Neuroscience

ApoE4 Damages Protective Barrier of the Brain – Being Patient

Researchers are making headway in explaining why people who carry the ApoE4 gene, the largest genetic risk factor for Alzheimers, are more likely to suffer from damaged blood-brain barriers.

It was never clear to researchers whether the ApoE4 gene was responsible for the early malfunction of the blood-brain barrier, a protective barrier shielding the brain from toxins or pathogens, or whether it worked together with the proteins beta-amyloid and tau.

Now, scientists have found that the gene may stimulate certain proteins in an inflammatory pathway, driving the blood-brain barrier to break down, regardless of the levels beta-amyloid and tau present in the brain.

Scientists have also pinpointed how ApoE4 may trigger the accumulation of beta-amyloid proteins along blood vessels influencing a condition known as cerebral amyloid angiopathy.

Researchers have overlooked vascular dysfunctions, said Axel Montagne, Associate Professor of Research Physiology & Neuroscience at University of Southern California. But in recent years with the advancement of new imaging tools and discovery of other biomarkers researchers realize that vascular functions are tightly linked to Alzheimers.

Nearly half of dementia cases are triggered, in part, by vascular disease which reduces blood supply to neurons in the brain. And lowering your risk of heart disease and stroke can help prevent dementia. As the saying goes: Whats good for the heart is good for the brain.

The blood-brain barrier is crucial as its endothelial cells are wedged closely together, forming the inner linings of the blood vessels and allowing only certain molecules and gases to flow into brain tissue. Meanwhile, cells like pericytes and astrocytes wrap along the surface of the blood vessels, upholding integrity of the blood-brain barrier.

In one of the recent studies, published in Nature, scientists examined the blood-brain barriers of participants who were either cognitively normal or displayed early symptoms of Alzheimers. The participants, aged 45 and older, underwent a battery of blood and cerebrospinal fluid tests, brain scans and imaging for the harmful proteins.

After accounting for variables such as lifestyle, demographics, and the presence of beta-amyloid and tau, the researchers found that carriers of ApoE4 with cognitive impairment had greater damage in their blood-brain barriers than ApoE3 carriers with cognitive impairment.

In fact, even healthy participants who carried the ApoE4 gene had greater blood-brain barrier dysfunctions compared to healthy participants without ApoE4.

People who have ApoE4 genes that are expressed in pericytes will have a cascade of molecular events that will release two proteins cyclophilin A and MMP9 for matrix metalloproteinase-9, Montagne said, who is an author of the study.

Those two molecules will destroy the tight junctions between endothelial cells You will see a physical gap between endothelial cells that will [become] a breach for blood to leak inside the brain.

The teams findings bolster growing evidence that vascular dysfunctions are linked with Alzheimers. Higher blood pressure especially at an earlier age increases risk of dementia later on. More than 90 percent of people with Alzheimers have cerebral amyloid angiopathy.

While researchers have known that ApoE4 is the strongest risk factor for the condition, the cellular and molecular links were unclear.

In a study published Monday, researchers sought to answer the question by developing lab models of the human blood-brain barrier.

It turned out that the pericytes from the ApoE4 cells drastically increased their expression level of ApoE, said Li-Huei Tsai, Picower Professor of Neuroscience and Director of the Picower Institute For Learning and Memory at MIT.

The scientists then identified a pathway that elevated ApoE expression, triggering more beta-amyloid to accumulate.

The reason why knowing the pathway is important is because we already have FDA-approved small molecules that can inhibit this pathway, Tsai said.

One of the FDA-approved drugs that the team tested is currently used to prevent organs from shrinking after transplants. And Tsai pointed to an intriguing finding from past studies: There are known publications following those individuals who received organ transplant under medication with this drug, Tsai said. These people turned out to have a much reduced incident of developing dementia.

Meanwhile, the researchers found that the drug reduced the levels of ApoE proteins and the buildup of beta-amyloid after administering it in mice and blood-brain barrier models.

A better understanding of the relationship between ApoE4 and the breakdown of a persons blood-brain barrier is critical to scientists ability to identify and engineer ways to prevent, mitigate, and cure that damage. Clinical trials to heal the blood-brain barrier are already underway.

Montagne and his team are testing various medications to treat impaired barriers in animal studies. Researchers are also conducting a clinical trial on a drug for stroke patients to heal their blood-brain barriers. And a clinical trial of ultrasound treatment is underway to disrupt the blood-brain barrier in the regions of the brain affected by Alzheimers, such as the hippocampus.

Link:
ApoE4 Damages Protective Barrier of the Brain - Being Patient

Neuroscience

Depression among 70-year-olds may be associated with gender expression – News-Medical.Net

Reviewed by Emily Henderson, B.Sc.Jun 10 2020

Over time, depression has decreased among older women. But it is still nearly twice as frequent as among older men. This difference between men and women appears to be connected with both biological sex and gender expression, as a University of Gothenburg thesis investigating the prevalence of depression in 70-year-olds shows.

As life expectancy rises, depression in the older population is an escalating public health problem. The thesis shows that the prevalence of depression among 70-year-olds decreased among women, but not among men, from the mid-1970s to the mid-2010s. Nevertheless, depression remains nearly twice as common among women compared to men.

The sex ratio in depression is a well-known phenomenon. Still, we don't know the whole explanation for why this occurs, especially within the older population."

Therese Rydberg Sterner, a new Ph.D. graduate at the Institute of Neuroscience and Physiology at the University of Gothenburg

Today, the causes of depression are known to comprise a mix of biological, psychological, and social factors. But how gender-related factors are linked specifically to the sex ratio in the prevalence of depression remains unknown.

