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Archive for the ‘Bio Instrumentation in Experimental Life Sciences Research’ Category


The Role of Exosomes in Metabolic Regulation

Author: Larry H. Bernstein, MD, FCAP

 

On 9/25/2017, Aviva Lev-Ari, PhD, RN commissioned Dr. Larry H. Bernstein to write a short article on the following topic reported on 9/22/2017 in sciencemission.com

 

We are publishing, below the new article created by Larry H. Bernstein, MD, FCAP.

 

Background

During the period between 9/2015  and 6/2017 the Team at Leaders in Pharmaceutical Business Intelligence (LPBI)  has launched an R&D effort lead by Aviva Lev-Ari, PhD, RN in conjunction with SBH Sciences, Inc. headed by Dr. Raphael Nir.

This effort, also known as, “DrugDiscovery @LPBI Group”  has yielded several publications on EXOSOMES on this Open Access Online Scientific Journal. Among them are included the following:

 

QIAGEN – International Leader in NGS and RNA Sequencing, 10/08/2017

Reporter: Aviva Lev-Ari, PhD, RN

 

cell-free DNA (cfDNA) tests could become the ultimate “Molecular Stethoscope” that opens up a whole new way of practicing Medicine, 09/08/2017

Reporter: Aviva Lev-Ari, PhD, RN

 

Detecting Multiple Types of Cancer With a Single Blood Test (Human Exomes Galore), 07/02/2017

Reporter and Curator: Irina Robu, PhD

 

Exosomes: Natural Carriers for siRNA Delivery, 04/24/2017

Reporter: Aviva Lev-Ari, PhD, RN

 

One blood sample can be tested for a comprehensive array of cancer cell biomarkers: R&D at WPI, 01/05/2017

Curator: Marzan Khan, B.Sc

 

SBI’s Exosome Research Technologies, 12/29/2016

Reporter: Aviva Lev-Ari, PhD, RN

 

A novel 5-gene pancreatic adenocarcinoma classifier: Meta-analysis of transcriptome data – Clinical Genomics Research @BIDMC, 12/28/2016

Curator: Tilda Barliya, PhD

 

Liquid Biopsy Chip detects an array of metastatic cancer cell markers in blood – R&D @Worcester Polytechnic Institute, Micro and Nanotechnology Lab, 12/28/2016

Reporters: Tilda Barliya, PhD and Aviva Lev-Ari, PhD, RN

 

Exosomes – History and Promise, 04/28/2016

Reporter: Aviva Lev-Ari, PhD, RN

 

Exosomes, 11/17/2015

Curator: Larry H. Bernstein, MD, FCAP

 

Liquid Biopsy Assay May Predict Drug Resistance, 11/16/2015

Curator: Larry H. Bernstein, MD, FCAP

 

Glypican-1 identifies cancer exosomes, 10/31/2015

Curator: Larry H. Bernstein, MD, FCAP

 

Circulating Biomarkers World Congress, March 23-24, 2015, Boston: Exosomes, Microvesicles, Circulating DNA, Circulating RNA, Circulating Tumor Cells, Sample Preparation, 03/24/2015

Reporter: Aviva Lev-Ari, PhD, RN

 

Cambridge Healthtech Institute’s Second Annual Exosomes and Microvesicles as Biomarkers and Diagnostics Conference, March 16-17, 2015 in Cambridge, MA, 03/17, 2015

Reporter: Aviva Lev-Ari, PhD, RN

 

The newly created think-piece on the relationship between regulatory functions of Exosomes and Metabolic processes is developed conceptually, below.

 

The Role of Exosomes in Metabolic Regulation

Author: Larry H. Bernstein, MD, FCAP

We have had more than a half century of research into the genetic code and transcription leading to abundant work on RNA and proteomics. However, more recent work in the last two decades has identified RNA interference in siRNA. These molecules may be found in the circulation, but it has been a challenge to find their use in therapeutics. Exosomes were first discovered in the 1980s, but only recently there has been a huge amount of research into their origin, structure and function. Exosomes are 30–120 nm endocytic membrane-bound extracellular vesicles (EVs)(1-23) , and more specifically multiple vesicle bodies (MVBs) by a budding process from invagination of the outer cell membrane that carry microRNA (miRNA), and have structures composed of protein and lipids (1,23-27 ). EVs are the membrane vesicles secreted by eukaryotic cells for intracellular communication by transferring the proteins, lipids, and RNA under various physiologic conditions as well as during the disease stage. EVs also act as a signalosomes in many biological processes. Inward budding of the plasma membrane forms small vesicles that fuse. Intraluminal vesicles (ILVs) are formed by invagination of the limiting endosomal membrane during the maturation process of early endosome.

