A retrospective, single-center cohort study on complications after dental extractions in patients taking biologic agents.

BACKGROUND: Although biologic agents represent a growing class of therapeutics, little is known about how these agents affect the provision of dental treatment. METHODS: This retrospective case-control study analyzed patients undergoing dental extraction treated with biologic agents from 2017 through 2020. Complications within 30 days postextraction were recorded. RESULTS: One-hundred twenty-one patients were treated during 147 encounters. Fifteen patients experienced complications during 16 encounters. Notable or excessive pain was most common (14/16; 88%). Patients who experienced complications were treated with 7 biologic agents: dulaglutide, belimumab, adalimumab, aflibercept, tofacitinib, ranibizumab, and ixekizumab. Complication after extraction-specifically, pain-was elevated for patients receiving aflibercept and ranibizumab. When grouped by class, complications were more common with vascular endothelial growth factor antagonism. CONCLUSIONS: The impact of biologics on the provision of and recovery after dental treatment remains unknown. Pain was most commonly reported. Patients treated with vascular endothelial growth factor antagonists experienced an elevated rate of complications. PRACTICAL IMPLICATIONS: This study provides preliminary data on how patients taking biologic agents heal after dental extraction. It is limited by small sample sizes. Further work will build on this data to determine appropriate management of patients taking biologics in the dental setting.

On the expanding roles of tRNA fragments in modulating cell behavior.

The fragments that derive from transfer RNAs (tRNAs) are an emerging category of regulatory RNAs. Known as tRFs, these fragments were reported for the first time only a decade ago, making them a relatively recent addition to the ever-expanding pantheon of non-coding RNAs. tRFs are short, 16-35 nucleotides (nts) in length, and produced through cleavage of mature and precursor tRNAs at various positions. Both cleavage positions and relative tRF abundance depend strongly on context, including the tissue type, tissue state, and disease, as well as the sex, population of origin, and race/ethnicity of an individual. These dependencies increase the urgency to understand the regulatory roles of tRFs. Such efforts are gaining momentum, and comprise experimental and computational approaches. System-level studies across many tissues and thousands of samples have produced strong evidence that tRFs have important and multi-faceted roles. Here, we review the relevant literature on tRF biology in higher organisms, single cell eukaryotes, and prokaryotes.

IsomiRs and tRNA-derived fragments are associated with metastasis and patient survival in uveal melanoma.

Uveal melanoma (UVM) is the most common primary intraocular malignancy in adults. With over 50% of patients developing metastatic disease, there is an unmet need for improved diagnostic and therapeutic options. Efforts to understand the molecular biology of the disease have revealed several markers that correlate with patient prognosis, including the copy number of chromosome 3, genetic alterations in the BAP1, EIF1AX and SF3B1 genes, and other transcriptional features. Here, we expand upon previous reports by comprehensively characterizing the short RNA-ome in 80 primary UVM tumor samples. In particular, we describe a previously unseen complex network involving numerous regulatory molecules that comprise microRNA (miRNAs), novel UVM-specific miRNA loci, miRNA isoforms (isomiRs), and tRNA-derived fragments (tRFs). Importantly, we show that the abundance profiles of isomiRs and tRFs associate with various molecular phenotypes, metastatic disease, and patient survival. Our findings suggest deep involvement of isomiRs and tRFs in the disease etiology of UVM. We posit that further study and characterization of these novel molecules will improve understanding of the mechanisms underlying UVM, and lead to the development of new diagnostic and therapeutic approaches.

tRNA Fragments Show Intertwining with mRNAs of Specific Repeat Content and Have Links to Disparities.

tRNA-derived fragments (tRF) are a class of potent regulatory RNAs. We mined the datasets from The Cancer Genome Atlas (TCGA) representing 32 cancer types with a deterministic and exhaustive pipeline for tRNA fragments. We found that mitochondrial tRNAs contribute disproportionally more tRFs than nuclear tRNAs. Through integrative analyses, we uncovered a multitude of statistically significant and context-dependent associations between the identified tRFs and mRNAs. In many of the 32 cancer types, these associations involve mRNAs from developmental processes, receptor tyrosine kinase signaling, the proteasome, and metabolic pathways that include glycolysis, oxidative phosphorylation, and ATP synthesis. Even though the pathways are common to multiple cancers, the association of specific mRNAs with tRFs depends on and differs from cancer to cancer. The associations between tRFs and mRNAs extend to genomic properties as well; specifically, tRFs are positively correlated with shorter genes that have a higher density in repeats, such as ALUs, MIRs, and ERVLs. Conversely, tRFs are negatively correlated with longer genes that have a lower repeat density, suggesting a possible dichotomy between cell proliferation and differentiation. Analyses of bladder, lung, and kidney cancer data indicate that the tRF-mRNA wiring can also depend on a patient's sex. Sex-dependent associations involve cyclin-dependent kinases in bladder cancer, the MAPK signaling pathway in lung cancer, and purine metabolism in kidney cancer. Taken together, these findings suggest diverse and wide-ranging roles for tRFs and highlight the extensive interconnections of tRFs with key cellular processes and human genomic architecture. SIGNIFICANCE: Across 32 TCGA cancer contexts, nuclear and mitochondrial tRNA fragments exhibit associations with mRNAs that belong to concrete pathways, encode proteins with particular destinations, have a biased repeat content, and are sex dependent.

