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Herpesvirus microRNAs for Use in Gene Therapy Immune-Evasion Strategies
Published in Yashwant Pathak, Gene Delivery, 2022
Vineet Mahajan, Shruti Saptarshi, Yashwant Pathak
Herpes viruses are able to maintain latency within the host by targeting viral transcripts. Several HCMV miRNAs, such as miR-UL148D and miR-US22, have been reported to play a key role in latency as well as reactivation. Interestingly, unlike other herpes viruses, very few HCMV miRNAs have been reported to target viral transcripts, although HCMV miR-UL112-1 was shown to downregulate the major immediate early trans activator, IE72, resulting in a reduction of viral replication and promotion of latency.22 HCMV miR-US5-1 miRNA was shown to regulate the kinetics of expression of the DNA replication inhibitor Geminin (GMNN) in order to sustain latency.33
Effects of Retinoids at the Cellular Level (Differentiation, Apoptosis, Autophagy, Cell Cycle Regulation, and Senescence)
Published in Ayse Serap Karadag, Berna Aksoy, Lawrence Charles Parish, Retinoids in Dermatology, 2019
In addition, many genes associated with cell adhesion, cytoskeletal and matrix remodeling, growth suppression, and intracellular signaling cascades are also activated by RA (7). Conversely, the majority of genes repressed by RA are involved in protein/RNA processing and turnover or metabolism, such as ZIC, Geminin (GMNN), NOTCH, and FOXD4L1, reviewed in Janesick et al. (15).
Ipatasertib, an oral AKT inhibitor, in combination with carboplatin exhibits anti-proliferative effects in uterine serous carcinoma
Published in Annals of Medicine, 2023
Wesley C. Burkett, Ziyi Zhao, Meredith A. Newton, Wenchuan Sun, Boer Deng, Angeles Alvarez Secord, Chunxiao Zhou, Victoria Bae-Jump
To clarify the combined effects of the IPAT combined with carboplatin on DNA damage, SPEC-2 and ARK-1 cells were treated with IPAT, carboplatin, or combination of both for 18–24 h. The results from western blotting demonstrated that carboplatin treatment increased the expression of Geminin, γ-H2AX, p-CHK2 and RAD50 in both cells, while IPAT also increased the expression of these proteins except for Geminin and γ-H2AX in the ARK-1 cells. The combination of IPAT and carboplatin revealed a more potent effect in most of these DNA damage markers (Figure 4). These results indicate that DNA damage pathways are involved in synergistic growth-inhibitory effects of combination therapy in USC cells.
RAD51 as a functional biomarker for homologous recombination deficiency in cancer: a promising addition to the HRD toolbox?
Published in Expert Review of Molecular Diagnostics, 2022
Lise M. van Wijk, Andreea B. Nilas, Harry Vrieling, Maaike P.G. Vreeswijk
One of the most frequently used RAD51-based functional HRD tests that has been validated on different tumor and specimen types is the REcombination CAPacity (originally termed REpair CAPacity) or RECAP test [79,80,82,83] (Table 1). An important characteristic of this test is the inclusion of geminin (GMN) as an S/G2 phase cell proliferation marker [9], as HR is only active during these phases of the cell cycle. DSBs are induced by irradiation of viable tumor specimens with 5 Gy ionizing radiation (IR) followed by a two hours recovery time. A GMN-positive (GMN+) cell with at least five RAD51 foci is considered RAD51+ and the RAD51 score is defined as the percentage of (GMN+/RAD51+) cells within a population of GMN+ cells. Tumors are classified into three HR groups depending on their RAD51 score: HR-Deficient (HRD; 0–20%), HR-Intermediate (HRI; 21–50%), and HR-Proficient (HRP; 51–100%). Evaluation of 125 BC samples resulted in the classification of 24 (19%) cases as HRD of which 16 (67%) could be explained by BRCA-deficiencies [80]. In a cohort of 25 endometrial cancer (EC) samples that was enriched for non-endometrioid tumors, six out of 25 (24%) cases were classified as HRD based on the RECAP test and only two of these (33%) could be explained by the presence of PVs in BRCA1/2 [82]. The RECAP test was also applied on OC samples where HRD cases were only identified among HGSOC samples. Ten out of 39 (26%) HGSOC samples were identified as HRD, and among the nine HRD cases that were sequenced, eight (89%) could be explained by BRCA-deficiencies [83]. No BRCA-deficiencies were observed in HRP cases in any of the above-mentioned studies, indicating that the RECAP test identified BRCA-deficient cases with a sensitivity of 100% in OC, BC, and EC [80,82,83]. Although sample sizes were small, two studies showed a trend towards improved OS in HGSOC patients with tumors with low RECAP scores treated with platinum-based chemotherapy [81,83]. While these studies show promising results, the need for fresh tumor tissue and the ex vivo induction of DNA damage by IR limits the clinical implementation of the RECAP test.