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NK-Cell-Derived Exosomes, Harvested from On‐Chip Biogenesis, Exhibit Antitumor Activity Vs Non-Small-Cell Lung Cancer Cells

Building on the promise of emerging therapies to deploy the body’s “natural killer” immune cells to fight cancer, researchers at the University of Michigan (U-M) Rogel Cancer Center and U-M College of Engineering have gone one step further. They’ve developed what is believed to be the first systematic way to capture natural killer cells and get them to release cancer-killing exosomes. These nano-scale exosomes are thousands of times smaller than natural killer (NK) cells and thus better able to penetrate cancer cells’ defenses. A proof-of-concept study in blood samples from five patients with non-small cell lung cancer demonstrated that the approach was able to capture natural killer cells on a microfluidic chip and use them to release NK exosomes. The multidisciplinary team, which included U-M engineers and oncologists, further demonstrated that the exosomes could effectively kill circulating tumor cells in cell cultures, according to findings published online on January 28, 2021 in Advanced Science. The open-access article is titled “On‐Chip Biogenesis of Circulating NK Cell‐Derived Exosomes in Non‐Small Cell Lung Cancer Exhibits Antitumoral Activity.” “Exosomes are small sacs, of proteins and/or other molecules, that are naturally released by almost every type of cell in the body,” says Yoon-Tae Kang, PhD, a Research Fellow in Chemical Engineering at U-M and co-lead author of the study. “In this case, we wanted to expand our understanding of NK exosomes and try to harness their cancer-killing potential.” Compared to NK cells, NK exosomes are more stable and easier to modify for therapeutic purposes, Dr. Kang says. The system also has potential to help diagnose and monitor cancer, the study notes. Harnessing the power of NK cells has long presented a tantalizing possibility for researchers.

LSD May Offer Viable Treatment for Certain Mental Disorders; New Work in Mouse Model Increases Understanding of the Mechanism of Psychedelic’s Impact on Brain and Potential for Therapeutic Use

Researchers from McGill University (Montreal, Canada) have discovered, for the first time, one of the possible mechanisms that contributes to the ability of lysergic acid diethylamide (LSD) to increase social interaction. The findings, which could help unlock potential therapeutic applications in treating certain psychiatric diseases, including anxiety and alcohol use disorders, we published online on January 25, 2021 in PNAS. The open-access article is titled “Lysergic Acid Diethylamide (LSD) Promotes Social Behavior Through mTORC1 in the Excitatory Neurotransmission.” Psychedelic drugs, including LSD, were popular in the 1970s (see image of early LSD advocate Dr. Timothy Leary) and have been gaining popularity over the past decade, with reports of young professionals claiming to regularly take small non-hallucinogenic micro-doses of LSD to boost their productivity and creativity and to increase their empathy. The mechanism of action of LSD on the brain, however, has remained a mystery. To conduct their study, the researchers administered a low dose of LSD to mice over a period of seven days, resulting in an observable increase in the sociability of the mice. "This increased sociability occurs because the LSD activates the serotonin 5-HT2A receptors and the AMPA receptors, which is a glutamate receptor--the main brain excitatory neurotransmitters--in the prefrontal cortex, and also activates a cellular protein called mTORC 1," explains Danilo De Gregorio, PharmD, PhD, who is a postdoctoral fellow in the Neurobiological Psychiatry Unit at McGill, and the study's first author. "These three factors, taken together, promote social interaction in mice, which is the equivalent of empathy and social behavior in humans." [Editor’s Note: 5-HT2A is the abbreviation for 5-hydroxytryptamine receptor 2A.

Scientists Discover New Transmission Mechanism (Exosome-Mediated) of Sorafenib Resistance Among Hepatocellular Carcinoma Cells; A Circular RNA (circRNA-SORE) Increases Sorafenib Resistance & Silencing of circRNA-SORE Overcomes This Resistance in Models

