Category Archives: Cell Medicine

Drug Target Review lists its 10 most popular news stories from 2019, summarising the drug targets that you wanted to read about.

Drug Target Review has published a wide range of news stories this year, from the identification of novel drug targets to improvements in toxicology studies and developments in screening.

As the year draws to a close, we reflect on the biggest and most popular stories from 2019. To read the full pieces, click on the title of each news story.

A genetic analysis study revealed that variants of hundreds of genes work together in contributing to the development of Tourettes syndrome, in our tenth most popular story this year.

According to the researchers, from the Massachusetts General Hospital (MGH) and collaborators, their findings confirm that the underlying basis for Tourettes syndrome is polygenic, meaning that hundreds of small DNA changes cause the condition, rather than one inactive gene.

The scientists said their next step is to expand their sample size to around 12,000 patients, made possible with a potential international collaboration.

The study was published in the American Journal of Psychiatry.

A group of researchers identified new genetic targets on which BRCA2-driven cancer cells are dependent upon, providing a potential avenue for drug development.

The study, conducted at Brigham and Womens Hospital, used CRISPR and short-hairpin RNAs (shRNAs) to test 380 genes with a known or suspected role in DNA-damage response. This allowed the team to narrow in on the most promising genes: APEX2 and FEN1, two novel targets for breast cancer.

The results were published in Molecular Cell.

Immunotherapy treatment could reduce the persistence of HIV in patients receiving triple therapy, found a group of researchers.

The researchers, from the University of Montreal Hospital Research Centre, discovered that these therapies expose the virus to the immune system. Three proteins PD-1, LAG-3 and TIGIT were uncovered by the scientists as frequently expressed on the surface of HIV-hiding cells; these proteins are also cancer targets.

According to the team, their study could lead to the development of new HIV therapies based on cancer immunotherapies.

The study was published in Nature Communications.

Researchers at the Indiana University School of Medicine developed a blood test to measure pain and improve diagnosis. The team analysed hundreds of patient samples to reveal biomarkers in their blood, which could be used as a scale to determine pain.

According to the researchers, the biomarkers act like a signature that can be matched against a prescription database. This could allow medical professionals to select the appropriate compound and reduce pain for the patient.

The study was published in Molecular Psychiatry.

A team of scientists revealed that immune cells could be key in causing endometriosis, a pelvic pain experienced by women, through an investigation into macrophages. The study was led by researchers from Warwick Medical School and the University of Warwick.

Macrophages can adapt their function according to local signals from their surroundings and so become modified by disease. This led the researchers to add modified macrophages to a cell culture, which resulted in the production of higher levels of insulin-like growth factor-1 (IGF-1).

The team conclude that macrophages therefore present a drug target for endometriosis.

The results can be found in The FASEB Journal.

Scientists from the University of Pennsylvania imaged a molecule that induces inflammation and leads to lupus, in our fifth most popular story of 2019. The researchers discovered that the molecule is comprised of two sections: SHMT2 and BRISC, a cluster of proteins. When these two sections bind to each other, they cause inflammation.

When mice models lacking BRISC were tested, they were resistant to lupus. This led the team to conclude that a molecule which blocks BRISC and SHMT2 could be a drug target for lupus.

The findings were published in Nature.

A team of researchers reported that a CRISPR-Cas9 gene therapy which specifically reduces fat tissue and obesity-related metabolic disease was successful in mice.

The scientists, from Hanyang University, argue that their technique could be used as a way to combat type 2 diabetes and other obesity-related diseases.

Targeting Fabp4, a fatty acid metabolism gene, the researchers observed a 20 percent reduction of body weight in obese mice. It also resulted in improved insulin resistance after only six weeks of treatment.

The findings were published in Genome Research.

A compound that promotes the rebuilding of the protective sheath around nerve cells has been developed by researchers at the Oregon Health & Science University (OHSU).

The team found that the S3 compound reverses the effect of hyaluronic acid (HA) in mice. HA has been found to accumulate in the brain of patients with multiple sclerosis, and accumulation of HA

has also been linked to maturity failure of cells called oligodendrocytes, which generate myelin, the protective layer of axons.

The team therefore believe that the S3 compound could provide a therapeutic strategy for treating nervous system disorders.

The study can be found in Glia.

A group of researchers formed a complex view of the functional dysbiosis in the gut microbiome during inflammatory bowel disease (IBD), to reveal new targets for treatments.

