Category Archives: Cell Biology

Cell Biology

IIT-M researchers identify role of microRNA in tongue cancer – Zee News

Chennai: Indian Institute of Technology Madras (IIT-M) on Monday said its researchers have identified a specific microRNA (miRNAs) called `miR-155 that is over-expressed in tongue cancer.

According to the researchers, miRNAs affect cancer growth by inhibiting or enhancing the functions of certain proteins. For example, it has been seen 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 the spread of oral, lung, breast, liver, brain and colon cancers.

For the current study, IIT Madras collaborated with researchers from Cancer Institute and Sree Balaji Dental College and Hospital at Chennai and Indian Institute of Science at Bengaluru.

"MicroRNAs (miRNAs) are short non-coding RNAs containing 20?24 nucleotides that participate in virtually all biological pathways in animals," study lead researcher Devarajan Karunagaran, Head, Department of Biotechnology, IIT Madras, said in a statement.

"They have 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`," Karunagaran added.

According to the researchers, 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.

For the findings, published in the peer-reviewed journal Molecular and Cellular biology, the research team went 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 benchtop assays.

"While it has been long suspected that miR-155 downregulates Pdcd4, there have, hitherto, been no evidence for such interaction," said study researcher Shabir Zargar.

The research team has shown beyond doubt 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," Karunagaran added.

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IIT-M researchers identify role of microRNA in tongue cancer - Zee News

Cell Biology

Neuroscientists Discover Neural Circuits That Control Hibernation-Like Behaviors in Mice – Newswise

At a glance:

Newswise The dream of suspended animation has long captivated the human imagination, reflected in countless works of mythology and fiction, from King Arthur and Sleeping Beauty to Captain America and Han Solo. By effectively pausing time itself for an individual, a state of stasis promises to enable the repair of lethal injuries, prolong life and allow for travel to distant stars.

While suspended animation may seem a fantasy, a strikingly diverse array of life has already achieved a version of it. Through behaviors like hibernation, animals such as bears, frogs and hummingbirds can survive harsh winters, droughts, food shortages and other extreme conditions by essentially entering into biological stasis, where metabolism, heart rate and breathing slow to a crawl and body temperature drops.

Now, Harvard Medical School neuroscientists have discovered a population of neurons in the hypothalamus that controls hibernation-like behavior, or torpor, in mice, revealing for the first time the neural circuits that regulate this state.

Reporting in Nature on June 11, the team demonstrated that when these neurons are stimulated, mice enter torpor and can be kept in that state for days. When the activity of these neurons is blocked, natural torpor is disrupted.

Another study published simultaneously in Nature by researchers from the University of Tsukuba in Japan also identified a similar population of neurons in the hypothalamus.

By better understanding these processes in mice and other animal models, the authors envision the possibility of one day working toward inducing torpor in humansan achievement that could have a vast array of applications, such as preventing brain injury during stroke, enabling new treatments for metabolic diseases or even helping NASA send humans to Mars.

The imagination runs wild when we think about the potential of hibernation-like states in humans. Could we really extend lifespan? Is this the way to send people to Mars? said study co-lead author Sinisa Hrvatin, instructor in neurobiology in the Blavatnik Institute at HMS.

To answer these questions, we must first study the fundamental biology of torpor and hibernation in animals, Hrvatin said. We and others are doing thisit is not science fiction.

To reduce energy expenditure in times of scarcity, many animals enter a state of torpor. Hibernation is an extended seasonal form of this. Unlike sleep, torpor is associated with systemic physiological changes, particularly significant drops in body temperature and suppression of metabolic activity. While common in nature, the biological mechanisms that underlie torpor and hibernation are still poorly understood.

The role of the brain, in particular, has remained largely unknown, a question that drove the research efforts of Hrvatin and colleagues, including co-lead author Senmiao Sun, a graduate student in the Harvard Program in Neuroscience, and study senior author Michael Greenberg, the Nathan Marsh Pusey Professor and chair of the Department of Neurobiology in the Blavatnik Institute at HMS.

Neural TRAP

The researchers studied mice, which do not hibernate but experience bouts of torpor when food is scarce and temperatures are low. When housed at 22 C (72 F), fasting mice exhibited a sharp drop in core body temperature and significant reduction in metabolic rate and movement. In comparison, well-fed mice retained normal body temperatures.

As mice began to enter torpor, the team focused on a gene called Fospreviously shown by the Greenberg lab to be expressed in active neurons. Labeling the protein product of the Fos gene allowed them to identify which neurons are activated during the transition to torpor throughout the entire brain.

