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Adult Stem Cell Plasticity
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
The first two attempts to demonstrate BM-derived neurons were published in the journal Science in December of 2000. Brazelton and colleagues59 used a GFP transgenic mouse strain as a donor to recipients lacking the transgene. Analysis focused on the olfactory bulb, but GFP+ (donor) cells were also found in the hippocampus, cortex, and cerebellum. Using laser scanning confocal microscopy to visualize very thin (~0.3μm) sections of the brain, GFP+ cells that coexpressed neuron specific antigens (NeuN, neurofilament NF-H, and class III β-tubulin) comprised 0.2-0.3% of all olfactory bulb neurons after BM transplantation. The highest frequency of BM-derived neurons was in the superficial axonal layer of the olfactory bulb, a region known to exhibit high rates of neurogenesis.60,61 The majority of the GFP+ neuron-like cells also had a triangular shape, indicative of neurons, and a few also possessed long cellular extensions, which could represent axonal outgrowths. The phosphorylation state of cyclic AMP response element-binding (CREB) transcription factor in the putative GFP+ neurons was similar to that in surrounding neurons, suggesting a functional similarity in how these cells and neighboring neurons interact with the extracellular environment.62 In contrast to other reports, no BM-derived astrocytes were detected in this study.
Papillary Glioneuronal Tumor
Published in Dongyou Liu, Tumors and Cancers, 2017
Immunohistochemistry includes glial fibrillary acidic protein positivity in the glial cells adjacent to the papillary core and synaptophysin-positive staining in the neuronal component, which also stains for other neuronal antigens such NSE, NeuN, and class III β-tubulin. MIB-1 labelling is in the range of 1%–2%.
Targeted drug therapy in non-small cell lung cancer: Clinical significance and possible solutions-Part I
Published in Expert Opinion on Drug Delivery, 2021
Archana Upadhya, Khushwant S. Yadav, Ambikanandan Misra
The taxanes (paclitaxel and docetaxel) inhibit depolymerization of microtubules thus changing microtubule dynamics and eventually causing cell death by blocking cellular mitosis [115]. The factors for resistance to taxane-based therapy are increased expression of class III tubulin [116] and its mutations, up-regulation of histone deacetylase 6 (HDAC 6) and impairment of the mitotic spindle checkpoint [111]. The function of the mitotic spindle checkpoint is to block the segregation of abnormal chromosomes. In lung cancer cells, the mitotic spindle checkpoint is dysregulated [79,111]. The taxanes bind specifically to class I β tubulin isoform which differs in critical binding residues from the class III β isoform [117]. Class III β – tubulin is one of the β isoforms that heterodimerize with α subunits to form microtubules essential for cell division [117] and its high expression correlates with poor survival in NSCLC [118]. Histone acetylation and deacetylation regulate transcription of DNA segments. Histone acetylases (HATs) promote transcription while histone deacetylases (HDACs) inhibit transcription by making DNA inaccessible. Histone deacetylase six interacts with histone and non-histone substrates. Non – histone interactors are α-tubulin, contractin and heat shock protein 90 (Hsp90) which when modified by HDAC6 can promote cell proliferation, metastasis, invasion, and mitosis [119].
Biomarkers of response to advanced prostate cancer therapy
Published in Expert Review of Molecular Diagnostics, 2020
Roberto Iacovelli, Chiara Ciccarese, Giovanni Schinzari, Ernesto Rossi, Brigida Anna Maiorano, Serena Astore, Tatiana D’Angelo, Antonella Cannella, Celeste Pirozzoli, Maria Anna Teberino, Francesco Pierconti, Maurizio Martini, Giampaolo Tortora
Taxanes act as anti-microtubules agents targeting the β-tubulin sub-unit. Overexpression of class III β-tubulin (TUBB3) is a key mechanism of resistance to taxanes, overcoming their effect [13–16]. However, its value as a biomarker of tumor behavior in PCa remains largely unexplored. The prognostic and predictive role of βIII-tubulin in mCRPC was tested in a cohort of 37 patients receiving first-line docetaxel: elevated βIII-tubulin expression predicted lower OS (p = 0.037), supporting its negative prognostic value. Moreover, βIII-tubulin hyper-expression was associated with a lower rate of PSA response (35% βIII-tubulin+ versus 52% βIII-tubulin− patients) and shorter time-to-progression (TTP) (4.7 months for βIII-tubulin+ patients versus 9.8 months for βIII-tubulin−), suggesting it as a candidate biomarker to predict the response to docetaxel-based chemotherapy. Interestingly, docetaxel treatment could increase the expression of βIII-tubulin: high levels of βIII-tubulin were associated with taxane-resistance, while βIII-tubulin silencing increased taxane-sensitivity [17]. To further confirm the role of βIII-tubulin as a marker of taxane-resistance, cabazitaxel (a second-generation taxane, developed to overcome resistance to docetaxel) showed an increased efficacy over docetaxel when βIII-tubulin was expressed [18].
Microtubule-targeting agents in the treatment of non-small cell lung cancer: insights on new combination strategies and investigational compounds
Published in Expert Opinion on Investigational Drugs, 2019
Marco Tagliamento, Carlo Genova, Giovanni Rossi, Simona Coco, Erika Rijavec, Maria Giovanna Dal Bello, Simona Boccardo, Francesco Grossi, Angela Alama
The mechanisms of resistance to tubulin inhibitors are generally complex and diverse, and only partially understood. One relevant type of mechanism involves gene expression changes, which might lead to structural, functional or metabolic alterations promoting drug resistance by inhibiting apoptosis. For example chronic hypoxia, which is typically associated with tumor growth, can lead to the activation of inducible transcriptional factors (such as NF-kB and STAT-3), inhibiting apoptosis and promoting angiogenesis. Furthermore, oxygen depletion induces anaerobic metabolism and glycolysis, which result in reduced potential for cell cycle arrest. Another mechanism of resistance to tubulin inhibitors is increased drug efflux, promoted by trans-membrane transporters such as P-glycoprotein (P-gp), which remove the drug from the intracellular space. Finally, an additional major mechanism of resistance to tubulin inhibitors is represented by either alterations of tubulin concentration, or qualitative alterations such as point mutations of the tubulin gene or altered expression of tubulin isotypes, for instance class III β-tubulin. The latter mechanisms lead to reduced ability of tubulin inhibitors to exert their action on tubulin molecules, due to decreased affinity between the drugs and potential binding sites [11].