EVs are the MVBs secreted that serve in intracellular communication by transferring a cargo consisting of proteins, lipids, and RNA under various physiologic conditions (4, 23). Exosome-mediated miRNA transfer between cells is considered to be necessary for intercellular signaling and exosome-associated miRNAs in biofluids (23). Exosomes carry various molecular constituents of their cell of origin, including proteins, lipids, mRNAs, and microRNAs (miRNAs) (. They are released from many cell types, such as dendritic cells (DCs), lymphocytes, platelets, mast cells, epithelial cells, endothelial cells, and neurons, and can be found in most bodily fluids including blood, urine, saliva, amniotic fluid, breast milk, hydrothoracic fluid, and ascitic fluid, as well as in culture medium of most cell types.Exosomes have also been shown to be involved in noncoding RNA surveillance machinery in generating antibody diversity (24). There are also a vast number of long non-coding RNAs (lncRNAs) and enhancer RNAs (eRNAs) that accumulate R-loop structures upon RNA exosome ablation, thereby, resolving deleterious DNA/RNA hybrids arising from active enhancers and distal divergent eRNA-expressing elements (lncRNA-CSR) engaged in long-range DNA interactions (25). RNA exosomes are large multimeric 3′-5′ exo- and endonucleases representing the central RNA 3′-end processing factor and are implicated in processing, quality control, and turnover of both coding and noncoding RNAs. They are large macromolecular cages that channel RNA to the ribonuclease sites (29). A major interest has been developed to characterize of exosomal cargo, which includes numerous non-randomly packed proteins and nucleic acids (1). Moreover, exosomes play an active role in tumorigenesis, metastasis, and response to therapy through the transfer of oncogenes and onco-miRNAs between cancer cells and the tumor stroma. Blood cells and the vascular endothelium is also exosomal shedding, which has significance for cardiovascular,   neurologicological disorders, stroke, and antiphospholipid syndrome (1). Dysregulation of microRNAs and the affected pathways is seen in numerous pathologies their expression can reflect molecular processes of tumor onset and progression qualifying microRNAs as potential diagnostic and prognostic biomarkers (30).

Exosomes are secreted by many cells like B lymphocytes and dendritic cells of hematopoietic and non-hematopoietic origin viz. platelets, Schwann cells, neurons, mast cells, cytotoxic T cells, oligodendrocytes, intestinal epithelial cells were also found to be releasing exosomes (4). They are engaged in complex functions like persuading immune response as the exosomes secreted by antigen presenting cells activate T cells (4). They all have a common set of proteins e.g. Rab family of GTPases, Alix and ESCRT (required for transport) protein and they maintain their cytoskeleton dynamics and participate in membrane fusion. However, they are involved in retrovirus disease pathology as a result of recruitment of the host`s endosomal compartments in order to generate viral vesicles, and they can either spread or limit an infection based on the type of pathogen and its target cells (5).

Upon further consideration, it is understandable how this growing biological work on exosomes has enormous significance for laboratory diagnostics (1, 3, 5, 6, 11, 14, 15, 17-20, 23,30-41) . They are released from many cell types, such as dendritic cells (DCs), lymphocytes, platelets, mast cells, epithelial cells, endothelial cells, and neurons, and can be found in most bodily fluids including blood, urine, saliva, amniotic fluid, breast milk, thoracic and abdominal effusions, and ascitic fluid (1). The involvement of exosomes in disease is broad, and includes: cancer, autoimmune and infectious disease, hematologic disorders, neurodegenerative diseases, and cardiovascular disease. Proteins frequently identified in exosomes include membrane transporters and fusion proteins (e.g., GTPases, annexins, and flotillin), heat shock proteins (e.g., HSC70), tetraspanins (e.g., CD9, CD63, and CD81), MVB biogenesis proteins (e.g., alix and TSG101), and lipid-related proteins and phospholipases. The exosomal lipid composition has been thoroughly analyzed in exosomes secreted from several cell types including DCs and mast cells, reticulocytes, and B-lymphocytes (1). Dysregulation of microRNAs of pathways observed in numerous pathologies (5, 10, 12, 21, 27, 35, 37) including cancers (30), particularly, colon, pancreas, breast, liver, brain, lung (2, 6, 17-20, 30, 33-36, 38, 39). Following these considerations, it is important that we characterize the content of exosomal cargo to gain clues to their biogenesis, targeting, and cellular effects which may lead to identification of biomarkers for disease diagnosis, prognosis and response to treatment (42).

