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Transformin Growth Factor-β
Published in Jason Kelley, Cytokines of the Lung, 2022
One mechanism by which TGF-β exerts its negative growth control is by down-regulating expression of protooncogenes involved in cell cycle progression. Indeed, certain cells may normally down-regulate their own growth through the autocrine secretion of TGF-β. According to this hypothesis, they would break free from such growth control if they lost the ability to activate latent TGF-β (Wakefield et al., 1987). Similarly, loss of TGF-β receptors would have vital implications for its subsequent growth function. There is intriguing evidence that TGF-β receptors provide an important autocrine pathway for limiting uncontrolled cell growth. Kimchi and colleagues (1988) have found that retinoblastoma tumor cells devoid of TGF-β receptors proliferate without control in presence of TGF-β. This suggests that loss of TGF-β receptors, albeit a rare event in tumor cells, represents one mechanism through which cells would escape negative growth control. When intracellular signal transduction pathways are subverted, the phenotypic response of cells can switch even more dramatically. For example, the response of murine fibroblasts to TGF-β1 can change from inhibition to stimulation in metastatic H-ras-transformed cells (Schwarz et al., 1988).
Immunomodulatory Therapies
Published in David E. Thurston, Ilona Pysz, Chemistry and Pharmacology of Anticancer Drugs, 2021
Gene delivery of the receptor is the distinguishing step between TCR-T and CAR-T cell therapies. Peripheral blood T cells are transduced by gamma-retroviral or lentiviral vectors which result in high expression of the introduced receptor in the final cell product. However, with viral vectors there is a concern relating to potential oncogenic gene insertion. Also, this process is presently labour intensive and expensive, although potentially cheaper methodologies based on Crispr/Cas9-technologies are being explored. The latter approach does not require the production of viral vectors and provides a more flexible and cheaper platform for gene transduction. Finally, the transduced T cells are expanded. The overall process is illustrated in Figure 9.7.
Antibiotics: The Need for Innovation
Published in Nathan Keighley, Miraculous Medicines and the Chemistry of Drug Design, 2020
Once drug resistance through chance mutation has arisen, other bacterial cells can acquire resistance through genetic transfer. Not only is the gene for resistance transferred to daughter cells as resistant bacteria divide, but also genes can be passed between bacterial cells. There are two main ways in which this can occur: conjugation and transduction. In conjugation, the genetic material is transferred directly between bacterial cells, through a connecting bridge of sex pili built between the two cells. Transduction involves small sections of genetic material, called plasmids, being transferred by means of bacterial viruses (bacteriophages) which may leave a resistant cell, then go on to infect a non-resistant cell with the relevant genetic material needed to acquire resistance; in by doing so, passing on the genetic information in the plasmid containing the instruction for resistance enzymes, such as β-lactamase.
There and back again: a dendrimer’s tale
Published in Drug and Chemical Toxicology, 2022
Barbara Ziemba, Maciej Borowiec, Ida Franiak-Pietryga
The signal transduction pathway is a cascade of biochemical reactions involving the transmission of molecular signals from a cell exterior to its interior. Signals received by cells must be transmitted effectively to the target molecules to assure an appropriate response. Signaling pathway dysregulation can influence cell growth, proliferation, division, metabolism, or survival and lead to disease development. Dendrimers, as nanoparticles, may easily disrupt signal transduction by affecting any element of the pathway. Such activity may have adverse effects, but also advantages, e.g., in cancer or metabolic diseases therapy. Therefore, findings on dendrimers’ biological effects in terms of their interactions with key cellular signal transduction pathways may have important clinical implications.
Determination of cytokine profile and associated genes of the signaling pathway in HNSCC
Published in Journal of Receptors and Signal Transduction, 2022
Aysel Kalayci Yigin, Ali Azzawri, Kayhan Ozturk, Tulin Cora, Mehmet Seven
Cytokines, chemokines and growth factors are important immunmodulators and prognostic markers which have a complex regulatory effect in the control of cellular processes. They act over short distances and at very low concentrations and are also coordinate intercellular signal transduction pathways [8]. To trigger these signal transduction pathways, they bind to receptors (receptor tyrosine kinases) on the membranes of responsive target cells and induce gene expression in target cells. Many cellular activities associated with survival, activation, proliferation, and differentiation of cells are under the control of intracellular signal transduction pathways. Aberrant activations of these components in the signal transduction pathways play a major role in the malignant transformation of many cancers [6]. Therefore, determining these activators involved in the etiopathogenesis of the HNSCC can be notable molecular targets for novel therapeutic approaches. The study aims to evaluate the cytokine, chemokine and growth factor profiling of HNSCC patients, and the relationship of genes involved in the pathway related to these cytokines.
Addressing high dose AAV toxicity – ‘one and done’ or ‘slower and lower’?
Published in Expert Opinion on Biological Therapy, 2022
Takashi Kei Kishimoto, Richard Jude Samulski
While there has been substantial progress and notable achievements in the use of adeno-associated virus (AAV) gene therapy vectors for treatment of rare diseases, setbacks related to vector toxicity and immunogenicity represent major challenges for the field. In many cases, these two issues appear to be inextricably linked[1–3]. Immunogenicity of AAV vectors is thought to cause or exacerbate some of the more serious adverse events associated with AAV gene therapy, such as hepatotoxicity and thrombotic microangiopathy (TMA). Moreover, these adverse events tend to be correlated with vector dose, increasing in both prevalence and severity with higher doses [1,4]. Not surprisingly, high vector doses are also associated with increased immunogenicity, leading to a vicious circle when vector doses of 1E14 vg/kg or higher are required for efficacy in neuromuscular diseases [1,5]. These issues will likely require a multipronged approach to improve vector transduction efficiency and mitigate vector immunogenicity, and a perhaps a shift from the ‘one-and-done’ paradigm of gene therapy to a ‘slower and lower’ model of administering multiple lower doses of vector to achieve a similar therapeutic benefit.