The scientists, from theBroad InstituteofMITandHarvard University, observed microbial changes and human gene regulatory shifts from stool and blood samples of patients.

This multi-omic study enabled the team to discover that during periods of disease activity, IBD patients had higher levels of polyunsaturated fatty acids in both the blood and stool. They also identified other varying levels of nutrients and vitamins, presenting several potential drug targets.

The findings were published in Nature.

In our most popular news piece this year, researchers found that the small molecule PJ34 reduces the number of human pancreatic cancer cells in transplanted tumours by 90 percent.

The team, from Tel Aviv University, built on previous research to treat xenografts with their small molecule. It is permeable in the cell membrane, but affects human cancer cells exclusively, making it an attractive compound for development.

The scientists found that PJ34 causes a rapid cell death and in one mouse, the tumour completely disappeared. They concluded that the molecule could be a potent therapeutic against pancreatic cancer.

The results were published in Oncotarget.

Related organisationsBrigham and Women's Hospital, Hanyang University, Harvard University, Indiana University School of Medicine, Massachusetts General Hospital (MGH), MIT, Oregon Health & Science University (OHSU), Pennsylvania University, Tel Aviv University, University of Montreal Hospital Research Centre, Warwick Medical School, Warwick University

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DTR's news round-up 2019: the stories that defined the year - Drug Target Review

In preclinical experiments, a metabolic inhibitor killed a variety of human cancer cells of the skin, breast, lung, cervix and soft tissues.

In preclinical experiments, a metabolic inhibitor killed a variety of human cancer cells of the skin, breast, lung, cervix and soft tissues.In laboratory experiments, a metabolic inhibitor was able to kill a variety of human cancer cells of the skin, breast, lung, cervix and soft tissues through a non-apoptotic route catastrophic macropinocytosis.

In mouse xenograft studies, the inhibitor acted synergistically with a common chemotherapy drug, cyclophosphamide, to reduce tumor growth. Thus macropinocytosis, a rarely described form of cell death, may aid in the treatment of cancer.

Understanding the signaling pathways underlying macropinocytosis-associated cell death is an important step in developing additional effective strategies to treat neoplasms that are resistant to apoptosis induced by chemotherapy, said Mohammad Athar, Ph.D., professor in the University of Alabama at Birmingham Department of Dermatology.

The inhibitor, OSI-027, affects the mTOR pathway, which plays a critical role in regulation cellular growth and metabolism. Significantly, this potent inhibitor simultaneously targets two distinct protein complexes of the mTOR pathway, mTORC1 and mTORC2. Aberrant activation of these components has been associated with many cancer types.

Macropinocytosis starts with formation of ruffles on the surface of a cell that reach out from the cell membrane. These ruffles then fuse back with the cell membrane, creating a bubble that holds extracellular fluid, and the bubble moves inside the cell to become a vacuole filled with fluid. In catastrophic micropinocytosis, large numbers of these vacuoles form inside the cell and then fuse together, causing cell death.

The UAB researchers showed that dual inhibition of the two mTORC1 and -C2 complexes was necessary for highly effective cell death through macropinocytosis.

In early experiments, the researchers found that OSI-027, and a related dual inhibitor, PP242, induced extensive vacuolization in a wide range of human cancer cell lines, including two subtypes of rhabdomyosarcoma. These vacuoles were then shown to be macropinosomes.

Xenograft mouse experiments with human rhabdomyosarcoma tumors showed that OSI-027 blocked tumor growth by inducing macropinocytosis; furthermore, the addition of the chemotherapy agent cyclophosphamide acted synergistically to enhance efficacy of tumor size reduction.

Mohammad Athar, Ph.D.In mechanistic studies, Athar and colleagues found that macropinocytosis depended on activation of the MAP kinase MKK4, which was induced by the presence of reactive oxygen species. However, the full role of MKK4 is not well understood, they say.

Previous work by others had shown that several specific inducers of macropinocytosis induced macropinocytosis mainly in glioblastomas and colorectal cells. In contrast, Athar said, our study demonstrates that the dual inhibitors we tested induce catastrophic vacuolization in tumor cell lines from a wide range of organs, including skin, breast, cervix, lung and soft tissues.

The effects were much less pronounced in immortalized human keratinocytes.