Gender expression includes various aspects of femininity, masculinity and androgyny. In Rydberg Sterner's study, it was measured by asking the participants to rate their own gender-stereotyped traits on a scale of one to seven. The participants are not classified as being exclusively masculine or feminine; instead, both men and women have a combination of feminine and masculine features."The purpose is to nuance the sex ratio in depression and investigate whether people's gender expression has any effect on their depression rates, irrespective of their biological sex," Rydberg Sterner says.

The thesis shows that the prevalence of depression was higher among both men and women with a higher self-rated level of femininity. For masculinity and androgyny, the inverse was found that is, men and women with higher self-rated levels of masculinity or androgyny had a lower depression rate."Since our survey was cross-sectional, we can't say anything about the chicken or the egg for this association."

To find out more about the association, Rydberg Sterner is currently collecting data about depression and gender expression in the follow-up examination of this cohort of septuagenarians who have now reached 75 years of age.

"We will be able to examine what comes first; is it depression that affects how we express ourselves and what we're like, or does our gender expression influence the risk of having depressive symptoms, or the way we perceive and talk about our experienced symptoms?"

Based on previous research, one of the researchers' hypotheses is that femininity might be connected with a greater propensity to communicate how one feels, compared with masculinity, but also that certain gender-stereotyped characteristics as such (e.g. problem-solving ability, logical thinking, self-assurance or worry), might be either risk or protective factors when it comes to depression.

The qualitative part of the thesis, which is based on focus group interviews, shows that the 70-year-olds who had suffered from depression expressed a lack of trust towards healthcare providers in terms of knowledge about, and treatment of, depression. In healthcare, there is no time for existential discussions before, during or after treatment.

"The interviewees feel that they aren't seen and listened to by the care providers while they are seeking help and being treated for depression. They'd like more communication, and to get more information about their clinical picture, possible treatment options and side-effects, as well as information about what they themselves can do to avoid depression to recur."

Rydberg Sterner hopes that her results will be used to further problematize the sex ratio in depression, and for giving depression among older people greater space in the research community in order to find additional preventive methods.

"It's also important to point out that the prevalence of depression in the population can be influenced. Otherwise, we wouldn't have seen it changing over time," she says.

Her thesis is based on the latest investigation of 70-year-olds, carried out from 2014 to 2016, in the longstanding Gothenburg H70 Birth Cohort Studies, and also on the prevalence of depression found in these studies' earlier cohorts of 70-year-olds.

Read more:
Depression among 70-year-olds may be associated with gender expression - News-Medical.Net

Neuroscience

We have a lot to learn about teaching while schools are closed, 2 superintendents say – NJ.com

By Michael LaSusa and Mackey Pendergrast

Instead of enjoying graduations and field days, students and teachers in New Jersey are laboring behind computer screens to move through curricula designed for a different context. But taking an instructional program intended for brick-and-mortar classrooms and recasting it in a virtual environment need not be a hastily executed shot in the dark. On the contrary, a purposeful approach rooted in established research in neuroscience and developmental psychology can guide school districts through this unprecedented shift to virtual learning. We see opportunities for reimagining and improving teaching and learning, both inside and outside the physical classroom.

The first opportunity involves instructional delivery. It is tempting to think that the best approach to virtual learning is to imitate a typical school day, with teachers and students logging on to their electronic classrooms at the same time as if they were all together. We do not think so. Those who have spent their careers working in preK-12 classrooms know how much skill and intentionality it takes to shepherd 20+ students through their learning -- managing behaviors, gauging understanding, and involving pupils meaningfully in lessons. This is difficult under ideal circumstances. When teachers are working with a class of students from their homes and through their screens, it is impossible.

Brain research explains why. In order to learn, the brain must be able to focus on one stimulus at a time. Attention is a limited capacity resource; there is only so much bandwidth available to select and attend to information. One of the biggest obstacles to learning, therefore, is cognitive overload.

In an online classroom, cognitive overload is a given: students are looking at a small screen divided among images of their classmates, teacher, and whatever instructional visuals the teacher may present. They must input and process all of that stimuli while at the same time listening, taking notes, and reflecting on the lesson content or others commentary. Additionally, students must contend with a host of possible distractions in their immediate environment -- cell phones, barking dogs, runaway siblings -- over which the teacher has no control. The brain needs focused attention long enough for the information to enter into the working memory. Virtual learning should seek to avoid cognitive overload by reducing unnecessary stimuli that compete with that attention. Thats a vote against lengthy periods of whole-class synchronous virtual instruction.

So what is the best method? To address this question, we need to look no further than to our students. Ask any kid how they figure out how to do something, and they will likely give you the same answer: YouTube. Whether its learning how to make a Rainbow Loom bracelet, memorize Steph Currys best moves, or play the chords to Living Colours Cult of Personality, YouTube is the go-to resource. Similarly, Khan Academy did not become a household name by brokering live tutoring sessions for groups of 25 students. Rather, founder Salman Khan realized that providing students with digestible video segments of mathematics content enabled students to work at an individualized pace, hit the pause button when necessary, and replay key moments as often as needed.

Think of the brain as a hiking path in a forest. Every time you travel down that path it becomes firmer and easier to discern. Similarly, every time a student rewatches a video clip to understand something more completely, to find a missing step, or to think slowly or rehearse, the neural connections and pathways are firming up in the brain, something neuroscientists call encoding and retrieval. A brain that is focused and relaxed is a brain that is ready to learn.

Dont students need to connect directly with their teachers and classmates? Of course! If the front end of virtual learning should rely on video content produced by teachers or thoughtfully selected from existing online platforms, the back end should focus on small group and individualized instruction. To accomplish this, teachers should use video conferencing apps to follow up with small groups of students, take questions, and check for understanding. This is also the place where teachers can encourage students to move through the learning pit-- that crucial stage of cognitive struggle where learners build their capacity and the brain embeds learning more concretely for future retrieval.

The second opportunity is for schools to permanently break away from the tyranny of time. Our current schooling structures date to the 19th century and our concept of credits and attendance are centered on those structures, including the Carnegie Unit -- an attempt to quantify how much seat time a student needs to acquire the material of a course.