We might continue in pursuit of a particular noteworthy exosome, the NLRP3 inflammasome, which is activated by a variety of external or host-derived stimuli, thereby, initiating an inflammatory response through caspase-1 activation, resulting in inflammatory cytokine IL-1b maturation and secretion (43).
Inflammasomes are multi-protein signaling complexes that activate the inflammatory caspases and the maturation of interleukin-1b. The NLRP3 inflammasome is linked with human autoinflammatory and autoimmune diseases (44). This makes the NLRP3 inflammasome a promising target for anti-inflammatory therapies. The NLRP3 inflammasome is activated in response to a variety of signals that indicate tissue damage, metabolic stress, and infection (45). Upon activation, the NLRP3 inflammasome serves as a platform for activation of the cysteine protease caspase-1, which leads to the processing and secretion of the proinflammatory cytokines interleukin-1β (IL-1β) and IL-18. Heritable and acquired inflammatory diseases are both characterized by dysregulation of NLRP3 inflammasome activation (45).
Receptors of innate immunity recognize conserved moieties associated with either cellular damage [danger-associated molecular patterns (DAMPs)] or invading organisms [pathogen-associated molecular patterns (PAMPs)](45). Either chronic stimulation or overwhelming tissue damage is injurious and responsible for the pathology seen in a number of autoinflammatory and autoimmune disorders, such as arthritis and diabetes. The nucleotide-binding domain leucine-rich repeat (LRR)-containing receptors (NLRs) are PRRs are found intracellularly and they share a unique domain architecture. It consists of a central nucleotide binding and oligomerization domain called the NACHT domain that is located between an N-terminal effector domain and a C-terminal LRR domain (45). The NLR family members NLRP1, NLRP3, and NLRC4 are capable of forming multiprotein complexes called inflammasomes when activated.

The (NLRP3) inflammasome is important in chronic airway diseases such as asthma and chronic obstructive pulmonary disease because the activation results, in pro-IL-1β processing and the secretion of the proinflammatory cytokine IL-1β (46). It has been proposed that Activation of the NLRP3 inflammasome by invading pathogens may prove cell type-specific in exacerbations of airway inflammation in asthma (46). First, NLRP3 interacts with the adaptor protein ASC by sensing microbial pathogens and self-danger signals. Then pro-caspase-1 is recruited and the large protein complex called the NLRP3 inflammasome is formed. This is followed by autocleavage and activation of caspase-1, after which pro-IL-1β and pro-IL-18 are converted into their mature forms. Ion fluxes disrupt membrane integrity, and also mitochondrial damage both play key roles in NLRP3 inflammasome activation (47). Depletion of mitochondria as well as inhibitors that block mitochondrial respiration and ROS production prevented NLRP3 inflammasome activation. Futhermore, genetic ablation of VDAC channels (namely VDAC1 and VDAC3) that are located on the mitochondrial outer membrane and that are responsible for exchanging ions and metabolites with the cytoplasm, leads to diminished mitochondrial (mt) ROS production and inhibition of NLRP3 inflammasome activation (47). Inflammasome activation not only occurs in immune cells, primarily macrophages and dendritic cells, but also in kidney cells, specifically the renal tubular epithelium. The NLRP3 inflammasome is probably involved in the pathogenesis of acute kidney injury, chronic kidney disease, diabetic nephropathy and crystal-related nephropathy (48). The inflammasome also plays a role in autoimmune kidney disease. IL-1 blockade and two recently identified specific NLRP3 inflammasome blockers, MCC950 and β-hydroxybutyrate, may prove to have value in the treatment of inflammasome-mediated conditions.

Autophagosomes derived from tumor cells are referred to as defective ribosomal products in blebs (DRibbles). DRibbles mediate tumor regression by stimulating potent T-cell responses and, thus, have been used as therapeutic cancer vaccines in multiple preclinical cancer models (49). It has been found that DRibbles could induce a rapid differentiation of monocytes and DC precursor (pre-DC) cells into functional APCs (49). Consequently, DRibbles could potentially induce strong innate immune responses via multiple pattern recognition receptors. This explains why DRibbles might be excellent antigen carriers to induce adaptive immune responses to both tumor cells and viruses. This suggests that isolated autophagosomes (DRibbles) from antigen donor cells activate inflammasomes by providing the necessary signals required for IL-1β production.