Our data reveal that therapeutic targeting of mTORC1 and mTORC2, together with standard care treatment, Athar said, may be an effective approach to block the pathogenesis of recurrent rhabdomyosarcoma and perhaps other drug-resistant invasive neoplasms of diverse tissue types as well. The underlying mechanism by which tumors become responsive to treatment involves macropinocytosis, a unique form of cell death.

Co-authors with Athar of the study, Combined mTORC1/mTORC2 inhibition blocks growth and induces catastrophic macropinocytosis in cancer cells, published Proceedings of the National Academy of Sciences, are Ritesh K. Srivastava, Changzhao Li and Jasim Khan, UAB Department of Dermatology; and Louise T. Chow and Nilam Sanjib Banerjee, UAB Department of Biochemistry and Molecular Genetics.

Support came from National Institutes of Health grant ES026219 and funds from the Anderson Family Endowed Chair through UAB.

At UAB, Athar holds the Eric W. Baum, M.D., Endowed Professorship in Dermatology, and Chow holds the Anderson Family Chair in Medical Education, Research and Patient Care in the School of Medicine. Both are senior scientists in the ONeal Comprehensive Cancer Center at UAB.

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Cancer therapy may be aided by induced macropinocytosis, a rarely reported form of cell death - The Mix

Christian Dye

A graduate student in the University of Hawaii at Mnoa John A. Burns School of Medicine (JABSOM) is conducting research that may have a significant impact on underserved and vulnerable populations. Christian Dye is probing the causes of diabetes and other chronic diseases prevalent in Native Hawaiian and other communities.

Dye, currently a faculty member at JABSOM, will earn his PhD from UH Mnoa in spring 2020.

My current research seeks to understand inflammation-associated disorders, like diabetes, from an epigenetics viewpointthe influence of environmental factors (diet, exercise, smoking, etc.) on how our cells function by influencing how genes are turned on, off, or even changed, he explained.

JABSOM has allowed me to be at the center of research that is not only meaningful, but was instrumental in allowing me to do so in the communities that I feel most passionate about, Native Hawaiians and Pacific Islanders, Dye said.

Dye focuses on epigenetics to determine the potential mechanisms underlying disease pathogenesis. We may be able to understand whether certain areas of the genome are epigenetically regulated and if such regulation may be involved in how immune cells function and whether this leads to immune dysfunction or inflammation.

Exciting results of Dyes research include the benefits of an intervention in Native Hawaiians with diabetes, which led to drastic changes in epigenetic profiles. The epigenetic alterations were linked to changes in gene expression and immune cell function (reduced inflammation) that were associated with better glycemic control. These findings have potentially bridged cell function and beneficial health outcomes with epigenetic modifications that may regulate genes enriched in biological functions important to immune cells, he said.

Dye plans to develop a network of community-based participatory research centers for investigation of cellular, molecular or biological mechanisms that may underlie the benefits of culturally-based practices and interventions. By bridging indigenous knowledge and practice within a western context of science, technology and medicine, we may be able to understand the science as to why these practices are beneficial to at-risk communities while also elucidating how certain cells, like immune cells, may function, and the potential that their regulation may be involved in beneficial health outcomes which can eventually be used in targeted strategies for understanding disease risk and possible therapeutics.

Dyes interest in the cellular and molecular biology of health disparities motivated him to work at the UH medical school. JABSOM has allowed me to be at the center of research that is not only meaningful, but was instrumental in allowing me to do so in the communities that I feel most passionate about, Native Hawaiians and Pacific Islanders, he said. JABSOM also allowed me to enter some of the communities where these health disparities are prevalent and use research to help understand them.

Read more on the JABSOM website.

The rest is here:
Native Hawaiian health focus of graduating JABSOM PhD - UH System Current News

The doctors said that shed not live till her birthday when Adrienne Shapiros kid Marissa was diagnosed with sickle cell disease. When Marissa managed to live past that standard, it didnt mean the end of the worries of Adrienne. It was the start of several years of disorders and blood transfusions. When a reaction resulting in the removal of kidney failure and Marissas gall urinary bladder was caused by a matched blood transfusion, she was unable to receive blood transfusions.

