All posts by medical

Cell Biology

Meet a superhero that fights breast cancer, neurofibromin – Baylor College of Medicine News

It is well known that neurofibromin (NF1), a tumor suppressor produced by the NF1 gene, keeps cancer growth in check by repressing the activity of a cancer driver gene called Ras. It then follows that when NF1 is lost, Ras can drive cancer growth by promoting treatment resistance and metastasis. NF1, however, can do more than regulate Ras.

Drs. Eric C. Chang, Matthew Ellis and Zeyi Zheng at Baylor College of Medicine and their colleagues have discovered new insights into the function of neurofibromin that improve our understanding of breast cancer resistance and suggest novel therapeutic approaches to overcome it.

The team first studied the importance of neurofibromin loss in a study they published in 2018. In this study, they sequenced tumor DNA seeking for mutations that can promote resistance to tamoxifen, a drug commonly used to prevent relapses from estrogen receptor positive (ER+) breast cancer.

When we examined the mutational patterns in NF1, we observed that poor patient outcome only occurred when neurofibromin was lost, not through mutations that selectively affect Ras regulation. This suggested that neurofibromin may have more than one function, said Chang, co-corresponding author of this work and associate professor in the Department of Molecular and Cellular Biology and a member in the Dan L Duncan Comprehensive Cancer Centers Lester and Sue Smith Breast Center.

This thought triggered studies, spearheaded by Zheng in Changs lab, into the function of neurofibromin in ER+ breast cancer cells. One of his early experiments showed that when expression of NF1 is inhibited (to mimic neurofibromin loss in tumors), the resulting ER+ breast cancer cells were stimulated by tamoxifen instead of inhibited, as it usually happens. Furthermore, these neurofibromin-depleted cells became sensitive to a very low concentration of estradiol, a form of estrogen.

The clinical relevance of these findings was immediately apparent because it suggested that tamoxifen or aromatase inhibitors, which lower estrogen levels available to the cancer cells, would be the wrong choice for treatment when neurofibromin is lost by the tumor, said Ellis, co-corresponding author and professor and director of the Lester and Sue Smith Breast Center. Dr. Ellis also is a McNair Scholar at Baylor.

Follow-up gene expression studies all strongly suggested that neurofibromin behaves like a classic ER co-repressor.

A co-repressor must bind ER directly, but the group hesitated to conduct such an experiment without more evidence because it is not trivial to do so, Chang said.

A breakthrough came when Dr. Charles Foulds, a co-author on the paper and assistant professor at the Center for Precision Environmental Health at Baylor, searched the Epicome, a massive proteomic database created by Dr. Anna Malovannaya and Dr. Jun Qin, also at Baylor. This is a part of an effort by Dr. Bert OMalley, chancellor and professor of Baylors Department of Molecular and Cellular Biology to comprehensively document all the proteins associated with ER.

Foulds found neurofibromin in the database, which encouraged the team to ultimately investigate whether estrogen receptor and neurofibromin interacted directly. However, to seriously consider NF1 as an ER co-repressor, there was still another missing piece of the puzzle.

One day Charles casually asked me whether neurofibromin had a region rich in the amino acids leucine and isoleucine, because co-repressors use these regions or motifs to bind ER, and it dawned on me that neurofibromin indeed does, Chang said. In fact, neurofibromin has two such motifs that mediate ER binding in a cooperative manner. These motifs are frequently mutated in cancer, but are not required for Ras regulation.

Since tamoxifen or aromatase inhibitors were found to be ineffective for neurofibromin-deficient ER+ breast cancer tumors, the researchers worked with animal models to determine whether the ER-degrading drug fulvestrant was still effective. However, fulvestrant only temporarily inhibited tumor growth because secondary Ras-dependent fulvestrant resistance was induced by neurofibromin loss. This Ras-dependent growth phase could be inhibited with the addition of a MEK inhibitor, which shuts off a key signaling pathway downstream of Ras.

The team validated this combination treatment strategy using a patient-derived xenograft (PDX) mouse model. In this model, a section of a human tumor taken from a patient is directly transplanted into a mouse under conditions that maintain the genomics and drug response of the original human tumor from which it was derived (Cell Reports, 2013). In this case, this PDX was derived from a patient who failed several lines of endocrine therapy and had already developed fulvestrant resistance.

The results of the combination of fulvestrant to degrade ER and a MEK inhibitor (e.g., selumetinib or binimetinib) to inhibit Ras downstream signaling, were encouraging the tumor shrunk to almost undetectable levels, Chang said.

Our next goal is to test this combination therapy in clinical trials in order to determine its therapeutic potential in the clinic.

Neurofibromin is lost in at least 10 percent of metastatic ER+ tumors. As a result of these new data, we are now working on a clinical trial that combines a MEK inhibitor with fulvestrant, said Ellis, Susan G. Komen scholar and associate director of Precision Medicine at the Dan L Duncan Comprehensive Cancer Center at Baylor. Interestingly, MEK inhibitors are also being used to control peripheral nerve tumors in patients with neurofibromatosis, where a damaged NF1 gene is inherited. Our findings contribute to an understanding of why female neurofibromatosis patients also have a much higher incidence of breast cancer.

Other contributors to this work include Meenakshi Anurag, Jonathan T. Lei, Jin Cao, Purba Singh, Jianheng Peng, Hilda Kennedy, Nhu-Chau Nguyen, Yue Chen, Philip Lavere, Jing Li, Xin-Hui Du, Burcu Cakar, Wei Song, Beom-Jun Kim, Jiejun Shi, Sinem Seker, Doug W. Chan, Guo-Qiang Zhao, Xi Chen, Kimberly C. Banks, Richard B. Lanman, Maryam Nemati Shafaee, Xiang H.-F. Zhang, Suhas Vasaikar, Bing Zhang, Susan G. Hilsenbeck, Wei Li and Charles E. Foulds. The authors are affiliated with one or more of the following institutions: Baylor College of Medicine, Chongqing Medical University, Adrienne Helis Malvin Medical Research Foundation, Zhengzhou University and Guardant Health.

