The buildup of scar tissue makes recovery from torn rotator cuffs, jumpers knee, and other tendon injuries a painful, challenging process, often leading to secondary tendon ruptures. New research led by Carnegies Chen-Ming Fan and published inNature Cell Biologyreveals the existence of tendon stem cells that could potentially be harnessed to improve tendon healing and even to avoid surgery.

Tendons are connective tissue that tether our muscles to our bones, Fan explained. They improve our stability and facilitate the transfer of force that allows us to move. But they are also particularly susceptible to injury and damage.

Unfortunately, once tendons are injured, they rarely fully recover, which can result in limited mobility and require long-term pain management or even surgery. The culprit is fibrous scars, which disrupt the tissue structure of the tendon.

Working with Carnegies Tyler Harvey and Sara Flamenco, Fan revealed all of the cell types present in the Patellar tendon, found below the kneecap, including previously undefined tendon stem cells.

Because tendon injuries rarely heal completely, it was thought that tendon stem cells might not exist, said lead author Harvey. Many searched for them to no avail, but our work defined them for the first time.

Stem cells are blank cells associated with nearly every type of tissue, which have not fully differentiated into a specific functionality. They can also self-renew, creating a pool from which newly differentiated cell types can form to support a specific tissues function. For example, muscle stem cells can differentiate into muscle cells. But until now, stem cells for the tendon were unknown.

Surprisingly, the teams research showed that both fibrous scar tissue cells and tendon stem cells originate in the same spacethe protective cells that surround a tendon. Whats more, these tendon stem cells are part of a competitive system with precursors of fibrous scars, which explains why tendon healing is such a challenge.

The team demonstrated that both tendon stem cells and scar tissue precursor cells are stimulated into action by a protein called platelet-derived growth factor-A. When tendon stem cells are altered so that they dont respond to this growth factor, then only scar tissue and no new tendon cells form after an injury.

Tendon stem cells exist, but they must outcompete the scar tissue precursors in order to prevent the formation of difficult, fibrous scars, Fan explained. Finding a therapeutic way to block the scar-forming cells and enhance the tendon stem cells could be a game-changer when it comes to treating tendon injuries.

Reference: Harvey, Flamenco and Fan. 2019.A Tppp3+Pdgfra+ tendon stem cell population contributes to regeneration and reveals a shared role for PDGF signalling in regeneration and fibrosis. Nature Cell Biology.DOI: https://doi.org/10.1038/s41556-019-0417-z.

This article has been republished from the following materials. Note: material may have been edited for length and content. For further information, please contact the cited source.

Read the original post:
Revolutionizing Injury Recovery With Tendon Stem Cells - Technology Networks

GammaDelta Therapeutics is a company that focusses on utilizing the unique properties of gamma delta () T cells to develop novel immunotherapies for patients.Through their research, the companys scientists have discovered a number of targets and antibodies that have the potential to modulate the activity of T-cells in situ. Therefore, GammaDelta Therapeutics recently announced the formation of Adaptate Biotherapeutics, a spin-out company that will focus on research in this area.

Technology Networks spoke with Natalie Mount, CEO of Adaptate BioTherapeutics, to learn more about the company's aims and the challenges faced when developing immunotherapies and advancing them into clinical studies.

Molly Campbell (MC) Please can you tell us more about T-cell based cell therapy products and their potential applications?Natalie Mount (NM): T cells play an increasingly appreciated critical role in immune surveillance, being able to recognize malignant/transformed cells through a pattern of stress markers. The recognition mechanism is not major histocompatibility complex (MHC) restricted and not dependent on a single antigen.

T cells therefore have potential in a range of disease indications, including both hematological and solid malignancies and a positive correlation between T cell infiltration and prognosis/survival in patients has been determined in a range of oncology indications in studies published in the literature by other groups. Additionally, as a cell therapy, T cells can be used in an allogeneic setting (ie, T cells can be used for unrelated recipients without a requirement for matching).

Both Adaptate Biotherapeutics and GammaDelta Therapeutics are focussed on harnessing the potential of T cells, in particular the V1 subtype which is the predominant T cell type in tissue.This is based on data originating from the labs of Professor Adrian Hayday of Kings College London and the Crick Institute, supported by Cancer Research Technology and also from Professor Bruno Silva Santos of Institute for Molecular Medicine at the University of Lisbon, Portugal.

Previous clinical trials conducted by other groups/companies targeting or using T cells in cancer have focussed on the V2 subtype which is predominant in the blood. These trials have demonstrated safety, but efficacy has been limited.Compared to V2 cells, V1 cells, which are the focus of work at Adaptate Biotherapeutics and GammaDelta Therapeutics, are less susceptible to exhaustion and activation induced cell death. Expansion of donor derived V1 has been shown to be a positive prognostic indicator for acute myeloid leukemia patients following hematopoietic stem cell transplant.

