone.

“For relatively healthy patients, such as athletes suffering from a MRSA infection, these molecules may be enough to clear an infection,” said Menachem Shoham, associate professor of biochemistry at Case Western Reserve University School of Medicine and senior author on the study. “For immunocompromised patients, combination therapy with the molecules and a low-dose antibiotic may be in order. The antibiotic in the combination could be one to which the bacteria are resistant in monotherapy, because our small molecules enhance the activity of conventional antibiotics, such as penicillin.”

With support from the small molecules, previously obsolete antibiotics could reenter the clinic.

Said Shoham: “This could provide a partial solution to the looming, global threat of antibiotic resistance.”

If available, antibiotics kill most bacteria, but a small number of bacteria with natural resistance survive. Over time, antibiotic-resistant bacteria multiply and spread. By Centers for Disease Control and Prevention estimates, at least two million Americans get an antibiotic-resistant infection annually. For some infections, effective antibiotics are no longer available. Disarming bacteria of disease-causing toxins represents a promising alternative to dwindling antibiotics.

Eliminating toxins frees up the immune system to eliminate bacterial pathogens instead of antibiotics, said Shoham, who also is affiliated with Q2 Pharma, Ltd., Haifa, Israel. “Without the toxins the bacteria become harmless. And since they don’t need the toxins to survive, there is less pressure to develop resistance.”

The small molecules work against multiple bacterial species. The new study included preliminary experiments showing the molecules prevent three other bacterial species from killing immune cells.

“These results indicate broad-spectrum efficacy against Gram-positive pathogens,” wrote the authors.

Added Shoham: “We have proven efficacy not only against MRSA but also against Staphylococcus epidermidis, which is notorious for clogging catheters, Streptococcus pyogenes that causes strep throat, Streptococcus pneumoniae, and other pathogens.”

Shoham led the study in collaboration with colleagues from the departments of biochemistry and dermatology and the Center for RNA and Therapeutics at Case Western Reserve University. The researchers developed two small molecules, F12 and F19, both of which potentiate antibiotic efficacy in the mouse models. The researchers are now working to commercialize both potential drugs. Case Western Reserve University has issued a license to Q2Pharma, Ltd., a biopharmaceutical startup company in Israel, to perform additional preclinical studies and develop F12 and F19 for clinical trials. Their initial trials will focus on patients suffering from systemic multi-drug resistant infections.

This research was supported by a Transformational Award to Menachem Shoham by the Dr. Ralph and Marian Falk Medical Research Trust Bank of America, N.A., Trustee. Some in vitro studies were supported by NIH/NIAID Preclinical Services under contract numbers HHSN272201100012I and HHSN27200007.

Greenberg, M, et al. “Small-molecule AgrA inhibitors F12 and F19 act as antivirulence agents against Gram-positive pathogens.” Scientific Reports. 2018 Oct 1;8(1):14578. doi: 10.1038/s41598-018-32829-w. PMID: 30275455.

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Bringing the filtering abilities of a fuel cell into the blood vessels of living organisms, a new device could cut down on toxic effects of cancer treatment.

At the heart of this approach — recently tested in pigs — is a tiny, cylindrical “sponge” created by 3-D printing. Wedged inside a vein near a tumor being treated with chemotherapy, the sponge could absorb excess drug before it spreads through the body — thus lessening chemotherapy’s harmful side effects, including vomiting, immune suppression or even heart failure.

A human study could launch “in a couple of years, if all the stars are aligned,” says Steve Hetts, a neuroradiologist at the University of California, San Francisco who came up with the drug-capture concept. He worked with engineers at UC Berkeley and elsewhere to create and test prototypes.

A test of the most recent prototype showed that the absorber captured nearly two-thirds of a common chemotherapy drug infused into a nearby vein, without triggering blood clots or other obvious problems in the pig, Hetts and his colleagues report January 9 in ACS Central Science.