Hepatocellular carcinoma (HCC) is the most common primary liver tumor with an increasing global incidence. In 2018, HCC was the sixth most frequently diagnosed cancer and the fourth-leading cause of cancer-related death worldwide. Sorafenib is the first FDA-approved targeted therapy for advanced HCC. A previous study showed that sorafenib prolonged the median overall survival (OS) by 2.3−3 months in advanced HCC patients that did not qualify for liver transplantation or resection. However, sorafenib resistance in HCC is usually observed within 6 months of treatment, thereby making the follow-up therapy rather formidable. Recently, a research team led by Professor Xiujun Cai (photo) (https://person.zju.edu.cn/en/0094417?utm_source=miragenews&utm_medium=mi...), PhD, from Sir Run-Run Shaw Hospital affiliated with the Zhejiang University School of Medicine has made breakthroughs in sorafenib resistance. Dr. Cai is the President of Sir Run Run Shaw Hospital of Zhejiang University and the Director of both the Institute of Minimally Invasive Surgery of Zhejiang University and the Key Lab of Surgery of Zhejiang Province. The new findings were published online on December 26, 2020 in Signal Transduction and Targeted Therapy. The open-access article is titled “CircRNA-SORE Mediates Sorafenib Resistance in Hepatocellular Carcinoma by Stabilizing YBX1” (https://www.nature.com/articles/s41392-020-00375-5.pdf?utm_source=mirage...). The experiment results elucidate the crucial role of circRNA-SORE (a circular RNA upregulated in sorafenib-resistant HCC cells) in sorafenib resistance and its functioning mechanism.

Split Biosciences, Now Parse Biosciences, Announces $7M in Series A Funding to Democratize Single-Cell RNA Sequencing

On January 26, 2021, Split Biosciences, a company providing researchers scalable and flexible single-cell sequencing solutions, announced $7M in Series A funding. The funding round was led by Bioeconomy Capital, an early-stage VC firm specializing in companies developing life science tools, with participation from new and existing angel investors. Split Bio also announced a rebrand of the company to Parse Biosciences (http://www.parsebiosciences.com/). The new funding will be used to continue scaling the commercial roll-out of Parse Bioscience’s Whole Transcriptome Kit, which enables researchers to profile up to 100,000 cells in parallel across up to 48 samples. In addition to increased scalability, Parse Biosciences’s technology also provides researchers with higher data quality. Parse enables researchers to increase gene detection in individual cells, while dramatically reducing confounding artifacts that are common in single-cell sequencing experiments. The new brand comes as Parse Biosciences matures beyond the initial academic research upon which the company was founded and in the wake of significant advancements in its technology. “We have spent the last three years developing a product that more scientists could actually use,” said Charlie Roco, PhD, Co-Founder and CTO of Parse Biosciences. “Our kits are now operating at a higher level than anything else we’ve seen on the market and our company has evolved beyond our original SPLiT-seq method. We wanted our brand to reflect that.” Researchers in both the pharmaceutical industry and academia have increasingly leveraged single-cell technologies to drive discovery.

Tony Fauci Interviewed by Science Legend Leroy Hood & Presented Luminary Award of Precision Medicine World Conference (PMWC 2021) at Opening Day of PMWC 2021 Virtual Meeting (January 25-27)--“21st Century Precision Medicine in the Age of COVID-19”

The highlight of Monday’s opening day of the Precision Medicine World Conference Virtual Meeting (PMWC 2021) “21st Century Precision Medicine in the Age of COVID-19” (Jan 25-27) (https://www.pmwcintl.com/covid/) was an hour-long Q&A session in which the extraordinary scientist Leroy Hood, MD, PhD, interviewed Anthony Fauci (photo, see additional photos at end), MD, Director of the National Institute of Allergy & Infectious Diseases (NIAID) & US Leading Coronavirus Task Force Expert, covering a wide range of key COVID-19 topics. Dr. Hood also presented Dr. Fauci with the PMWC Luminary Award, which “recognizes individuals who have made significant contributions to accelerate personalized medicine within the clinical setting.” In presenting the Award, Dr. Hood added that, in addition to all his earlier achievements, the Award recognized Dr. Fauci’s “utterly stellar service in the last year.” Dr. Hood (https://www.pmwcintl.com/speaker/lee-hood_providence-health_2021covi) is world-renowned for his visionary work in spearheading the development of a suite of five automated instruments that have revolutionized biomedical, biochemical, genetic, and biologic research, as well as pharmaceutical development--the automated protein synthesizer, the automated protein sequencer, the automated DNA synthesizer, the automated DNA sequencer, and the ink-jet oligonucleotide synthesizer. Dr. Hood is currently Senior Vice President and Chief Strategy Officer for the Institute for Systems Biology (ISB) and Senior Vice President and Chief Science Office for Providence St. Joseph Health.