MC: Why are current immunotherapy treatment approaches limited?NM: Immunotherapy approaches have had very significant success and impact in Oncology recently, however, challenges and unmet needs remain.One challenge is effective treatment of solid tumors. The hypoxic, low nutrient tumor environment provides a challenge for successful infiltration and activation of T cells. However, V1 T cells have real potential as they are naturally tissue resident and hence primed for this environment. In addition, their ability to recognize malignant cells by a pattern of markers expressed by dysregulated, transformed cells rather than one specific antigen presented by the MHC provides an additional advantage for both specificity of response and maintenance of efficacy.

T cells act as orchestrators of an immune response and, following recognition of a cell as malignant, they induce maturation of monocytes and signal to alpha beta T cells, hence increasing immunogenicity of the tumor and providing a sustained response, with potential even in tumors with low mutational load which have proven challenging with other immunotherapies.

MC: The new spin-out company, Adaptate Biotherapeutics, will build on GammaDelta's knowledge to modulate T-cell activity using therapeutic antibodies. Why have you decided to create a spin-out focusing on this area of research?NM: GammaDelta Therapeutics was formed in 2016 to harness the unique properties of T cells, and since then has gained extensive knowledge of T-cell biology. In addition to gaining insight into cell growth and isolation, the companys scientists have also discovered a number of targets and antibodies that have potential to modulate the activity of T-cells in situ.

GammaDelta Therapeutics now has a pipeline of cell therapy products progressing into clinical development under the guidance of CEO, Dr Paolo Paoletti.

Adaptate Biotherapeutics will be developing antibodies which will be administered to cancer patients to modulate activity of the patient's gamma delta T cells in situ.

Delivery of cell therapy and antibody therapeutics each needs focus and specific skillsets and formation of two independent entities will facilitate this. The two companies share a common goal to harness the potential of T cells to bring effective therapies to patients. Both benefit from support of the scientific founding team and have common investors, Abingworth and Takeda Pharmaceuticals.MC; Your goal is to develop targets and antibodies that can modulate the activity of T-cells and advance them into clinical studies. What challenges exist here, and how do you hope to overcome them?

Our assets at Adaptate Biotherapeutics are currently at the pre-clinical stage and therefore face the non-clinical development risks for a novel therapy. However, these risks are mitigated by biology understanding from our scientific founders and the work at GammaDelta Therapeutics to date.

One of our challenges is in selecting the most suitable patient population for initial trials. There is potential for opportunity for our therapeutics in multiple indications but the utility of animal models in modelling the human immune compartment and human tumor setting is limited. Therefore in vitro and ex vivo models are important, in addition to the learnings from other clinical studies.

MC: GammaDelta Therapeutics formed in 2016 to gain extensive knowledge of T-cell biology and to developing a portfolio of investigational cell therapies. Some of these cell therapies are poised to enter clinical development. Can you tell us any further information about these therapies?NM: GammaDelta was set up to develop cell-based therapy utilizing ex-vivo expanded tissue resident gd T cells. Subsequent acquisition of Lymphact SAS allowed GammaDelta to augment its capabilities with a platform for ex-vivo expansion of blood derived V1 cells. GammaDelta is focussed on progressing ex-vivo expanded skin and blood derived V1 cells to the clinic both in unengineered and engineered formats. Clinical trials are currently on track to commence in the next 12-18 months.

MC: Your press release states: "The two companies will continue sharing their insights into T-cell biology as they work towards developing different therapeutic modalities". How will you continue to share insights here?NM: Antibodies and cells represent complementary approaches to realizing the potential of T cell activity for patients with solid and haematological malignancies.

The two companies will work together in areas of common interest in the biology of these fascinating cells, such as understanding the phenotype and behavior of T cells in tumors and mechanisms of cell regulation as well as the effects of antibody on the T cells.

We have deliberately established a contractual framework that allows efficient collaboration between scientists of both the companies via formal and informal meetings.

MC: What are your hopes for the future of Adaptate Biotherapeutics?NM: This is a remarkable time in the development of new immune therapies, and the role of "non-conventional" cell types of the immune system is coming to the fore as we recognize the successes achieved to date and the needs of patients and related scientific challenges that remain.

Both GammaDelta Therapeutics and Adaptate Biotherapeutics are at the lead of translating our increasing understanding of T cell biology and its potential into therapies to address these unmet needs.

Adaptate Biotherapeutics has a fantastic opportunity to build and accelerate a portfolio of antibody-based approaches in this novel area and I look forward to the successful translation of this science into therapies with the support of our investors at Abingworth and Takeda Pharmaceuticals.

Dr Natalie Mount, CEO of Adaptate Biotherapeutics was speaking with Molly Campbell, Science Writer, Technology Networks.

The rest is here:
Harnessing Gamma T Cells To Bring Effective Therapies to Patients - Technology Networks

Debilitating tendon injuries may soon be a thing of the past now that researchers have discovered the existence of tendon stem cells for the first time.