Based on the need for seat time, the high school day is too long. We are hearing directly from our students during this prolonged school closure that they are sleeping more and feeling healthier. It is perverse that it has taken a pandemic to provide our adolescent students with a basic life need: sleep. Any conceptualization of schooling that aligns with brain research must afford students sufficient time for both sleep and exercise, both are essential ingredients for deep learning. When this school closure ends, we should leverage what we have learned, reduce the length of the school day, and rethink the demands of time that we impose on our students.

A final opportunity in this national experiment is to seize a salient takeaway: that going to school is vital to children. We need students to gather and learn how to navigate social relationships. We need students to interface with positive adult role models. We need students to take part in extracurricular programs that impart critical life skills.

When school resumes, we will better appreciate what we have been missing, but we should build upon what we have learned. After Hurricane Sandy, we better fortified New Jersey. We raised homes along the shore. We installed generators at critical facilities. We revised building codes. We should now take the same approach with our public schools.

We should make our instructional design stronger, better aligned with how the brain actually learns, and more conducive to helping students become independent learners. This will be crucial to position us for the next school closure and also to enable us to better serve our students at all times. Lets use this experience to fortify New Jersey again, this time for our children.

Michael LaSusa is the superintendent of schools in Chatham and was the 2018 New Jersey Region One Superintendent of the Year.

Mackey Pendergrast is the superintendent of schools in Morristown and is the 2020 New Jersey Superintendent of the Year.

Our journalism needs your support. Please subscribe today to NJ.com.

The Star-Ledger/NJ.com encourages submissions of opinion. Bookmark NJ.com/Opinion. Follow us on Twitter @NJ_Opinion and on Facebook at NJ.com Opinion. Get the latest news updates right in your inbox. Subscribe to NJ.coms newsletters.

Continued here:
We have a lot to learn about teaching while schools are closed, 2 superintendents say - NJ.com

Cell Biology

Study provides new evidence that liver dysfunction may lead to heart disease – News-Medical.net

A new study that looks closely at the cardiac health of flies provides new evidence that liver dysfunction may lead to deterioration of the heart.

The research fills in gaps in how scientists understand the links between heart health and other tissues and could inform the development of new therapies in human medicine, said Hua Bai, an assistant professor of genetics, development and cell biology at Iowa State University. Bai's lab has performed previous studies on how cardiac health in flies changes with age. The new study, published in the academic journal Nature Communications, also covers new ground in the function of a poorly understood organelle called the peroxisome, which may play a major role in how organisms age.

We were thinking outside the heart for this paper. We wanted to find out if other tissues affect cardiac function during aging. There is significant data suggesting that liver function actually is a risk factor for cardiac disease. A patient with a lot of liver dysfunction often develops cardiac disease. This is a concern because you may have two diseases that you have to deal with for these patients."

Hua Bai, Assistant professor of genetics, development and cell biology at Iowa State University

But Bai said no direct link between liver and heart disease has emerged in experiments, leaving medical professionals unsure if the two factors share a causal relationship or if there's simply a correlation. Bai's lab attempted to fill that gap by studying the interaction between liver disease and the function of cardiac muscles in flies.

Previous studies from Bai's lab showed that manipulating genes in the cardiac muscles of flies could restore the heart function of older flies to a state similar to younger flies, essentially turning back the clock on cardiac tissues. In the new experiments, the researchers manipulated various genes governing liver function in flies to see how that would affect heart health as the flies aged.

"Our findings demonstrate we can protect the liver of old animals and maintain the health of the heart without doing any direct intervention on the heart tissue," said Kerui Huang, a graduate student in Bai's laboratory and the lead author of the study.

Much of the genetic work the researchers conducted focused on peroxisomes, understudied organelles inside cells that regulate key lipid metabolic processes and detoxification critical for brain and liver function.

"Looking at all the biology literature, we don't know much about how peroxisome function changes in aged animals," Bai said. "We show that peroxisomal protein import function is significantly impaired in aged flies. Research like ours could open up another new field to study how peroxisomes regulate tissue aging."

Huang said although flies appear to be highly dissimilar to humans, human medicine still has much to gain from studying fly biology. For instance, the functions of a fly's liver and heart share many similar functions with the human liver and heart.

Pharmaceutical companies have shown great interest in finding new avenues to treat age-related disease, Bai said. The relationship between peroxisomes, liver function and heart aging described in the new study might become a promising target for new therapies and drugs, he said.

Source:

Journal reference:

Huang, K., et al. (2020) Impaired peroxisomal import in Drosophila oenocytes causes cardiac dysfunction by inducing upd3 as a peroxikine. Nature Communications. doi.org/10.1038/s41467-020-16781-w.

See the original post here:
Study provides new evidence that liver dysfunction may lead to heart disease - News-Medical.net

Cell Biology

UK Researcher Part of Team That Found How Plants Forget – UKNow

LEXINGTON, Ky. (June 10, 2020)A University of Kentucky researcher is part of an international team of scientists that has discovered how plants forget.

Plants need memories of their environment to help them know things like when to flower each spring. These types of memories are part of what is called the plants epigenetic memory. Seeds need to lose this memory, so they can flower at the right time for the environment in which they are placed.

Led by Michael Borg, a postdoctoral scholar in the Frederic Berger lab in Austria, the team found that plant pollen does not have a protein inside its sperm cells that is critical for memories. Instead, sperm has another protein that prevents the memory protein from accumulating. In a prior study, Bergers lab identified the protein critical for plant memory.

Tomokazu Kawashima, assistant professor in the UKCollege of Agriculture, Food and Environment, was part of the international project. In the study, he identified which genes were active and which ones were silenced in the sperm found in pollen cells of plants.