This work appears in Cancer Cell,

See the publication for a complete list of the sources of support for this work.

By Ana Mara Rodrguez, Ph.D.

See the original post:
Meet a superhero that fights breast cancer, neurofibromin - Baylor College of Medicine News

Cell Biology

A new AI system has enabled the discovery of a novel role for ‘smell-sensing’ genes in colon cancer – Healthcare IT News

Humans havearound400olfactorysmell-sensing genes the largest gene familyin humansthat are turnedon in the noseand other parts of the body, allowing us to smell at least one trillion different odours.Up until now, the role of theseolfactorygenes outside the nose has been largely unknown.

A recent study, published in Molecular Systems Biology, usedmultiple layers of artificial intelligence (AI) toidentifythesegenes involved inthe organisation ofcolon cancer cells. Thisrevealed thatsmell-sensinggenescancontribute to this cancer-associated processalong with keycoloncancer genesandhighlighted their potential role indisease spread andprognosis.

The discoverywas enabled by thedevelopmentof an innovativeAI system, calledKnowledge-and Context-driven Machine Learning (KCML)that enables researchers to studymicroscopy imagesin greater detail to understand more about the function of genes in specific context. KCML has first been applied to colon cancerbut is widely applicable in other diseases too.

The researchers usedcomputer vision algorithm to detect changes in cell appearance and organisation. The algorithm was fed information from robotic microscopy, in collaboration with researchers from the University of Zurich, to image millions of colon cancer cells.By reducing the expression of the smelling genes within these cells, they were able to understand more about the role they play in carcinogenesis.

Expression is whengenes are activated to produce certain proteinsand molecules. Researchers in this study found that reducing the expression of smell-sensing genes in colon cancer cells, a process known as perturbation,can inhibit cells from spreading, potentially by restraining the ability of cells to move. The same behaviour is also observed in the perturbation of key cancer genes.

Dr Heba Sailem,Sir Henry Wellcome Research Fellow at theInstitute of Biomedical Engineering in the UK, alead author on the study,explained: With all this big imaging data, we have a powerfulmeans tobetter understand how every single gene contributes to cancer cell behaviour. I have developed an AI system that is guided by prior knowledge of gene function that allows us to learn much more from this data than would be possible using existing methods.

When humans look atcomplex scenes, theyinterpret the images in light of their previous experience and visual memories (prior knowledge). However, computersjust seeimages asalargematrix of numbers, they will not see shapes and structures.Computer vision is about training the computer to see whatthe human can see. Through AI, we are able to identifyhow turning genes off affectsthe characteristics, shape and structureof cells and tissue. Usually, it is a very lengthy process for humans to interpret numbers from thousands of images, each with thousands of cells.Computer vision can achieve that in a few days,she added.

Dr Sailemswork has focussed on studying cells in culture, and the next step will beto link these findingsthroughto real patient data. She is also keen to apply her AI modelto study the behaviour of genes indifferent cancers, including prostrate, breast and lung.

WHY IT MATTERS

Colorectal cancer is the third most common cancer in the UK and the second most common cause of cancer deaths.

Professor Mark Lawler, chair in translational cancer genomics, Centre for Cancer Research and Cell Biology, Queens University Belfast and Bowel Cancer UK medical advisor,welcomed the application of the new AI model in colorectal cancer, commenting the study showed the power of data in revealing new mechanisms.

One of the biggest challenges in colorectal cancer is metastasis. This is the point at which most patients die. Something that tells us more about that and maybe indicates how this could be controlled is verypromising, he added.

Dr Sailem explained:Cancer is not one disease - itcan be classified intomany diseases depending ontissue type and origin. Wecan takecellsfrom diseased tissueand look at what the genes in theseparticular cellsare doing. We can then identify genes to target for therapy or genesfor which targeted therapies already exist.

THE LARGER TREND

AIand machine learningis increasingly being used to acceleratethe development oftargeted therapies in cancer and other diseases, with leading technology and pharmaceuticalcompanies forming high profile partnerships in recent months.

One such collaboration between Novartis and Microsoft was announced in October to transform medicine with AI. Vas Narasimhan, CEO of Novartis, said, As Novartis continues evolving into a focused medicines company powered by advanced therapy platforms and data science, alliances like this will help us deliver on our purpose to reimagine medicine to improve and extend lives. Pairing our deep knowledge of human biology and medicine with Microsofts leading expertise in AI could transform the way we discover and develop medicines for the world.

ON THE RECORD

Professor Tim Maughan,professor of clinical oncology at the University of Oxford and advisor to Bowel Cancer UK,saidDr Sailemsstudy linked to his own research into howcellswithin tumourstalkto each other.

He said: What they say to each other is determined by molecular make up but also by the conversation going on between the cells. The shape that the cellshave, theway that theyareorganised, the distance they are apart, how close the immune cells get into the cancer,is all a result of the conversation going on between the different cell types within a cancer

DrSailemin this study has found that inadditiontoidentifyingwhole new genes which are important in bowel cancer, she has also picked up that genes that are part of thatolfactorysmell system play a part of this conversation.

Commentingon the research, Professor Lawler said:It is saying something about why there areolfactorygenes in other parts of the body and how they might be responding to the microbiome in the gut. It will be interesting to see what stimulates these genes to upregulate or down regulate in their environment. From there we may be able to identify important biomarkers.

He added: Big data for better health makes sense. You can use that data to change lives, diagnose patients earlier, develop better treatment and improve their quality of life and above all, data can really save lives.

For more information on bowel cancer go to http://www.bowelcanceruk.org.uk.

More:
A new AI system has enabled the discovery of a novel role for 'smell-sensing' genes in colon cancer - Healthcare IT News

Cell Biology

New Research Leads to Binding Protein Development for Cancer Treatment – Pharmacy Times

A research team from the Technical Unveristy of Munich is focused on designing artificial binding proteins for therapeutic applications. Their findings may lead to the development of new types of binding proteins for biological sugar structures, which play a significant role in cancer and infectious diseases.

