Lifeboat Foundation

Turning genes on and off as easily and predictably as flicking a switch could be a powerful tool in medicine and biotech. A type of technology called a riboswitch might be the key. The Okinawa Institute of Science and Technology (OIST) in Japan, in collaboration with Astellas Pharma Inc., has developed a new toolkit that uses small molecules to control the activity of a piece of synthetic RNA, and ultimately regulate gene expression. The technology, which was described in the Journal of the American Chemical Society, worked in mammalian cell cultures and in mice.

The ability to precisely control whether a gene is turned on or off is expected to lead to more efficient production of compounds that are made using animal cells, and make gene therapy, cell therapy, and regenerative medicine safer.

For genes to be expressed, cells make many RNA copies of a section of DNA. These RNA copies, called transcripts, are then used to make the protein. This can lead to the introduction of additional genes (either as DNA or RNA) into cells, which can then be used to make new proteins for a wide variety of applications.

Why do cancer immunotherapies work so extraordinarily well in a minority of patients, but fail in so many others? By analyzing the role of neutrophils, immune cells whose presence usually signals treatment failure, scientists from the University of Geneva (UNIGE), from Harvard Medical School, and from Ludwig Cancer Center have discovered that there is not just one type of neutrophil, but several. Depending on certain markers on their surface, these cells can either promote the growth of tumors, or fight them and ensure the success of a treatment. By boosting the appropriate factors, neutrophils could become great agents of anti-tumor immunity and reinforce the effects of current immunotherapies. These results have been published in the journal Cell.

Immunotherapy involves activating immune cells —mainly T cells—to recognize and destroy cancer cells. While this treatment is very efficient for some patients, and sometimes even exceeds expectations, it is unfortunately not the case in most cases. “The reasons for these failures remain largely unknown,” says Mikaël Pittet, full professor at the UNIGE Faculty of Medicine, holder of the ISREC chair in immuno-oncology, director of the Centre for Translational Research in Onco-Hematology and member of the Ludwig Cancer Center, who directed this work. “This is why deciphering the immune components involved is key to develop more advanced treatments and make immunotherapies a real therapeutic revolution.”

Neutrophils are the most abundant immune cells in the blood and are very useful in infections or injuries by being quickly mobilized to the affected area and releasing antimicrobial factors. In the context of cancer, however, their presence is generally bad news as they promote vascularization and tumor progression.

In a recent study on the medRxiv preprint server, researchers identified an interleukin 6 (IL-6) dependent alternative pathway as a therapeutic strategy against coronavirus disease 2019 (COVID-19).

Study: A Complement Atlas identifies interleukin 6 dependent alternative pathway dysregulation as a key druggable feature of COVID-19. Image Credit: MarynaOlyak/Shutterstock.com

The expanded availability of opioid use disorder-related telehealth services and medications during the COVID-19 pandemic was associated with a lowered likelihood of fatal drug overdose among Medicare beneficiaries, according to a new study.

“The results of this study add to the growing research documenting the benefits of expanding the use of telehealth services for people with opioid use disorder, as well as the need to improve retention and access to medication treatment for opioid use disorder,” said lead author Christopher M. Jones, PharmD, DrPH, director of the National Center for Injury Prevention and Control, Centers for Disease Control and Prevention. “The findings from this collaborative study also highlight the importance of working across agencies to identify successful strategies to address and get ahead of the constantly evolving overdose crisis.”

Published today in JAMA Psychiatry, this study is a collaborative research effort led by researchers at the National Center for Injury Prevention and Control, a part of CDC; the Office of the Administrator and the Center for Clinical Standards and Quality, both part of the Centers for Medicare & Medicaid Services (CMS); and the National Institute on Drug Abuse, a part of the National Institutes of Health.

Advances in antiaging drug/lead discovery in animal models constitute a large body of literature on novel senotherapeutics and geroprotectives. However, with little direct evidence or mechanism of action in humans—these drugs are utilized as nutraceuticals or repurposed supplements without proper testing directions, appropriate biomarkers, or consistent in-vivo models. In this study, we take previously identified drug candidates that have significant evidence of prolonging lifespan and promoting healthy aging in model organisms, and simulate them in human metabolic interactome networks. Screening for drug-likeness, toxicity, and KEGG network correlation scores, we generated a library of 285 safe and bioavailable compounds. We interrogated this library to present computational modeling-derived estimations of a tripartite interaction map of animal geroprotective compounds in the human molecular interactome extracted from longevity, senescence, and dietary restriction-associated genes. Our findings reflect previous studies in aging-associated metabolic disorders, and predict 25 best-connected drug interactors including Resveratrol, EGCG, Metformin, Trichostatin A, Caffeic Acid and Quercetin as direct modulators of lifespan and healthspan-associated pathways. We further clustered these compounds and the functionally enriched subnetworks therewith to identify longevity-exclusive, senescence-exclusive, pseudo-omniregulators and omniregulators within the set of interactome hub genes. Additionally, serum markers for drug-interactions, and interactions with potentially geroprotective gut microbial species distinguish the current study and present a holistic depiction of optimum gut microbial alteration by candidate drugs. These findings provide a systems level model of animal life-extending therapeutics in human systems, and act as precursors for expediting the ongoing global effort to find effective antiaging pharmacological interventions.