Nevertheless, a project headed by Don Kohn started a clinical trial. The aim of this project was to remove bone marrow and fix the flaw that is genetic in the blood. Those cells could be reintroduced to the patient to create a brand new. he trials success has given hope to Adrienne that using assistance from regenerative medicine her kid will be able to lead a healthful and pain-free life. The Stem Cell Regenerative Medicine Center at the University of Wisconsin Madison clarifies Regenerative Medicine as a brand-new medical and scientific field focused on harnessing the power of the bodys own regenerative capacities and stem cells to restore function. stem cells that are found in the cord blood of new children that are born have the ability.

A stem cell, throughout this process of mitosis, could divide itself to either become a specialized cell like a brain cell or muscle cell or remain a stem cell. Theyre also able to repair internal harm caused by any type of disease, disorder or trauma. Stem cell transplantation, stem cell grafting and also regenerative medicine are a number of the ways wherein these cells are utilized to cure disorders and illnesses. Regenerative medicine includes a broad range of scientific disciplines, like biochemistry, genetics, molecular biology and immunology. Scientists from all of these fields have been conducting research and also studies in the area and have identified 3 methods of using regenerative medicine.

Theyre cellular therapies, tissue engineering, and scientific devices and artificial organs. In the method, cellular materials, in most cases adult stem cells, are extracted and also stored and also after that injected into the site of injury, damage to the tissues or disease. These cells, thereafter, repair these damaged cells or regenerate new cells to replace these damaged ones. This method is directly related to this field of biomaterials development and uses a combination of functioning tissues, cells, and scaffolds to engineer a fully working organ which is then implanted in this body of this receiver in place of a damaged organ or tissue.

Read more from the original source:
Regenerative Medicine is way to New Life in Future - News Cast Report

A mechanism has been revealed that could be used to deny RAS mutant tumour cells (which is known to encourage the growth seen in pancreatic cancer patients) of a key survival mechanism.

A mechanism has been revealed by scientists that helps pancreatic cancer cells avoid starvation within dense tumours by hijacking a process that pulls nutrients in from their surroundings.

The study explains how changes in the gene RAS (which is known to encourage the abnormal growth seen in 90 percent of pancreatic cancer patients) also accelerate a process that supplies the building blocks required for that growth. Called macropinocytosis, the process engulfs proteins and fats, which can be broken down into amino acids and metabolites used to build new proteins, DNA strands and cell membranes. Cancer cells cannot multiply without these resources on hand, say the study authors.

The new study, led by researchers at NYU Grossman School of Medicine, US, identifies the key molecular steps that are marshalled by the cancer cells to boost micropinocytosis.

We found a mechanism related to nutrient supply that we believe could be used to deny RAS mutant tumour cells of a key survival mechanism, said first study author Craig Ramirez, PhD, a postdoctoral fellow in the Department of Biochemistry and Molecular Pharmacology at NYU School of Medicine.

Specifically, the research team found that RAS mutations further activate the protein SLC4A7, which enables the protein called bicarbonate-dependent soluble adenylate cyclase to activate the enzyme protein kinase A. This, in turn, was found to change the location of a protein called v-ATPase.

By shifting where v-ATPase operates from the depths of cells to areas near their outer membranes, the reaction positions the enzyme to deliver the cholesterol needed by RAC1 to attach to cell membranes, the researchers say. Build-up of v-ATPase near outer membranes, and the related positioning of Rac1, enable membranes to temporarily bulge, roll over on themselves and form nutrient-engulfing pockets (vesicles) during macropinocytosis.

In cell culture studies, treatment of mutant RAS cells with the SLC4 family inhibitor S0859 led to a significant reduction in RAS-dependent v-ATPase localisation to outer membranes, as well as to the inhibition of micropinocytosis.

the research team found that RAS mutations further activate the protein SLC4A7

Furthermore, analysis of molecular data from human pancreatic ductal adenocarcinoma (PDAC) tissue revealed that the gene for SLC4A7 is expressed four-fold higher in tumours than in normal nearby pancreatic tissue.

The scientists also showed that silencing the gene for SLC4A7 in pancreatic cancer cells slowed down or shrunk tumours in mice.

We are now searching for drug candidates that might inhibit the action of SLC4A7 or v-ATPase as potential future treatments that block macropinocytosis, added study senior author Dafna Bar-Sagi, PhD, Senior Vice President, Vice Dean for Science and Chief Scientific Officer at NYU Langone Health. Both of these proteins are in principle good targets because theyre linked to cancer growth and operate near the cancer cell surfaces, where a drug delivered through the bloodstream could reach them.

The study was published in Nature.