The Hsp90 system is characterized by a cohort of co-chaperones that bind to Hsp90 and affect its function (50). The co-chaperones enable Hsp90 to chaperone structurally and functionally diverse client proteins. Sahasrabudhe et al. (50) show that the nature of the client protein dictates the contribution of a co-chaperone to its maturation. The study reveals the general importance of the cochaperone Sgt1 (50). In addition to Hsp90, we have to consider Hsp60. Adult cardiac myocytes release heat shock protein (HSP)60 in exosomes. Extracellular HSP60, when not in exosomes, causes cardiac myocyte apoptosis via the activation of Toll-like receptor 4. the protein content of cardiac exosomes differed significantly from other types of exosomes in the literature and contained cytosolic, sarcomeric, and mitochondrial proteins (21).

A new Protein Organic Solvent Precipitation (PROSPR) method efficiently isolates the EV repertoire from human biological samples. Proteomic profiling of PROSPR-enriched CNS EVs indicated that > 75 % of the proteins identified matched previously reported exosomal and microvesicle cargoes. In addition lipidomic characterization of enriched CNS vesicles identified previously reported EV-specific lipid families and novel lipid isoforms not previously detected in human EVs. The characterization of these structures from central nervous system (CNS) tissues is relevant to current neuroscience, especially to advance the understanding of neurodegeneration in amyotrophic lateral sclerosis (ALS), Parkinson’s disease (PD) and Alzheimer’s disease (AD)(15). In addition, study of EVs in brain will enable characterization of the degenerative posttranslational modifications (DPMs) occurring in those proteins.
Neurodegenerative disease is characterized by dysregulation because of NLRP3 inflammasome activation. Alzheimer’s disease (AD) and Parkinson’s disease (PD), both neurodegenerative diseases are associated with the NLRP3 inflammasome. PD is characterized by accumulation of Lewy bodies (LB) formed by a-synuclein (aSyn) aggregation. A recent study revealed that aSyn induces synthesis of pro-IL-1b by an interaction with TLR2 and activates NLRP3 inflammasome resulting in caspase-1 activation and IL-1b maturation in human primary monocytes (43). In addition mitophagy downregulates NLRP3 inflammasome activation by eliminating damaged mitochondria, blocking NLRP3 inflammasome activating signals. It is notable that in this aberrant activation mitophagy downregulates NLRP3 inflammasome activation by eliminating damaged mitochondria, blocking NLRP3 inflammasome activating signals (43).

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Genomic Diagnostics: Three Techniques to Perform Single Cell Gene Expression and Genome Sequencing Single Molecule DNA Sequencing

Curator: Aviva Lev-Ari, PhD, RN

 

This article presents Three Techniques to Perform Single Cell Gene Expression and Genome Sequencing Single molecule DNA sequencing

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Ido Sagi – PhD Student @HUJI, 2017 Kaye Innovation Award winner for leading research that yielded the first successful isolation and maintenance of haploid embryonic stem cells in humans.

Reporter: Aviva Lev-Ari, PhD, RN

 

Ido Sagi – PhD Student, Silberman Institute of Life Sciences, HUJI, Israel

  • Ido Sagi’s research focuses on studying genetic and epigenetic phenomena in human pluripotent stem cells, and his work has been published in leading scientific journals, including NatureNature Genetics and Cell Stem Cell.
  • Ido Sagi received BSc summa cum laude in Life Sciences from the Hebrew University, and currently pursues a PhD at the laboratory of Prof. Nissim Benvenisty at the university’s Department of Genetics in the Alexander Silberman Institute of Life Sciences.

The Kaye Innovation Awards at the Hebrew University of Jerusalem have been awarded annually since 1994. Isaac Kaye of England, a prominent industrialist in the pharmaceutical industry, established the awards to encourage faculty, staff and students of the Hebrew University to develop innovative methods and inventions with good commercial potential, which will benefit the university and society.