The buildup of scar tissue makes recovery from torn rotator cuffs, jumpers knee, and other tendon injuries a painful, challenging process, often leading to secondary tendon ruptures.

New research led by Carnegies Chen-Ming Fan and published in Nature Cell Biology reveals the existence of tendon stem cells that could potentially be harnessed to improve tendon healing and even to avoid surgery.

Tendons are connective tissue that tether our muscles to our bones, Fan explained. They improve our stability and facilitate the transfer of force that allows us to move. But they are also particularly susceptible to injury and damage.

LOOK: Revolutionary New Arm Cast is Waterproof, Breathable, and Itch-Free

Unfortunately, once tendons are injured, they rarely fully recover, which can result in limited mobility and require long-term pain management or even surgery. The culprit is fibrous scars, which disrupt the tissue structure of the tendon.

Working with Carnegies Tyler Harvey and Sara Flamenco, Fan revealed all of the cell types present in the Patellar tendon, found below the kneecap, including previously undefined tendon stem cells.

Because tendon injuries rarely heal completely, it was thought that tendon stem cells might not exist, said lead author Harvey. Many searched for them to no avail, but our work defined them for the first time.

Stem cells are blank cells associated with nearly every type of tissue, which have not fully differentiated into a specific functionality. They can also self-renew, creating a pool from which newly differentiated cell types can form to support a specific tissues function. For example, muscle stem cells can differentiate into muscle cells. But until now, stem cells for the tendon were unknown.

CHECK OUT: Researchers Create AI System That Can Predict Epileptic Seizures One Hour Ahead of Time With 99.6% Accuracy

Surprisingly, the teams research showed that both fibrous scar tissue cells and tendon stem cells originate in the same spacethe protective cells that surround a tendon. Whats more, these tendon stem cells are part of a competitive system with precursors of fibrous scars, which explains why tendon healing is such a challenge.

The team demonstrated that both tendon stem cells and scar tissue precursor cells are stimulated into action by a protein called platelet-derived growth factor-A. When tendon stem cells are altered so that they dont respond to this growth factor, then only scar tissue and no new tendon cells form after an injury.

Tendon stem cells exist, but they must outcompete the scar tissue precursors in order to prevent the formation of difficult, fibrous scars, Fan explained. Finding a therapeutic way to block the scar-forming cells and enhance the tendon stem cells could be a game-changer when it comes to treating tendon injuries.

When asked how his team would be continuing their work, Dr. Fan told Good News Network: As to the next stage of our research, we are tackling two areas. First, we want to find out the fundamental differences between tendon stem cells versus fibrotic scar cells, so we can find ways to enhance the former and eliminate the latter and make healing tendon scar-less.Second, we want to be able to grow tendon stem cells for transplantation, so we can speed up the healing process after tendon injuries.

Reprinted from the Carnegie Institution for Science

Heal Your Friends Of Negativity By Sharing The Exciting News To Social Media

Excerpt from:
Discovery of 'Tendon Stem Cells' Could Revolutionize How We Recover From Injuries - Good News Network

The air, earth and water of our planet are pulsating with living things. Yet, a vast and diverse web of life exists, about which almost nothing is known.

This is the world of flagellates, tiny organisms that persist in staggering numbers in many diverse ecosystems around the world.

According to Jeremy Wideman, a researcher at the Biodesign Center for Mechanisms in Evolution at Arizona State University, we have a great deal to learn from these delicate and wildly varied creatures. Among other surprises, flagellates could provide valuable clues about a shadowy event that may have occurred 1.5-2 billion years ago, (no one is really sure of the timing), with the arrival of a new type of cell.

Known as LECA, it was a sort of primal egg out of which the astonishing profusion of complex lifefrom flagellate organisms, fungi and plants, to insects, zebra, and humans, exploded and spread over the earth.

In new research appearing today in the journal Nature Microbiology, Wideman and his colleagues, including Prof. Thomas Richards at the University of Exeter describe a new method for investigating the genomes of eukaryotic flagellate organisms, which have been notoriously tricky to pinpoint and sequence.

Specifically, they explored samples of mitochondrial DNA, sequencing around 100 such genomes for previously undocumented flagellates. The new technique could help scientists like Wideman begin to fill in the largely blank region of the eukaryotic puzzle, where flagellate life flourishes.

Cellular worlds

Wideman, originally a traditional cell biologist, became frustrated with the many unaddressed questions in the field, recently joining the emerging discipline of evolutionary cell biology. This rapidly advancing research area uses cells as fundamental units for the study of evolutionary processes and imports concepts from evolutionary biology to better understand how cells work. Im literally a cell biologist that wants to know more about things we know nothing about, he says.

Evolutionary cell biology is a profoundly transdisciplinary endeavor, fusing evolutionary theory, genomics and cell biology with quantitative branches of biochemistry, biophysics, and population genetics.