The study addresses a major need, says Eleni Liapi, a radiologist at Johns Hopkins University School of Medicine not involved with the new work. Existing methods for controlling chemotherapy delivery do not fully block drug escape, she notes. “A technological advancement to reduce unwanted circulating drug is always welcome.”


This image shows a cross-sectional view of a new 3-D printed cylindrical device that could cut down on toxic side effects from cancer treatment. Resin coatings (gold) bind to a chemo drug used to treat liver cancer, experiments show.

Chemo is often delivered intravenously in the hope that some treatment reaches the cancer site. In a more localized form of chemotherapy used to treat hard-to-remove tumors, the drug travels through catheter wires snaked into arteries going straight to the tumor. Although this technique, known as transarterial chemo embolization, or TACE, is given to tens of thousands of people each year, typically some of the injected drug bypasses the tumor site and slips into general circulation where it can wreak havoc elsewhere.

Hetts uses the transarterial method to treat babies with a rare eye tumor called retinoblastoma – and it was those experiences that birthed the “sponge” idea in the first place. After the chemotherapy ran its course through transarterial catheters, the infants’ eye tumors shrank. However, several weeks later, their blood cell counts tanked, suggesting to Hetts that some of the chemo drugs were escaping the eye and affecting other cells. Those observations eight years ago led Hetts to think that “if only I had a device I could put into the vein to bind up the excess drug, then maybe these little babies wouldn’t get the side effect” of immune suppression.

Heart surgeons use a similar “filter” to remove bits of cholesterol plaque from arteries of people with atherosclerosis, a disease characterized by the clogging and hardening of arteries. Hetts envisioned a similar device for chemotherapy treatment — “but not just a dumb, inert membrane to capture debris,” he says. “I wanted a ‘smart’ membrane that chemically binds to a drug.”

Instead of trying to develop a drug-trap device for a super rare tumor — retinoblastoma has just 300 new cases per year in the United States — Hetts’ team focused on a chemo drug for liver cancer, which is estimated to strike more than 40,000 Americans this year and kill three-quarters of them.

Anand Patel, a trainee in the Hetts’ lab with a bioengineering background, tested a batch of resins and found several that could bind to this drug, known as doxorubicin. To optimize the resins and get them onto the tips of guide wires, Patel sought help with “cold call” e-mails to local professors. Nitash Balsara — a UC Berkeley chemical engineer with expertise in polymer chemistry and membranes — “was actually crazy enough to return my e-mail with interest,” says Patel, who now works as an interventional radiologist in the Los Angeles area.

Balsara’s lab develops materials to regulate ion flow in batteries and fuel cells. As it turns out, these filtration processes are “very similar to those that we needed to capture excess chemotherapy drugs from the blood,” Patel says. The team worked with Carbon, Inc., a 3-D printing company in the San Francisco Bay area, to get the drug-binding material onto a 30-millimeter-long, cylinder-shaped “sponge” about as wide as a drinking straw. Hee Jeung Oh of UC Berkeley spent more than a year working out how to attach the drug-binding material to the 3-D printed cylinder with crisscrossing struts.

In experiments, the team injected the liver cancer drug through the pigs’ leg and pelvic veins — which are similar in width to human liver veins, Hetts says. Before infusing the chemotherapy drug, the researchers inserted the 3-D printed sponge a few centimeters from the infusion site — as well as catheters above and below the sponge for collecting blood samples to measure drug absorption over time. Within a half hour, the device absorbed, on average, 64 percent of the liver cancer drug.

The next round of studies will monitor the capture of doxorubicin by drug sponges inserted directly into the pigs’ liver veins.

https://www.sciencenews.org/article/new-3d-printed-sponge-sops-excess-chemo-cancer-drugs


This combined MR/PET image highlights areas of the brain in which patients with fibromyalgia were found to have increased glial activation, compared with unaffected control volunteers. Credit: Marco Loggia, PhD, Martinos Center for Biomedical Imaging, Massachusetts General Hospital).