Profiles of miRNA Isoforms and tRNA Fragments in Prostate Cancer.

MicroRNA (miRNA) isoforms ("isomiRs") and tRNA-derived fragments ("tRFs") are powerful regulatory non-coding RNAs (ncRNAs). In human tissues, both types of molecules are abundant, with expression patterns that depend on a person's race, sex and population origin. Here, we present our analyses of the Prostate Cancer (PRAD) datasets of The Cancer Genome Atlas (TCGA) from the standpoint of isomiRs and tRFs. This study represents the first simultaneous examination of isomiRs and tRFs in a large cohort of PRAD patients. We find that isomiRs and tRFs have extensive correlations with messenger RNAs (mRNAs). These correlations are disrupted in PRAD, which suggests disruptions of the regulatory network in the disease state. Notably, we find that the profiles of isomiRs and tRFs differ in patients belonging to different races. We hope that the presented findings can lay the groundwork for future research efforts aimed at elucidating the functional roles of the numerous and distinct members of these two categories of ncRNAs that are present in PRAD.

MINTbase v2.0: a comprehensive database for tRNA-derived fragments that includes nuclear and mitochondrial fragments from all The Cancer Genome Atlas projects.

MINTbase is a repository that comprises nuclear and mitochondrial tRNA-derived fragments ('tRFs') found in multiple human tissues. The original version of MINTbase comprised tRFs obtained from 768 transcriptomic datasets. We used our deterministic and exhaustive tRF mining pipeline to process all of The Cancer Genome Atlas datasets (TCGA). We identified 23 413 tRFs with abundance of ≥ 1.0 reads-per-million (RPM). To facilitate further studies of tRFs by the community, we just released version 2.0 of MINTbase that contains information about 26 531 distinct human tRFs from 11 719 human datasets as of October 2017. Key new elements include: the ability to filter tRFs on-the-fly by minimum abundance thresholding; the ability to filter tRFs by tissue keywords; easy access to information about a tRF's maximum abundance and the datasets that contain it; the ability to generate relative abundance plots for tRFs across cancer types and convert them into embeddable figures; MODOMICS information about modifications of the parental tRNA, etc. Version 2.0 of MINTbase contains 15x more datasets and nearly 4x more distinct tRFs than the original version, yet continues to offer fast, interactive access to its contents. Version 2.0 is available freely at http://cm.jefferson.edu/MINTbase/.

Knowledge about the presence or absence of miRNA isoforms (isomiRs) can successfully discriminate amongst 32 TCGA cancer types.

Isoforms of human miRNAs (isomiRs) are constitutively expressed with tissue- and disease-subtype-dependencies. We studied 10 271 tumor datasets from The Cancer Genome Atlas (TCGA) to evaluate whether isomiRs can distinguish amongst 32 TCGA cancers. Unlike previous approaches, we built a classifier that relied solely on 'binarized' isomiR profiles: each isomiR is simply labeled as 'present' or 'absent'. The resulting classifier successfully labeled tumor datasets with an average sensitivity of 90% and a false discovery rate (FDR) of 3%, surpassing the performance of expression-based classification. The classifier maintained its power even after a 15× reduction in the number of isomiRs that were used for training. Notably, the classifier could correctly predict the cancer type in non-TCGA datasets from diverse platforms. Our analysis revealed that the most discriminatory isomiRs happen to also be differentially expressed between normal tissue and cancer. Even so, we find that these highly discriminating isomiRs have not been attracting the most research attention in the literature. Given their ability to successfully classify datasets from 32 cancers, isomiRs and our resulting 'Pan-cancer Atlas' of isomiR expression could serve as a suitable framework to explore novel cancer biomarkers.