Blocking enzyme SMYD5 inhibits tumour growth and primes lab models for combination therapy, offering hope for more effective treatments.
Category: biotech/medical – Page 113
Microbial systems have been synthetically engineered to deploy therapeutic payloads in vivo.
To enable effective cancer vaccination, we developed an engineered bacterial system in probiotic Escherichia coli Nissle 1917 (EcN) to enhance expression, delivery and immune-targeting of arrays of tumour exonic mutation-derived epitopes highly expressed by tumour cells and predicted to bind major histocompatibility complex (MHC) class I and II (Fig. 1a). This system incorporates several key design elements that enhance therapeutic use: optimization of synthetic neoantigen construct form with removal of cryptic plasmids and deletion of Lon and OmpT proteases to increase neoantigen accumulation, increased susceptibility to phagocytosis for enhanced uptake by antigen-presenting cells (APCs) and presentation of MHC class II-restricted antigens, expression of listeriolysin O (LLO) to induce cytosolic entry for presentation of recombinant encoded neoantigens by MHC class I molecules and T helper 1 cell (TH1)-type immunity and improved safety for systemic administration due to reduced survival in the blood and biofilm formation.
To assemble a repertoire of neoantigens, we conducted exome and transcriptome sequencing of subcutaneous CT26 tumours. Neoantigens were predicted from highly expressed tumour-specific mutations using established methods14,15, with selection criteria inclusive of putative neoantigens across a spectrum of MHC affinity16,17. Given the importance of both MHC class I and MHC class II binding epitopes in antitumour immunity15,18,19, we integrated a measure of wild-type-to-mutant MHC affinity ratio—termed agretopicity17,20—for both epitope types derived from a given mutation, to help estimate the ability of adaptive immunity to recognize a neoantigen. Predicted neoantigens were selected from the set of tumour-specific mutations satisfying all criteria, notably encompassing numerous recovered, previously validated CT26 neoantigens15 (Extended Data Fig. 1a).
We then sought to create a microbial system that could accommodate the production and delivery of diverse sets of neoantigens to lymphoid tissue and the tumour microenvironment (TME). For the purpose of assessing neoantigen production capacity, a prototype gene encoding a synthetic neoantigen construct (NeoAgp) was created by concatenating long peptides encompassing linked CD4+ and CD8+ T cell mutant epitopes—previously shown as an optimal form for stimulating cellular immunity21—derived from CT26 neoantigens (Extended Data Fig. 1b and Extended Data Table 1). The construct was cloned into a stabilized plasmid22 under constitutive expression and transformed into EcN; however, both immunoblot and enzyme-linked immunosorbent assay (ELISA) assessment showed low production of the prototype construct by EcN across several tested promoters (Extended Data Fig. 1c).
Oxford Nanopore Technologies observes that direct analysis has already enhanced research across species, disease states, and applications.
The researchers used electrospinning to produce the patch—a method where high voltage is applied to a polymer solution to produce synthetic nanofibers. The fibers are then used to make a fiber mat that may be attached to the skin like a plaster.
The researchers are still working on the patch. More research, product development and clinical trials are needed before the method is ready for use.
According to Andrea Heinz, though, it has great potential that extends beyond psoriasis treatment, “A patch containing active ingredients may be an alternative to creams and ointments in the treatment of other inflammatory skin diseases, for instance atopic eczema. It may also be useful in connection with wound healing.”
Bioluminescence is the natural chemical process of light creation in some living creatures that makes fireflies flicker and some jellyfish glow. Scientists have long been interested in borrowing the secrets of these animals’ light-producing genes to create similar effects in vertebrates, for a variety of biomedical applications.
DNA repair and DNA damage signaling pathways are critical for the maintenance of genomic stability.
In this review, Hopkins et al. review the major classes of DNA repair and damage signaling defects in cancer, the genomic instability that they give rise to, and therapeutic strategies to exploit the resulting vulnerabilities. They also discuss the impacts of DNA repair defects on both targeted therapy and immunotherapy, and highlight emerging principles for targeting DNA repair defects in cancer therapy.
A research team from the University of Basel has succeeded in synthesizing simple, environmentally sensitive cells complete with artificial organelles. For the first time, the researchers have also been able to emulate natural cell-cell communication using these protocells—based on the model of photoreceptors in the eye. This opens up new possibilities for basic research and applications in medicine.
For example, enhancers (DNA segments that promote gene expression) and gene promoters (regions that initiate transcription) can interact more readily in open, accessible regions of chromatin.
On the other hand, DNA in tightly packed chromatin regions remains less active. Through analyzing these contact points, researchers have developed models to map chromatin configurations across various species, such as humans, mice, birds, and more recently, turtles.
In a recent paper published in the journal Genome Research, Valenzuela’s team described the chromatin arrangement in the genomes of two turtle species, the spiny softshell and northern giant musk turtles, uncovering a structure previously unobserved in other organisms.
Researchers found that neural crest stem cells are uniquely capable of reprogramming, challenging current reprogramming theories and opening possibilities for stem cell-based treatments.
A research team from the University of Toronto has identified that neural crest stem cells, a group of cells found in the skin and other parts of the body, are the origin of reprogrammed neurons previously found by other scientists.
Their findings refute the popular theory in cellular reprogramming that any developed cell can be induced to switch its identity to a completely unrelated cell type through the infusion of transcription factors. The team proposes an alternative theory: there is one rare stem cell type that is unique in its ability to be reprogrammed into different types of cells.
Carbon is a gregarious little atom, bending over backwards to link with a wide variety of elements in what is collectively referred to as organic chemistry. Life itself wouldn’t be possible without carbon’s knack for making connections.
Yet even this friendly fellow has its limits. Take Bredt’s rule for instance, which says stable two-laned connections known as covalent double bonds won’t form adjacent to any V-shaped bridges that happen to form across ‘bicyclic’ molecules.
Now a team of chemists from the University of California, Los Angeles has uncovered a solution that violates Bredt’s century-old rule. This encourages future drug research to explore the use of molecules that we thought could not exist.