Publications – Ido Sagi

Comparable frequencies of coding mutations and loss of imprinting in human pluripotent cells derived by nuclear transfer and defined factors.
Cell Stem Cell 2014 Nov 6;15(5):634-42. Epub 2014 Nov 6.
The New York Stem Cell Foundation Research Institute, New York, NY 10032, USA; Naomi Berrie Diabetes Center & Department of Pediatrics, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address:

November 2014

 



Stem cells: Aspiring to naivety.
Nature 2016 12 30;540(7632):211-212. Epub 2016 Nov 30.
The Azrieli Center for Stem Cells and Genetic Research, Department of Genetics, Silberman Institute of Life Sciences, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.
November 2016

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    Milestones in Physiology: Discoveries in Medicine, Genomics and Therapeutics (Series E: Patient-Centered Medicine Book 3)

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    Regenerative and Translational Medicine: The Therapeutic Promise for Cardiovascular Diseases

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Reporter and Curator: Dr. Sudipta Saha, Ph.D.

 

Low sperm count and motility are markers for male infertility, a condition that is actually a neglected health issue worldwide, according to the World Health Organization. Researchers at Harvard Medical School have developed a very low cost device that can attach to a cell phone and provides a quick and easy semen analysis. The device is still under development, but a study of the machine’s capabilities concludes that it is just as accurate as the elaborate high cost computer-assisted semen analysis machines costing tens of thousands of dollars in measuring sperm concentration, sperm motility, total sperm count and total motile cells.

 

The Harvard team isn’t the first to develop an at-home fertility test for men, but they are the first to be able to determine sperm concentration as well as motility. The scientists compared the smart phone sperm tracker to current lab equipment by analyzing the same semen samples side by side. They analyzed over 350 semen samples of both infertile and fertile men. The smart phone system was able to identify abnormal sperm samples with 98 percent accuracy. The results of the study were published in the journal named Science Translational Medicine.

 

The device uses an optical attachment for magnification and a disposable microchip for handling the semen sample. With two lenses that require no manual focusing and an inexpensive battery, it slides onto the smart phone’s camera. Total cost for manufacturing the equipment: $4.45, including $3.59 for the optical attachment and 86 cents for the disposable micro-fluidic chip that contains the semen sample.

 

The software of the app is designed with a simple interface that guides the user through the test with onscreen prompts. After the sample is inserted, the app can photograph it, create a video and report the results in less than five seconds. The test results are stored on the phone so that semen quality can be monitored over time. The device is under consideration for approval from the Food and Drug Administration within the next two years.

 

With this device at home, a man can avoid the embarrassment and stress of providing a sample in a doctor’s clinic. The device could also be useful for men who get vasectomies, who are supposed to return to the urologist for semen analysis twice in the six months after the procedure. Compliance is typically poor, but with this device, a man could perform his own semen analysis at home and email the result to the urologist. This will make sperm analysis available in the privacy of our home and as easy as a home pregnancy test or blood sugar test.

 

The device costs about $5 to make in the lab and can be made available in the market at lower than $50 initially. This low cost could help provide much-needed infertility care in developing or underdeveloped nations, which often lack the resources for currently available diagnostics.

 

References:

 

https://www.nytimes.com/2017/03/22/well/live/sperm-counts-via-your-cellphone.html?em_pos=small&emc=edit_hh_20170324&nl=well&nl_art=7&nlid=65713389&ref=headline&te=1&_r=1

 

http://www.npr.org/sections/health-shots/2017/03/22/520837557/a-smartphone-can-accurately-test-sperm-count

 

https://www.ncbi.nlm.nih.gov/pubmed/28330865

 

http://www.sciencealert.com/new-smartphone-microscope-lets-men-check-the-health-of-their-own-sperm

 

https://www.newscientist.com/article/2097618-are-your-sperm-up-to-scratch-phone-microscope-lets-you-check/

 

https://www.dezeen.com/2017/01/19/yo-fertility-kit-men-test-sperm-count-smartphone-design-technology-apps/

 

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3D Liver Model in a Droplet

Curator: Marzan Khan, BSc

Recently, a Harvard University Professor of Physics and Applied Physics, David Weitz and his team of researchers have successfully generated 3D models of liver tissue composed of two different kinds of liver cells, precisely compartmentalized in a core-shell droplet, using the microfluidics approach(1). Compared to alternative in-vitro methods, this approach comes with more advantages – it is cost-effective, can be quickly assembled and produces millions of organ droplets in a second(1). It is the first “organ in a droplet” technology that enables two disparate liver cells to physically co-exist and exchange biochemical information, thus making it a good mimic of the organ in vivo(1).