Parental memories of environmental stresses such as drought and extreme temperatures can influence the growth and yield of its offspring, he said. We can now start understanding how plants control such epigenetic memory reprogramming. We may be able to remove any negative influences of a parents epigenetic memory on offspring productivity for sustainable crop production in the future.

At UK, Kawashima is a faculty member in theDepartment of Plant and Soil Scienceswhere he studies evolutionary changes that have occurred in land plant sperm inside pollen cells. Prior to joining the faculty at UK, Kawashima was a senior research fellow in the Bergers lab at the Gregor Mendel Institute, which is part of the Austria Academy of Sciences.

The paper was published in the academic journal Nature Cell Biology and is available online athttps://www.nature.com/articles/s41556-020-0515-y.

Additional collaborators on the project include scientists at the Cold Spring Harbor Laboratory, Yale University, Purdue University, Nagoya University in Japan, University of Edinburgh in the United Kingdom, and the Instituto Gulbenkian Cincia in Portugal. Researchers received funding for the project from Austrian Science Fund, European Research Area Network for Coordinating Action in Plant Sciences, the Howard Hughes Medical Institute, National Institutes of Health, the Japan Society for the Promotion of Science, the Wellcome Trust and the European Research Council.

Here is the original post:
UK Researcher Part of Team That Found How Plants Forget - UKNow

Cell Biology

Senolytic drugs: can this antibiotic treat symptoms of ageing? – Health Europa

Professor Michael P Lisanti, Chair in Translational Medicine at the University of Salford, has been an active research scientist for more than 30 years and is an expert in the field of cellular senescence. In 2018 Lisanti, along with his wife and research partner Professor Federica Sotgia, co-authored a paper entitled Azithromycin and Roxithromycin define a new family of senolytic drugs that target senescent human fibroblasts, which identified the FDA-approved antibiotic azithromycin as a senolytic drug: a compound which can be used to treat the symptoms of ageing.

Their research was made possible through generous funding contributions from Lunella Biotech, Inc, a Canadian-based pharmaceutical developer which fosters medical innovation; the Foxpoint Foundation, also based in Canada; and the Healthy Life Foundation, a UK charity which funds research into ageing and age-related conditions. Lisanti speaks to HEQ about his work and the future of senescence studies.

We started out focusing on cancer, but the relationship between cancer and ageing led us to shift our focus towards senescence, the process by which cells chronologically age and go into cell cycle arrest. Senescence leads to chronic inflammation: the cells secrete a lot of inflammatory mediators, which allows the cells to become almost infectious; so then neighbouring normal cells become senescent it has a kind of cataclysmic effect. As you age especially as you approach around 50 you begin to accumulate more senescent cells, which are thought to be the root cause of ageing; this then leads to various ageing-associated diseases, such as heart disease, diabetes, dementia and cancer, the most life threatening conditions in the Western world.

The goal, therefore, would be to remove the senescent cells. It is possible to use a genetic trick to remove senescent cells from mice: this causes them to live longer by preventing ageing-associated diseases; but it is not possible to use the same genetic trick for humans. We would therefore need a drug that only kills or removes senescent cells; and that could then potentially lead to rejuvenation, thereby extending the patients healthy lifespan.

We set up a drug assay using normal, commercially available, human fibroblasts: MRC-5, which comes from the lungs, and BJ-1, which comes from the skin. The idea was to artificially induce ageing, which we did using a compound called BrdU. This compound is a nucleoside: it incorporates into the DNA and that leads to DNA damage; and the DNA damage in turn induces the senescence phenotype. The overarching concept was to create a population of cells artificially that were senescent; and then to compare primary cells that were normal with cells which were senescent, with the goal of identifying drugs which could only selectively kill the senescent cells and not harm the normal cells.

We had previously observed positive results in tests on the metabolic effects of antibiotics, so our drug screening identified two drugs called azithromycin and roxithromycin, which constitute a new family of senolytic drugs. Theyre both clinically approved drugs azithromycin has been around longer; and has a strong safety profile and we looked at other members of the same drug family such as erythromycin, which is the parent compound, but erythromycin has no senolytic activity. The characteristics we were looking for appeared to be relatively restricted to azithromycin, which in our observation was very efficiently killing the senescent cells. As we reported in the paper, it had an efficacy of approximately 97%, meaning that it was able to facilitate the growth of the normal cells, while concurrently selectively killing the senescent cells.

We tested the drug on normal and senescent cells which were otherwise identical. The senescent cells underwent apoptosis programmed cell death so that led us to the conclusion that the drug selectively kills the senescent cells, while at the same time the normal cells are able to continue to proliferate. That selective effect of removing exclusively the senescent cells is what we were searching for; because in this instance we would want a drug that could potentially be used in humans and which would only kill senescent cells.

Obviously, we would have to do clinical trials going forward, but the first step should be to identify the pharmaceutical application. Given that this drug appears to selectively kill and remove the senescent cells, it could be used potentially to prevent ageing-associated disease; and it could therefore potentially extend the human lifespan, especially in terms of reducing diseases and conditions like diabetes, heart disease, dementia and even cancer.

Cystic fibrosis is the most common genetic disease in humans; patients with cystic fibrosis are prone to bacterial lung infections. Researchers started to explore the possibility of using azithromycin preventatively in patients with cystic fibrosis; and they found that, while it didnt necessarily affect patients susceptibility to infection, it did prevent lung fibrosis where the lungs become stiff and the patient is unable to breathe and in doing so, extended the patients lifespan. These studies were focused on myofibroblasts, which at the time werent really seen as senescent; whereas the literature now acknowledges a general consensus that myofibroblasts are indeed senescent cells.