A study by Massachusetts General Hospital (MGH) researchers – collaborating with a team at the Karolinska Institutet in Sweden – has documented for the first time widespread inflammation in the brains of patients with the poorly understood condition called fibromyalgia. Their report has been published online in the journal Brain, Behavior and Immunity.

“We don’t have good treatment options for fibromyalgia, so identifying a potential treatment target could lead to the development of innovative, more effective therapies,” says Marco Loggia, PhD, of the MGH-based Martinos Center for Biomedical Imaging, co-senior author of the report.

“And finding objective neurochemical changes in the brains of patients with fibromyalgia should help reduce the persistent stigma that many patients face, often being told their symptoms are imaginary and there’s nothing really wrong with them.”

Characterized by symptoms including chronic widespread pain, sleep problems, fatigue, and problems with thinking and memory, fibromyalgia affects around 4 million adults in the U.S., according to the Centers for Disease Control and Prevention.

Previous research from the Karolinska group led by Eva Kosek, MD, PhD, co-senior author of the current study, suggested a potential role for neuroinflammation in the condition – including elevated levels of inflammatory proteins in the cerebrospinal fluid – but no previous study has directly visualized neuroinflammation in fibromyalgia patients.

A 2015 study by Loggia’s team used combined MR/PET scanning to document neuroinflammation – specifically activation of glial cells – in the brains of patients with chronic back pain. Hypothesizing that similar glial activation might be found in fibromyalgia patients as well, his team used the same PET radiopharmaceutical, which binds to the translocator protein (TSPO) that is overexpressed by activated glial cells, in their study enrolling 20 fibromyalgia patients and 14 control volunteers.

At the same time, Kosek’s team at Karolinska had enrolled a group of 11 patients and an equal number of control participants for a similar study with the TSPO-binding PET tracer. Since that radiopharmaceutical binds to two types of glial cells – microglia and astrocytes – they also imaged 11 patients, 6 who had the TSPO imaging and 5 others, and another 11 controls with a PET tracer that is thought to bind preferentially to astrocytes and not to microglia. At both centers, participants with fibromyalgia completed questionnaires to assess their symptoms. When the MGH team became aware of the similar investigation the Karolinska group had underway, the teams decided to combine their data into a single study.

The results from both centers found that glial activation in several regions of the brains of fibromyalgia patients was significantly greater than it was in control participants. Compared to the MGH team’s chronic back pain study, TSPO elevations were more widespread throughout the brain, which Loggia indicates corresponds to the more complex symptom patterns of fibromyalgia. TSPO levels in a structure called the cingulate gyrus – an area associated with emotional processing where neuroinflammation has been reported in patients with chronic fatigue syndrome – corresponded with patients reported levels of fatigue. The Karolinska team’s studies with the astrocyte-binding tracer found little difference between patients and controls, suggesting that microglia were primarily responsible for the increased neuro-inflammation in fibromyalgia patients.

“The activation of glial cells we observed in our studies releases inflammatory mediators that are thought to sensitize pain pathways and contribute to symptoms such as fatigue,” says Loggia, an assistant professor of Radiology at Harvard Medical School. “The ability to join forces with our colleagues at Karolinska was fantastic, because combining our data and seeing similar results at both sites gives confidence to the reliability of our results.”

This article has been republished from materials provided by Massachusetts General Hospital. Note: material may have been edited for length and content. For further information, please contact the cited source.