Liver tissue models are used by researchers to investigate the effect of drugs and other chemical compounds, either alone or in combination on liver toxicity(2). The liver is the primary center of drug metabolism, detoxification and removal and all of these processes need to be carried out systematically in order to maintain a homeostatic environment within the body(2) Any deviation from the steady state will shift the dynamic equilibrium of metabolism, leading to production of reactive oxygen species (ROS)(2). These are harmful because they will exert oxidative stress on the liver, and ultimately cause the organ to malfunction. Drug-induced liver toxicity is a critical problem – 10% of all cases of acute hepatitis, 5% of all hospital admissions, and 50% of all acute liver failures are caused by it(2).

Before any novel drug is launched into the market, it is tested in-vitro, in animal models, and then progresses onto human clinical trials(1). Weitz’s system can produce up to one-thousand organ droplets per second, each of which can be used in an experiment to test for drug toxicity(1). Clarifying further, he asserts that “Each droplet is like a mini experiment. Normally, if we are running experiments, say in test tubes, we need a milliliter of fluid per test tube. If we were to do a million experiments, we would need a thousand liters of fluid. That’s the equivalent of a thousand milk jugs! Here, each droplet is only a nanoliter, so we can do the whole experiment with one milliliter of fluid, meaning we can do a million more experiments with the same amount of fluid.”

Testing hepatocytes alone on a petri dish is a poor indicator of liver-specific functions because the liver is made up of multiple cells systematically arranged on an extracellular matrix and functionally interdependent(3). The primary hepatocytes, hepatic stellate cells, Kupffer cells, endothelial cells and fibroblasts form the basic components of a functioning liver(3). Weitz’s upgraded system contains hepatocytes (that make up the majority of liver cells and carry out most of the important functions) supported by a network of fibroblasts(3). His microfluidic chip is comprised of a network of constricted, circular channels spanning the micrometer range, the inner phase of which contains hepatocytes mixed in a cell culture solution(3). The surrounding middle phase accommodates fibroblasts in an alginate solution and the two liquids remain separated due to differences in their chemical properties as well as the physics of fluids travelling in narrow channels. Addition of a fluorinated carbon oil interferes with the two aqueous layers, forcing them to become individual monodisperse droplets(3). The hydrogel shell is completed when a 0.15% solution of acetic acid facilitates the cross-linking of alginate to form a gelatinous shell, locking the fibroblasts in place(3). Thus, the aqueous core of hepatocytes are encapsulated by fibroblasts confined to a strong hydrogel network, creating a core-shell hydrogel scaffold of 3D liver micro-tissue in a droplet(3). Using empirical analysis, scientists have shown that albumin secretion and urea synthesis (two important markers of liver function) were significantly higher in a co-culture of hepatocytes and fibroblasts 3D core-shell spheroids compared to a monotypic cell-culture of hepatocyte-only spheroids(3). These results validate the theory that homotypic as well as heterotypic communication between cells are important to achieve optimal organ function in vitro(3).

This system of creating micro-tissues in a droplet with enhanced properties is a step-forward in biomedical science(3). It can be used in experiments to test for a myriad of drugs, chemicals and cosmetics on different human tissue samples, as well as to understand the biological connectivity of contrasting cells(3).

diagram

Image source: DOI: 10.1039/c6lc00231

A simple demonstration of the microfluidic chip that combines different solutions to create a core-shell droplet consisting of two different kinds of liver cells.

References:

  1. National Institute of Biomedical Imaging and Bioengineering. (2016, December 13). New device creates 3D livers in a droplet.ScienceDaily. Retrieved February 9, 2017 from https://www.sciencedaily.com/releases/2016/12/161213112337.htm
  2. Singh, D., Cho, W. C., & Upadhyay, G. (2015). Drug-Induced Liver Toxicity and Prevention by Herbal Antioxidants: An Overview.Frontiers in Physiology,6, 363. http://doi.org/10.3389/fphys.2015.00363
  3. Qiushui Chen, Stefanie Utech, Dong Chen, Radivoje Prodanovic, Jin-Ming Lin and David A. Weitz; Controlled assembly of heterotypic cells in a core– shell scaffold: organ in a droplet; Lab Chip, 2016, 16, 1346; DOI: 10.1039/c6lc00231