Flagellates include many parasites implicated in human disease, from the intestinal bug Giardia to more damaging trypanosomes, and leishmania. Flagellates also perform more benevolent tasks. As the major consumers of bacteria and other protists in aquatic ecosystems, they help ensure the recycling of limiting nutrients.

Single-celled eukaryotic organisms, which include flagellates, constitute the overwhelming majority of eukaryotic diversity, vastly outpacing the more familiar multicellular plants, animals, and fungi. Despite their importance and ubiquity across the globe, flagellates are, as Wideman stresses, an almost entirely unknown inhabitant of the living world and one of the most enigmatic. When viewed under a microscope, their often science fiction-like appearance is markedly distinct from the kinds of eukaryotic cells commonly described in biology textbooks. Their emergence from comparatively rudimentary prokaryotes marks the most momentous transition in the history of life on earth.

Novel lineages of heterotrophic flagellates are being discovered at an alarming, rate, Wideman says. In the last two years 2 kingdom level lineages have been discovered (see here and here), meaning lineages that have been evolving independently of animals and fungi for over a billion years. Nevertheless, researchers have barely scratched the surface of this astonishing diversity and new methods must be brought to bear to speed up the quest. (Heterotrophs are organisms that cannot synthesize their own food, relying instead on other organisms for nutrition.)

Microbial safari

Any drop of pond, lake or ocean water is likely to contain many flagellates, but separating them from a multitude of non-flagellates and accurately reading their genomes by conventional means has been slow and painstaking work. Only a minute fraction of extant flagellates have known genomic sequences and its even possible that the overwhelming majority have never actually been seen. According to Wideman, flagellate life forms represent the dark matter of the eukaryotic universe.

Heterotrophic flagellates are the target, Wideman says. Theyre not a lineage. Theyre many, many lineages that are from all over the tree of life. LECA, the Last Eukaryotic Common Ancestor, was a heterotrophic flagellate, which means, that every major lineage (of eukaryotes) evolved from some sort of heterotrophic flagellate.

To access the elusive flagellate mitochondrial DNA, the researchers exploited a feature common to all flagellates and from which they take their namethe existence of flagella, which, unlike in animal sperm are on the front of cells and are often used to pull them forward like a microscopic breast stroke but are also involved in sensation, feeding, and perhaps other, as-yet unknown functions.

Flagella are rich in a particular protein known as tubulin. The new method for identifying flagellates and distinguishing them from their aquatic neighborsprimarily algae and bacteriacapitalizes on this fact by applying a selective stain to flagella-bearing organisms, activated by their high tubulin content. (Algal cells are naturally marked by their chloroplasts, which the flagellates of interest in the new study lack.)

Samples of sea water collected in 2014 off the coast of California provided a test case. Using the technique, the researchers gathered a windfall of mitochondrial sequence data, significantly expanding the catalog of flagellates identified by molecular means. Indeed, they doubled the existing mitochondrial DNA library for flagellate organisms. We got many, many different kinds of organisms. So it was a very rich sample and very few were identical, Wideman says.

In search of LECA

Apart from the mystery of lifes origin, the puzzle of where eukaryotes came from and how the LECA event transpired is the most important and vexing unanswered question in all of biology. (It has been dubbed the black hole at the heart of the living world.)

Correctly establishing the sequence of events underlying the crucial innovations within eukaryotes, from whence all complex life sprang, will take much more research in unexplored regions of the existing eukaryotic domain, particularly, the flagellates. Wideman believes the rapid advance of techniques for identifying and sequencing these organisms, such as the one outlined in the new study, offer hope such questions may one day find answers.

ARIZONA STATE UNIVERSITY

Header Image Public Domain

Planet Knowledge is a FREE to watch video on demand channel available on Freeview HD (Channel 265), Youview, Samsung connected TVs, selected smart tvs, tablets and smartphones using Android or iOS.

See the original post here:
Aquatic microorganisms offer important window on the history of life - HeritageDaily

Diversity at least among cancer cells is not a good thing. Now, research from the Weizmann Institute of Science in Rehovot shows that in melanoma, tumors with cells that have differentiated into more diverse subtypes are less likely to be affected by the immune system, thus reducing the chance that immunotherapy will be effective.

The findings of this research, published in Cell, may provide better tools for designing personalized protocols for cancer patients, as well as pointing toward new avenues of research into anti-cancer vaccines.

Prof. Yardena Samuels of the Institutes Department of Molecular Cell Biology wanted to know why, despite the fact that cancer deaths from melanoma have dropped in recent years (thanks to new immunotherapy treatments), many patients do not respond to therapy. The reasons have not been clear, though the leading hypothesis, supported by a few studies, has been that tumors with more mutations are more likely to respond to immunotherapy. Some patients even spend large sums to undergo radiation or chemical treatments to increase tumor mutations, but a causal relationship between the two has not yet been proven.

Samuels and her colleagues were intrigued by studies that suggested a different possible correlation one between heterogeneity (that is, the genetic diversity among tumor cells) and the response to therapy. To investigate this theory, however, the team had to develop a new experimental system to check exactly which factors play a role.