We havent specifically examined anything relating ageing to antimicrobial resistance; but azithromycin is an antibiotic, which is not ideal within the context of AMR. Potentially in the future, once researchers identify what it is about the azithromycin that is causing the senescent cells to die, they could develop future drugs azithromycin is a stepping stone in this context, but what it shows is proof of principle that a drug can be identified which selectively kills senescent cells. This indicates that senescent cells are clearly biochemically distinct from the normal cells, and that it is possible to find a drug that selectively kills them and that is relatively safe. It provides a starting point for further new drug discovery to identify other drugs which might also be selective.

Ideally, we would want a drug which is not an antibiotic; but that means further research will be necessary to find additional drugs or to refine the senolytic activity which weve discovered in this drug. We are in the early stages; the point is that it is experimentally feasible and this would then lend itself to doing new clinical trials in the future, because azithromycin is relatively safe and it probably wont need to be administered over a long period of time to remove senescent cells you might not need to use it for any longer than you would as an antibiotic.

This research has been supported by the Foxpoint Foundation (Canada), the Healthy Life Foundation (UK), and Lunella Biotech, Inc. (Canada).

Professor Michael P Lisanti is Chair of Translational Medicine at the University of Salford School of Science, Engineering & Environment, UK. His current research programme is focused on eradicating cancer stem cells (CSCs); and anti-ageing therapies, in the context of age-associated diseases, such as cancer and dementia.

Lisanti began his education at New York University, US, graduating magna cum laude in chemistry (1985); before completing an MD-PhD in cell biology and genetics at Cornell University Medical College, US (1992). In 1992, he moved to MIT, US, where he worked alongside Nobel laureate David Baltimore and renowned cell biologist Harvey Lodish as a Whitehead Institute fellow (1992-96).

His career has since taken him to the Albert Einstein College of Medicine, US (1997-2006), the Kimmel Cancer Center, US (2006-12), and the University of Manchester, UK (2012-16), where he served as the Muriel Edith Rickman chair of breast oncology, director of the Breakthrough Breast Cancer and the Breast Cancer Now Research Units, and founder and director of the Manchester Centre for Cellular Metabolism.

Lisanti has contributed to 564 publications in peer-reviewed journals and been cited more than 90,000 times. A list of his works can be found at: https://pubmed.ncbi.nlm.nih.gov/?term=lisanti+mp&sort=date

Professor Federica Sotgia currently serves as chair in cancer biology and ageing at the University of Salford School of Science, Engineering and Environment, UK, where she focuses on, inter alia, the role of the tumour microenvironment in cancer and the metabolic requirements of tumour-initiating cells.

Sotgia graduated magna cum laude with an MS in biological sciences (1996) from the University of Genova, Italy, where she later completed a PhD in medical genetics (2001). She moved to the Albert Einstein College of Medicine, US, in 1998, originally as a visiting student and then postdoctoral fellow, and she was appointed an instructor in 2002.

Sotgia has since worked as an assistant professor at the Kimmel Cancer Center, US (2006-12), a senior lecturer at the University of Manchester, UK (2012-16), and a Professor in biomedical science at the University of Salford (2016-present).

She has contributed to 206 publications in peer-reviewed journals and been cited upwards of 27,000 times.

A list of her works can be found at: https://pubmed.ncbi.nlm.nih.gov/?term=sotgia+f&sort=date

Professor Michael P Lisanti, MD-PhD, FRSA, FRSBChair in Translational MedicineSchool of Science, Engineering & EnvironmentUniversity of Salford+44 (0)1612 950 240M.P.Lisanti@salford.ac.uk

This article is from issue 13 of Health Europa. Clickhere to get your free subscription today.

Link:
Senolytic drugs: can this antibiotic treat symptoms of ageing? - Health Europa

Cell Biology

Relief Therapeutics and NeuroRx Expand Clinical Trial Evaluating RLF-100 in Critically Ill COVID-19 Patients with Respiratory Failure to Houston…

HOUSTON, June 11, 2020 (GLOBE NEWSWIRE) -- RELIEF THERAPEUTICS Holding AG (SIX:RLF) Relief and its U.S. partner, NeuroRx, Inc. today announced that Houston Methodist Hospital is participating in their Phase 2 clinical trial evaluating RLF-100 as a research intervention for critically ill patients with COVID-19 and respiratory failure. RLF-100 is a patented formulation of Aviptadil, (synthetic human vasoactive intestinal polypeptide or VIP), which targets alveolar type 2 cells in the lungs that are a major target of the SARS-CoV-2 virus. VIP is known from numerous animal models of lung injury and lung disease to inhibit inflammatory cytokines and to protect pulmonary epithelial cells that line the air sacs (alveolae) of the lungs.

The multicenter clinical trial will enroll patients with COVID-19 and respiratory failure in the hopes that RLF-100 can decrease mortality in this condition and help to improve the ability of the patients lungs to transfer oxygen to the body. Based on recent FDA guidance, the trial has been expanded to include patients treated with high flow nasal oxygen and noninvasive forms of ventilation, instead of only enrolling patients on mechanical ventilators.

The Principal Investigator at Houston Methodist Hospital is J. George Youssef, M.D., assistant professor of Critical Care Medicine & Pulmonology. Dr. Youssef was a co-investigator in the earlier study evaluating RLF-100 as a treatment for Acute Respiratory Distress (ARDS), a primary cause of COVID-19 related deaths, under the late Professor Sami Said, who discovered VIP in 1970 and treated the first patients.

We are encouraged by findings from the previous clinical trial of RLF-100 as a treatment for ARDS in patients with sepsis which showed seven out of eight patients on mechanical ventilation experienced substantial improvement and six ultimately left the hospital alive, Dr. Youssef said. If the early ARDS results can be replicated in critically ill COVID-19 patients with respiratory failure, this approach could present a significant advancement in the treatment of these patients.

Jonathan Javitt, M.D., MPH, CEO of NeuroRx, added, We at NeuroRx are enormously excited to have Dr. Youssef join our study, in light of his long involvement in the VIP story. While we can read about Dr. Saids breakthrough, Dr. Youssef witnessed it firsthand and participated in the early clinical care of patients. Its rare to have science come full circle in service of patients.

