Soft Tissue Sarcomas
Pat Price, Karol Sikora in Treatment of Cancer, 2020
Most synovial cell sarcomas are characterized by the translocation t(x;18)(p11.2;q11.2). The breakpoint of this translocation fuses the SYT gene (also known as the SS18 gene) from chromosome 18 to one of two homologous genes, SSX1 or SSX2, on the X chromosome. The SYT–SSX gene has recently been shown to increase the transcription of genes, such as Sox2 that is necessary for synovial cell sarcoma proliferation. The nature of the chimeric gene may have prognostic and pathogenetic importance. In some studies, metastasis-free survival was higher with SYT–SSX2 compared to SYT–SSX1. SYT–SSX1 is associated with biphasic tumors (glandular epithelial differentiation on a background of spindle tumor cells), whereas SYT–SSX2 is associated with monophasic tumors that lack glandular epithelial differentiation, although other studies have questioned these findings.
Role of Engineered Proteins as Therapeutic Formulations
Peter Grunwald in Pharmaceutical Biocatalysis, 2019
Homologous recombination techniques are based on high sequence homology of the parental gene sequences. The resultant chimeric gene shows an amalgamation of characteristic features of the combining parental sequences. The homologous recombination methods have been classified into in vitro and in vivo homologous recombination methods. DNA shuffling is the most prominent in vitro homologous recombination technique developed by Stemmer and coworkers (Stemmer, 1994b). Later advancements in the DNA shuffling method resulted in improvised schemes such as family shuffling (Crameri et al., 1998), and DOGs (degenerate oligonucleotide gene shuffling) (Gibbs et al., 2001). Other in vitro homologous recombination methods include: random priming in vitro recombination (RPR) (Shao et al., 1998), truncated metagenomic gene-specific PCR (TMGS-PCR) (Wang et al., 2010), staggered extension process (StEP) (Zhao et al., 1998), random chimeragenesis on transient templates (RACHITT) (Coco, 2003), synthetic shuffling (Ness et al., 2002). The in vivo homologous recombination methods include: cloning performed in yeast (CLERY) (Abecassis et al., 2003), Mutagenic organized recombination process by homologous in vivo grouping (MORPHING) (Gonzalez-Perez et al., 2014), and phage assisted continuous evolution (PACE) (Esvelt et al., 2011).
Order Nodamuvirales
Paul Pumpens, Peter Pushko, Philippe Le Mercier in Virus-Like Particles, 2022
The MrNV VLPs remarkably contributed to the viral nanotechnology as a novel promising platform to display foreign epitopes. First, a putative hepatitis B vaccine was constructed. Thus, Yong et al. (2015a) displayed the determinant “a” located at aa 121–149 of surface protein (HBs) of hepatitis B virus (see Chapter 37). The MrNV coat of 1–377 aa residues was provided C-terminally with the HBs “a” determinant of 49 aa residues corresponding to the HBs 111–159 aa stretch, myc epitope EQKLISEEDL and His6 tag. The total length of the C-terminal addition reached 79 aa residues. The chimeric gene was expressed in E. coli and ensured generation of the appropriate VLPs. The immunization of mice with the purified chimeric VLPs induced specific antibodies against the HBs determinant “a” as well as more natural killer and cytotoxic T cells, which are vital for virus clearance (Yong et al. 2015a).
ClonoSEQ assay for the detection of lymphoid malignancies
Published in Expert Review of Molecular Diagnostics, 2019
Anna Monter, Josep F. Nomdedéu
‘Minimal or measurable’ residual disease (MRD) is a post-diagnostic marker that correlates with clinical outcomes in hematologic malignancies [17,18]. MRD assessment at different time points is used for risk stratification and treatment planning [19]. The most commonly used techniques to assess MRD in B-ALL are multiparameter flow cytometry (MPFC) and sensitive molecular protocols that make use of distinctive features present in malignant cells, for example, in this case, highly variable junctional regions of immunoglobulin (Ig) and T-cell receptor (TCR) gene rearrangements [4,5]. Most laboratories are using real-time PCR methods but they are fast moving to HTS approaches. In leukemic cases with chimeric gene fusions as bcr-abl or MLL-AF4 rearrangements, sensitive and standardized real-time PCR methods are routinely used. HTS protocols are also employed at diagnosis to detect driver mutations with prognostic relevance or which could be suitable for specific drug targeting as in Ph-like ALL [20].
Pharmaceutical strategies in improving anti-tumour efficacy and safety of intraperitoneal therapy for peritoneal metastasis
Published in Expert Opinion on Drug Delivery, 2021
Puxiu Wang, Xiujuan Qu, Xiaofang Che, Qiuhua Luo, Xing Tang, Yunpeng Liu
Combinatorial therapy with multiple genes by different mechanisms could provide desirable efficacy and safety due to their synergistic effects. Cholesterol-modified polymeric nanoparticles (PCX), containing a triple therapeutic gene, were developed as vectors with high tumor accumulation, low systemic toxicity, and improved anti-tumor efficacy for the IP treatment of metastatic pancreatic cancer [101]. Moreover, chimeric gene fusion has been developed to provide synergistic effects or overcome some disadvantages of the single gene in tumor therapy. p53-Bad, designed by combining p53 with the mitochondrial pro-apoptotic factor Bad, could target the key driver p53 mutation and facilitate mitochondrial priming to overcome drug resistance in ovarian cancer cells.
DNA methyltransferase-1 in acute myeloid leukaemia: beyond the maintenance of DNA methylation
Published in Annals of Medicine, 2022
Above we discussed how DNMT1 participates in the different biological processes of AML by regulating DNA methylation; however, DNMT1 also interacts with some crucial regulating factors, which belongs to non-epigenetic processes. Fatty acid-binding protein 4 (FABP4) has been reported to promote AML aggressiveness through enhanced DNMT1-dependent DNA methylation, FABP4 regulates DNMT1 expression through the IL-6/STAT3 axis, whereas DNMT1 controls FABP4 through VEGF signal pathway, which constitutes a feedback loop, in turn, affecting the process of leukaemia [73]. Currently, most studies focus on aberrant methylation regulated by DNMT1, while this study provided a new understanding of the function of DNMT1 in AML, particularly from a metabolic standpoint. Furthermore, USP7 was identified as an interaction partner of DNMT1 that could regulate its stability and activity by the connection with the TS domain of DNMT1 and domain 3 of USP7, then affecting the survival outcomes of the haematological malignancies [24,74]. AML1-ETO AML derives from the translocation t (8;21) (q22; q22), creating a novel chimeric gene, RUNX1/MTG8, AML patients with this genetic abnormality usually achieve a relatively favourable prognosis [75]. It has been reported that a physical and functional interaction between endogenous RUNX1/MTG8 and endogenous DNMT1 exists in Kasumi-1 cells, and RUNX1/MTG8 modulates its targeted genes by recruiting DNMT1 to their promoters [76]. Based on these results of the study, it is not difficult to find that DNMT1 is an important molecule in AML1-ETO AML, whereas a specific interacting site has been far from clear. Moreover, the stem cell factor spalt-like transcription factor 4 (SALL4) is a key molecule in normal haematopoiesis and also in leukaemogenesis, which blocks self-repression by recruiting DNMT1 to its promoter, which affects its function in AML [77,78].
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