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Archive - 2018

December 11th

Plants Produce Catnip Terpene (Nepetalactone) in Two-Step Enzymatic Process Not Seen Before; Unusual Process May Be Useful in Synthesis of Anti-Cancer Drugs Such As Vinblastine & Vincristine

Researchers at John Innes Centre in the UK have shed light on how catnip – a plant from the genus Nepeta and also known as catmint - produces the chemical that sends cats into a state of wanton abandon. The remarkable effect catnip has on cats is well known thanks to the scores on online videos showing pets enjoying its intoxicating highs. The substance that triggers this state of feline ecstasy is called nepetalactone, a type of chemical called a terpene. This simple, small molecule is part of an unusual chain of events, not previously seen by chemists. The researchers believe that understanding the production of these nepetalactones could help them recreate the way that plants synthesize other chemicals like vinblastine, which is used for chemotherapy. This could lead to the ability to create these useful medicines more efficiently and quickly than we are currently able to harvest them from nature. Usually in plants, for example peppermint, terpenes are formed by a single enzyme. In their paper published online on December 10, 2018 in Nature Chemical Biology, the John Innes researchers report that, in catnip, terpenes are formed in a two-step process; an enzyme activates a precursor compound which is then acted on by a second enzyme to produce the substance of interest. The article is titled “Uncoupled Activation and Cyclization in Catmint Reductive Terpenoid Biosynthesis.” This two-step process has previously never been observed, and the researchers also expect something similar is occurring in the synthesis of anti-cancer drugs vincristine and vinblastine from Madagascan periwinkle, Catharanthus roseus, and elsewhere in olive and snapdragon. In the publication, the team describe the process by which catmint produces nepetalactone in microscopic glands on the underside of its leaves.

December 10th

Study Supports Potential for Tailoring Patient-Specific Treatments for Acute Myeloid Leukemia (AML)

Advances in rapid screening of leukemia cells for drug susceptibility and resistance are bringing scientists closer to patient-tailored treatment for acute myeloid leukemia (AML). Research on the drug responses of leukemia stem cells may reveal why some attempts to treat are not successful or why initially promising treatment results are not sustained. AML is a serious disorder of certain blood-forming cells. In this disease, certain early precursor cells in the bone marrow that usually develop into white blood cells don't mature properly. They remain frozen as primitive cells called blasts, unable to further differentiate and mature. These can accumulate and cause low blood counts that reduce the ability to fight infections, and low platelet counts that cause risk of life-threatening hemorrhage. Leukemia stem cells - the progenitors for the immature, cancerous blood cells - propagate AML, and also play a role in the cancer returning after treatment. Cancer researchers are interested in how genes are expressed in this cell population, because this data may hold clues to resistance to standard therapies and answers to why some patients relapse. A study presented at the 60th Annual Meeting of the American Society of Hematology in San Diego (December 1-4, 2018) looked at the drug response patterns of stem cells and blast cells taken from individual patients diagnosed with AML. The information was gathered through high-throughput screening, a state-of-the-art method for quickly evaluating and testing many samples. The researchers found that leukemia stem cells and blast cells diverged in their drug susceptibility patterns, and also that these patterns differed from patient to patient.

Lifespan Extension at Low Temperatures Is Actively Controlled by Genes, Not by Passive Lowering of Metabolic Rate Reducing Reactive Oxygen Species (ROS), New Study Suggests

Why do we age? Despite more than a century of research (and a vast industry of youth-promising products), what causes our cells and organs to deteriorate with age is still largely unknown. One known factor is temperature: Many animal species live longer at lower temperature than they do at higher temperatures. As a result, "there are people out there who believe, strongly, that if you take a cold shower every day it will extend your lifespan," says Kristin Gribble (photo), PhD, an Assistant Scientist at the Marine Biological Laboratory(MBL) in Woods Hole, Massachusetts (the MBL is an affiliate of the University of Chicago). But a new study from Dr. Gribble's lab indicates that it's not just a matter of turning down the thermostat. Rather, the extent to which temperature affects lifespan depends on an individual's genes. The study from Dr. Gribble's group, which was published in Experimental Gerontology (114: 99-106; 2018), was conducted in the rotifer, a tiny animal that has been used in aging research for more than 100 years. Gribble's team exposed 11 genetically distinct strains of rotifers (Brachionus) to low temperature, with the hypothesis that if the mechanism of lifespan extension is purely a thermodynamic response, all strains should have a similar lifespan increase. However, the median lifespan increase ranged from 6 percent to 100 percent across the strains, they found. They also observed differences in mortality rate. The new study is titled “Congeneric Variability in Lifespan Extension and Onset of Senescence Suggest Active Regulation of Aging in Response to Low Temperature.” This study clarifies the role of temperature in the free-radical theory of aging, which has dominated the field since the 1950s.

