Bacterial nano-syringe injects the toxic protein.

Pathogens can use a range of toxins to damage their host organism. Bacteria, such as those responsible for causing the deadly Plague, use a special injection mechanism to deliver their poisonous contents into the host cell. Stefan Raunser, Director at the Max Planck Institute for Molecular Physiology in Dortmund, together with his team, has already produced a detailed analysis of this toxins sophisticated mechanism. They have now succeeded in replacing the toxin in this nano-syringe with a different substance. This accomplishment creates a basis for their ultimate goal to use bacterial syringes as drug transporters in medicine.

As soon as bacteria have entered a host organism, they deploy their lethal weapon. Just like a syringe needle, they insert a channel through the outer protective layer of the host cell. The toxic protein contained in the capsule is then injected and attacks the cells structural framework. Within just a few minutes, the cell dies.

Raunsers team discovered this lethal mechanism by using cryo-electron microscopy, a technique employed by only a few research groups in the world. What this technique reveals is the three-dimensional structure of proteins in near-atomic resolution.

Targeted injection into body cells

Stefan Raunsers researchers have now found a way to replace the toxin in the bacterias nano-syringe with different proteins, and then inject them into cells. For the exchange to work, however, the proteins must fulfil certain criteria: they must be a particular size, be positively charged, and must not interact with the toxin capsule. With this technique, we have taken the first step towards our ultimate goal of using these nano-syringes in medicine to introduce drugs into body cells in a targeted manner, says Raunser, describing the successful research results.

To transfer its toxic charge into the host cell, the injection mechanism must first dock with the cell. But the bacteria must trick the host cell- by pretending that the toxin is a substance that can be safely absorbed similar to the famous trojan horse trick. To do this, they have areas that are recognized by sensors on the cell surface.

We are currently looking for the toxins docking stations. Once we have found them and understood how the toxin binds to the cell surface, we aim to specifically modify the injection mechanism so that it can recognize cancer cells. We could then inject a killer protein exclusively into tumour cells. This would open up completely new possibilities in cancer medicine with minimal side effects, predicts Raunser.

More here:
Protein Injections in Medicine - Global Health News Wire

XconomyNational

More than 250 miles above the Earths surface aboard the International Space Station, a first-in-kind study of neurodegenerative disease is expected to reveal never-before-seen cell interactions.

The National Stem Cell Foundation (NSCF) is funding the study, which is the result of a bi-coastal collaboration between the New York Stem Cell Foundation (NYSCF) Research Institute and Aspen Neuroscience, a San Diego startup developing personalized cell therapies for Parkinsons disease.

Collaborating with the New York Stem Cell Foundation (NYSCF) Research Institute on the other side of the country, the two teams have been working together for more than two years, exchanging and sharing technology to develop patient-derived, induced pluripotent stem cell (iPSC) organoid models.

The 3D human organoid models were launched to the International Space Station earlier this month for research in microgravity, with the goal of furthering our understanding of neurogenerative diseases back on earth.

The models incorporate microglia, the inflammatory cells of the immune system that are implicated in the development of Parkinsons, multiple sclerosis, and other neurodegenerative diseases, explains Paula Grisanti, CEO of NSCF.

Studying the 3D models in microgravity, researchers are able to observe cell interaction, gene expression, and other developments not seen in a regular lab.

Its not possible for you to have this same 3D model of cell interaction on Earth. This will be the first time in space where we can that in 3D, Grisanti tells Xconomy.

Cells behave differently in space, though its not completely understood why. Cartilage grows faster and bigger, proteins fold differently, and cells mature more rapidly. Being able to see this happen in real-timethe models will be filmed for the full 30 dayswill offer researchers unprecedented insight into neurodegenerative disease.

To see how those cells talk to each other for 30 days when they are up on the international space station will allow scientists to see the point at which things start to go awry in those diseases and hopefully identify a new place or a new point at which you could intervene with a cell or gene therapy that may or may not currently exist, says Grisanti.

The research will touch back down to earth in early January at which time both labs will analyze the models to determine what exactly happened during their time in space. All data will be published for full dissemination.

(Paul Kuehl, Jason Rexroat, Gentry Barnett, Valentina Fossati, Jason Stein, Scott Noggle, Jana Stoudemire. Image courtesy of Space Tango)

NSCF has budgeted for a year of post-flight research after which the researchers will send the models back to the space station for a second flight to confirm what they saw and test new hypotheses, explains Grisanti. A second year of post-flight research also is funded, as is a second flight at the end of 2020.

We know were going to see something new because it has never been done before, says Grisanti, who explains that the budget and project will continue to be extended as long as new theories and opportunities are being developed.

The December flight was the second for the research teams at Apsen and NYSCF. A preliminary flight was conducted in July 2019 to test the hardware systems and prepare for the SpaceX CRS-19 launch.

Aspen has also been pressing ahead with its own research on solid ground. Last week, the company closed a $6.5 million seed round led by Domain Associates and Axon Ventures.