The recognition of specific sugar molecules, or so-called carbohydrates, is of vital importance in many biological processes, said researcher Ame Skerra, professor of biological chemistry, in a press release.

Most cells carry a marker consisting of sugar chains, which are attached to the outside of the cell membrane or to the membrane proteins, thus enabling the body to identify where the cells belong or whether certain cells are foreign. Pathogens also have sugar structures of their own or they can bind to these, according to the study authors.

Proteins perform a wide range of functions within cells, generally have only low affinity to sugars. Thus, their molecular recognition poses a challenge due to the fact that water molecules look similar to sugar molecules, which means that they are hidden in aqueous environment within cells. Therefore, the research team set out to design an artificial binding protein with a chemical composition that makes it easier to bind to biological sugar structures.

Using the possibilities opened by synthetic biology, the research team employed an additional artificial amino acid, a boric acid group, into the amino acid chain of a protein. In doing so, researchers created an entirely new class of binding protein for sugar molecules. This artificial sugar-binding function is superior to natural binding proteins, known as lectins, both in strength and in possible sugar specificities, according to the study authors.

The sugar-binding activity of boric acid and its derivatives has been known for nearly a century, Skerra said. The chemical element boron is common on earth and has low toxicity, but so far has largely remained unexplored by organisms.

By using X-ray crystallography, the research team succeeded in unraveling the crystal structure of a model complex of the artificial protein, allowing them to validate the biomolecular concept.

Following approximately 5 years of fundamental scientific research, the findings from professor Skerras laboratory can now be applied to practical medical needs. Skerra explained, our results should not only be used to support the future development of new carbohydrate ligands in biological chemistry, but should also pave the way for creating high-affinity agents for controlling or blocking medically-relevant sugar structure on cell surfaces.

A blocking agent could be used for conditions in which strong cell growth is evident or when pathogens are attaching themselves to cells, such as in oncology and virology. If the study authors are successful in blocking the sugar-binding function and in slowing down the progress of a disease, they said it would give the patients immune system sufficient time to mobilize the bodys natural defenses.

Reference

Read more:
New Research Leads to Binding Protein Development for Cancer Treatment - Pharmacy Times

Cell Biology

What India must do to break the Covid-19 chain – Economic Times

Early in March, India became the fifth country in the world to sequence the genome of the novel Coronavirus, or Covid-19, and share its data with the international community.

Pune-based National Institute of Virology, an institution under the Indian Council of Medical Research, the countrys nodal health research body, sent the first two data sets to an open database shared by researchers globally.

Labs, largely from China, the United States and the Netherlands, have so far contributed just over 1,100 samples to the database, which researchers across the world can use to analyse and work on tests, vaccines and drugs to combat the pandemic.

In India, the first set of genome data -- detailing the complete DNA of the virus came from individuals in Kerala who had contracted the virus.

The volume of the sample and the concentration of the virus play a crucial role during the sequencing of the virus genome. In some samples that we received, there was less virus concentration and in case of clinical samples, sometimes the volume was less. These were some of the challenges, says Professor Priya Abraham, Director of the National Institute of Virology.

The SARS-CoV2 genome, as it is formally known, has about 30,000 base pairs, somewhat like a long string with 30,000 places where each one of these occupy one of four chemicals called nucleotides. This long string, with its unique combination of nucleotides, is what uniquely identifies the virus and is called its genomic sequence. To put that in context, a human genome, which is more complex, has 3 billion base pairs.

Genome data is essential to build tests, find drugs and vaccines. It is also needed to figure out if there has been a mutation of the virus and how that will affect different populations. It is also key to finding measures to deal with its spread.

We need to know how the virus mutates, correlate sequence variation and its severity on patients, says Professor S Vijaya of the Department of Microbiology and Cell Biology at the Indian Institute of Science who has done extensive research on tuberculosis and the Japanese Encephalitis virus.

Scientists are of the view that India needs to sequence more strains as the virus mutates.

It is important to understand whether there are new variants, why is a cluster seeing more serious patients and some milder? Vijaya says. In Italy, the fatality rate is in 10% of the infected patients, in China it was 2%. We need to isolate strains that have a sequence variation that are more pathogenic, she adds.

The novel Coronavirus, whose initial host is suspected to be a bat, originated in Hubei province of China last December.

China was initially slow to realise the magnitude of the virus, which affects the respiratory organs. Since then, the contagious disease that spreads through droplets, either through saliva or when a person coughs or sneezes, has turned into a global pandemic.

There is no vaccine or drug yet for the outbreak that has killed thousands, largely people with underlying medical conditions such as cardiac, diabetes and respiratory problems.

So far, the most effective measure has been to isolate people who have tested positive, quarantine them and increase social distancing to contain its spread.

India has seen the disease enter the third phase of community spread -- people who have not had any contact with those infected, testing positive for the virus.

On Monday, the World Health Organisation warned that the pandemic was accelerating.

It took 67 days for cases to reach the 100,000 mark globally, 11 days to hit 200,000 and just four days to touch 300,000 cases.

So far, more than 6,000 people in Italy have died from the virus, surpassing even that of China. More than 16,500 people have died across the world.

Given the severity of the problem and the global lockdowns in place, India needs to do more sequencing of the virus before it spreads, researchers say.

Since reporting its first positive case on January 30, the country has seen that number swell to more than 500, and nine people dead so far.

If we do more sequencing, we can identify what is the rate of change in the virus, how it is spreading and the how much of the virus (based on its variations) is there in the population, says Chitra Pattabiraman, India Alliance Early Career Fellow at the Department of Neurovirology of the Bengaluru-based National Institute of Mental Health and Neurosciences (Nimhans).

Pattabiraman, a virologist who has done genome sequencing to identify pathogens in brain infections, says sequencing in the earliest phases of an outbreak is valuable because it helps in faster decision making on how to tackle its spread.