This approach revealed widespread neuronal activity, including in brain regions that regulate hunger, feeding, body temperature and many other functions. To see if brain activity was sufficient to trigger torpor, the team combined two techniquesFosTRAP and chemogeneticsto genetically tag neurons that are active during torpor. These neurons could then be re-stimulated later by adding a chemical compound.

The experiments confirmed that torpor could indeed be inducedeven in well-fed miceby re-stimulating neurons in this manner after the mice recovered from their initial bout of inactivity.

However, because the approach labeled neurons throughout the entire brain, the researchers worked to narrow in on the specific area that controls torpor. To do so, they designed a virus-based tool that they used to selectively activate neurons only at the site of injection.

Focusing on the hypothalamus, the region of the brain responsible for regulating body temperature, hunger, thirst, hormone secretion and other functions, the researchers carried out a series of painstaking experiments. They systematically injected 54 animals with minute amounts of the virus covering 226 different regions of the hypothalamus, then activated neurons only in the injected regions and looked for signs of torpor.

Neurons in one specific region of the hypothalamus, known as the avMLPA, triggered torpor when activated. Stimulating neurons in other areas of the hypothalamus had no effect.

When the initial experiment worked, we knew we had something, Greenberg said. We gained control over torpor in these mice using FosTRAP, which allowed us to then identify the subset of cells that are involved in the process. Its an elegant demonstration of how Fos can be used to study neuronal activity and behavioral states in the brain.

Worthwhile goal

The team further analyzed the neurons that occupy the region, using single-cell RNA sequencing to look at almost 50,000 individual cells representing 36 different cell types, ultimately pinpointing a subset of torpor-driving neurons, marked by the neurotransmitter transporter gene Vglut2 and the peptide Adcyap1.

Stimulating only these neurons was sufficient to induce rapid drops in body temperature and motor activity, key features of torpor. To confirm that these neurons are critical for torpor, the researchers used a separate virus-based tool to silence the activity of avMLPA-Vglut2 neurons. This prevented fasting mice from entering natural torpor, and in particular disrupted the associated decrease in core body temperature. In contrast, silencing these neurons in well-fed mice had no effect.

In warm-blooded animals, body temperature is tightly regulated, Sun said. A drop of a couple of degrees in humans, for example, leads to hypothermia and can be fatal. However, torpor circumvents this regulation and allows body temperatures to fall dramatically. Studying torpor in mice helps us understand how this fascinating feature of warm-blooded animals might be manipulated through neural processes.

The researchers caution that their experiments do not conclusively prove that one specific neuron type controls torpor, a complex behavior that likely involves many different cell types. By identifying the specific brain region and subset of neurons involved in the process, however, scientists now have a point of entry for efforts to better understand and control the state in mice and other animal models, the authors said.

They are now studying the long-term effects of torpor on mice, the roles of other populations of neurons and the underlying mechanisms and pathways that allow avMLPA neurons to regulate torpor.

Our findings open the door to a new understanding of what torpor and hibernation are, and how they affect cells, the brain and the body, Hrvatin said. We can now rigorously study how animals enter and exit these states, identify the underlying biology, and think about applications in humans. This study represents one of the key steps of this journey.

The implications of one day being able to induce torpor or hibernation in humans, if ever realized, are profound.

Its far too soon to say whether we could induce this type of state in a human, but it is a goal that could be worthwhile, Greenberg said. It could potentially lead to an understanding of suspended animation, metabolic control and possibly extended lifespan. Suspended animation in particular is a common theme in science fiction, and perhaps our ability to traverse the stars will someday depend on it.

Additional authors include Oren Wilcox, Hanqi Yao, Aurora Lavin-Peter, Marcelo Cicconet, Elena Assad, Michaela Palmer, Sage Aronson, Alexander Banks and Eric Griffith.

The study was supported by the National Institutes of Health (R01 NS028829, R01 MH114081, R01 DK107717) and a Warren Alpert Distinguished Scholar Award.

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Neuroscientists Discover Neural Circuits That Control Hibernation-Like Behaviors in Mice - Newswise

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.

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

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.

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

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.

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

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.

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

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

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

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

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

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.

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

Cell Biology

The 2019 3Rs prize awarded to two pieces of novel research – News-Medical.Net

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

The 2019 3Rs prize has been jointly awarded to Dr Francesca Nunn and Dr Marta Shahbazi for papers describing research that reduces the number of chickens and mice respectively. The 3Rs prize is awarded by the NC3Rs and sponsored by GSK.