December 9th

A-T Children’s Project Announces Selection of First Child to Receive ASO Gene Therapy for Ataxia-Telangiectasia

On November 30, 2018, the Ataxia-Telangiectasia (A-T) Children’s Project and its President Brad Margus announced that the Project has selected a little, 18-month girl on the west coast of the U.S. to be the first A-T child in history to receive gene therapy. The Project had the pleasure of letting th girl's parents know the exciting news last week. How was the first child selected? The laboratory of Dr. Tim Yu at Boston Children’s Hospital/Harvard collected and grew skin, blood, and stem cells from three different young children who we believed had the right type of mutations in their A-T genes to be treated with an antisense oligonucleotide (ASO) gene therapy approach. The scientists then made many different oligonucleotides designed to silence each of the children’s mutations and tested them in each child’s cells. In the end, the group identified several oligonucleotide molecules that worked really well in this little girl’s cells, not only silencing her mutation and causing the A-T protein to be made correctly, but also causing downstream biological pathways to be activated as though her cells were from a healthy child (confirming this downstream function took us longer than planned to do, but now gives us more confidence to move forward). This means that we now have both our drug and our patient selected. Very soon, we’ll be signing a contract to begin the manufacture of enough quantity of the drug to run our “n of 1” clinical trial (we’ll keep the other oligonucleotides that worked as backups). We’ll also make sure that the drug produced will be clinical-grade to satisfy the FDA. As soon as we receive the first batch of this final version of the drug, we’ll test it for safety in rats before applying to the FDA for approval to start testing it in a human.

November 27th

Sugars & Microbiome in Mother's Milk Influence Neonatal Rotavirus Infection

Using a multidisciplinary approach, an international team of researchers from several institutions, including Baylor College of Medicine, reveals that complex interactions between sugars and the microbiome in human milk influence neonatal rotavirus infection. Reported online on November 27, 2018 in the journal Nature Communications, this study provides new understanding of rotavirus infections in newborns and identifies maternal components that could improve the performance of live, attenuated rotavirus vaccines. The open-access article is titled “Human Milk Oligosaccharides, Milk Microbiome and Infant Gut Microbiome Modulate Neonatal Rotavirus Infection.” "Rotavirus infection causes diarrhea and vomiting primarily in children younger than 5, with the exception of babies younger than 28 days of age, who usually have no symptoms. However, in some places, infections in newborns are associated with severe gastrointestinal problems. What factors mediate differences between newborns with and without symptoms are not clearly understood," said first and corresponding author Dr. Sasirekha Ramani (photo), Assistant Professor of Molecular Virology and Microbiology at Baylor College of Medicine. "We began our investigation years ago by determining that a particular strain of rotavirus was associated with both asymptomatic infections and clinical symptoms in newborns." Dr. Ramani and her colleagues first looked for answers from the perspective of the virus. They investigated whether factors such as the amount of virus in newborns or the genome of the virus could be linked to the presence of symptoms in newborns, but did not find any connection between those factors. The researchers then posed the question from the perspective of the newborn.

International Society for Extracellular Vesicles (ISEV) Releases 2018 Update of 2014 Guidelines for Studies of Extracellular Vesicles

On November 23, 2018, The International Society for Extracellular Vesicles (ISEV) published online an open-access position paper titled “Minimal Information for Studies of Extracellular Vesicles 2018 (MISEV2018); A Position Statement of the International Society for Extracellular Vesicles and Update of the MISEV2014 Guidelines.” The article is scheduled for hard-copy publication in Volume 8, Issue 1, of the 2019 Journal of Extracellular Vesicles. In the article abstract, the authors note the following: “The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The ISEV proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation.

Researching Rare Genetic Disease, Scientists Uncover Key Immune Regulator

Scientists at Scripps Research in California have found an important immune system-regulating protein that in principle could be targeted to treat cancers and chronic viral infections. In a study published online on November 12, 2018 in Nature Chemical Biology, the scientists set out to determine the function of a protein, ABHD12 (abhydrolase domain containing protein 12), whose absence causes a rare genetic disease featuring a host of brain and nerve problems. The article is titled “Selective Blockade of the Lyso-PS Lipase ABHD12 Stimulates Immune Responses in Vivo.” The researchers found that ABHD12 normally acts as a powerful "brake" on the immune system to keep it from becoming harmfully overactive. Mice engineered without the protein have signs of elevated inflammation, and their immune systems are more likely to overreact to a viral infection. The discovery suggests that the absence of ABHD12 in people with mutant versions of its gene may cause neurological disease at least in part via excessive immune activity. It also indicates that ABHD12 may be a useful target for drugs that boost the immune system--for example against cancers and viruses that normally persist by shutting down people's immune defenses. "This is a good example of how the study of a rare genetic disease can reveal a pathway that plays a key role in human biology," says study co-senior author Benjamin Cravatt, PhD, Professor and Chair of the Department of Chemical Physiology at Scripps Research. The rare disease in this case is a mix of progressive brain, peripheral nerve, and eye problems that scientists have given the acronym PHARC (polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, and cataract). Since 2010, researchers have known that PHARC is caused by gene mutations that prevent ABHD12 from being made.