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Mechanism revealed which help pancreatic cancer cells avert starvation - Drug Target Review

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Rheos Medicines, a biopharmaceutical company harnessing insights in immunometabolism to create a new class of therapeutics for patients with severe autoimmune disorders, inflammatory diseases and cancer, today announced the online publication of a perspective in Cell Metabolism that highlights the rationale and potential of employing principles of immunometabolism to discover and develop novel medicines. The article, entitled The Untapped Opportunity and Challenge of Immunometabolism: A New Paradigm for Drug Discovery, was published online today in Cell Metabolism (DOI: 10.1016/j.cmet.2019.11.014).

Immune cells modulate their energy requirements in response to changes in their environment, which include interactions with pathogens, tumor cells, other immune system cells and molecules such as growth factors and antibodies. The metabolic programs that are induced or inhibited as immune cells respond to such stimuli can drive immune cell activation, differentiation, or suppression. Understanding the mechanisms through which metabolism can dictate the function or fate of immune cells is a new platform for target and biomarker discovery with a goal of identifying new medicines with potential to selectively tune the immune system to amplify or dampen its response. The perspective reviewed the underlying biology of immunometabolism and the new tools to discover and develop novel therapeutics based on this paradigm.

"To exploit this new field of immunometabolism, we have developed and industrialized a platform that comprehensively elucidates the metabolic pathways and targets with potential to control immune cell fate or function, as well as their associated metabolite biomarkers, said Laurence Turka, M.D., Chief Scientific Officer and co-founder of Rheos. Our approach employs a proprietary integration of metabolomic, transcriptomic, and other data to generate immunometabolism network maps (imMAPs) that characterize immune cell activation and differentiation through a metabolic lens. Our imMAPs have potential to tap currently undiscovered or poorly understood biology and enable development of new therapeutics for a wide range of diseases including autoimmunity and cancer.

Barbara Fox, Ph.D., Chief Executive Officer of Rheos, added, Immunometabolism has the potential to be the next frontier in drug discovery. Our pioneering product engine has the breadth and power to identify novel metabolic targets across a diverse set of pathways, better understand the metabolic impact of existing therapies and bring the benefits of personalized medicine to autoimmunity. Based on our work to-date, we have initiated drug discovery efforts in a number of programs and we look forward to providing further updates as we continue to make progress.

About Rheos Medicines

Rheos Medicines is a biopharmaceutical company harnessing insights in immunometabolism to develop novel therapeutics for patients with severe autoimmune disorders, inflammatory diseases and cancer. Our approach targets the underlying intracellular metabolism of immune cells and has the potential to unlock a new frontier in drug discovery for immune-mediated disease. Through a proprietary platform and product engine that integrates multiple omic datasets, we systematically define the biologic links between immune cell metabolism and function and simultaneously identify new drug targets and biomarkers of disease to bring precision to the treatment of immune-mediated diseases. We have assembled leading scientists whose discoveries opened the field of immunometabolism, clinicians with a deep understanding of immune-mediated diseases, and an experienced biotech leadership team. Rheos was founded by Third Rock Ventures and is located in Cambridge, MA. For more information, please visit http://www.rheosrx.com.

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Rheos Medicines Announces Publication of Perspective in Cell Metabolism Highlighting the Rationale and Potential of Employing Principles of...

Though the research was intended as a proof of concept, the experimental gene therapy slowed tumour growth and prolonged survival in mice with gliomas, which constitute about 80% of malignant brain tumours in humans.

The technique takes advantage of exosomes, fluid-filled sacs that cells release as a way to communicate with other cells.

The research was carried out by scientists at the Ohio State University and published in the journal Nature Biomedical Engineering.

While exosomes are gaining ground as biologically friendly carriers of therapeutic materials because there are a lot of them and they dont prompt an immune response the trick with gene therapy is finding a way to fit those comparatively large genetic instructions inside their tiny bodies on a scale that will have a therapeutic effect.

This new method relies on patented technology that prompts donated human cells such as adult stem cells to spit out millions of exosomes that, after being collected and purified, function as nanocarriers containing a drug.

When they are injected into the bloodstream, they know exactly where in the body to find their target even if its in the brain.

Senior study author L. James Lee, professor emeritus of chemical and biomolecular engineering at Ohio State University, said: Think of them like Christmas gifts: the gift is inside a wrapped container that is postage paid and ready to go. This is a Mother Nature-induced therapeutic nanoparticle.

