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Research

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15 pages, 1570 KiB

Open AccessArticle

Multiple Administration Routes, Including Intramuscular Injection, of Oncolytic Tanapoxvirus Variants Significantly Regress Human Melanoma Xenografts in BALB/c Nude Mice Reconstituted with Splenocytes from Normal BALB/c Donors

by Michael L. Monaco, Omer A. Idris, Grace A. Filpi, Steven L. Kohler, Scott D. Haller, Jeffery E. Burr, Robert Eversole and Karim Essani

Genes 2023, 14(8), 1533; https://doi.org/10.3390/genes14081533 - 27 Jul 2023

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Abstract

Human melanoma is the most aggressive form of skin cancer and is responsible for the most deaths of all skin cancers. Localized tumors, and those which have limited spread, have 5-year survival rates of over 90%, with those numbers steadily rising over the past decade. However, metastatic melanomas have a sharp decrease in 5-year survival rates and are still an area of need for new, successful therapies. Immuno-oncolytic viruses (OVs) have emerged as a promising class of immunovirotherapy that can potentially address this disease. The Food and Drug Administration in the United States has approved one oncolytic herpes simplex virus expressing granulocyte-macrophage colony-stimulating factor (Talimogene Laherparepvec) for the treatment of metastatic melanoma, and others could soon follow for this and other cancers. In previous studies, Tanapoxvirus (TPV) recombinants expressing mouse interleukin-2 (mIL-2) and another expressing bacterial flagellin from Salmonella typhimurium (FliC) have demonstrated anti-tumor efficacy in nude mouse models. TPV replicates only in humans and monkeys, including tumor cells, which makes the use of syngeneic tumor models impossible for the study of this OV in a standard immunocompetent system. In this study, TPV/Δ66R/mIL-2 and TPV/Δ2L/Δ66R/FliC were tested for their ability to treat human melanoma xenografts (SK-MEL3) in a BALB/c nude mouse model reconstituted with splenocytes from genetically compatible, normal BALB/c donor mice. Two SK-MEL3 tumors were transplanted into each flank of BALB/c nude mice, and the larger tumor was treated intratumorally (IT) with virus or mock injection. In one set of animals, mice received adoptive transfers of splenocytes from BALB/c mice on day 4 to reconstitute their immune systems and allow for adaptive immune responses to occur in a xenograft model. Direct IT injection of TPV/Δ66R/mIL-2 led to significantly greater rates of tumor regression compared to reconstituted control (RC) mice in the primary and distant tumor sites, whereas TPV/Δ2L/Δ66R/FliC treatment led to significantly greater rates of tumor regression in distant tumor sites only. A second experiment used TPV/Δ66R/mIL-2 to test whether TPV could be administered intravenously (IV), intramuscularly (IM), or both routes simultaneously to exert similar anti-tumor effects in an indirectly treated tumor. A single SK-MEL3 tumor was transplanted into one flank of BALB/c nude mice and was treated either into the tail vein, the nearest rear leg to the tumor, or both. All mice then received adoptive transfers of splenocytes in the same way as previously described on day 4 and received an additional TPV treatment on day 14. The results demonstrated that TPV/Δ66R/mIL-2 treatment IV or IM had significantly greater rates of tumor regression than RC-treated mice but failed to exert this effect when both routes were used simultaneously. Data obtained through these experiments support the continued development of Tanapoxvirus for the treatment of human melanoma and using immune reconstitution to create intact adaptive immunity in a xenograft context, which can allow other tropism-limited OVs to be studied against human cancers. Full article

(This article belongs to the Special Issue Cancer Systems Biology and Genomics)

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13 pages, 887 KiB

Open AccessArticle

Whole Exome Sequencing to Find Candidate Variants for the Prediction of Kidney Transplantation Efficacy

by Seyed Mohammad Kazem Aghamir, Hassan Roudgari, Hassan Heidari, Mohammad Salimi Asl, Yousef Jafari Abarghan, Venous Soleimani, Rahil Mashhadi and Fatemeh Khatami

Genes 2023, 14(6), 1251; https://doi.org/10.3390/genes14061251 - 11 Jun 2023

Viewed by 1563

Abstract

Introduction: Kidney transplantation is the optimal treatment strategy for some end-stage renal disease (ESRD); however, graft survival and the success of the transplantation depend on several elements, including the genetics of recipients. In this study, we evaluated exon loci variants based on a high-resolution Next Generation Sequencing (NGS) method. Methods: We evaluated whole-exome sequencing (WES) of transplanted kidney recipients in a prospective study. The study involved a total of 10 patients (5 without a history of rejection and 5 with). About five milliliters of blood were collected for DNA extraction, followed by whole-exome sequencing based on molecular inversion probes (MIPs). Results: Sequencing and variant filtering identified nine pathogenic variants in rejecting patients (low survival). Interestingly, in five patients with successful kidney transplantation, we found 86 SNPs in 63 genes 61 were variants of uncertain significance (VUS), 5 were likely pathogenic, and five were likely benign/benign. The only overlap between rejecting and non-rejecting patients was SNPs rs529922492 in rejecting and rs773542127 in non-rejecting patients’ MUC4 gene. Conclusions: Nine variants of rs779232502, rs3831942, rs564955632, rs529922492, rs762675930, rs569593251, rs192347509, rs548514380, and rs72648913 have roles in short graft survival. Full article

(This article belongs to the Special Issue Cancer Systems Biology and Genomics)

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Review

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24 pages, 2949 KiB

Open AccessReview

The Role of the AT-Rich Interaction Domain 1A Gene (ARID1A) in Human Carcinogenesis

by Jing Jing Li and Cheok Soon Lee

Genes 2024, 15(1), 5; https://doi.org/10.3390/genes15010005 - 19 Dec 2023

Viewed by 1135

Abstract

The switch/sucrose non-fermentable (SWI/SNF) (SWI/SNF) complex uses energy from ATP hydrolysis to mobilise nucleosomes on chromatin. Components of SWI/SNF are mutated in 20% of all human cancers, of which mutations in AT-rich binding domain protein 1A (ARID1A) are the most common. ARID1A is mutated in nearly half of ovarian clear cell carcinoma and around one-third of endometrial and ovarian carcinomas of the endometrioid type. This review will examine in detail the molecular functions of ARID1A, including its role in cell cycle control, enhancer regulation, and the prevention of telomerase activity. ARID1A has key roles in the maintenance of genomic integrity, including DNA double-stranded break repair, DNA decatenation, integrity of the cohesin complex, and reduction in replication stress, and is also involved in mismatch repair. The role of ARID1A loss in the pathogenesis of some of the most common human cancers is discussed, with a particular emphasis on gynaecological cancers. Finally, several promising synthetic lethal strategies, which exploit the specific vulnerabilities of ARID1A-deficient cancer cells, are briefly mentioned. Full article

(This article belongs to the Special Issue Cancer Systems Biology and Genomics)

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