Study Finds Especially High Rates of Lupus in Certain U.S. Racial/Ethnic Groups: American Indians/Alaska Natives & Black Females

The U.S. prevalence of the autoimmune disease systemic lupus erythematosus (lupus) is 72.8 cases per 100,000 individuals, according to an analysis of population-based registries. The analysis, which was published online on January 20, 2021 in Arthritis & Rheumatology, found that the rate is 9 times higher for females than males (128.7 vs. 14.6 per 100,000), and it's highest among American Indians/Alaska Natives and Black females. The open-access article is titled “Prevalence of Systemic Lupus Erythematosus in the United States: Estimates from a Meta‐Analysis of the Centers for Disease Control and Prevention National Lupus Registries.” The study's investigators estimate that in 2018, a total of 204,295 persons in the United States had lupus. "This meta-analysis is a culmination of almost two decades of work from a network of five Centers of Disease Control and Prevention (CDC)-funded population-based registries and provides prevalence estimates for systemic lupus erythematosus among the major racial/ethnic demographics in the United States," said lead author Peter M. Izmirly (photo), MD, of the New York University (NYU) School of Medicine. "These detailed estimates on how many Americans are affected by lupus may have implications for the various stakeholders who study and treat the disease."

[News release] [Arthritis & Rheumatology article]

BrainStorm Announces Publication of Preclinical Data Highlighting the Potential of NurOwn®-Derived Exosome-Based Treatment for COVID-19 Acute Respiratory Distress Syndromw (ARDS)

On January 20, 2021, BrainStorm Cell Therapeutics Inc. (NASDAQ: BCLI), a leading developer of adult stem cell therapies for neurodegenerative diseases, announced the peer-reviewed publication of a preclinical study in Stem Cell and Research Therapy (https://stemcellres.biomedcentral.com/articles/10.1186/s13287-021-02143-w). The open-access article, entitled "MSC-NTF (NurOwn®) Exosomes: A Novel Therapeutic Modality in the Mouse LPS-Induced ARDS Model," and published online on January 19, 2021, evaluated the use of NurOwn® (MSC-NTF cell)-derived exosomes in a mouse model of acute respiratory distress syndrome (ARDS). ARDS is a type of respiratory failure that is frequently associated with COVID-19 and mediated by dysregulated cytokine production. While there are currently no effective therapies to prevent or reverse ARDS, mesenchymal stem cell (MSC)-derived exosomes have been suggested as a potential novel treatment option due to their ability to penetrate deep into tissues and efficiently deliver immunomodulatory molecules. Results from the recently published study showed that intratracheal administration of NurOwn®-derived exosomes led to a statistically significant reduction in lung disease severity score (p < 0.05; based on criteria set forth by the American Thoracic Society Documents: Matute-Bello et al., Am J Respir Cell Mol Biol 44: 725-738, 2011) and improvements in several additional clinically relevant lipopolysaccharide (LPS)-induced ARDS markers such as lung function, fibrin presence, neutrophil accumulation, cytokine expression, and blood oxygenation levels. Notably, these improvements were significantly superior to those observed following administration of naïve MSC-derived exosomes.

Cryo-Electron Microscopy Study Allows Researchers to Visualize Structural Changes in E. coli Enzyme Synthesizing Ribosomal RNA That Shift It Between Turbo- and Slow-Modes Depending on Bacteria's Growth Rate

The enzyme that makes RNA from a DNA template is altered to slow the production of ribosomal RNA (rRNA), the most abundant type of RNA within cells, when resources are scarce and the bacteria Escherichia coli needs to slow its growth. Researchers used cryo-electron microscopy (cryo-EM) to capture the structures of the RNA polymerase (see image left and below) while in complex with DNA and showed how its activity is changed in response to poor-growth conditions. A paper describing this research, led by Penn State scientists, was published online on January 22, 2020 in the journal Nature Communications. The open-access article is titled “Structural Basis of Ribosomal RNA Transcription Regulation.” "RNA polymerase is an enzyme that produces a variety of RNAs using information encoded in DNA," said Katsuhiko Murakami, Professor of Biochemistry and Molecular Biology at Penn State and leader of the research team. "This is one of the key steps in the central dogma of molecular biology: transferring genetic information from DNA to RNA, which in turn often codes for protein. It's required for life and the process is basically shared from bacteria to humans. We are interested in understanding how the structure of RNA polymerase is changed for modulating its activity and function, but it's been difficult to capture using traditional methods like X-ray crystallography, which requires crystallizing a sample to determine its structure." RNA polymerase functions by binding to specific DNA sequences called "promoters" found near the beginning of genes that are going to be made into RNA. To understand the structure and function of the polymerase during this interaction, researchers need to capture the polymerase while it is bound to the promoter DNA, but the interaction can be very unstable at some promoters.