In 2017, Lee and colleagues made waves with news of a regenerative medicine discovery called tissue nanotransfection (TNT). The technique uses a nanotechnology-based chip to deliver biological cargo directly into skin, an action that converts adult cells into any cell type of interest for treatment within a patients own body.

By looking further into the mechanism behind TNTs success, scientists in Lees lab discovered that exosomes were the secret to delivering regenerative goods to tissue far below the skins surface.

The scientists placed about one million donated cells on a nano-engineered silicon wafer and used an electrical stimulus to inject synthetic DNA into the donor cells. As a result of this DNA force-feeding, as Lee described it, the cells need to eject unwanted material as part of DNA transcribed messenger RNA and repair holes that have been poked in their membranes.

The electrical stimulation had a bonus effect of a thousand-fold increase of therapeutic genes in a large number of exosomes released by the cells, a sign that the technology is scalable to produce enough nanoparticles for use in humans.

Essential to any gene therapy is knowing what genes need to be delivered to fix a medical problem. For this work, the researchers chose to test the results on glioma brain tumours by delivering a gene called PTEN, a cancer-suppressor gene. Mutations of PTEN that turn off that suppression role can allow cancer cells to grow unchecked.

For Lee, founder of Ohio States Center for Affordable Nanoengineering of Polymeric Biomedical Devices, producing the gene is the easy part. The synthetic DNA force-fed to donor cells is copied into a new molecule consisting of messenger RNA, which contains the instructions needed to produce a specific protein. Each exosome bubble containing messenger RNA is transformed into a nanoparticle ready for transport, with no blood-brain barrier to worry about.

The testing in mice showed the labelled exosomes were far more likely to travel to the brain tumours and slow their growth compared to substances used as controls.

Because of exosomes safe access to the brain, Lee said, this drug-delivery system has promise for future applications in neurological diseases such as Alzheimers and Parkinsons disease.

Excerpt from:
Mother Nature provides new gene therapy strategy to reverse disease - Health Europa

Chaojia Wang,1 Shulan Huang,2 Shanshan Rao,1 Juntao Hu,1 Yuqiang Zhang,1 Jie Luo,1 Hui Wang1

1Department of Neurology, Taihe Affiliated Hospital, Hubei University of Medicine, Shiyan 442000, Peoples Republic of China; 2Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, Peoples Republic of China

Correspondence: Hui WangDepartment of Neurology, Taihe Hospital Affiliated to Hubei University of Medicine, No. 32 South Renmin Road, Shiyan 442000, Peoples Republic of ChinaTel +86 719 880 1712Email hwang0915@163.com

Background: Gliomas are the most common type of primary tumors in the central nervous system. This study aimed to investigate the biological role of miR-410-3p in glioma and elucidate the potential molecular mechanisms involved.Methods: The expression levels of miR-410-3p in clinical tissue samples and glioma cell lines were determined using qRT-PCR analysis. The clinical significance of miR-410-3p in glioma was evaluated using Kaplan-Meier survival analysis and Fishers exact test. The effects of miR-410-3p on glioma cell proliferation, apoptosis, migration and invasion were investigated using MTT assays, flow cytometry, transwell migration and invasion assays. Besides, corresponding mechanistic studies were carried out.Results: miR-410-3p was significantly down-regulated in glioma tissues. Besides, Kaplan-Meier analysis demonstrated that patients with low miR-410-3p expression had a shorter overall survival. Decreased miR-410-3p expression was associated with larger tumor size, lower Karnofsky performance score (KPS), and higher World Health Organization (WHO) grade. Over-expression of miR-410-3p suppressed cell proliferation, migration, and invasion, and accelerated apoptosis; whereas depletion of miR-410-3p facilitated cell proliferation, migration, and invasion, and inhibited apoptosis. Mechanistic investigations demonstrated that Ras-related protein 1A (RAP1A) was a direct target of miR-410-3p, and that rescue of RAP1A expression reversed miR-410-3p over-expression-induced inhibitory effects on cell proliferation, migration, and invasion. Notably, miR-410-3p over-expression repressed tumor growth in mouse xenograft models.Conclusion: Our findings indicate that miR-410-3p functions as a tumor suppressor in glioma by directly targeting RAP1A. Thus, this study may provide some new insights into gliomagenesis and progression.