Reference:
Albrecht, D. S., Forsberg, A., Sandström, A., Bergan, C., Kadetoff, D., Protsenko, E., . . . Loggia, M. L. (2018). Brain glial activation in fibromyalgia – A multi-site positron emission tomography investigation. Brain, Behavior, and Immunity. doi:10.1016/j.bbi.2018.09.018

https://www.technologynetworks.com/cell-science/news/glial-activation-found-in-the-brains-of-fibromyalgia-patients-310084?utm_campaign=NEWSLETTER_TN_Breaking%20Science%20News&utm_source=hs_email&utm_medium=email&utm_content=68543465&_hsenc=p2ANqtz–8ZbNt7sDLF6bujB3qX9CeJA-hpSQwPHeSLoR5Ju1WYXA6SnOEepdO0o-J7qw_1aGB3nfwldpf30hV3pAvVi7SzJa8fw&_hsmi=68543465

by Laura Elizabeth Mason

Elephants have developed a way to resist cancer, by resurrecting a ‘zombie’ gene known as leukemia inhibitory factor 6 (LIF6). Activated LIF6 responds to damaged DNA and efficiently kills cells that are destined to become cancer cells.

Cancer is a complex genetic disease that is caused by specific changes to the genes in one cell or group of cells. These genetic alterations cause the cell to divide uncontrollably. If all mammalian cells were equally susceptible to the genetic mutations that cause cancer, then theoretically the risk of developing cancer should be greater in larger animals – due to them having more cells and a longer life-span. However, previous studies have demonstrated that elephants have a lower-than-expected rate of cancer, compared to other mammals.

“Elephants get cancer far less than we’d expect based on their size, so we want to understand the genetic basis for this cancer resistance,” said senior author Vincent Lynch from the University of Chicago, in a recent press release.

“We found that elephants and their relatives have many non-functioning copies of the LIF gene, but that elephants themselves evolved a way to turn one of these copies, LIF6, back on.”

p53 wakes up LIF6

The TP53 gene is found in all animals, it codes for the protein p53, a tumor suppressor, that stops cells with damaged DNA from dividing. Unlike humans, who only have one copy of TP53, elephants have 20. An increased number of TP53 genes enhances the DNA-damage response, providing elephants with a distinct advantage – they are able to either repair the damaged cells or ‘kill off’ irreparable cells more efficiently.

In their latest study the researchers found that in response to DNA damage, LIF6 is transcriptionally upregulated by p53. LIF6 codes for a protein that rapidly translocates to the cell’s mitochondria. Once it reaches the mitochondrion it causes the outer mitochondrial membrane pore to open – leading to mitochondrial dysfunction, causing the cell to die.

The researchers plan to conduct additional studies to further define the molecular mechanisms by which LIF6 induces cell death.

The team hope their findings will aid efforts to therapeutically target cancer. “Maybe we can find ways of developing drugs that mimic the behaviors of the elephant’s LIF6 or of getting cancerous cells to turn on their existing zombie copies of the LIF gene,” concluded Lynch.

Reference
Vazquez et al. A zombie LIF gene in elephants is up-regulated by TP53 to induce apoptosis in response to DNA damage. Cell Reports. 2018. http://dx.doi.org/10.1016/j.celrep.2018.07.042

By Yasemin Saplakoglu

The newest neuron has been named the “rosehip neuron,” thanks to its bushy appearance. The brain cell, with its unique gene expressions, distinctive shape and diverse connections with other neurons, has not been described before and, what’s more, it isn’t present in neuroscientists’ favorite subject: mice.

“It’s very bushy,” said Trygve Bakken, one of the lead authors of the paper and senior scientist at the Allen Institute for Brain Science in Seattle. Neurons have long branches called dendrites that receive signals from other neurons. In the rosehip cells, these dendrites are “very compact with lots of branch points, so it kind of looks a little bit like a rosehip,” Bakken told Live Science. (Rosehips are a type of fruit produced by rose plants.)

Also adding to the rosehip appearance are the large bulbs at the end of their axons that release neurotransmitters or chemical signals to other neurons, Bakken added.

The new finding is the result of a collaboration between Bakken and his team and researchers at the University of Szeged in Hungary. Both teams independently identified the distinctive-looking neurons and, when the teams learned they were looking at the same thing, they decided to work together, Bakken said.