Aspens cell therapy approach was developed by its co-founders, Jeanne Loring, professor emeritus and founding director of the Center for Regenerative Medicine at The Scripps Research Institute and Andres Bratt-Leal, a former post-doctoral researcher in Lorings lab. Also serving as Aspens chief scientific officer, Jeanne Loring was in May named Xconomys Stem Cell Pioneer of the Year.

(Main image: Experiment loaded for launch at Kennedy Space Center. Courtesy of Space Tango)

Melissa Fassbender is an Xconomy editor based in Chicago. You can reach her at mfassbender@xconomy.com.

View post:
Orbiting Organoids: Research in Space to Unveil New Neurodegeneration Insight - Xconomy

CAMBRIDGE, Mass.--(BUSINESS WIRE)--Ribon Therapeutics, a clinical stage biotechnology company developing first-in-class therapeutics targeting novel enzyme families activated under cellular stress conditions, today announced the appointment of Neal Rosen, M.D., Ph.D., to its scientific advisory board (SAB). Dr. Rosen is a Member of the Molecular Pharmacology Program and the Department of Medicine at Memorial Sloan Kettering Cancer Center (MSK).

Neals experience identifying and elucidating new molecular signaling pathways and understanding how to transform these early discoveries into effective drug development strategies fits perfectly with the work were undertaking at Ribon, said Victoria Richon, Ph.D., President and Chief Executive Officer, Ribon Therapeutics. We see great untapped potential for the development of novel, first-in-class therapeutics that target the novel stress response pathways that many cancers rely on for survival, and working with experts such as Neal, who have successfully forged new paths in drug development will be invaluable.

Targeting stress response pathways to treat cancer has great potential, and shares similarities with the discovery and therapeutic targeting of kinase pathways, an area I have spent much of my career working to better understand and advance, commented Dr. Rosen. It is now understood that stress response pathways play a wide range of roles aiding cancer development and growth. I look forward to working with this truly pioneering team.

Ribon has done tremendous work taking its foundational discoveries and translating them into development programs, as evidenced by how quickly the Company was able to advance their lead program, RBN-2397, into the clinic, said Jim Audia, Ph.D., Chairman of the Ribon SAB. At this point in the Company's development, Neal is a fantastic addition to Ribons already stellar SAB, bringing his vast experience in the development and understanding of novel cancer targets and therapeutics to Ribon's developing pipeline.

Dr. Rosen's major interests involve identification and study of the key molecular events and growth signaling pathways responsible for the development of human cancers, and the use of this information for the development of mechanism-based therapeutic strategies. Dr. Rosen has pioneered the concepts that feedback inhibition of physiologic signaling is an important consequence of oncogene activation that shapes the phenotype of cancer cells and that relief of this feedback in tumors treated with inhibitors of oncoprotein-activated signaling causes adaptive resistance to these drugs. Recent work from the Rosen laboratory includes the elucidation of the underlying mechanisms whereby mutated BRAF genes cause cancer and the discovery that these mutations may be divided into three different classes that determine the effective strategies for their treatment. These studies predicted several of the cellular mechanisms whereby tumors develop acquired resistance and adaptive resistance to standard therapy and the discovery and development of new drugs that will reverse this resistance. Recently, the Rosen laboratory has also focused on the development of the first direct inhibitor of RAS, a gene involved in the development of 25% of human cancers. This work, in addition to other recent studies by the Rosen laboratory on the consequences of relief of negative feedback by oncoprotein inhibitors, has led to multiple clinical trials of combination therapies at Memorial Sloan Kettering and other cancer centers in the United States and internationally that have shown promising early results. He is the incumbent of the Enid A. Haupt Chair in Medical Oncology at MSK and the recipient of the Lifetime Achievement Award from the Society for Melanoma Research.

Dr. Rosen received his undergraduate degree in chemistry from Columbia College and an M.D. and Ph.D. in Molecular Biology from the Albert Einstein College of Medicine. He completed a residency in Internal Medicine at the Brigham and Womens Hospital, and postdoctoral training and a fellowship in Medical Oncology at the National Cancer Institute. He was on the senior staff of the Medicine Branch at the NCI prior to joining the faculty of MSK.

RBN-2397 Inhibiting PARP7, a Key MonoPARP Cancer Dependency

Ribons lead program, RBN-2397, is focused on inhibiting overactive PARP7 in tumors, which has been shown to play a key role in cancer survival. Ribons research has discovered that many cancer cells rely on PARP7 for intrinsic cell survival, and that PARP7 allows cancer cells to hide from the immune system. Ribon has demonstrated that inhibition of PARP7 with RBN-2397 can potently inhibit the growth of cancer cells and restore interferon signaling, effectively releasing the brake cancer uses to hide from the immune system and suppress both innate and adaptive immune mechanisms. In several cancer models, RBN-2397 demonstrated durable tumor growth inhibition, potent antiproliferative activity and restoration of interferon signaling. Ribon plans to initially develop RBN-2397 in squamous cell carcinoma of the lung, where research has shown PARP7 to be genetically amplified. The company also plans to explore RBN-2397 for the treatment of additional cancers, including cancers of the aerodigestive tract, pancreatic cancer and ovarian cancer.

