CancerHERVdb: Human Endogenous Retrovirus (HERV) Expression Database for Human Cancer Accelerates Studies of the Retrovirome and Predictions for HERV-Based Therapies.

In this study, we sought to create a database summarizing the expression of human endogenous retroviruses (HERVs) in various human cancers. HERVs are suitable therapeutic targets due to their abundance in the human genome, overexpression in various malignancies, and involvement in various cancer pathways. We identified articles on HERVs from PubMed and then prescreened and automatically categorized them using the portable document format (PDF) data extractor (PDE) R package. We discovered 196 primary research articles with HERV expression data from cancer tissues or cancer cell lines. HERV RNA and protein expression was reported in brain, breast, cervical, colorectal, endocrine, gastrointestinal, kidney/renal/pelvis, liver, lung, genital, oral cavity, pharynx, ovary, pancreas, prostate, skin, testicular, urinary/bladder, and uterus cancers, leukemias, lymphomas, and myelomas. Additionally, we discovered reports of HERV RNA-only overexpression in soft tissue cancers including heart, thyroid, bone, and joint cancers. The CancerHERVdb database is hosted in the form of interactive visualizations of the expression data and a summary data table at https://erikstricker.shinyapps.io/cancerHERVdb/. The user can filter the findings according to cancer type, HERV family, HERV gene, or a combination thereof and easily export the results with the corresponding reference list. In our report, we provide examples of potential uses of the CancerHERVdb, such as identification of cancers suitable for off-target treatment with the multiple sclerosis-associated retrovirus (MSRV)-Env-targeting antibody GNbAC1 (now named temelimab) currently in phase 2b clinical trials for multiple sclerosis or the discovery of cancers overexpressing HERV-H long terminal repeat-associating 2 (HHLA2), a newly emerging immune checkpoint. In summary, the CancerHERVdb allows cross-study comparisons, encourages data exploration, and informs about potential off-target effects of HERV-targeting treatments. IMPORTANCE Human endogenous retroviruses (HERVs), which in the past have inserted themselves in various regions of the human genome, are to various degrees activated in virtually every cancer type. While a centralized naming system and resources summarizing HERV levels in cancers are lacking, the CancerHERVdb database provides a consolidated resource for cross-study comparisons, data exploration, and targeted searches of HERV activation. The user can access data extracted from hundreds of articles spanning 25 human cancer categories. Therefore, the CancerHERVdb database can aid in the identification of prognostic and risk markers, drivers of cancer, tumor-specific targets, multicancer spanning signals, and targets for immune therapies. Consequently, the CancerHERVdb database is of direct relevance for clinical as well as basic research.

OralOpioids: Harnessing R Programming and Data Science to Combat Opioid Misuse.

Aims: This study aims to introduce the OralOpioids R package, a novel research tool for the in-depth study and analysis of opioid prescriptions in Canada, which reports a significant per-capita pharmaceutical opioid consumption. Methods: The OralOpioids R package employs data from Health Canada's Drug Product Database (DPD), focusing on authorized oral opioids. It systematically filters drug identification numbers (DINs) by narcotic schedules and administration routes. Moreover, it calculates the morphine equivalent dose (MED) for each DIN using the CDC table. Core functions include MED calculation for specific drugs, brand name retrieval, opioid content extraction, and unit computations based on Canadian MED guidelines. Results: When juxtaposed against renowned opioid calculators such as MDCalc, Oregon Pain, and Ohio Pain, the OralOpioids package exhibited a near-perfect correlation, with R-squared values consistently at 0.99. Conclusions: The OralOpioids package, distinctively tailored for research, marks a significant stride in understanding and monitoring Canada's opioid milieu. By encompassing data on discontinued opioids, it fosters a nuanced comprehension of the opioid panorama, enabling historical insight and post-marketing watchfulness. Primarily targeting researchers, its scope extends to healthcare providers, insurers, and administrative boards, all of whom can leverage its potent capabilities for informed decision-making. Although currently centered on Canadian opioids, its flexible design is primed for future expansion, potentially capturing a global audience and catalyzing efforts against the opioid crisis.

HERVs and Cancer-A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers.

Genomic instability and genetic mutations can lead to exhibition of several cancer hallmarks in affected cells such as sustained proliferative signaling, evasion of growth suppression, activated invasion, deregulation of cellular energetics, and avoidance of immune destruction. Similar biological changes have been observed to be a result of pathogenic viruses and, in some cases, have been linked to virus-induced cancers. Human endogenous retroviruses (HERVs), once external pathogens, now occupy more than 8% of the human genome, representing the merge of genomic and external factors. In this review, we outline all reported effects of HERVs on cancer development and discuss the HERV targets most suitable for cancer treatments as well as ongoing clinical trials for HERV-targeting drugs. We reviewed all currently available reports of the effects of HERVs on human cancers including solid tumors, lymphomas, and leukemias. Our review highlights the central roles of HERV genes, such as gag, env, pol, np9, and rec in immune regulation, checkpoint blockade, cell differentiation, cell fusion, proliferation, metastasis, and cell transformation. In addition, we summarize the involvement of HERV long terminal repeat (LTR) regions in transcriptional regulation, creation of fusion proteins, expression of long non-coding RNAs (lncRNAs), and promotion of genome instability through recombination.