India should sequence more strains so that it can contribute to research globally, she says.

We need to develop more capacity and share more strains with the global network. We have forever used other peoples databases for our research, this provides us the opportunity to contribute to the world community, she says.

The country has around 40 labs, including at the Indian Institute of Science and Manipal University, that have the required bio-safety limits (BSL-3) for sequencing the virus, yet it has not opened up the samples to labs outside of the ICMR network.

If more labs are allowed to get into studying the strains, I think we can get more understanding of the virus, says Professor Vijay Chandru, cofounder of Strand Genomics, which was among the first private labs to receive permission to test samples of Covid-19 infections.

ICMR is cautious about opening up more labs for genome sequencing because of the stringent standards required to extract the strains, Chandru says.

Lots of people have capabilities, doing this right is important.

Availability of the Indian sequences will help in understanding the diversity of the viral sequences circulating in the country and its similarities with global strains, Abraham of NIV says.

This would further help in designing specific primers, develop vaccines and drugs that would work better, and local companies would benefit, she says.

Here is the original post:
What India must do to break the Covid-19 chain - Economic Times

Cell Biology

Pattern of Waves Found in Growing Organisms Similar to Ocean Circulations and Quantum Fluids – SciTechDaily

Ocean Currents. Credit: NASA/Goddard Space Flight Center Scientific Visualization Studio

Study shows ripples across a newly fertilized egg are similar to other systems, from ocean and atmospheric circulations to quantum fluids.

When an egg cell of almost any sexually reproducing species is fertilized, it sets off a series of waves that ripple across the eggs surface. These waves are produced by billions of activated proteins that surge through the eggs membrane like streams of tiny burrowing sentinels, signaling the egg to start dividing, folding, and dividing again, to form the first cellular seeds of an organism.

Now MIT scientists have taken a detailed look at the pattern of these waves, produced on the surface of starfish eggs. These eggs are large and therefore easy to observe, and scientists consider starfish eggs to be representative of the eggs of many other animal species.

MIT researchers observe ripples across a newly fertilized egg that are similar to other systems, from ocean and atmospheric circulations to quantum fluids. Credit: Courtesy of the researchers

In each egg, the team introduced a protein to mimic the onset of fertilization, and recorded the pattern of waves that rippled across their surfaces in response. They observed that each wave emerged in a spiral pattern, and that multiple spirals whirled across an eggs surface at a time. Some spirals spontaneously appeared and swirled away in opposite directions, while others collided head-on and immediately disappeared.

The behavior of these swirling waves, the researchers realized, is similar to the waves generated in other, seemingly unrelated systems, such as the vortices in quantum fluids, the circulations in the atmosphere and oceans, and the electrical signals that propagate through the heart and brain.

Not much was known about the dynamics of these surface waves in eggs, and after we started analyzing and modeling these waves, we found these same patterns show up in all these other systems, says physicist Nikta Fakhri, the Thomas D. and Virginia W. Cabot Assistant Professor at MIT. Its a manifestation of this very universal wave pattern.

It opens a completely new perspective, adds Jrn Dunkel, associate professor of mathematics at MIT. You can borrow a lot of techniques people have developed to study similar patterns in other systems, to learn something about biology.

Fakhri and Dunkel have published their results today in the journal Nature Physics. Their co-authors are Tzer Han Tan, Jinghui Liu, Pearson Miller, and Melis Tekant of MIT.

Previous studies have shown that the fertilization of an egg immediately activates Rho-GTP, a protein within the egg which normally floats around in the cells cytoplasm in an inactive state. Once activated, billions of the protein rise up out of the cytoplasms morass to attach to the eggs membrane, snaking along the wall in waves.

Imagine if you have a very dirty aquarium, and once a fish swims close to the glass, you can see it, Dunkel explains. In a similar way, the proteins are somewhere inside the cell, and when they become activated, they attach to the membrane, and you start to see them move.

Fakhri says the waves of proteins moving across the eggs membrane serve, in part, to organize cell division around the cells core.

The egg is a huge cell, and these proteins have to work together to find its center, so that the cell knows where to divide and fold, many times over, to form an organism, Fakhri says. Without these proteins making waves, there would be no cell division.

In their study, the team focused on the active form of Rho-GTP and the pattern of waves produced on an eggs surface when they altered the proteins concentration.

For their experiments, they obtained about 10 eggs from the ovaries of starfish through a minimally invasive surgical procedure. They introduced a hormone to stimulate maturation, and also injected fluorescent markers to attach to any active forms of Rho-GTP that rose up in response. They then observed each egg through a confocal microscope and watched as billions of the proteins activated and rippled across the eggs surface in response to varying concentrations of the artificial hormonal protein.

In this way, we created a kaleidoscope of different patterns and looked at their resulting dynamics, Fakhri says.

The researchers first assembled black-and-white videos of each egg, showing the bright waves that traveled over its surface. The brighter a region in a wave, the higher the concentration of Rho-GTP in that particular region. For each video, they compared the brightness, or concentration of protein from pixel to pixel, and used these comparisons to generate an animation of the same wave patterns.

From their videos, the team observed that waves seemed to oscillate outward as tiny, hurricane-like spirals. The researchers traced the origin of each wave to the core of each spiral, which they refer to as a topological defect. Out of curiosity, they tracked the movement of these defects themselves. They did some statistical analysis to determine how fast certain defects moved across an eggs surface, and how often, and in what configurations the spirals popped up, collided, and disappeared.

In a surprising twist, they found that their statistical results, and the behavior of waves in an eggs surface, were the same as the behavior of waves in other larger and seemingly unrelated systems.

When you look at the statistics of these defects, its essentially the same as vortices in a fluid, or waves in the brain, or systems on a larger scale, Dunkel says. Its the same universal phenomenon, just scaled down to the level of a cell.

The researchers are particularly interested in the waves similarity to ideas in quantum computing. Just as the pattern of waves in an egg convey specific signals, in this case of cell division, quantum computing is a field that aims to manipulate atoms in a fluid, in precise patterns, in order to translate information and perform calculations.