Communicated by Ramaswamy H. Sarma.

Advanced age is a shared risk factor for many chronic and debilitating skeletal diseases including osteoporosis and periodontitis. Mesenchymal stem cells develop various aging phenotypes including the onset of senescence, intrinsic loss of regenerative potential and exacerbation of inflammatory microenvironment via secretory factors. This review elaborates on the emerging concepts on the molecular and epigenetic mechanisms of MSC senescence, such as the accumulation of oxidative stress, DNA damage and mitochondrial dysfunction. Senescent MSCs aggravate local inflammation, disrupt bone remodeling and bone-fat balance, thereby contributing to the progression of age-related bone diseases. Various rejuvenation strategies to target senescent MSCs could present a promising paradigm to restore skeletal aging.

Periodic prolonged fasting (PF) extends lifespan in model organisms and ameliorates multiple disease states both clinically and experimentally owing, in part, to its ability to modulate the immune system. However, the relationship between metabolic factors, immunity, and longevity during PF remains poorly characterized especially in humans.

This study aimed to observe the effects of PF in human subjects on the clinical and experimental markers of metabolic and immune health and uncover underlying plasma-borne factors that may be responsible for these effects.

In this rigorously controlled pilot study ( ClinicalTrial.gov identifier, NCT03487679), 20 young males and females participated in a 3D study protocol including assessments of 4 distinct metabolic states: 1) overnight fasted baseline state, 2) 2-h postprandial fed state, 3) 36-h fasted state, and 4 ) final 2-h postprandial re-fed state 12 h after the 36-h fasting period. Clinical and experimental markers of immune and metabolic health were assessed for each state along with comprehensive metabolomic profiling of participant plasma. Bioactive metabolites identified to be upregulated in circulation after 36 h of fasting were then assessed for their ability to mimic the effects of fasting in isolated human macrophage as well as the ability to extend lifespan in Caenorhabditis elegans.

Nanomedicine uses nanomaterials [e.g., carbon nanotubes (CNTs), nanoparticles, and nanodiscs] or organic nanostructures (e.g., DNA origami and liposomes) for drug delivery (8–10), medical imaging (11–14), and tissue regeneration (15). Nanomaterials offer therapeutic efficacy through their tissue permeation, interaction with an external energy source, and capability to be combined with other therapeutic modalities (16, 17). Because we recently demonstrated that GBM cells are mechanosensitive (18), we set to use nanomaterials to develop a nanoscale mechanical approach to treat GBM. Mechanical perturbation has been investigated as an approach to target cancer cells. For example, magnetic field–actuated nanomaterials compromise the integrity of plasma membrane, leading to the death of in vitro–cultured GBM cells (19) and breast cancer cells (20). GBM cells, which were preincubated with magnetic nanoparticles, were implanted into mice to generate xenograft tumors. A rotating magnetic field, which was then applied to these magnetic particles–harboring tumors, suppressed GBM growth (21). Similarly, magnetic field mobilization of mitochondria-targeting magnetic nanoparticle chains demonstrated efficacy in inhibiting GBM growth in mice (22). While these studies showed that magnetic field–controlled nanomaterials can be used in cancer treatment, the utility of magnetic nanomaterials in treating chemoresistant tumors, the root cause of tumor relapse and patient death, remains unexplored.

GBM displays an extreme level of heterogeneity at genomic, epigenetic, biochemical signaling, and cellular composition levels (23). The heterogeneous nature of GBM confers treatment resilience to tumors and leads to a unifying therapy resistance mechanism; i.e., suppressing selected proteins or biochemical pathways provides a fertile ground for alternative signaling mechanisms, which are not targeted by the given therapy, to fuel GBM growth (24). In other words, the “whack-a-mole” approach failed to benefit patients with GBM for decades. For this reason, we hypothesized that nanomaterial-based mechanical treatment of cancer cells, rather than specific targeting of signaling pathways, can overcome the therapy resistance of this biologically plastic disease. To this end, we engineered a mechanical nanosurgery approach using magnetic CNTs (mCNTs; nanotubes with carbon surface and a cavity filled with iron particles) based on the following reasons.

Combining an optical tweezer technology called C-trap that manipulates a single molecule of DNA and a novel approach, researchers were able to receive a detailed view into how cells find and repair damaged DNA.

Their findings are described in an article titled, “Single-molecule analysis of DNA-binding proteins from nuclear extracts (SMADNE),” published in Nucleic Acids Research.

In the new study, the researchers used the C-trap to investigate how different DNA repair proteins identify and bind to their respective forms of damage.