Trends in Overall Survival among Patients Treated for Sarcoma at a Large Tertiary Cancer Center between 1986 and 2014.

Sarcomas are relatively rare malignancies accounting for about 1% of all cancer diagnoses. Studies on sarcomas comprising large cohorts covering extended time periods are lacking. Therefore, this study aimed to evaluate the impact of demographic, behavioral, and clinical characteristics on overall survival (OS) among individuals diagnosed with soft tissue sarcoma (STS) or bone sarcoma at the Moffitt Cancer Center between 1986 and 2014. Unadjusted and multivariable Cox proportional hazard regression (CPHR) models were constructed to generate hazard ratios (HRs) and 95% confidence intervals (CIs) to evaluate associations between a range of demographic, behavioral, and clinical characteristics, and OS. Additionally, Kaplan-Meier survival curves, associated log-rank statistics, and adjusted CPHR models were generated by time periods based on the year of first contact (1986-1994, 1995-1999, 2000-2005, 2006-2010, 2011-2014) to evaluate for temporal differences in OS. Of the 2570 patients, 2037 were diagnosed with STS, whereas 533 were diagnosed with bone sarcoma. At the time of analysis, 50% of the population were alive. In multivariable analyses, we observed poorer survival for patients ≥ 40 years of age (HR = 1.54, 95% CI = 1.34-1.78), current smokers (HR = 1.18, 95% CI = 1.01-1.37), patients with metastasis (HR = 2.19, 95% CI = 1.95-2.47), and patients not receiving first-line surgery treatment (HR = 2.11, 95% CI = 1.82-2.45). We discovered limited improvements in OS over time among individuals diagnosed with STS or bone sarcomas with the exception of gastrointestinal stromal tumors (GIST), which showed a significant improvement in OS across time periods (p = 0.0034). Overall, we identified well-established characteristics associated with OS (e.g., metastasis) in addition to factors (e.g., smoking status) not previously reported to impact OS. Improvements in survival over time have been relatively modest, suggesting the need for improved therapeutic options, especially for those diagnosed with less frequent sarcomas.

Supercoiling and looping promote DNA base accessibility and coordination among distant sites.

DNA in cells is supercoiled and constrained into loops and this supercoiling and looping influence every aspect of DNA activity. We show here that negative supercoiling transmits mechanical stress along the DNA backbone to disrupt base pairing at specific distant sites. Cooperativity among distant sites localizes certain sequences to superhelical apices. Base pair disruption allows sharp bending at superhelical apices, which facilitates DNA writhing to relieve torsional strain. The coupling of these processes may help prevent extensive denaturation associated with genomic instability. Our results provide a model for how DNA can form short loops, which are required for many essential processes, and how cells may use DNA loops to position nicks to facilitate repair. Furthermore, our results reveal a complex interplay between site-specific disruptions to base pairing and the 3-D conformation of DNA, which influences how genomes are stored, replicated, transcribed, repaired, and many other aspects of DNA activity.

Functional Analyses of Bovine Foamy Virus-Encoded miRNAs Reveal the Importance of a Defined miRNA for Virus Replication and Host-Virus Interaction.

In addition to regulatory or accessory proteins, some complex retroviruses gain a repertoire of micro-RNAs (miRNAs) to regulate and control virus-host interactions for efficient replication and spread. In particular, bovine and simian foamy viruses (BFV and SFV) have recently been shown to express a diverse set of RNA polymerase III-directed miRNAs, some with a unique primary miRNA double-hairpin, dumbbell-shaped structure not known in other viruses or organisms. While the mechanisms of expression and structural requirements have been studied, the functional importance of these miRNAs is still far from understood. Here, we describe the in silico identification of BFV miRNA targets and the subsequent experimental validation of bovine Ankyrin Repeat Domain 17 (ANKRD17) and Bax-interacting factor 1 (Bif1) target genes in vitro and, finally, the suppression of ANKRD17 downstream genes in the affected pathway. Deletion of the entire miRNA cassette in the non-coding part of the U3 region of the long terminal repeats attenuated replication of corresponding BFV mutants in bovine cells. This repression can be almost completely trans-complemented by the most abundant miRNA BF2-5p having the best scores for predicted and validated BFV miRNA target genes. Deletion of the miRNA cassette does not grossly affect particle release and overall particle composition.