Possible Parkinson's Disease Therapeutics (BMP5 & BMP7) Discovered in Alpha-Synuclein Mouse Model

Researchers at the Ben-Gurion University (BGU) of the Negev, and collaborators, have discovered that the bone morphogenetic proteins BMP5 and BMP7 (BMP5/7) offer promising therapeutics that could slow down or halt the progression of Parkinson's disease. The findings were published online on November 30, 2020 in Brain. The open-access article is titled “BMP5/7 Protect Dopaminergic Neurons in an Alpha-Synuclein Mouse Model of Parkinson’s Disease.” Parkinson's disease, which affects over one million people in U.S. and 10 million worldwide, causes tremors and severe movement impairment due to progressive degeneration of dopamine-producing brain cells. It is believed that the protein "alpha-synuclein," present in all human brains, misfolds and forms toxic clumps in these cells, which causes the disease. While current Parkinson's disease therapies improve symptoms, they are not effective in advanced illness stages and, unfortunately, do not slow or cure the disease. Claude Brodski (photo), MD, head of the BGU's Laboratory for Molecular Neuroscience, discovered that BMP5/7 signaling in neurons was significantly reduced in dopamine-producing brain cells, which could contribute to Parkinson's disease advancement. "Indeed, we found that BMP5/7 treatment can, in a Parkinson's disease mouse model, efficiently prevent movement impairments caused by the accumulation of alpha-synuclein and reverse the loss of dopamine-producing brain cells," says Dr. Brodski. "These findings are very promising, because they suggest that BMP5/7 could slow or stop Parkinson's disease progression. Currently, we are focusing all our efforts on bringing our discovery closer to clinical application." BGN Technologies, Ben-Gurion University's technology transfer company, has filed several patent applications covering this breakthrough discovery.

Journal Article Published on Codiak’s Versatile engEx™ Platform for Engineered Exosomes; Publication Details Characterization of Novel Scaffold Proteins That Can Enable Engineered Exosomes with Defined Therapeutic Properties

On January 21, 2021, Codiak BioSciences, Inc. (NASDAQ: CDAK), a clinical-stage biopharmaceutical company focused on pioneering the development of exosome-based therapeutics as a new class of medicines, announced the advance online publication of a new manuscript. The paper, entitled “A Versatile Platform for Generating Engineered Extracellular Vesicles with Defined Therapeutic Properties” by Kevin Dooley (PhD, Associate Director, Protein & Cellular Engineering, Codiak) et al., was published online on January 20, 2021 (https://www.cell.com/molecular-therapy-family/molecular-therapy/fulltext/S1525-0016(21)00020-4), and will appear in an upcoming print issue of Molecular Therapy, the journal of the American Society of Gene and Cell Therapy. The publication describes the identification and characterization of two novel exosome-associated proteins, PTGFRN and BASP1, that enable Codiak’s proprietary engEx Platform and facilitate precise design and engineering of exosomes for potential therapeutic purposes. PTGFRN and BASP1 are highly abundant, naturally-occurring proteins that, through Codiak’s research, have been found to enable high-density exosome surface display and luminal loading of a wide range of macromolecules that can be directed to specific target cells of interest. In preclinical models, the use of PTGFRN and BASP1 to display biologically active molecules on the surface of or inside exosomes, respectively, resulted in uniform incorporation and increased potency, suggesting the potential utility of these engineered exosomes in a wide variety of therapeutic settings. These two proteins can also be used in combination, which further broadens the utility and modular approach to designing engineered exosomes for targeted delivery of numerous drug payloads to specific cells.

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