Other related articles on 3D on a Chip published in this Open Access Online Scientific Journal include the following:

 

What could replace animal testing – ‘Human-on-a-chip’ from Lawrence Livermore National Laboratory

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One blood sample can be tested for a comprehensive array of cancer cell biomarkers: R&D at WPI

Curator: Marzan Khan, B.Sc

 

A team of mechanical engineers at Worcester Polytechnic Institute (WPI) have developed a fascinating technology – a liquid biopsy chip that captures and detects metastatic cancer cells, just from a small blood sample of cancer patients(1). This device is a recent development in the scientific field and holds tremendous potential that will allow doctors to spot signs of metastasis for a variety of cancers at an early stage and initiate an appropriate course of treatment(1).

Metastasis occurs when cancer cells break away from their site of origin and spread to other parts of the body via the lymph or the bloodstream, where they give rise to secondary tumors(2). By this time, the cancer is at an advanced stage and it becomes increasingly difficult to fight the disease. The cells that are shed by primary and metastatic cancers are called circulating tumor cells (CTCs) and their numbers lie in the range of 1–77,200/m(3). The basis of the liquid biopsy chip test is to capture these circulating tumor cells in the patient’s blood and identify the cell type through specific interaction with antibodies(4).

The chip is comprised of individual test units or small elements, about 3 millimeters wide(4). Each small element contains a network of carbon nanotube sensors in a well which are functionalized with antibodies(4). These antibodies will bind cell-surface antigens or protein markers unique for each type of cancer cell. Specific interaction between a cell surface protein and its corresponding antibody is a thermodynamic event that causes a change in free energy which is transduced into electricity(3). This electrical signature is picked up by the semi-conducting carbon nanotubes and can be seen as electrical spikes(4). Specific interactions create an increase in electrical signal, whereas non-specific interactions cause a decrease in signal or no change at all(4). Capture efficiency of cancer cells with the chip has been reported to range between 62-100%(4).

The liquid biopsy chip is also more advanced than microfluidics for several reasons. Firstly, the nanotube-chip arrays can capture as well as detect cancer cells, while microfluidics can only capture(4). Samples do not need to be processed for labeling or fixation, so the cell structures are preserved(4). Unlike microfluidics, these nanotubes will also capture tiny structures called exosomes spanning the nanometer range that are produced from cancer cells and carry the same biomarkers(4).

Pancreatic cancer is the fourth leading cause of cancer-associated deaths in the United states, with a survival window of 5 years in only 6% of the cases with treatment(5). In most patients, the disease has already metastasized at the time of diagnosis due to the lack of early-diagnostic markers, affecting some of the major organs such as liver, lungs and the peritoneum(5,6). Despite surgical resection of the primary tumor, the recurrence of local and metastatic tumors is rampant(5). Metastasis is the major cause of mortality in cancers(5). The liquid biopsy chip, that identifies CTCs can thus become an effective diagnostic tool in early detection of cancer as well as provide information into the efficacy of treatment(3). At present, ongoing experiments with this device involve testing for breast cancers but Dr. Balaji Panchapakesan and his team of engineers at WPI are optimistic about incorporating pancreatic and lung cancers into their research.

REFERENCES

1.Nanophenotype. Researchers build liquid biopsy chip that detects metastatic cancer cells in blood: One blood sample can be tested for a comprehensive array of cancer cell biomarkers. 27 Dec 2016. Genesis Nanotechnology,Inc

https://genesisnanotech.wordpress.com/2016/12/27/researchers-build-liquid-biopsy-chip-that-detects-metastatic-cancer-cells-in-blood-one-blood-sample-can-be-tested-for-a-comprehensive-array-of-cancer-cell-markers/

2.Martin TA, Ye L, Sanders AJ, et al. Cancer Invasion and Metastasis: Molecular and Cellular Perspective. In: Madame Curie Bioscience Database [Internet]. Austin (TX): Landes Bioscience; 2000-2013.

https://www.ncbi.nlm.nih.gov/books/NBK164700/

3.F Khosravi, B King, S Rai, G Kloecker, E Wickstrom, B Panchapakesan. Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells. 23 Dec 2013. IEEE Nanotechnology Magazine 7 (4), 20-26

Nanotube devices for digital profiling of cancer biomarkers and circulating tumor cells

