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Gastrointestinal Stromal Tumors: From Molecular Pathogenesis to Therapy
Published in Sherry X. Yang, Janet E. Dancey, Handbook of Therapeutic Biomarkers in Cancer, 2021
Joaquina Baranda, Stafinur Atay, Andrew K. Godwin
More recently, Agaram and colleagues used microarray analysis to compare gene expression in 13 tumor nodule samples from eight WT pediatric GIST patients (2 within the Carney Triad) to five adult WT GIST samples. Again, the pediatric group formed a tight cluster that segregated from the adult group. In this study a total of 1,532 genes were found to be differentially expressed (> 2-fold change) between the two groups. To help rule out the possibility that the expression profiles were biased because all samples in the pediatric group were gastric, a second analysis was performed comparing the pediatric WT group to a group of adult gastric GISTs with varying genotype (3 WT, 4 PDGFRA mutants, 12 KIT mutants). This analysis yielded 1,335 differentially expressed genes (> 2-fold change), 814 of which were in common with the first analysis. The genes with significantly different expression in the pediatric group as compared to the adult tumors included FGF4 (fibroblast growth factor 4), BAALC (brain and acute leukemia, cytoplasmic), IGF1R, NELL1 (NEL-like 1), CRLF1 cytokine receptor-like factor 1), PLAG1 (pleomorphic adenoma gene 1) and FGF3 (fibroblast growth factor 3). The only common gene to show up in both studies was IGF1R. Although work from the Godwin group has not focused exclusively on pediatric GISTs, they have performed extensive studies on WT GISTs and were the first to report that IGF1R mRNA and protein is frequently overexpressed in WT adult and pediatric GISTs as compared with mutant GISTs [87, 93]. For example, IHC analysis on a primary GIST and a paraganglioma from the Carney triad patient shows strong IGF1R expression [87, 93]. A recent study using a larger sample set of pediatric WT GISTs (n = 9) confirmed that IGF1R is overexpressed in all pediatric cases compared to mutant GISTs [94]. With respect to IGF1R and its downstream signaling molecules, Tarn and colleagues showed that the small-molecule tyrosine kinase inhibitor, NVP-AEW541 (Novartis), which has activity against IGF1R can lead to cytotoxicity in mutant GIST cell lines, via AKT and MAPK signaling that is independent from KIT signaling. Similar findings were observed when IGF1R levels were impaired using targeted siRNAs. They observed additive effects by combining NVP-AEW541 and IM, suggesting a potential therapeutic benefit in targeting IGF1R in GISTs that are unresponsive to IM, including pediatric GISTs which overexpress IGF1R as well as combination therapies in all tumors [87].
Therapeutic apheresis in kidney diseases: an updated review
Published in Renal Failure, 2022
Yi-Yuan Chen, Xin Sun, Wei Huang, Fang-Fang He, Chun Zhang
The pathogenesis of membranous nephropathy (MN) has been confirmed since the discovery of autoantibodies against podocyte M-type phospholipase A2 receptor (PLA2R) and thrombospondin type 1 domain-containing protein 7 A (THSD7A) [19,20]. Other autoantigens, such as neural epidermal growth factor-like 1 protein (NELL-1), exostosin 1 and 2, have also been discovered recently [21,22]. The titers of autoantibodies are closely related to the prognosis of MN. Despite advances in understanding the pathogenesis, treatment regimens remain intractable. For severe patients, the standard treatment is still a six-month regimen of rotating high-dose steroids and immunosuppression, such as the modified Ponticelli regimen (steroids and CYC) or modified Cattran regimen (steroids and Cyclosporine A) [23–25]. But these regimens are always accompanied by significant adverse effects, including infection, osteoporosis, diabetes mellitus, weight gain, hemorrhagic cystitis, infertility, or cancer [26]. The discovery of nephritogenic autoantibodies provides a new therapy choice that targets B-cell lineages to prevent antibody production [27].
Chitosan-coated bovine serum albumin nanoparticles for topical tetrandrine delivery in glaucoma: in vitro and in vivo assessment
Published in Drug Delivery, 2022
Salma El-Sayed Radwan, Riham M. El-Moslemany, Radwa A. Mehanna, Eman H. Thabet, Elsayeda-Zeinab A. Abdelfattah, Amal El-Kamel
Chitosan-coated albumin NPs were first formulated by Karimi et al. (Karimi et al., 2013) using the phase separation method and ionic interaction to prepare albumin–CS core–shell NPs for DNA delivery. In preceding research, they were functionalized by MUC-1 to target cancers that overexpress MUC-1. The system was able to encapsulate the hydrophobic drug, paclitaxel, in the albumin inner core, enhancing its permeation to the cells which was attributed to CS positive charge and the active targeting moiety (Esfandyari-Manesh et al., 2016). Albumin NPs were designed as a growth factor carrier by desolvation method and were further stabilized by CS coating by Li et al. (2018). The CS-coated albumin NPs presented favorable stability and sustained release kinetics of the osteogenic protein NELL-1. Moreover, Piazzini et al. (2019) reported the study of CS coated albumin NPs as a promising strategy for the nose to brain drug delivery. However, to our knowledge, this is the first time that CS-coated albumin NPs are studied as an ocular drug delivery platform for topical delivery.
The spectrum of renal diseases with lupus-like features: a single-center study
Published in Renal Failure, 2022
Maliha Ahmed, Tanzy Love, Catherine Moore, Thu H. Le, Jerome Jean-Gilles, Bruce Goldman, Hae Yoon Grace Choung
IF, LM, and EM data for both LN and LLN are presented in Table 4, and more detailed pathologic data for LLN are in Table 5. The majority of both LN and LLN showed FH of immune deposits by IF. Although EGID staining by IgG and/or C1q was approximately three times more frequent in LN compared to LLN, the difference was not statistically significant (p = .081). IF intensity (Table 6) in both were not significantly different and showed the strongest positivity for IgG, followed by C3, kappa, lambda, IgM, IgA, and C1q. IgG-subclass staining was performed on 6 LLN cases. The mean intensity for the IgG subclasses revealed from strongest to weakest: IgG1 (1.8+), IgG3 (1.8+), IgG4 (1.5+), and IgG2 (1.0+). The prevalence of TRI by EM was statistically significantly greater in the LN (83.3%) than the LLN-group (29.4%), (p < .0001). The differences in SLE class were not statistically significant between LLN and LN (p = .093). However, proliferative glomerulonephritis, specifically class-III/IV(±V) (61.4 vs. 35.2%), was seen with greater frequency in LN, while non-proliferative class-V (28.1 vs. 35.2%) and mesangial proliferative class-II (9.3 vs. 23.5%) were more commonly encountered in LLN. All LLN cases with class V only were negative for anti-PLA2R antibody. NELL-1, THSD7A, and EXT1/2 were performed on 4 cases with tissue available for staining, all of which were negative for those markers. Fibrous crescents were more often present in LN (p = .04), while LLN cases tended to have more tubulointerstitial scarring (p = .011). Two LLN patients had repeat biopsies performed. Patient #1’s second biopsy showed class 4 + 5, which appeared more proliferative than the biopsy from 10 years prior (class 5 only). Both first and second biopsies for patient #6 were class 4, but with more chronic changes in the second biopsy.