Perhaps now we can borrow ideas from quantum fluids, to build minicomputers from biological cells, Fakhri says. We expect some differences, but we will try to explore [biological signaling waves] further as a tool for computation.

This research was supported, in part, by the James S. McDonnell Foundation, the Alfred P. Sloan Foundation, and the National Science Foundation.

Excerpt from:
Pattern of Waves Found in Growing Organisms Similar to Ocean Circulations and Quantum Fluids - SciTechDaily

Cell Biology

New Anticancer Therapy Prospects After Brake on Immune Activity Identified – SciTechDaily

The immune system is like a carefully regulated machine, complete with its own built-in brakes that prevent it from overreacting and causing excess inflammation in otherwise healthy tissues. This preventative safety net, however, is highly vulnerable, particularly in cancer, where tumor cells step on the brakes constantly, because doing so allows the tumor cells to escape immune detection.

Several molecules that act as natural brakes on immune activity have been discovered, which has opened the door to immunotherapy a potentially highly effective way of leveraging the immune system to attack cancer cells. For immunotherapy to reach its full potential in human patients, however, more must be learned about factors driving cancer immunity.

Now, researchers at the Lewis Katz School of Medicine at Temple University (LKSOM) and Fox Chase Cancer Center show for the first time that a molecule called EGR4 known mainly for its role in male fertility serves as a critical brake on immune activation. The new study, published online today (March 25, 2020) in the journal EMBO Reports, shows that taking EGR4 away effectively releasing the brake promotes the activation of so-called killer T cells, which infiltrate and attack tumors and thereby boost anticancer immunity.

Other early growth response proteins, or EGRs, are important to T cell activity, but whether EGR4 also has a role in immunity has been largely overlooked, explained Jonathan Soboloff, PhD, Professor of Medical Genetics and Molecular Biochemistry at the Fels Institute for Cancer Research and Molecular Biology at LKSOM. Our study reveals a new side to the importance of EGR4.

Dr. Soboloffs team examined the influence of EGR4 expression in immune cells in collaboration with Dietmar J. Kappes, PhD, Professor of Blood Cell Development and Cancer at Fox Chase Cancer Center.

In initial experiments, the researchers found that T cell activation is associated with EGR4 upregulation. They then showed that knocking-out, or eliminating, EGR4 from immune cells results in a dramatic increase in calcium signaling and expansion of T helper type 1 (Th1) cell populations. Th1 cells, in response to the presence of foreign entities, including tumor cells, activate cytotoxic, or killer, T cells, which then wipe out the invader.

We know from our previous work that T cells control calcium signaling and that when intracellular calcium levels are elevated, calcium signaling can drive T cell activation, Dr. Soboloff said.

The Soboloff and Kappes labs next studied the functional importance of EGR4 in cancer immunity by utilizing an adoptive mouse model of melanoma in which some host animals lacked EGR4 expression. Compared to mice with typical EGR4 levels, EGR4 knockout animals showed evidence of expanded populations of Th1 cells and enhanced anticancer immunity. In particular, EGR4 knockout mice had reduced lung tumor burden and fewer metastases than mice with normal EGR4 expression.

In future work, the Soboloff and Kappes groups plan to further explore strategies for EGR4 targeting. The development of an agent to target EGR4 specifically may be difficult, due to the diverse actions of EGR pathways. But eliminating EGR4 specifically from a patients T cells, and then putting those cells back into the patient, may be a viable immunotherapeutic approach, Dr. Kappes said.

Reference: 25 March 2020, EMBO Reports.DOI:

Other investigators who contributed to the new study include Jayati Mookerjee-Basu, Jonathan Ladner, and Emmanuelle Nicolas, Fox Chase Cancer Center; Robert Hooper, Scott Gross, Bryant Schultz, Christina K. Go, Elsie Samakai, Yuanyuan Tian, Bo Zhou, M. Raza Zaidi, Shan He, and Yi Zhang, Fels Institute for Cancer Research and Molecular Biology and the Departments of Medical Genetics & Molecular Biochemistry and Immunology, LKSOM; and Warren Tourtellotte, Cedars Sinai Medical Center, Department of Pathology and Laboratory Medicine, West Hollywood, CA.

The research was supported by National Institutes of Health grants R01GM117907, 1R56AI43256, R01AI068907, R01GM107179, and R01NS040748.

Follow this link:
New Anticancer Therapy Prospects After Brake on Immune Activity Identified - SciTechDaily

Cell Biology

Redpin Launches with $15.5 Million Series A to Focus on Pain and Epilepsy – BioSpace

Redpin Therapeutics closed on a $15.5 million Series A financing round. The round was led by 4BIO Capital and Arkin Bio Ventures. They were joined by new investor Takeda Venture Investments, as well as existing seed-round investors, New York Ventures and Alexandria Venture Investments.

Based in New York City, Redpin has a proprietary chemogenetics platform for targeted cell therapies. Its a mix of synthetic biology, gene therapy and traditional pharmacotherapy. The focus is built on an ultrapotent ion channel-based chemogenetics platform that allows targeted cell activation or inhibition controlled by low doses of the Pfizers anti-smoking drug varenicline (Chantix). The company has a worldwide exclusive license from the Howard Hughes Medical Institute for therapeutic use of the technology.

The funds will let Redpin continue to progress its platform to disorders with neural circuit dysfunction, including epilepsy, neuropathic pain and Parkinsons disease. Treatment for these usually uses systemic drugs that target local neuron dysfunction. This has the downside of adverse, off-target side effects. The lead programs are for epilepsy and chronic pain.

Redpins approach, the company believes, will be more targeted on the dysfunctional neurons while not affecting normal functioning cells. The company indicates its approach will only be activated in the presence of Chantix.

These new funds combined with the support and expertise of our new and existing investors will allow Redpin to swiftly progress to the next phase of its development in bringing highly targeted treatments to patients with neurological and psychiatric disorders, said Elma Hawkins, co-founder, president and chief executive officer of Redpin.