4.Farhad Khosravi, Patrick J Trainor, Christopher Lambert, Goetz Kloecker, Eric Wickstrom, Shesh N Rai and Balaji Panchapakesan. Static micro-array isolation, dynamic time series classification, capture and enumeration of spiked breast cancer cells in blood: the nanotube–CTC chip. 29 Sept 2016. Nanotechnology. Vol 27, No.44. IOP Publishing Ltd

http://iopscience.iop.org/article/10.1088/0957-4484/27/44/44LT03/meta

5.Seyfried, T. N., & Huysentruyt, L. C. (2013). On the Origin of Cancer Metastasis. Critical Reviews in Oncogenesis18(1-2), 43–73.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3597235/

6.Deeb, A., Haque, S.-U., & Olowoure, O. (2015). Pulmonary metastases in pancreatic cancer, is there a survival influence? Journal of Gastrointestinal Oncology6(3), E48–E51. http://doi.org/10.3978/j.issn.2078-6891.2014.114

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4397254/

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Translation of whole human genome sequencing to clinical practice: The Joint Initiative for Metrology in Biology (JIMB) is a collaboration between the National Institute of Standards & Technology (NIST) and Stanford University.

Reporter: Aviva Lev-Ari, PhD, RN

 

JIMB’s mission is to advance the science of measuring biology (biometrology). JIMB is pursuing fundamental research, standards development, and the translation of products that support confidence in biological measurements and reliable reuse of materials and results. JIMB is particularly focused on measurements and technologies that impact, are related to, or enabled by ongoing advances in and associated with the reading and writing of DNA.

Stanford innovators and industry entrepreneurs have joined forces with the measurement experts from NIST to create a new engine powering the bioeconomy. It’s called JIMB — “Jim Bee” — the Joint Initiative for Metrology in Biology. JIMB unites people, platforms, and projects to underpin standards-based research and innovation in biometrology.

Genome in a Bottle
Authoritative Characterization of
Benchmark Human Genomes


The Genome in a Bottle Consortium is a public-private-academic consortium hosted by NIST to develop the technical infrastructure (reference standards, reference methods, and reference data) to enable translation of whole human genome sequencing to clinical practice. The priority of GIAB is authoritative characterization of human genomes for use in analytical validation and technology development, optimization, and demonstration. In 2015, NIST released the pilot genome Reference Material 8398, which is genomic DNA (NA12878) derived from a large batch of the Coriell cell line GM12878, characterized for high-confidence SNPs, indel, and homozygous reference regions (Zook, et al., Nature Biotechnology 2014).

There are four new GIAB reference materials available.  With the addition of these new reference materials (RMs) to a growing collection of “measuring sticks” for gene sequencing, we can now provide laboratories with even more capability to accurately “map” DNA for genetic testing, medical diagnoses and future customized drug therapies. The new tools feature sequenced genes from individuals in two genetically diverse groups, Asians and Ashkenazic Jews; a father-mother-child trio set from Ashkenazic Jews; and four microbes commonly used in research. For more information click here.  To purchase them, visit:

Data and analyses are publicly available (GIAB GitHub). A description of data generated by GIAB is published here. To standardize best practices for using GIAB genomes for benchmarking, we are working with the Global Alliance for Genomics and Health Benchmarking Team (benchmarking tools).

High-confidence small variant and homozygous reference calls are available for NA12878, the Ashkenazim trio, and the Chinese son with respect to GRCh37.  Preliminary high-confidence calls with respect to GRCh38 are also available for NA12878.   The latest version of these calls is under the latest directory for each genome on the GIAB FTP.

The consortium was initiated in a set of meetings in 2011 and 2012, and the consortium holds open, public workshops in January at Stanford University in Palo Alto, CA and in August/September at NIST in Gaithersburg, MD. Slides from workshops and conferences are available online. The consortium is open and welcomes new participants.

SOURCE

Stanford innovators and industry entrepreneurs have joined forces with the measurement experts from NIST to create a new engine powering the bioeconomy. It’s called JIMB — “Jim Bee” — the Joint Initiative for Metrology in Biology. JIMB unites people, platforms, and projects to underpin standards-based research and innovation in biometrology.

JIMB World Metrology Day Symposium

JIMB’s mission is to motivate standards-based measurement innovation to facilitate translation of basic science and technology development breakthroughs in genomics and synthetic biology.

By advancing biometrology, JIMB will push the boundaries of discovery science, accelerate technology development and dissemination, and generate reusable resources.

 SOURCE

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