November 26th

FDA Approves ACTpen for Genentech’s ACTEMRA, a Single-Dose, Prefilled Autoinjector for Treatment of Rheumatoid Arthritis, Giant Cell Arteritis, & Two Forms of Juvenile Arthritis

On November 26,2018, Genentech, a member of the Roche Group (SIX: RO, ROG; OTCQX: RHHBY), announced that the U.S. Food and Drug Administration (FDA) has approved ACTPen™ 162 mg/0.9 mL, a single-dose prefilled autoinjector for Actemra® (tocilizumab) as an additional formulation for adult patients with moderate to severe active rheumatoid arthritis (RA) who have had an inadequate response to one or more disease-modifying anti-rheumatic drugs (DMARDs), and for adult patients with giant cell arteritis (GCA). Further, the ACTPen can be administered by caregivers to patients two years of age and older with active polyarticular juvenile idiopathic arthritis (PJIA) or active systemic juvenile idiopathic arthritis (SJIA). The ability of pediatric patients to self-inject with the ACTPen has not been tested. The ACTPen is expected to be available in January 2019. “When it comes to the administration of medicines, we believe patients should have choices, when possible,” said Sandra Horning, MD, Chief Medical Officer and Head of Global Product Development for Roche/Genentech. “With ACTPen for Actemra, we are pleased to offer an additional option to patients who may prefer using the new autoinjector over other formulations.”The FDA first approved Actemra intravenous infusion formulation (IV) for adults with RA in January 2010 and Actemra pre-filled syringe (PFS) formulations for subcutaneous injection (SC) for adults with RA in October 2013. In May 2017, Actemra SC became the first therapy approved by the FDA for the treatment of adult patients with GCA, a chronic and severe form of vasculitis characterized by inflammation of certain large blood vessels.

Perivascular Dendritic Cells Elicit Anaphylaxis by Relaying Allergens to Mast Cells Via Microvesicles

In work published online on November 9, 2018, in Science, Duke University Medical Center researchers, and colleagues, demonstrate that IgE-sensitized mast cells (MCs) (image) are indirectly activated by blood-borne allergens. In addition, the study revealshow perivascular dendritic cells (DCs) continuously sample blood and initiated and markedly enhance inflammatory and immune responses by rapidly discharging antigen-bearing microvesicles (MVs) to surrounding immune cells. the Science article is titled “Perivascular Dendritic Cells Elicit Anaphylaxis by Relaying Allergens to Mast Cells Via Microvesicles.” The results may resolve the conundrum of how mast cells, which are extravascular, are able to perceive and react to blood-borne allergens. The scientists describe the existence of a CD301b+ perivascular DC subset that continuously samples blood and relays antigens to neighboring MCs, which vigorously degranulate and trigger anaphylaxis. DC antigen transfer involved the active discharge of surface-associated antigens on 0.5- to 1.0-micrometer MVs generated by vacuolar protein sorting 4 (VPS4). Antigen sharing by DCs is not limited to MCs, as neighboring DCs also acquire antigen-bearing MVs. This capacity of antigen-bearing MVs to various immune cells in the perivascular space potentiates inflammatory and immune responses to blood-borne antigens. Anaphylaxis is a life-threatening allergic reaction triggered after antigen-specific immunoglobulin E (IgE) antibodies bind to target allergens. These antibodies than cross-link IgE-specific Fc receptors on the surface of MCs. The MCs rapidly release inflammatory mediators, including histamine, resulting in smooth muscle contraction, vasodilation, and blood vessel leakage.

Exosome-Like Nanoparticles (ELNs) Derived from Plants Are Taken Up by Mouse Gut Microbiota and Can Ameliorate Disease

In work published in the November 14, 2018 issue of Cell Host & Microbe, researchers from the James Graham Brown Cancer Center, Department of Microbiology & Immunology, University of Louisville in Kentucky, together with colleagues, demonstrate that plant-derived exosome-like nanoparticles (ELNs) are taken up by the gut microbiota and contain RNA that alter the mouse microbiome composition and host physiology. The article is titled “Plant-Derived Exosomal MicroRNAs Shape the Gut Microbiota.” Specifically, the authors show that ginger ELNs (GELNs) are preferentially taken up by Lactobacillaceae in a GELN lipid-dependent manner and contain microRNAs (miRNAs) that target various genes in Lactobacillus rhamnosus (LGG). In particular, the authors noted that the GELN mdo-miR7267-3p-mediated targeting of the LGG monooxygenase ycnE yields increased indole-3-carboxaldehyde (I3A). GELN-RNAs or I3A, a ligand for aryl hydrocarbon receptor, are sufficient to induce production of IL-22, which is linked to barrier function improvement. According to the authors, these functions of GELN-RNAs can ameliorate mouse colitis via IL-22-dependent mechanisms. The authors conclude that their findings indicate how plant products and their effects on the microbiome can be used to target specific host processes to alleviate disease. Note that the image here was taken from the article abstract and can be much better viewed at the abstract itself (at the link below).

[Cell Host & Microbe abstract]