The researchers at the Allen Institute documented the strange new neuron by examining the brain tissue of two deceased middle-age men. When the researchers looked at the genes of the rosehip neuron in this post-mortem tissue, they found that the neurons acted differently. “There are a number of genes that are turned on just in that cell and not in other[s],” Bakken said

Meanwhile, the team in Hungary further documented the rosehip neuron by studying the electrical activity and shapes of neurons in brain tissue that had been removed from people’s brains during surgery and kept alive in a solution.

A rare neuron

One reason rosehip neurons eluded neuroscientists for so long is likely because the cells are so rare in the brain, Bakken said. Another reason, he added, is because human brain tissue is difficult for scientists to obtain for study. Indeed, in the study, the researchers examined only one layer of the brain. It’s possible, however, that rosehip neurons could be found in other layers, too, Bakken said.

Specifically, the researchers found that the rosehip neurons make up about 10 percent of the first layer of the neocortex — the most recently evolved part of the cortex that’s involved in sight and hearing. They also found that rosehip neurons connect to neurons called pyramidal cells, a type of excitatory neuron that makes up two-thirds of all the neurons in the cortex, according to Cell.

The full extent of the rosehip neurons relationship to the pyramidal neurons is unclear, but the researchers did find that the rosehip neurons act as inhibitory neurons, or those that restrain the activity of other neurons. “They have the potential to sort of put the brakes on the excitability” of pyramidal neurons, Bakken said. But as to how this influences the brain’s behavior, “we don’t really know yet,” he added.

Absent in mice

All mammals have a cortex, and within it a neocortex, Bakken said. But there are about “a thousand times more cells in the human cortex compared to the mouse,” he said. In other words, it makes up a much bigger part of our brain than it does a mouse’s. So then, perhaps it’s not surprising that the team didn’t find any genetic hint of rosehip neurons in mice.

“Finding cell types that are uniquely human… helps our understanding of the physiological differences that under[lie] our higher cognitive abilities and may better inform upon treatment strategies for brain-related disorders,” said Blue B. Lake, an assistant project scientist in the bioengineering department at the University of California, San Diego who was not part of the study.

The absence of the rosehip neuron in mice brains might serve as a cautionary reminder that the results of some brain studies done on rats can’t be translated to humans, the researchers said.

“Mice have been a wonderful model organism for understanding how brains work in general and can help us understand how human brains work,” Bakken said. “But I think finding a part of that circuit that is not seen in a mouse that points to needing to study actual human tissue.”

There are enough parts of the brain conserved among mice, humans and other mammals that people can make “inferences about things we learn in the mouse and sort of, at least, hypothesize that something similar is likely to be happening in the human brain,” Bakken said. But, sometimes things present in human brains are “just not there” in mouse brains.


The brain anatomy is consistently shaped by socioeconomic status from childhood to early adulthood, a study has found.

The brain anatomy is consistently shaped by socioeconomic status from childhood to early adulthood, a study has found. The findings, published in the journal JNeurosci, draws attention to the importance of preschool life as a period when associations between SES and brain organisation may first develop.

Researchers from the National Institute of Mental Health in the US analysed brain scans of the same individuals collected over time between five and 25 years of age. Comparing this data to parental education and occupation and each participants’ intelligence quotient (IQ) allowed the researchers to demonstrate positive associations between socioeconomic status (SES) and the size and surface area of brain regions involved in cognitive functions such as learning, language, and emotions.

This is the first study to associate greater childhood SES with larger volumes of two subcortical regions — the thalamus and striatum — thereby extending previous SES research that has focused on its relationship to the cortex.

Finally, the researchers identify brain regions underlying the relationship between SES and IQ. A better understanding of these relationships could clarify the processes by which SES becomes associated with a range of life outcomes, and ultimately inform efforts to minimise SES-related variation in health and achievement, they said.

https://www.timesnownews.com/health/article/socioeconomic-status-shapes-developing-brains-study/336480


Before light reaches these rods and cones in the retina, it passes through some specialized cells that send signals to brain areas that affect whether you feel happy or sad.

by Jon Hamilton

Just in time for the winter solstice, scientists may have figured out how short days can lead to dark moods.

