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Participation of Cytokines and Growth Factors in Biliary Epithelial Proliferation and Mito-Inhibition during Ductular Reactions
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
Anthony J. Demetris, J.G. Lunz, Vladimir Subbotin, Tong Wu, Isao Nozaki, Sarah Contrucci, Xia Yin
The active form of TGF (beta) binds to the TGFβ receptor II (TβR-II), which dimerizes with and phosphorylates TGF(beta) receptor I (TβR-I). Similarly, activin A binds to the activin receptor II, which dimerizes with activin receptor I. Signal transduction by either of these family members (Fig. 5) is perpetuated by receptor complex phosphorylation of a receptor-regulated SMAD protein (SMAD2 or 3), followed by heterodimerization of the receptor-regulated SMAD with a coSMAD (SMAD4). This complex can then enter the nucleus, where it can interact with a DNA binding partner (DBP) to influence gene transcription. TGF(beta) family members can stimulate transcription of growth inhibitory genes such as p21, or inhibit transcription of growth promoting genes, such as c-myc.165
Colorectal cancer
Published in J. K. Cowell, Molecular Genetics of Cancer, 2003
To date, more than 100 different germ-line mutations have been identified in the MMR genes known to be associated with Lynch syndrome. Mutations in MSH2 and MLH1 account for roughly equal proportions of Lynch kindreds, and are together responsible for a majority of CRC in these families (Aaltonen et al., 1998). However, germ-line disease-associated mutations are found in only approximately 40–70% of probable Lynch syndrome families. Other germ-line mutations, and/or different classes of genes, may be discovered which play an etiologic role in susceptible individuals. One family has been described in which a probable pathological mutation has occurred in the TGF-beta Receptor II gene (Yagi et al., 1997), a gene known to show altered expression in CRC. This, and the attenuated form of FAP, might be regarded as falling into the broader category of HNPCC (hereditary nonpolyposis colon cancer) but not Lynch syndrome.
Surface markers of human embryonic stem cells: a meta analysis of membrane proteomics reports
Published in Expert Review of Proteomics, 2018
Faezeh Shekari, Chia-Li Han, Jaesuk Lee, Mehdi Mirzaei, Vivek Gupta, Paul A. Haynes, Bonghee Lee, Hossein Baharvand, Yu-Ju Chen, Ghasem Hosseini Salekdeh
Prokhorova et. al. and Sarkar et. al. (Figure 1(c,f)) used a SILAC labeling approach in hESC membrane proteomics [108,109] . Prokhorova and colleagues showed that six membrane proteins (CD133/Prominin-1, Glypican-4, Neuroligin-4, ErbB2, PTPRZ, and Glycoprotein M6B) have greater than three-fold higher expression in the undifferentiated state, which was confirmed by real time PCR analysis and fluorescence-activated cell sorting [109]. Sarkar et al. performed subcellular fractionation of a SILAC labeled H9 hESC line by utilizing a discontinuous sucrose gradient [108], followed by LTQ-Orbitrap XL high-resolution mass spectrometry analysis. Based on the combination of relative protein expression and subcellular localization, the components of a number of signaling pathways such as BMP receptor, FGF and TGF-beta receptor signaling were identified in undifferentiated hESCs [108]. Compared to Prokhrova et al. [109], subcellular fractionation [108] was relatively more successful in resolving MAP proteins (33% compared to 20%, Figure 1(c,f)).
Emerging treatment options for prostate cancer
Published in Expert Review of Anticancer Therapy, 2023
Mohammad Atiq, Elias Chandran, Fatima Karzai, Ravi A. Madan, Jeanny B. Aragon-Ching
CAR-T cell therapy is a new area of therapy being evaluated in prostate cancer. A first-in-human phase I study of PSMA CAR-T by Narayan et al. (NCT03089203) enrolled mCRPC patients and treated them with a PSMA-directed armored CAR-T cell that was modified with a dominant-negative transforming growth factor (TGF)-beta receptor [50]. This study utilized a 3+3 safety design with and without lymphodepletion. Patients were dosed in four cohorts at a range of 10–30 million cells or 100–300 million cells with or without lymphodepletion. Of the 13 patients treated, 4 had PSA reductions of at least 30%. It must be noted, however, that one of the four patients died in the context of grade 4 cytokine release syndrome (CRS) and sepsis, emphasizing the need for continued vigilance regarding toxicity monitoring. A second phase I study by Dorff et al. (NCT03873805) looked at CAR-T cell therapy targeted to prostate stem cell antigen (PSCA) in mCRPC after at least abiraterone or enzalutamide [51]. Patients were also required to have disease that expressed PSCA as confirmed by City of Hope’s Pathology Department. These CAR-T cells are also using the 4-1BB costimulatory molecule. Four cohorts were planned for treatment with cohort 1 receiving 100 million cells without lymphodepletion chemotherapy. The other three cohorts were planned to receive lymphodepletion first followed by 100 million, 300 million, or 600 million cells per each cohort, respectively. This first-in-human study encountered two DLTs (grade 3 noninfective cystitis and fatigue in both) at a dose of 100 million cells after lymphodepletion chemotherapy. However, upon amendment of the lymphodepletion chemotherapy to reduce the cyclophosphamide portion, no DLTs were encountered in an additional three patients. All three patients treated at the 100 million cell dose level without lymphodepletion progressed, while seven of the nine patients treated at the same cell number but with lymphodepletion had stable disease. The data acquired at this level allowed for escalation to the next dose level of 300 million cells.
The role of Foxp3 and Tbet co-expressing Treg cells in lung carcinoma
Published in OncoImmunology, 2018
Katerina Kachler, Corinna Holzinger, Denis I. Trufa, Horia Sirbu, Susetta Finotto
To add functional studies, we analyzed activated SMAD3 (pSMAD3) expression downstream of TGF-beta Receptor (Fig 6e). Consistent with TGF-beta induction in the tumoural region here pSMAD3 was found induced along with Foxp-3 at the protein level (Fig 6e, f).