PARP7 is a member of the monoPARP family of proteins, which are key regulators of stress responses that enable cancer cells to survive and also evade immune detection, and emerging science has linked their activity with disease development. MonoPARPs are a family of 12 enzymes that are functionally and structurally distinct from the more well-known polyPARPs, such as PARP1/2. MonoPARPs function across a variety of stress responses relevant to disease development in cancer, inflammatory conditions and neurodegenerative diseases. Ribon has built an integrated technology platform to interrogate monoPARPs to develop first-in-class, small molecule therapeutics.

About Ribon Therapeutics

Ribon Therapeutics is a biotechnology company developing first-in-class therapeutics targeting novel enzyme families activated under cellular stress conditions that contribute to disease. We are exploring novel areas of biology to develop effective treatments for patients with limited therapeutic options. Leveraging a chemical biology approach and our proprietary discovery platform, we are building a pipeline of selective, small molecule inhibitors to numerous NAD+ utilizing enzymes, beginning with monoPARPs, which have applications across multiple therapeutic areas. Our lead program is RBN-2397, a first-in-class PARP7 inhibitor in development for the treatment of cancer. Ribon is located in Cambridge, Massachusetts. For more information, please visit http://www.ribontx.com.

Read more from the original source:
Ribon Therapeutics Strengthens Scientific Advisory Board with Appointment of Neal Rosen, M.D., Ph.D. - Business Wire

UC San Diego School of Medicine researchers developed a mathematical equation to predict when healthy liver cells become cancerous before tumors are visible in a standard clinical setting.

By combining RNA sequencing, bioinformatics and mathematical modeling, University of California San Diego School of Medicine and Moores Cancer Center researchers identified a sudden transcriptomic switch that turns healthy liver tissue cancerous. The finding was used to develop a quantitative analytical tool that assesses cancer risk in patients with chronic liver disease and to predict tumor stages and prognosis for patients with liver cancer.

In the December 16, 2019 online edition of the Proceedings of the National Academy of Science (PNAS), Gen-Sheng Feng, PhD, professor of in the Department of Pathology and Section of Molecular Biology, Division of Biological Sciences at UC San Diego, and team describe developing a tumorigenic index score that identifies a shift from healthy to malignant cells.

Because we do not have an effective drug to treat liver cancer in its late stages, early detection of liver cancer, when a tumor is less than 10 millimeters, allows oncologists to better treat, surgically remove and kill cancer cells, said Feng, senior author on the paper. For the first time, we have a mathematical equation that can predict when healthy liver cells become cancerous and, importantly, we are able to detect cancer cells before tumors are visible in a standard clinical setting.

The new analytical tool focused on the analysis of transcription factor clusters. Transcription factors are proteins that bind to specific DNA sequences in order to direct which genes should be turned on or off in a cell. By quantitatively measuring changes in transcription factors together with downstream target genes as a unit (transcription factor clusters), the research group interrogated RNA-sequencing data collected in the pre-cancer and cancer stages of mouse models with different forms of liver cancer and chronic liver diseases like steatosis, fibrosis and cirrhosis.

The analysis found 61 transcription factor clusters that were either up- or down-regulated in mice with cancer, even identifying transcription factors that have not been previously reported in liver cancer.

Gaowei Wang, PhD, a computational biologist and postdoctoral fellow in Fengs lab, helped design a comprehensive analysis of a liver cell transcriptome the entire collection of RNA sequences in a cell. This allowed the team to compare expression of transcription factor clusters in healthy livers and those with chronic liver diseases at various stages to identify when cells became cancerous in mice.

After developing the math model using mouse data, researchers applied the analytical tool to a public database to re-analyze human patient data and were able to identify which people had cancer and which had chronic liver disease. In patients with cirrhosis, who are at high risk of developing cancer, they could see a positive tumor index score and in some cases tumor nodules that were not yet visible in the clinic.

This mathematical approach can be developed into a risk assessment and early diagnostic tool of liver cancer development for a larger population of people living with chronic liver disease, particularly those with cirrhosis, said Feng. The analysis of individuals at high risk may have an important application in precision medicine. And, with further development and optimization, this tool might be modified to predict the development of other cancers.

According to the American Cancer Society, more than 700,000 new cases of liver cancer are diagnosed globally and 600,000 deaths occur each year, making it among the leading causes of cancer death in the world. In 2019, an estimated 42,000 new cases of liver cancer will be diagnosed and 31,000 people will die in the United States alone.

Further testing is needed before it can be used in a clinical setting. The next step is to analyze liver biopsies, with the ultimate goal of using blood samples to predict risk and stage liver cancer, said Feng.

Co-authors include: Xiaolin Luo, Yan Liang, Kota Kaneko, Hairi Li and Xiang-Dong Fu, all from UC San Diego.

Funding for this research came, in part, from the National Institutes of Health (R01CA188506, R01CA176012).

Read this article:
Math Equation Predicts and Detects Liver Cancer - UC San Diego Health

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

Go here to see the original:
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.

Read the original here:
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.

See more here:
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.

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