Keywords: miR-410-3p, RAP1A, poor prognosis, tumorigenesis, glioma

This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution - Non Commercial (unported, v3.0) License.By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms.

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Decreased expression of miR-410-3p correlates with poor prognosis and | CMAR - Dove Medical Press

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The first girl in the trial came in with chronic diarrhea and the immune system of an untreated HIV patient. Born with a rare genetic disease that impeded her ability to make B and T cells, she had once been given a stem cell transplant but it didnt take. Back in the hospital, she was injected with a new experimental antibody and then given a new stem cell transplant. Soon, she gained weight. The diarrhea stopped.

She has normal T cells now, Judith Shizuru, the Stanford scientist who pioneered the antibody, told Endpoints News. Shes in school.

Its the kind of medical story to launch a biotech around, and thats what Shizuruis doing. Today, her company Jasper Therapeutics is emerging out of stealth-mode with $35 million in Series A funding led by Abingworth and Qiming, a molecule from Amgen, and a Phase I trial set for its first readout on Monday at ASH.

Jasper is broadly aimed at making stem cell transplants safer, more accessible and more effective by using antibodies as conditioning agents. Theseagents clear out bone marrow to make room for the new stem cells to graft onto the body.

Their Phase I uses a naked antibody called JSP191 to help patients with severe combined autoimmune deficiency receive stem cell transplants the only possible cure for the life-threatening disease but such transplants are used in a wide variety of conditions and Jasper has broader aims. Those include other autoimmune diseases, acute myeloid leukemia and cell-directed gene therapy.

Theres a significant amount of progress being made in gene therapy, interim CEO William Lis told Endpoints, but no progress being made in a conditioning agent that will help graft gene therapy.

Shizuru path to the new antibody was long and fortuitous. In 1987, Arl Arzst, the legendary ad executive and president of Proctor and Gamble international flew in on a recruiting trip for Stanford business students. There he visited Shizuru, a young biologyPhD candidate, because he knew her roommate. Arzsts daughter had diabetes and as Shizuru explained the work she was doing on pancreatic islet cell transplants, he told her to come to Europe.

Shizuru had never been to Europe, but there Arszt introduced her to Ken Farber and the other founders of the Juvenile Diabetes Foundation (now the JDRF). The founders struck a years-long correspondence and encouraged Shizuru to go to medical school, where she decided that if scientists were ever going to develop transplants that didnt trigger an immune response, it would be through stem cell work. She continued her work at the Irv Weissman Stanford regenerative lab, where eventually a graduate student made a discovery that piqued her interest.

To put new stem cells in, you have to get the old stem cells out. Thats not always easy. The cells sit inthese pockets in the bone marrow, and theyre pretty comfortable there. Doctors have to force them out, often using chemotherapy or radiation, which damage DNA and cause severe side effects. The costs sometimes outweigh the benefits.

There are diseases were not treating because its too dangerous, Shizuru said. And the kids were treating, theyre so, so fragile.

The grad student had shown in mice that antibodies could be used to deplete the stem cells and potentially eliminate the need for chemotherapy or radiation. Shizuru and her team began looking to see if anyone had developed a human version of the antibody, CD117. It turned out Amgen had already developed a version of this antibody for a different use. It also turned out she had a former postdoc and a former advisor who worked there. They began a collaboration.

We set out to cross the valley of death, Shizuru said, using an industry slang term for the jump from animal models to human uses.

After making a variety of tweaks to the treatment, they published a paper inScience Translational Medicine in 2016showing the antibodies created a 10,000 fold reduction in the number of stem cells in mice.

The same year, they began a clinical trial on 90 SCID patients. These patients had received stem cell transplants when they were very young but hadnt been given chemo or radiation for fear the side effects would be too severe. The original transplants boosted their numberof immune cells, but without chemo or radiation, the stem cells dont graft into those pockets and the body wont continue producing T cells. Without those, they are extraordinarily prone to infection. Many pass away before age 2.

The hope is that the antibodies allowed the stem cells to graft, and the preliminary answer to that question will be out on Monday. For the first girl in the trial, life has improved but questions about how long her body will make immune cells remain. Still, for that girl and others, Shizuru is confident.

We see there is stem cell engraftment, Shurizi said. They are actually making new T cells.

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Jasper Therapeutics launches out of Stanford with new approach to stem cell treatment - Endpoints News