We showed the difference between two extremes highly homogeneous and highly heterogeneous but most cancers fall somewhere in between, says Dr. Bartok. To systematically generate tumors with intermediate levels of genetic heterogeneity, we created a phylogenetic tree of the parental heterogeneous line, and mapped out how subtypes appear over time.

Then we created cocktails of homogeneous cell lines based on this tree, with more or less heterogeneous combinations of cells, and injected them into mice.

As predicted, the more homogeneous the cell cocktail, the easier it was for the mices immune systems to eradicate the cancer, whereas the more heterogeneous the tumors were, the more aggressive they became.

Ultimately, we intend to use the experimental system we created to work on developing applicable personalized protocols for cancer patients, Samuels said.

View original post here:
Weizmann Institute of Science Works on New Cancer Study Detroit Jewish News - The Jewish News

How many of the thousands of newly discovered molecules finally become drugs which effectively cure patients? Unfortunately, only a very low percentage (recently quantified around 12%). Why do so many candidate drugs fail before entering the market, although they show promising results at a research level? A recent paper indicates a lack of specific drug efficacy as the primary cause of trial failure in late phase development, failures that can be reduced by a more efficient screening of candidate drugs in early phases.

However, current 2D in vitro strategies, mostly based on cell lines cultured on 2D rigid substrates, represent the cheapest and easiest drug screening tool, but with major drawbacks as low-precision and un-natural environments. In vivo experimentation provides higher systemic physiological relevance, although associated to high running costs, increasing ethical issues and limited analytical depth. Moreover, animal models have been increasingly questioned about their power to faithfully reproduce human biological mechanisms.

Thus, alternative models better predicting the outcomes of new molecules in patients are desperately needed. Recently, innovative techniques such as microfluidics and tissue engineering have been emerging, aiming at reproducing the complex architecture and function of native human tissues. So-called organs-on-a-chip or microphysiological systems have recently been defined as microfabricated cell culture devices designed to model the functional units of human organs in vitro, thus representing an ideal platform for improving the predictability of drugs and biological therapies efficacy and safety in humans.

Our group believes that microphysiological systems hold the key to next generation health solutions. Following our 10+ years experience and specialisation in this area, we have emerged in the development of microphysiological systems in the musculoskeletal field, for platforms to study physio-pathological mechanisms and to perform reliable screening and testing of drugs for diagnostic and therapeutic aims.

In particular, these systems are used for currently uncurable bone diseases such as bone tumours and metastases, but also for pathological conditions of muscle tissue such as fibrosis, disabling pathologies (such as osteoarthritis), as well as ageing and metabolic diseases of the musculoskeletal system. This is achieved by reproducing human tissue districts focusing on high-fidelity biomimicking models through human multi-cellular and architecturally accurate models (i.e. whole joint model including all parts as bone, cartilage, synovium, vascular, immune in a single model).

The first example of a microfluidic, vascularised, human bone model for the study of bone metastatic invasion has been published on Biomaterials in 2014 and highlighted in The Economist journal. With this work, in collaboration with prof R Kamm from MIT, we were able to monitor the invasion of breast cancer cells in a bone-like matrix and the formation of micro-metastases in real time. In a subsequent work, we reproduced organotypic metastases from breast cancer, comparing engineered bone-like and muscle-like environments, and demonstrating the secretion of molecules in the muscle environment able to counteract tumour invasion.

To better mimic the metastatic process, blood and immune cells were also included in our recent models, demonstrating that the presence of blood cells (particularly platelet) increase metastatisation and that a drug used as antiaggregant clinical therapy can also decrease cancer invasion.

Microfluidic multi-tissue models have been also designed to investigate diseases affecting the joints, such as osteoarthritis.

A multichannel device, including the tissues of the native joint, as a cartilage compartment, separated from a compartment embedding synovial fibroblasts by a channel containing synovial fluid has been developed. The device mimicked the inflammatory processes at the basis of osteoarthritis and is being exploited to evaluate potential biological therapies, such as the injection of stem cells in the joint.

Microfluidics is a powerful technology however it comes with its own drawbacks too as the microenvironment into a microfluidic chip is not properly 3D, being able to host tissues with a thickness of just few cells (between 10 and 15), and thus also a scarce availability of biological material which makes it difficult to apply standard analytical techniques.

To overcome these limitations, in our lab we are exploiting both Micro- and Bio- fabrication techniques to generate miniaturised multicellular microphysiological systems, bigger and more user friendly than microfluidic ones which allow you to more accurately reproduce the 3D microarchitecture of native musculoskeletal tissues.

