RESUMEN
Patients with advanced or malignant renal cell carcinoma at the time of diagnosis have historically had a poor prognosis. Immunonologic agents have significantly altered the therapeutic landscape and clinical outcomes of these patients. In this review, we highlight recent and upcoming clinical trials investigating the role of immunotherapies in clear cell RCC. In particular, we emphasize immunotherapy-based combinations, including immune checkpoint inhibitor (ICI) combinations, neoadjuvant, and adjuvant ICI, and ICI agents combined with anti-VEGF therapy.
RESUMEN
BACKGROUND: The autonomous retroelement Long Interspersed Element-1 (LINE-1) mobilizes though a copy and paste mechanism using an RNA intermediate (retrotransposition). Throughout human evolution, around 500,000 LINE-1 sequences have accumulated in the genome. Most of these sequences belong to ancestral LINE-1 subfamilies, including L1PA2-L1PA7, and can no longer mobilize. Only a small fraction of LINE-1 sequences, approximately 80 to 100 copies belonging to the L1Hs subfamily, are complete and still capable of retrotransposition. While silenced in most cells, many questions remain regarding LINE-1 dysregulation in cancer cells. RESULTS: Here, we optimized CRISPR Cas9 gRNAs to specifically target the regulatory sequence of the L1Hs 5'UTR promoter. We identified three gRNAs that were more specific to L1Hs, with limited binding to older LINE-1 sequences (L1PA2-L1PA7). We also adapted the C-BERST method (dCas9-APEX2 Biotinylation at genomic Elements by Restricted Spatial Tagging) to identify LINE-1 transcriptional regulators in cancer cells. Our LINE-1 C-BERST screen revealed both known and novel LINE-1 transcriptional regulators, including CTCF, YY1 and DUSP1. CONCLUSION: Our optimization and evaluation of gRNA specificity and application of the C-BERST method creates a tool for studying the regulatory mechanisms of LINE-1 in cancer. Further, we identified the dual specificity protein phosphatase, DUSP1, as a novel regulator of LINE-1 transcription.
RESUMEN
Lymph node involvement in renal cell carcinoma (RCC) portends a poor prognosis. However, the role of lymph node dissection (LND) at the time of tumor resection is not fully understood. Conflicting data have been published regarding the survival implications of LND during RCC surgery, and the optimal patient population for which LND might be beneficial has yet to be identified. Based on recent data characterizing the outcomes of node-positive RCC, some have advocated for revising the current staging guidelines to better reflect these findings. Given the paucity of high-quality evidence supporting or refuting the routine use of LND in RCC, further research is needed to shed light on this important topic. There are a number of ongoing clinical trials evaluating the role of perioperative (neoadjuvant and adjuvant) systemic therapy, which include patients with node-positive RCC, and will serve to guide changes in treatment practices for this patient population moving forward.