Chantix attaches to proteins called ion channels, which control neuron signaling. By controlling which neurons receive these proteins, researchers can modulate specific cells. In March 2019, Scott Sternson, group leader at the Howard Hughes Medical Institutes Janelia Research Campus, noted that chemogenetics often use molecules that would not be appropriate for human therapy. Its still many steps to the clinic, but were trying to shorten that route.

Sternson is one of the companys founders, along with Hawkins, Jeffrey M. Friedman at Howard Hughes, Michael Kaplitt, with Weill Cornell Medicine, Sarah Stanley at Icahn School of Medicine Mount Sinai, and Jonathan S. Dordick, Rensselaer Polytechnic Institute.

At that time, Sternson and his team modified the structure of two different ion channel proteins so the drug would be more likely to bind. One protein stimulates neurons to send messages when Chantix attaches. Another protein blocks neurons from sending those messages when Chantix is present. At that time, doses of Chantix much lower than required to quit smoking were found to have a large effect on neural activity.

Redpins technology uses adeno-associated virus (AAV) vectors to transport engineered ion channels to targeted cells. Once activated, they can control the function of the particular cell. Chantix was chosen because it is approved in 80 countries, has the necessary pharmacokinetic properties, and can penetrate the blood-brain barrier. The company has other small molecule-receptor pairs in its pipeline.

Chantix basically acts as a switch to turn the ion channel on and off.

Dmitry Kuzmin, managing partner at 4BIO, said, Our goal is to support and grow advanced therapy companies with the potential to cure chronic disease. Redpin has a highly compelling, validated chemogenetics approach that could have significant potential in the targeted treatment of neuropathic disorders. The strength of Redpins science alongside the world-class knowledge and expertise of the Companys founders and management team make us fully confident in the future success of the Company towards this goal.

See the original post here:
Redpin Launches with $15.5 Million Series A to Focus on Pain and Epilepsy - BioSpace

Cell Biology

Announcing The Scientist’s NEW 2020 Editorial Advisory Board – PR Web

MIDLAND, Ontario (PRWEB) March 24, 2020

We at The Scientist felt it was high time to revisit the purpose and benefits of maintaining an editorial advisory board. Our board members have served nobly for many years, and we thank all of them for their time and invaluable input. We are excited to name a new panel of leading thinkers in the life sciences and also to announce that this new editorial advisory board (EAB) will function a bit differently. Editors at The Scientist plan on conducting regular check-ins with EAB members to take the pulse of biology and to hear what is exciting the practitioners at the front lines of life science research and development. Readers may also be hearing directly from EAB members, who will be encouraged to contribute their opinions in written pieces that will appear in print or online at regular intervals. This will help us continue to bring you high-quality stories about the realities of pursuing a life in science and will aid our expansion into new topics and disciplines that resonate with researchers and science-curious lay people alike.

So without further ado:

James Allison, University of Texas MD Anderson Cancer Center

James Allison is Regental Professor and Chair of the Department of Immunology, the Olga Keith Wiess Distinguished University Chair for Cancer Research, Director of the Parker Institute for Cancer Research, and the Executive Director of the Immunotherapy Platform at MD Anderson Cancer Center. He has spent his career studying the regulation of T cell responses and developing strategies for cancer immunotherapy. He earned the 2018 Nobel Prize in Physiology or Medicine, which he shared with Kyoto Universitys Tasuku Honjo, for their discovery of cancer therapy by inhibition of negative immune regulation. Among many honors, he is a member of the National Academies of Science and Medicine and received the Lasker-Debakey Clinical Medical Research award in 2015. Allisons current work seeks to improve immune checkpoint blockade therapies currently used by our clinicians and identify new targets to unleash the immune system in order to eradicate cancer.

Deborah Blum, Knight Science Journalism Program at MIT

Deborah Blum is a Pulitzer Prizewinning science writer and the author of six books, most recently The Poison Squad: One Chemists Single-Minded Crusade for Food Safety at the Turn of the Twentieth Century, a New York Times Notable Book and the subject of an American Experience documentary on PBS. Blum serves as director of the Knight Science Journalism Program at MIT, where she is also the publisher of the award-winning science magazine Undark. She has written for a wide range of publications including The New York Times, Slate, The Wall Street Journal, TIME, and Wired. Blum is a fellow of the American Association for the Advancement of Science, a life-time association of the National Academy of Sciences, and serves on the board of the Council for the Advancement of Science Writing.

Jack Gilbert, University of California, San Diego

Jack Gilbert is a professor in the University of California, San Diego, Department of Pediatrics and the Scripps Institution of Oceanography. He was previously a professor in the Department of Surgery and Faculty Director of the Microbiome Center at the University of Chicago Medicine and senior fellow at the Marine Biological Laboratory and Argonne National Laboratory. Currently, he is editor-in-chief of the American Society for Microbiology journal mSystems. Gilbert is also the co-founder of both the Earth Microbiome Project and American Gut Project, as well as the coauthor of Dirt Is Good: The Advantage of Germs for Your Child's Developing Immune System.

Joseph L. Graves, Jr., Joint School for Nanoscience and Nanoengineering

Joseph L. Graves, Jr. is a professor of nanoengineering at the Joint School of Nanoscience and Nanoengineering in Greensboro, North Carolina. His research concerns the evolutionary genomics of adaptation, particularly as relevant to postponed aging and bacterial responses to nanomaterials. He has served as a member of the external advisory board for the National Human Genome Center at Howard University and as the chair of the Senior Advisory Board for the National Evolutionary Synthesis Center (NESCent) at Duke University. Graves is currently a member of the executive boards of the National Science Foundations Science and Technology Center: Biocomputational Evolution in Action (BEACON); NSF NRT: Integrative Bioinformatics for Investigating and Engineering Microbiomes; and NSF NNCI: Southeast Nanoinnovation Corridor.