The trial is being led by NeuroRx, Inc., the US development partner of Relief Therapeutics, whose clinical operations are based in Radnor, PA. Patients are being treated under an FDA Investigational New Drug clearance, as part of the FDAs Corona Treatment Acceleration Program (CTAP). Details of the study are posted on clinicaltrials.gov NCT04311697.

About VIP in Lung Injury

Vasoactive Intestinal Polypeptide (VIP) was first discovered by the late Dr. Sami Said in 1970. Although first identified in the intestinal tract, VIP is now known to be produced throughout the body and to be primarily concentrated in the lungs. VIP has been shown in more than 100 peer-reviewed studies to have potent anti-inflammatory/anti-cytokine activity in animal models of respiratory distress, acute lung injury and inflammation. Most importantly, 70% of the VIP in the body is bound to a rare cell in the lung, the Alveolar Type II cell, that is critical to transmission of oxygen to the body. VIP has a 20-year history of safe use in humans in multiple human trials for sarcoidosis, pulmonary fibrosis, asthma/allergy and pulmonary hypertension.

COVID-19-related deaths are primarily caused by Respiratory Failure. Before an acute deterioration in lung function, there is evidence of early viral infection of the alveolar type 2 cells. These cells are known to have angiotensin converting enzyme 2 (ACE2) receptors at high levels, which serve as the route of entry for the SARS-CoV-2 into the cells. Coronaviruses are shown to replicate in alveolar type 2 cells, but not in the more numerous type 1 cells.1,2Since type 2 alveolar cells have high concentrations of VIP receptors on their cell surfaces, the research hypothesis is VIP administration could specifically protect these cells from injury.

Injury to the type 2 alveolar cells is an increasingly plausible mechanism of COVID-19 disease progression.3 These specialized cells replenish the more common type 1 cells that line the lungs. More importantly, type 2 cells manufacture surfactant that coats the lung and are essential for oxygen exchange. Other than RLF-100, no currently proposed treatments for COVID-19 specifically target these vulnerable type 2 cells.

About RLF-100

RLF-100 (Aviptadil) is a patented formulation of Vasoactive Intestinal Polypeptide (VIP)that was developed based on Dr. Saids original work and was originally approved for human trials by the FDA in 2001 and the European Medicines Agency in 2005. VIP is known to be highly concentrated in the lungs and to inhibit a variety of inflammatory cytokines. Reliefs predecessor company, Mondo Biotech, was awarded Orphan Drug Designation in 2001 by the U.S. FDA for Aviptadil in the treatment of Acute Respiratory Distress Syndrome and in 2005 for treatment of Pulmonary Arterial Hypertension. Mondo was awarded Orphan Drug Designation by the European Medicines Agency in 2006 for the treatment of acute lung injury and in 2007 for the treatment of sarcoidosis. Both the U.S. FDA and the EMEA have granted Investigational New Drug licenses for human trials of Aviptadil.

About RELIEF THERAPEUTICS Holding AG

The Relief group of companies focus primarily on clinical-stage projects based on molecules of natural origin (peptides and proteins) with a history of clinical testing and use in human patients or a strong scientific rationale. Currently, Relief is concentrating its efforts on developing new treatments for respiratory disease indications.

Relief Therapeutics holds orphan drug designations from the U.S. Food and Drug Administration and the European Union for the use of VIP to treat ARDS, pulmonary hypertension, and sarcoidosis. Relief Therapeutics also holds a U.S. patent4 for RLF-100 and proprietary manufacturing processes for its synthesis.

RELIEF THERAPEUTICS Holding AG is listed on the SIX Swiss Exchange under the symbol RLF.

About NeuroRx, Inc.

NeuroRx draws upon more than 100 years of collective drug development experience and is led by former senior executives of Johnson & Johnson, Eli Lilly, Pfizer, and AstraZeneca, PPD. In addition to its work on RLF-100, NeuroRx has been awarded Breakthrough Therapy Designation and a Special Protocol Agreement to develop NRX-101 for the treatment of suicidal bipolar depression and is currently in Phase 3 trials. Its Board of Directors and Advisors includes Hon. Sherry Glied, former Assistant Secretary, U.S. Dept. of Health and Human Services; Mr. Chaim Hurvitz, former President of the Teva International Group, Lt. Gen. HR McMaster, the 23rd National Security Advisor, Wayne Pines, former Associate Commissioner of the U.S. Food and Drug Administration, Judge Abraham Sofaer, and Daniel Troy, former Chief Counsel, U.S. Food and Drug Administration.

Disclaimer: This communication expressly or implicitly contains certain forward-looking statements concerning RELIEF THERAPEUTICS Holding AG, NeuroRx, Inc. and their businesses. Such statements involve certain known and unknown risks, uncertainties and other factors, which could cause the actual results, financial condition, performance or achievements of RELIEF THERAPEUTICS Holding AG and/or NeuroRx, Inc. to be materially different from any future results, performance or achievements expressed or implied by such forward-looking statements. RELIEF THERAPEUTICS Holding AG is providing this communication as of this date and does not undertake to update any forward-looking statements contained herein as a result of new information, future events or otherwise.

CORPORATE CONTACTS

Jonathan C. Javitt, M.D., MPHChief Executive OfficerNeuroRx, Inc.ceo@neurorxpharma.com

Yves Sagot, Ph.D.Relief Therapeutics Holding, SAyves.sagot@relieftherapeutics.com

MEDIA CONTACT

Gloria GasaaturaLifeSci Communicationsggasaatura@lifescicomms.com646-970-4688

1 US 8,178,489 Formulation for Aviptadil

2 Jonathan C. J. Perspective: The Potential Role of Vasoactive Intestinal Peptide in treating COVID-19 Authorea, DOI:10.22541/au.158940764.42332418

3 Mason R. J. (2020). Pathogenesis of COVID-19 from a cell biology perspective.The European respiratory journal,55(4), 2000607. https://doi.org/10.1183/13993003.00607-2020

4US 8,178,489 Formulation for Aviptadil

Original post:
Relief Therapeutics and NeuroRx Expand Clinical Trial Evaluating RLF-100 in Critically Ill COVID-19 Patients with Respiratory Failure to Houston...