In 2016 we generated a mm-scale construct, embedding osteoblasts, osteoclasts, vascular cells and calcium nanoparticles, to recreate the mineral part of the bone. This represented the first example of a bone-remodelling microscale model able to reproduce the balanced deposition and resorption of minerals by bone cells, recently further improved with the addition of macrophages. To test the potential of the device as a drug screening platform, we added breast cancer cells in the bone-like matrix and effects of different drugs have recently been tested. The model showed a significantly better reproduction of cancer cell resistance to drugs as compared to standard in vitro models.

Beside bone, also a hierarchical microscale model of skeletal muscle has been described with multiple human muscle fibres engineered in a 3D gel. Here we showed for the first time the formation of the typical fibroblast layer surrounding each fibre intertwined with a microvascular network. Fibroblasts isolated from dystrophic patients and inserted in our model naturally exerted the traditional onset of fibrosis characteristics as compared to standard models requiring external induction for such behaviour.

To summarise, microphysiological systems represent the leading approach to achieve more reliable preclinical testing platforms for the quantification of drug efficacy, as compared to standard 2D models. However, further challenges lie ahead for their widespread use. In basic and translational research towards clinical application, a better understanding of pathophysiological mechanisms is mandatory.

Thus, faithful reproduction of complex native-like microenvironments should be achieved, including appropriate physical stimuli, whereby the exploitation of advanced microfabrication techniques can be of help towards this goal. Biofabrication of functional units of human tissues and organs is fundamental also for pharma companies, along with relevant automation and ease of use, to achieve more reliable readouts of novel drugs and highly predictive tests for biological therapies.

Depending on its final application, the complexity level of 3D in vitro models should be tailored to sufficiently improve relevance but without unnecessary additions and increasing costs. Anyhow, considering the multiple issues involved in the development of microphysiological systems, multidisciplinary expertise and knowhow in biological and bioengineering fields are mandatory, and fostering of translational researchers training will be needed to guarantee the emergence of such next generation systems.

Lastly, the huge amount of heterogenous data originating from such complex models need to be analysed with systems biology techniques, based on machine learning algorithms and similarly advanced techniques gathered from big data management. Fuelling research in these fields can help the research community in achieving better models of human organs, thus leading to drugs more effectively impacting patient care.

Matteo MorettiHead Regenerative Medicine Technologies LabUnit di Ortopedia e Traumatologia, Ente Ospedaliero CantonaleLugano (CH)+41(0)918117076Matteo.moretti@eoc.chhttps://www.eoc.ch/

Originally posted here:
Microphysiological systems: advancing drug and biological therapies discovery - SciTech Europa

CINCINNATI, Nov. 27, 2019 /PRNewswire/ -- Stem cell therapy helps hearts recover from a heart attack, although not for the biological reasons originally proposed two decades ago that today are the basis of ongoing clinical trials. This is the conclusion of a Nov. 27 studyin Nature that shows an entirely different way that heart stem cells help the injured heart not by replacing damaged or dead heart cells as initially proposed.

The study reports that injecting living or even dead heart stem cells into the injured hearts of mice triggers an acute inflammatory process, which in turn generates a wound healing-like response to enhance the mechanical properties of the injured area.

Mediated by macrophage cells of the immune system, the secondary healing process provided a modest benefit to heart function after heart attack, according to Jeffery Molkentin, PhD,principal investigator, director of Molecular Cardiovascular Microbiologya Cincinnati Children's Hospital Medical Centerand a professor of the Howard Hughes Medical Institute (HHMI).

"The innate immune response acutely altered cellular activity around the injured area of the heart so that it healed with a more optimized scar and improved contractile properties," Molkentin said. "The implications of our study are very straight forward and present important new evidence about an unsettled debate in the field of cardiovascular medicine."

The new paper builds on a 2014 study publishedby the same research team, also in Nature. As in that earlier study, the current paper shows that injecting c-kit positive heart stem cells into damaged hearts as a strategy to regenerate cardiomyocytes doesn't work. The findings prompted Molkentin and his colleagues to conclude that there is a need to "re-evaluate the current planned cell therapy based clinical trials to ask how this therapy might really work."

An Unexpected Discovery

The study worked with two types of heart stem cells currently used in the clinical trialsbone marrow mononuclear cells and cardiac progenitor cells. As the researchers went through the process of testing and re-verifying their data under different conditions, they were surprised to discover that in addition to the two types of stem cells, injecting dead cells or even an inert chemical called zymosan also provided benefit to the heart by optimizing the healing process. Zymosan is a substance designed to induce an innate immune response

Researchers reported that stem cells or zymosan therapies tested in this study altered immune cell responses that significantly decreased the formation of extra cellular matrix connective tissue in the injury areas, while also improving the mechanical properties of the scar itself. The authors concluded: "injected hearts produced a significantly greater change in passive force over increasing stretch, a profile that was more like uninjured hearts."

Molkentin and his colleagues also found that stem cells and other therapeutic substances like zymosan have to be injected directly into the hearts surrounding the area of infarction injury. This is in contrast to most past human clinical trials that for patient safety reasons simply injected stem cells into the circulatory system.