Erich Jarvis, Rockefeller University

Erich Jarvis is a professor at the Rockefeller University, where he studies the molecular pathways involved in the perception and production of learned vocalizations and the development of brain circuits involved in vocal learning, focusing on observations of songbirds, parrots, and hummingbirds. He also is chair of the international Vertebrate Genomes Project, which has the goal to generate complete genome assemblies of all vertebrate species. In 2002, he was awarded the National Science Foundations Alan T. Waterman Award, in 2005 he won the National Institutes of Health Directors Pioneer Award, and in 2019 he won an NIH Directors Transformative Research Award. Jarvis was named a Howard Hughes Medical Institute Investigator in 2008.

Ellen Jorgensen, Biotech Without Borders

Ellen Jorgensen is the Chief Science Officer at Aanika Biosciences, a biotech startup that uses microbe-based molecular tags to track, trace, and authenticate products throughout supply chains. She is passionate about increasing science literacy in both student and adult populations, particularly in the areas of molecular and synthetic biology. In 2017, Fast Company magazine named her one of their Most Creative Leaders in Business. Jorgensens two TED talks, Biohacking: You Can Do It Too and What You Need to Know About CRISPR, have received more than 2 million views.

Mary-Claire King, University of Washington

Mary-Claire King has been the American Cancer Society Professor of Medical Genetics and of Genome Sciences at the University of Washington since 1995. She has received many honors, including being elected to the National Academy of Medicine in 1994, to the American Academy of Arts and Sciences in 1999, and to the National Academy of Sciences in 2005. King served as the President of the American Society of Human Genetics in 2012, she won the Lasker-Koshland Award for Medical Research in 2014, and was awarded the National Medal of Science in 2016. She uses genomics, population genetics, molecular and cell biology, and the genetics of model organisms to study inherited breast and ovarian cancer, schizophrenia, inherited hearing loss, and neurological disorders in children. King has also been active in the development and application of genomics tools for human rights investigations.

Elaine Mardis, Nationwide Childrens Hospital

Elaine Mardis is co-Executive Director of the Institute for Genomic Medicine at Nationwide Childrens Hospital and the Nationwide Foundation Endowed Chair in Genomic Medicine. She also is Professor of Pediatrics at The Ohio State University College of Medicine. Mardis did postgraduate work in industry at BioRad Laboratories. She was a member of the faculty of Washington University School of Medicine from 19932016. She has authored more than 350 articles in prestigious peer-reviewed journals and has written book chapters for several medical textbooks. She serves as an associate editor for three peer-reviewed journals (Disease Models and Mechanisms, Molecular Cancer Research, and Annals of Oncology) and is Editor-in-Chief of Molecular Case Studies. Mardis has been listed since 2013 as one of the most highly cited researchers in the world by Thompson Reuters, she has been a member of the American Association for Cancer Research (AACR) since 2007, she is serving as the AACR President (20192020), and was elected in 2019 to be a member of the National Academy of Medicine.

Joseph S. Takahashi, University of Texas Southwestern Medical Center

Joseph S. Takahashi is Chair of the Department of Neuroscience and an Investigator of the Howard Hughes Medical Institute at UT Southwestern Medical Center. He currently holds the Loyd B. Sands Distinguished Chair in Neuroscience. He is the author of more than 300 scientific publications and the recipient of many awards including the Honma Prize in Biological Rhythms Research, the National Science Foundations Presidential Young Investigator Award, Searle Scholars Award, Bristol-Myers Squibb Unrestricted Grant in Neuroscience, and the C.U. Ariens Kappers Medal. He received the W. Alden Spencer Award in Neuroscience from Columbia University in 2001 and the Gruber Neuroscience Prize in 2019, was elected a Fellow of the American Academy of Arts and Sciences in 2000, a Member of the National Academy of Sciences in 2003, and a Member of the National Academy of Medicine in 2014. Takahashi has served on a number of advisory committees for the National Institutes of Health, as well as scientific advisory boards for Eli Lilly and Company, Bristol-Myers Squibb Neuroscience Committee, the Genomics Research Institute for the Novartis Foundation, the Klingenstein Fund, the Searle Scholars Foundation, the McKnight Foundation, the Allen Institute for Brain Science, the Max Planck Institute for Biophysical Chemistry, and the Restless Legs Syndrome Foundation. He was also a co-founder of Hypnion, Inc., a biotech discovery company in Worcester, MA, that investigated sleep/wake neurobiology and pharmaceuticals (now owned by Eli Lilly and Co.). He is a co-founder of Synchronicity Pharma, a biotech company that works on the role of clocks in metabolism. He has served on the editorial boards for PNAS, eLife, Neuron, the Journal of Biological Rhythms, Neurobiology of Sleep and Circadian Rhythms, Genes, Brain and Behavior, and F1000, Section Head, Animal Genetics, among others.

H. Steven Wiley, Pacific Northwest National Laboratory

H. Steven Wiley is Laboratory Fellow and Senior Scientist in Systems Biology at Pacific Northwest National Laboratory (PNNL). He is a fellow of the American Association for the Advancement of Science and is notable for having received awards for both technical achievements (R&D 100) and scientific communications. Wiley was a pioneer in computational and systems biology, publishing some of the first models of receptor dynamics and signaling in the early 1980s. His work is notable for using quantitative measurements from multiple technologies, such as imaging, proteomics, genomics, and molecular biology to build predictive computational models of cellular networks, especially those involved in cancer. He started the systems biology program at PNNL as Director of the Biomolecular Systems Initiative, exploiting PNNLs unique capabilities in proteomics, imaging, and computational biology. He has served as a scientific advisor to industry, multiple National Institutes of Health and National Science Foundation systems biology programs and consortia, and several systems biology programs in Europe. He is the author or coauthor of more than 160 scientific publications, including more than 25 review articles and book chapters. He also has written several commercial graphics and data analysis software packages. Wiley has served as a reviewer for more than 45 scientific journals, is an associate editor of Frontiers in Genetics, and serves on the editorial boards of BMC Biology and Biophysical Journal.