Cell Biology

FDA Approves Elixirgen Therapeutics IND Application for Therapy for Telomere Biology Disorders with Bone Marrow Failure – Herald-Mail Media

BALTIMORE, June 4, 2020 /PRNewswire/ -- Elixirgen Therapeutics, Inc., a Baltimore-based biotechnology company focused on the discovery, development, and commercialization of therapies for genetic diseases and vaccines, received confirmation from the U.S. Food and Drug Administration (FDA) that its Investigational New Drug (IND) application for its lead candidate, EXG34217, was approved on May 23, 2020. EXG34217 is an autologous cell therapy for telomere biology disorders with bone marrow failure.

The FDA's approval allows Elixirgen Therapeutics to proceed with its planned Phase I/II, open label, single center clinical trial to assess the safety and tolerability of EXG34217 at Cincinnati Children's Hospital Medical Center (ClinicalTrials.gov Identifier: NCT04211714). This program's treatment paradigm uses Elixirgen Therapeutics' proprietary ZSCAN4 technology to extend the telomeres of the hematopoietic stem cells of the patients.

About Elixirgen Therapeutics, Inc.Elixirgen Therapeutics, Inc. is a Baltimore-based biotechnology company co-founded by Akihiro Ko and Minoru Ko, MD, PhD, which is focused on curing humanity's ailments through innovations in stem cell biology.The company's experienced team of researchers has a wide variety of specialties, enabling it to use both basic and translational research approaches to developing therapies for genetic diseases and vaccines. For more information visit https://ElixirgenTherapeutics.com

Forward-Looking StatementsThis press release may contain "forward-looking" statements, including statements regarding the effectiveness of EXG34217 to treat telomere biology disorders with bone marrow failure and statements relating to the planned clinical trials of EXG34217. Actual results may differ materially from those set forth in this press release due to the risks and uncertainties inherent in drug research and development. In light of these and other uncertainties, the forward-looking statements included in this press release should not be regarded as a representation by Elixirgen Therapeutics that its plans and objectives regarding EXG34217 will be achieved. Any forward-looking statements in this press release speak only as of the date of this press release, and Elixirgen Therapeutics undertakes no obligation to update or revise the statementsin the future, even if new information becomes available.

Contact:Media RelationsElixirgen Therapeutics, Inc.(443) 869-5420Media@ElixirgenTherapeutics.com

Originally posted here:
FDA Approves Elixirgen Therapeutics IND Application for Therapy for Telomere Biology Disorders with Bone Marrow Failure - Herald-Mail Media

Cell Biology

Cancer cells are comfy havens for bacteria: Weizmann Institute of Science study – Express Healthcare

The research suggests that understanding relationship between a cancer cell, its mini-microbiome may help predict potential effectiveness of certain treatments or may point, in future, to ways of manipulating those bacteria to enhance actions of anticancer treatments

Cancer cells are comfy havens for bacteria. That conclusion arises from a rigorous study of over 1,000 tumour samples of different human cancers. The study, headed by researchers at the Weizmann Institute of Science, found bacteria living inside the cells of all the cancer types from brain to bone to breast cancer and even identified unique populations of bacteria residing in each type of cancer. The research suggests that understanding the relationship between a cancer cell and its mini-microbiome may help predict the potential effectiveness of certain treatments or may point, in the future, to ways of manipulating those bacteria to enhance the actions of anticancer treatments. The findings of this study were published in Science.

Dr Ravid Straussman, Department of Molecular Cell Biology, Weizmann Institute of Science had, several years ago, discovered bacteria lurking within human pancreatic tumour cells; these bacteria were shown to protect cancer cells from chemotherapy drugs by digesting and inactivating these drugs. When other studies also found bacteria in tumour cells, Straussman and his team wondered whether such hosting might be the rule, rather than the exception. To find out, Dr Deborah Nejman and Dr Ilana Livyatan in Straussmans group and Dr Garold Fuks, Physics of Complex Systems Department, Weizmann Institute of Science worked together with a team of oncologists and researchers around the world. The work was also led by Dr Noam Shental, Mathematics and Computer Science Department, Open University of Israel.

Ultimately, the team would produce a detailed study describing, in high resolution, the bacteria living in these cancers brain, bone, breast, lung, ovary, pancreas, colorectal and melanoma. They discovered that every single cancer type, from brain to bone, harboured bacteria and that different cancer types harbour different bacteria species. It was the breast cancers, however, that had the largest number and diversity of bacteria. The team demonstrated that many more bacteria can be found in breast tumours compared to the normal breast tissue surrounding these tumours, and that some bacteria were preferentially found in the tumour tissue rather than in the normal tissue surrounding it.

To arrive at these results, the team had to overcome several challenges. For one, the mass of bacteria in a tumour sample is relatively small, and the researchers had to find ways to focus on these tiny cells-within-cells. They also had to eliminate any possible outside contamination. To this end they used hundreds of negative controls and created a series of computational filters to remove the traces of any bacteria that could have come from outside the tumour samples.

The team was able to grow bacteria directly from human breast tumours, and their results proved that the bacteria found in these tumours are alive. Electron microscopy visualisation of these bacteria demonstrated that they prefer to nestle up in a specific location inside the cancer cells close to the cell nucleus.