Two recent studies suggest the culprit is a brain circuit that connects special light-sensing cells in the retina with brain areas that affect whether you are happy or sad.

When these cells detect shorter days, they appear to use this pathway to send signals to the brain that can make a person feel glum or even depressed.

“It’s very likely that things like seasonal affective disorder involve this pathway,” says Jerome Sanes, a professor of neuroscience at Brown University.

Sanes was part of a team that found evidence of the brain circuit in people. The scientists presented their research in November at the Society for Neuroscience meeting. The work hasn’t been published in a peer-reviewed journal yet, but the researchers plan to submit it.

A few weeks earlier, a different team published a study suggesting a very similar circuit in mice.

Together, the studies offer a strong argument that seasonal mood changes, which affect about 1 in 5 people, have a biological cause. The research also adds to the evidence that support light therapy as an appropriate treatment.

“Now you have a circuit that you know your eye is influencing your brain to affect mood,” says Samer Hattar, an author of the mouse study and chief of the section on light and circadian rhythms at the National Institute of Mental Health. The finding is the result of a decades-long effort to understand the elusive link between light and mood. “It is the last piece of the puzzle,” Hattar says.

The research effort began in the early 2000s, when Hattar and David Berson, a professor of neuroscience at Brown University, were studying cells in the retina.

At the time, most scientists thought that when light struck the retina, only two kinds of cells responded: rods and cones. But Hattar and Berson thought there were other light-sensitive cells that hadn’t been identified.

“People used to laugh at us if we say there are other photoreceptors distinct from rods and cones in the retina,” Hattar says.

The skeptics stopped laughing when the team discovered a third kind of photoreceptor that contained a light-sensitive substance called melanopsin not found in rods and cones. (The full name of these cells, if you’re interested, is intrinsically photosensitive retinal ganglion cells, or ipRGCs.) These receptors responded to light but weren’t part of the visual system.

Instead, their most obvious function was keeping the brain’s internal clock in sync with changes in daylight. And many scientists assumed that this circadian function also explained seasonal depression.

“People thought that the only reason you get mood problems is because your clock is misaligned,” Hattar says.

Other potential explanations included speculation that reduced sunlight was triggering depression by changing levels of serotonin, which can affect mood, or melatonin, which plays a role in sleep patterns and mood. But the evidence for either of these possibilities has been weak.

Hattar and Berson were pretty sure there was a better reason. And, after years of searching, they found one.

In September, Hattar’s team published a study about mice suggesting a direct pathway between the third kind of photoreceptor in the retina and brain areas that affect mood.

When these cells were present, an artificially shortened cycle of light and dark caused a version of depression in a mouse. But when the team removed the cells with gene-editing tools, the mouse didn’t become depressed.

Sanes knew about the research, in part because he and Berson are neuroscientists at Brown. And he was so intrigued by the discovery of the new pathway between retina and brain in mice that he decided to see whether something similar was going on in human brains.

Sanes’ team put young adults in an MRI machine and measured their brain activity as they were exposed to different levels of light. This allowed the team to identify brain areas that seemed to be receiving signals from the photoreceptors Hattar and Berson had discovered.

Two of these areas were in the front of the brain. “It’s interesting because these areas seem to be the areas that have been shown in many studies to be involved in depression and other affective disorders,” Sanes says.

The areas also appeared to be part of the same circuit found in mice.

The finding needs to be confirmed. But Hattar is pretty confident that this circuit explains the link between light exposure and mood.

So now he’s trying to answer a new question: Why would evolution produce a brain that works this way?

“You will understand why you would need light to see,” he says, “but why do you need light to make you happy?”

Hattar hopes to find out. In the meantime, he has some advice for people who are feeling low: “Try to take your lunch outside. That will help you adjust your mood.”

https://www.npr.org/sections/health-shots/2018/12/21/678342879/scientists-find-a-brain-circuit-that-could-explain-seasonal-depression