About The Scientist:

The Scientist is a publication for life-science professionals that is dedicated to covering a wide range of topics central to the study of cell and molecular biology, genetics, neuroscience, and other biological fields. The Scientist provides print and online coverage of the latest developments in the life sciences, including trends in research, new technology, news, business, and careers. It is read by leading researchers in industry and academia who value penetrating analyses and broad perspectives on life-science topics both within and beyond their areas of expertise. Written by prominent scientists and professional journalists, articles in The Scientist are concise, accurate, accessible, and entertaining.

See the original post here:
Announcing The Scientist's NEW 2020 Editorial Advisory Board - PR Web

Neuroscience

Neuroscience News: Exploring the psychological impact of sheltering in place – Los Altos Town Crier

Residents of Santa Clara County have been ordered to shelter in place until at least April 7. Desperate times call for desperate measures, and social distancing is currently the most effective strategy to curtail the rampant spread of novel coronavirus.

Coronavirus testing has been slow, and there is limited accurate data on the true number of community cases in the U.S., with estimates in the tens to hundreds of thousands, doubling every five to seven days.

With recommendations to stay home and venture out only for essential supplies, telework in place and close K-12 schools and most colleges, the psychological impact of the curfew is a major concern. The current pandemic is triggering fear on a societal level.

Research published in Lancet last week by Dr. Samantha Brooks and her team highlights the psychological impact of quarantine measures and self-isolation on well-being. The psychological cost of quarantine measures includes confusion, anger, insomnia, anxiety, depression and symptoms of post-traumatic stress disorder. Fear of infection, inadequate information, lack of supplies, stigma, xenophobia and financial loss are strong contributing factors.

A history of mental health issues has emerged as a demographic risk factor likely to exacerbate the impact of the current war time social isolation measures. Appraisal of any physical symptoms during periods of quarantine presents real anxiety and fear associated with being infected or having infected others, especially vulnerable loved ones. The reduced social and physical contact and the absence of typical routine during the shelter-in-place order lead to boredom and a sense of isolation. In the general population, health-care workers report the greatest level of psychological impairment from dealing with pandemics.

This is not the first time we have heard of quarantine measures to prevent the spread of a potentially deadly virus. Canada and China implemented similar quarantine measures during the SARS outbreak in 2003, and West African countries in 2014 during the Ebola outbreak. The psychological impact of those shelter-in-place measures was profound, including increased suicide rates associated with efforts to minimize the spread of the viruses.

Parents with school-age children may already be experiencing the frustration of trying to work remotely and home school their kids. Gov. Gavin Newsom shocked parents and students last week when he announced he does not expect schools and colleges to reopen before the end of this school year.

The long-term impact of the stress experienced by families and the 500,000 school-age children in Santa Clara County particularly lower-income families and those working in the service industry, unable to work because they must care for children at home or experiencing loss of jobs is uncertain.

Rita Hitching is a local researcher and teacher who writes on teen brain development. She aims to help teens understand themselves by using the latest neuroscience data to explain how the teen body and brain develop and publishes the explanations on her website, teenbrain.info.

Read more:
Neuroscience News: Exploring the psychological impact of sheltering in place - Los Altos Town Crier

Neuroscience

The fifth secret of accelerated learning: how the brain works to maximise retention – TrainingZone.co.uk

In this article Ill look at how we can use the latest neuroscience to maximise the learning retention. Last time we looked at the physical, emotional and social environments and how they can help to accelerate learning. In that article I mentioned some of the latest thinking about social learning and safety, as well as the part dopamine plays in keeping participants attention. These cross over into this fifth secret about the brain and knowing how it works in order to learn in the best possible way.

Let me say from the outset that I am not a neuroscientist and do not wish to take away from some of the many experts out there in this field. My fascination has never been in the brain and naming all the parts, but in the practical application of the latest neuroscience to help us in the field of learning and development.

Therefore, this article will help you to take away a handful of nuggets from the latest neuroscience, while offering some practical applications that you can implement immediately to maximise the retention of learning.

We already know that dopamine plays a big part in engaging people, whether in a live learning situation or virtually. Dopamine activates your reward systems. It controls arousal levels in the brain.

So here are some ways in which we can arouse curiosity and increase those dopamine levels in the brain:

On the use of emotion in learning, Nick Shackleton-Jones (in his book, How to Learn) says, It makes perfect sense for memory to work in this way: your memory needs to be efficient so it only stores the stuff that matters but which stuff matters? Answer: the stuff that has an emotional impact.

If this is true, then the connection with the content and the participants in learning has to be a strong one. They have to be brought in to the learning and its application in order for them to be engaged as fully as possible. Here are some suggestions for what you might do practically:

There used to be a myth that brains could not change as you got older, but Eleanor Maguire conducted research that uncovered that our brains are not fixed as we had previously thought. Her study on taxi drivers in fact showed the opposite.

This does not help however, when you have participants who think that they are bad at learning. This limiting belief soon becomes a self-fulfilling prophecy. To remove this barrier, you might:

Until I read Make it Stick: The Science of Successful Learning, I thought that knowledge testing was just a way for me as a trainer or facilitator to find out whether participants had learned what they were supposed to learn. After reading this book, it became clear that testing, or retrieval practice as it is known, is a key part of the learning process.

Here are some ways that you can make it a fun and engaging part of the learning process:

Is guessing a valid form of learning? Can it really make a difference to how much you retain? Well according to Stella Collins: it seems, perhaps counter-intuitively, that we learn better after guessing, even if we have guessed a wrong answer first.

The basic idea is that this activation (the guessing) affords a richer encoding of the information, she explains.

You can incorporate a guessing element to any learning by:

Were now at the end of my five secrets of accelerated learning. If youd like to catch up on the rest of these secrets you can visit the content series page here. I welcome any questions and feedback you might have in the comments below.

Link:
The fifth secret of accelerated learning: how the brain works to maximise retention - TrainingZone.co.uk