- Nunn F, et al (2019). A novel, high-welfare methodology for evaluating poultry red mite interventions in vivo. Veterinary Parasitology. 267:42-46. doi.org/10.1016/j.vetpar.2019.01.011

- Shahbazi, MN, et al (2017). Pluripotent state transitions coordinate morphogenesis in mouse and human embryos. Nature. 552:239-243. doi.org/10.1038/nature24675

Dr Francesca Nunn, a post-doctoral scientist at the Moredun Research Institute

Francesca and colleagues developed and optimized a device to improve the testing of treatments against poultry red mites, reducing the number of hens used in field trials.

Poultry red mites are a blood feeding ectoparasite. They are a global problem for the egg industry, affecting the welfare of laying hens through irritation and anaemia. Mites are controlled using chemicals, however, repeated use has led to resistance and recent research efforts have focused on developing vaccines and novel biopesticides.

Assessment of vaccine control methods is initially done in vitro using blood assays before field trials are conducted, with 750 to 800 hens exposed to mites for each vaccine candidate, with an adjuvant control group. In vitro assays can be unreliable, for example, due to high levels of non-specific mite mortality. As a consequence, vaccine efficacy measured in vitro is not always translated into mite population reduction in field trials.

Francesca developed an "on-hen" mite feeding device that improves the screening of vaccine candidates to avoid unnecessary field trials. The device consists of a mesh pouch containing approximately 100 mites that have been starved for three weeks. The pouch is fitted to the thigh of the vaccinated hen - the mesh is large enough to allow the mites' mouth parts to access the hen's skin but small enough to contain the mites. Four hens are used per vaccine candidate and after three hours, the mesh is removed and the mites are recovered and maintained in 96-well plates for up to six days to assess mortality.

The device has already been used to provide data that has prevented seven vaccines and vaccine delivery methods from going into field trials. The initial pre-screening using the on-hen device involved 56 hens in total, each exposed to 100 mites for three periods of three hours - the field studies would have used almost 5,500 birds exposed to 10,000 mites for 100 days.

The on-hen device has been used by academic and commercial laboratories in the UK and internationally. By varying the size of the mesh, the device has the potential to be used in research on other parasites.

Dr Marta Shahbazi, a research leader at the MRC Laboratory of Molecular Biology

Marta and colleagues have developed advanced 3D cultures of human and mouse embryonic stem cells to mimic the development of the embryo at implantation and the subsequent morphogenesis and formation of the amniotic cavity, providing an opportunity to replace and reduce the use of live mice in some developmental biology studies.

Implantation of an embryo into the uterus is a critical step with a high rate of pregnancies lost at this stage. Studying implantation and other early embryonic events is technically and ethically challenging. The majority of work is carried out in mice, typically genetically modified animals where associated surgery and breeding of large numbers of animals are required.

Marta's research has shown that it is possible to minimise this use with reproducible and novel 3D cultures of mouse embryonic stem cells that reliably mimic development at the time of, and beyond, implantation, avoiding the need for recipient mice for embryo transfer and the subsequent culling of animals to access early stage embryos.

Marta and colleagues have previously described an in vitro method to culture human embryos beyond the point of implantation, overcoming the technical challenges that have traditionally limited the use of human embryos in research. The winning paper builds on this by reporting comparative functional experiments using mouse and human embryonic stem cell 3D cultures that have identified key factors involved in the remodelling of the embryo at implantation to form the amniotic cavity. This has revealed a previously unknown link between cell potency and tissue shape, with a loss of stem cell "nave pluripotency" (that is the ability to become any cell type in the organism) triggering the formation of the cavity and developmental progression of the embryo. The use of the 3D cultures for these studies replaced the use of 500 mice and importantly by demonstrating that they can be used to answer fundamental biological questions, the research has led to multiple groups worldwide adopting the cultures, further reducing the use of animals.

Professor Kevin Shakesheff, Chair of the NC3Rs Board and 3Rs Prize Panel said: "The vibrancy of research into the 3Rs was evident from the quality and breadth of the papers we considered. The winning papers and authors demonstrate that 3Rs research can the quality of science and unlock new types of experiments with wide applicability. Both papers are making an impact across the world and the prizes are richly deserved."

GSK is incredibly proud of being able to support the important work done by the NC3Rs and it was a real pleasure to participate in the presentation of these awards as the quality of the science was truly outstanding. The ambition to reduce, refine and replace that is at the core of the work that we are happily able to recognise in the winners is more crucial than ever. The need to ensure that every intervention, measurement and outcome helps to move science and the development of medicines forward is especially critical today in the context of Covid19 where great, reproducible, impactful science has to lead the way."

Dr Rab Prinjha, GSK Vice President of Adaptive Immunity and Immuno-epigenetics

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The 2019 3Rs prize awarded to two pieces of novel research - News-Medical.Net