"Most of the current trials were also incorrectly designed because they infuse cells into the vasculature," Molkentin explained. "Our results show that the injected material has to go directly into the heart tissue flanking the infarct region. This is where the healing is occurring and where the macrophages can work their magic."

The researchers also noted an interesting finding involving zymosan, a chemical compound that binds with select pattern recognition receptors to cause an acute innate immune response. Using zymosan to treat injured hearts in mice resulted in a slightly greater and longer-lasting benefit on injured tissues than injecting stem cells or dead cell debris.

Looking to the Future

Molkentin said he and other collaborating scientists will follow up the findings by looking for ways to leverage the healing properties of the stem cells and compounds they tested.

For example, considering how heart stem cells, cell debris and zymosan all triggered an acute innate immune response involving macrophages in the current paper, Molkentin explained they will test a theory that harnesses the selective healing properties of macrophages. This includes polarizing or biologically queuing macrophages to only have healing-like properties.

Further testing of this, he said, could therapeutically be very important for developing future treatment strategies.

The study's first author was Ronald Vagnozzi, PhD, a fellow and investigator in the Molkentin laboratory. Key collaboration also came from scientists in the Cincinnati Children's Heart Institute, the University of Cincinnati Department Of Pediatrics and the Center for Systems Biology (Department of Imaging) and the Cardiovascular Research Center at Massachusetts General Hospital and Harvard Medical School in Boston.

Funding support for the study came in part by grants from the National Institutes of Health (R01 HL132391) and an NIH Research Service Award via the National Heart Blood and Lung Institute (F32 HL128083), the Howard Hughes Medical Institute, and a Career Development Award from the American Heart Association (19CDA34670044). Flow cytometric data were acquired using equipment maintained by the Research Flow Cytometry Core in the Division of Rheumatology at Cincinnati Children's.

Post Embargo Study Link: https://www.nature.com/articles/s41586-019-1802-2

View original content to download multimedia:http://www.prnewswire.com/news-releases/stem-cell-therapy-helps-broken-hearts-heal-in-unexpected-way-300965608.html

SOURCE Cincinnati Children's Hospital Medical Center

See the rest here:
Stem Cell Therapy Helps Broken Hearts Heal in Unexpected Way - BioSpace

Studies now report that babies are able to see more in the womb than what we originally thought. According to Science Daily, a study done by the researchers at the University of California -Berkeley has concluded that babies in the fetus can see more images early that previously reported. The researchers note this is a significant and detrimental phenomenon to their development.

The University of California, Berkeley, scientists have found evidence that these regular cells are actually talking to one another. The cells are part of an interconnected network that gives the retina a lot more light sensitivity than once thought. This enhanced light sensitivity enhances the influence of light on behavior and brain development in ways that aren't totally understood yet.

RELATED:15 Bizarre Facts About What Babies Can See In The Womb

View this post on Instagram

39 . Son petit coin dans notre chambre est presque prt . Les dernires semaines n'ont pas t faciles... 36 semaines, je me suis rendue l'hpital pour avoir une version, puisque mademoiselle E. avait toujours la tte en haut. Elle a t tourne manuellement par une gyncologue, mais cette manipulation pouvais me faire accoucher prmaturment... a s'est trs bien pass, ce n'est pas agrable, c'est sur, mais bb E. Est en parfaite sant et la tte en bas depuis... Mais tout le stress accumul est tomb d'un coup et la fatigue du dernier trimestre s'en est aussi ml. Mais l, tout va bien . J'ai plus que hte d'accoucher, de vivre cette exprience chez moi, accompagne par d'extraordinaires sages-femmes, mon mari, mon bb qui deviendra grand frre, ainsi que ma maman et ma belle-maman. Bb E. sera accueillie dans ce monde dans l'amour et la joie . . . #39weekspregnant #39semaines #babybump #love #amour #tiredbuthappy #babygirl #bebefille #babyE #momsclubqc

A post shared by Mylou (@mylou1390) on Nov 28, 2019 at 8:55am PST

In developing baby fetuses eyes there is roughly 3% of ganglion cells and those cells send messages through the optic nerve into the brain. Those developing cells are sensitive to light and so far researchers have found about six different subtypes that communicate with various places in the brain. The developing baby sight isn't the only thing that is evolving but theperihabenula, which regulates mood, and the amygdala also deals with emotions.

The study examined how this occurs in mice and monkeys and the evidence suggests that these ganglion cells talk to one another through the electrical connections named gap junctions which implies more complexity in immature rodent and primate eyes than previously recorded.

These cells are called intrinsically photosensitive retinal ganglion cells (ipRGCs) and were discovered approximately 10 years ago.Marla Feller, a UC Berkeley professor of molecular and cell biology has been studying the developing retina for almost 20 years. She and her mentor,Carla Shatz of Stanford University played a major rolein showing that the spontaneous electrical activity in the eye during development in the fetus or better known as retinal waves are critical for developing the correct brain networks that process images later on post-delivery.