The team also reported that bacteria can be found not only in cancer cells, but also in immune cells that reside inside tumours. Some of these bacteria could be enhancing the anticancer immune response, while others could be suppressing it a finding that may be especially relevant to understanding the effectiveness of certain immunotherapies, says Dr Straussman. Indeed, when the team compared the bacteria from groups of melanoma samples, they found that different bacteria were enriched in those melanoma tumours that responded to immunotherapy as compared to those that had a poor response.

Dr Straussman thinks that the study can also begin to explain why some bacteria like cancer cells and why each cancer has its own typical microbiome: The differences apparently come down to the choice of amenities offered in each kind of tumour-cell environment. That is, the bacteria may live off certain metabolites that are overproduced by or stored within the specific tumour types. For example, when the team compared the bacteria found in lung tumours from smokers with those from patients who had never smoked, they found variances. These differences stood out more clearly when the researchers compared the genes of these two groups of bacteria: Those from the smokers lung cancer cells had many more genes for metabolising nicotine, toluene, phenol and other chemicals that are found in cigarette smoke.

In addition to showing that some of the most common cancers shelter unique populations of bacteria within their cells, the researchers believe that the methods they have developed to identify signature microbiomes with each cancer type can now be used to answer some crucial questions about the roles these bacteria play: Are the bacteria freeloaders on the cancer cells surplus metabolites, or do they provide a service to the cell? At what stage do they take up residence? How do they promote or hinder the cancers growth? What are the effects that they have on response to a wide variety of anticancer treatments?

Tumors are complex ecosystems that are known to contain, in addition to cancer cells, immune cells, stromal cells, blood vessels, nerves, and many more components, all part of what we refer to as the tumour microenvironment. Our studies, as well as studies by other labs, clearly demonstrate that bacteria are also an integral part of the tumour microenvironment. We hope that by finding out how exactly they fit into the general tumour ecology, we can figure out novel ways of treating cancer, says Dr Straussman.

Dr Straussmans research is supported by theRoel C Buck Career Development Chair; theMoross Integrated Cancer Center; the Maurice and Vivienne Wohl Biology Endowment; theFabricant-Morse Families Research Fund for Humanity; theChantal Dadesky-Scheinberg Research Fund; theRising Tide Foundation; and theEuropean Research Council.

Read more:
Cancer cells are comfy havens for bacteria: Weizmann Institute of Science study - Express Healthcare

Cell Biology

New study may help develop therapeutics for tongue cancer – India Education Diary

New Delhi: A team of researchers from IIT Madras, Cancer Institute, Sree Balaji Dental College and Hospital, Chennai, and Indian Institute of Science (IISc) Bengaluru have identified a specific microRNA (miRNAs) called miR-155 that is over-expressed in tongue cancer. MicroRNAs (miRNAs) are small Ribo Nucleic Acid. They are non-coding RNAs involved in the regulation of a variety of biological and pathological processes, including the formation and development of cancer. This finding is important in that molecular strategies can potentially be devised to manipulate miR-155 expression to develop therapeutics for tongue cancer.

The main function of miRNA is to silence the expression of the other genes. If the silence oncogenes then the cancer will be suppressed. On the other hand, if they suppress tumour suppressor gene, the cancer will progress. Accordingly, miRNA can act as oncogenes or tumour suppressor genes depending on what they act upon. There are only two therapeutic approaches that can be possible. If the miRNA has been shown to work as oncogenes, then one wants to inhibit; this is known as miRNA inhibition therapy. If the miRNA acts as tumour suppressor genes, then you want to introduce to the system so that tumour can be suppressed; such therapy is called miRNA replacement therapy, said, Prof. Karunagaran, Head, Department of Biotechnology, IIT Madras, while speaking with India Science Wire. miRNA manipulation is being combined with conventional cancer treatment methods such as chemotherapy, radiotherapy, and immunotherapy, and the study reported by collaborative team can enable such emerging therapeutics for cancer.

Elaborating about this research, Prof. Karunagaran said, miRNA is already known to be an oncogene in tongue cancer and has been found to play important roles in many cancers, in carcinogenesis (start of cancer), malignant transformation and metastasis the development of secondary cancer. The miRNAs associated with cancer are called Oncomirs.

Further, Prof. Karunagaran added, Many of the oncomirs affect cancer by suppressing the performance of tumour-suppressing agents that can prevent growth and spread of cancer cells, although some oncomirs are also involved in preventing tumour growth itself. It is, therefore, important to identify the types of miRNAs that are associated with both suppression and proliferation of cancer cells.

miRNAs affect cancer growth through inhibiting or enhancing the functions of certain proteins. For example, it has been shown that a type of protein called programmed cell death 4 (pdcd4) helps in stopping cancer cells from growing and spreading. Inhibition of this protein has been known to cause spread of oral, lung, breast, liver, brain and colon cancers.

The team has gone beyond showing the connection between miR-155 and pdcd4. They have also shown that knocking out miR-155 causes death of cancer cells, arrests the cell cycle, and regresses tumour size in animal models and reduces cell viability and colony formation in bench top assays.

Adding on, Shabir Zargar, research scholar said, While it has been long suspected that miR-155 downregulates pdcd4, there have, hitherto, been no evidence for such interaction.

The collaborative team headed by Prof. Karunagaran has shown that miR-155 is overexpressed in tongue cancer cells and tongue tumour tissues. This overactivity of miR-155 hinders the action of pdcd4, which, in turn, causes spread and growth of cancer of the tongue.

Our study has shown that the restoration of pdcd4 levels through molecular manipulation of miR-155 can lead to potential therapeutic developments for cancers, especially of tongue cancer, said Prof. Karunagaran.

The research findings have been published in the journal Molecular and Cellular Biology. The research team included Shabir Zargar, Vivek Tomar, Vidyarani Shyamsundar, Ramshankar Vijayalakshmi, Kumaravel Somasundaram, and Prof. Karunagaran.

View original post here:
New study may help develop therapeutics for tongue cancer - India Education Diary