"Given the variety of these ganglion cells and that they project to many different parts of the brain, it makes me wonder whether they play a role in how the retina connects up to the brain," said Feller, who also is the author of a paper that appeared in the journal Current Biology. "Maybe not for visual circuits, but for non-vision behaviours. Not only the pupillary light reflex and circadian rhythms, but possibly explaining problems like light-induced migraines, or why light therapy works for depression."

The researchers also found evidence that supports that the eyes and brain signals tune itself in such a way that it could adapt to the intensity of light. Feller believes this probably has an important role in development.

NEXT:20 Amazing Facts About Baby Developing In The Womb

Doctors Reveal How Much Weight You Should Gain During Pregnancy

Tags:pregnancy

Here is the original post:
Babies Inside The Womb Can See Much More Than Initially Thought - BabyGaga

Our scientists and many biomedical researchers across the world use small molecules called chemical probes to understand the complex interplay between proteins in cells.

These molecules are designed to bind to a target in a cell, most commonly a protein, and alter or inhibit its function. They can be used as investigational tools or prototype drugs, and ultimately help to discover new treatments for a range of diseases, including cancer.

But the use of poor-quality compounds as chemical probes, often based on out-of-date information, is widespread among the global biomedical research community. It has frequently compromised the robustness of research findings and led to incorrect conclusions.

Scientists at The Institute of Cancer Research have for some time been working to help researchers choose their chemical probes more wisely.

In 2015, we were co-founders of the Chemical Probes Portal (described in a Nature Chemical Biology article), an open-access online resource which provides expert reviews of chemical probes for use in biomedical research and drug discovery.

To be listed on the Chemical Probes Portal, a chemical probe needs to be peer-reviewed by a member of the Scientific Advisory Board, made up of experts from the medicinal chemistry, pharmacology and chemical biology communities.

Users of the portal can now sort through close to 200 high-quality chemical probes, and select the most suitable for their needs, quickly and efficiently.

Although the expert-review approach is valuable and the portal is widely used, a limitation is its far-from-complete coverage of the full range of proteins in human cells.

More recently, our researchers have also launched a highly innovative web resource called Probe Minerthat provides a very complementary approach to selecting chemical probes.

Jointly conceived by Dr Albert Antolin, Professor Bissan Al-Lazikani, Professor Ian Collinsand Professor Paul Workmanfrom the ICR, Probe Miner uses data science and statistical analysis to sort through hundreds of thousands of actual or potential chemical probes.

It ranks their suitability for use against a large number of human proteins based on quantitative statistical assessment according to critical criteria or fitness factors that were defined previously by ICR scientists.

Probe Miner uses data about probes and proteins from canSAR, a knowledgebase also created by researchers at the ICR, which brings together and stores data across biology, chemistry, pharmacology, structural biology, cellular networks, clinical annotations and more.

Looking at the interactions between the chemical probes and the target protein of interest, Probe Miner scores each probe for six fitness factors including their potency, selectivity, cell activity and other features and ranks their suitability for use to study target proteins.

This is quite an undertaking: within canSAR, there are 355,305 potential chemical probes and 2,220 possible human protein targets. But Probe Miners computational methodology can quickly and efficiently produce a quantitative, data-driven assessment of each chemical probe against a given target, and accurately suggest the best probes for use in the laboratory.

Since its conception in 2017, Probe Miner has had more than 4,000 users including researchers from biotech companies such as BenevolentAI, pharmaceutical companies such as GSK and Novartis, and academic institutions such as the Broad Institute of Harvard and MIT, and the University of Oxford.

At the ICR, we are leading in innovative cancer informatics. From mapping the paths of cancer evolution, to the design and discovery of novel drugs, to the precision tailoring of radiation therapy. Informatics research at the ICR spans bioinformatics and computational biology, biostatistics, mathematical biology, in-silico medicinal chemistry, digital pathology and computational physics.

Read more

The creators of Probe Miner are now looking at how to advance and further improve the scope and usability of the site. As well as presentational changes, the team is looking to increase the amount of data accessible to Probe Miner.

ICR scientists have recently called for more integration between Probe Miner and other resources developed to help researchers use chemical probes more wisely, including the Chemical Probes Portal. The two approaches are highly complementary.

With better integration between online resources, the potential for more effective probe selection will be greater than ever before.

As Dr Albert Antolin, Sir Henry Wellcome Postdoctoral Fellow in the Division of Cancer Therapeuticsand the Department of Data Science, explains:

We are bringing together the data and methodology that facilitates objective assessment and selection of chemical probes for scientists who are not experts in chemical biology.

This way we will hopefully address some of the problems around data robustness that we are currently facing in biomedical research, and facilitate the translation of biological discoveries into new drugs for patients.

Original post:
Science Talk - Enhancing the selection and use of chemical probes in cancer research using innovative data science - The Institute of Cancer Research