Eric Russ

All Publications

• Strict retroelement regulation is frequently lost following cancer transformation and generates a promising reservoir of cancer biomarkers. Mobile DNA Russ, E., Iordanskiy, S. 2025; 16 (1): 37

  Abstract

  Retroelements are repetitive sequences that comprise 42% of the human genome and are strictly regulated through various epigenetic mechanisms. Examining retroelement expression on a locus-specific level in relation to cancer can uncover distinct disease signatures.Using over 5000 RNA-sequencing samples, we assessed retroelement transcription across 23 tissue systems, 159 cell types, 1019 cancer cell lines, and cells isolated from various stages of embryogenesis using the specialized software tool, Telescope. In healthy individuals, 11,388 retroelements were found to be actively transcribed and dynamically regulated in a tissue- and cell type-dependent manner. Using the adult human body as a reference, we observed that 94% of cancer cell lines displayed elevated transcription of at least one cancer-specific retroelement, providing a three-fold larger reservoir of cancer biomarkers (1182) than our comparable analysis of annotated protein-coding genes (338). The precise retroelements that were transcribed following tumorigenesis were influenced by the originating location, with cancers of the blood, lungs, and soft tissue displaying the highest origin-specific activation. Moreover, nearly half of the cancer-specific retroelement loci, mostly from the HERV-H family, were found to be expressed during early embryonic development.Our data demonstrate that elevated transcription of certain tissue-specific and embryonic retroelements can be considered as a hallmark of tumorigenesis.

  View details for DOI 10.1186/s13100-025-00376-7

  View details for PubMedID 41044661

  View details for PubMedCentralID PMC12495673

• Serum microRNA profile of rhesus macaques following ionizing radiation exposure and treatment with a medical countermeasure, Ex-Rad. Scientific reports Russ, E., Fatanmi, O. O., Wise, S. Y., Carpenter, A. D., Maniar, M., Iordanskiy, S., Singh, V. K. 2024; 14 (1): 4518

  Abstract

  Exposure to ionizing radiation (IR) presents a formidable clinical challenge. Total-body or significant partial-body exposure at a high dose and dose rate leads to acute radiation syndrome (ARS), the complex pathologic effects that arise following IR exposure over a short period of time. Early and accurate diagnosis of ARS is critical for assessing the exposure dose and determining the proper treatment. Serum microRNAs (miRNAs) may effectively predict the impact of irradiation and assess cell viability/senescence changes and inflammation. We used a nonhuman primate (NHP) model-rhesus macaques (Macaca mulatta)-to identify the serum miRNA landscape 96 h prior to and following 7.2 Gy total-body irradiation (TBI) at four timepoints: 24, 36, 48, and 96 h. To assess whether the miRNA profile reflects the therapeutic effect of a small molecule ON01210, commonly known as Ex-Rad, that has demonstrated radioprotective efficacy in a rodent model, we administered Ex-Rad at two different schedules of NHPs; either 36 and 48 h post-irradiation or 48 and 60 h post-irradiation. Results of this study corroborated our previous findings obtained using a qPCR array for several miRNAs and their modulation in response to irradiation: some miRNAs demonstrated a temporary increased serum concentration within the first 24-36 h (miR-375, miR-185-5p), whereas others displayed either a prolonged decline (miR-423-5p) or a long-term increase (miR-30a-5p, miR-27b-3p). In agreement with these time-dependent changes, hierarchical clustering of differentially expressed miRNAs showed that the profiles of the top six miRNA that most strongly correlated with radiation exposure were inconsistent between the 24 and 96 h timepoints following exposure, suggesting that different biodosimetry miRNA markers might be required depending on the time that has elapsed. Finally, Ex-Rad treatment restored the level of several miRNAs whose expression was significantly changed after radiation exposure, including miR-16-2, an miRNA previously associated with radiation survival. Taken together, our findings support the use of miRNA expression as an indicator of radiation exposure and the use of Ex-Rad as a potential radioprotectant.

  View details for DOI 10.1038/s41598-024-54997-8

  View details for PubMedID 38402257

  View details for PubMedCentralID PMC10894202

• Cellular RNA and DNA sensing pathways are essential for the dose-dependent response of human monocytes to ionizing radiation. Frontiers in immunology Mikhalkevich, N., Russ, E., Iordanskiy, S. 2023; 14: 1235936

  Abstract

  Circulating monocytes are important players of the inflammatory response to ionizing radiation (IR). These IR-resistant immune cells migrate to radiation-damaged tissues and differentiate into macrophages that phagocytize dying cells, but also facilitate inflammation. Besides the effect of damage-associated molecular patterns, released from irradiated tissues, the inflammatory activation of monocytes and macrophages is largely dependent on IR-induced DNA damage and aberrant transcriptional activity, which may facilitate expression of type I interferons (IFN-I) and numerous inflammation-related genes. We analyzed the accumulation of dsRNA, dsDNA fragments, and RNA:DNA hybrids in the context of induction of RNA-triggered MAVS-mediated and DNA-triggered STING-mediated signaling pathways, in primary human monocytes and a monocytic cell line, THP1, in response to various doses of gamma IR. We found that exposure to lower doses (<7.5 Gy) led to the accumulation of dsRNA, along with dsDNA and RNA:DNA hybrids and activated both MAVS and STING pathway-induced gene expression and signaling activity of IFN-I. Higher doses of IR resulted in the reduced dsRNA level, degradation of RNA-sensing mediators involved in MAVS signaling and coincided with an increased accumulation of dsDNA and RNA:DNA hybrids that correlated with elevated STING signaling and NF-κB-dependent gene expression. While both pathways activate IFN-I expression, using MAVS- and STING-knockout THP1 cells, we identified differences in the spectra of interferon-stimulated genes (ISGs) that are associated with each specific signaling pathway and outlined a large group of STING signaling-associated genes. Using the RNAi technique, we found that increasing the dose of IR activates STING signaling through the DNA sensor cGAS, along with suppression of the DDX41 helicase, which is known to reduce the accumulation of RNA:DNA hybrids and thereby limit cGAS/STING signaling activity. Together, these results indicate that depending on the applied dose, IR leads to the activation of either dsRNA-induced MAVS signaling, which predominantly leads to the expression of both pro- and anti-inflammatory markers, or dsDNA-induced STING signaling that contributes to pro-inflammatory activation of the cells. While RNA:DNA hybrids boost both MAVS- and STING-mediated signaling pathways, these structures being accumulated upon high IR doses promote type I interferon expression and appear to be potent enhancers of radiation dose-dependent pro-inflammatory activation of monocytes.

  View details for DOI 10.3389/fimmu.2023.1235936

  View details for PubMedID 38152396

  View details for PubMedCentralID PMC10751912

• Expression of Human Endogenous Retrovirus Group K (HERV-K) HML-2 Correlates with Immune Activation of Macrophages and Type I Interferon Response. Microbiology spectrum Russ, E., Mikhalkevich, N., Iordanskiy, S. 2023; 11 (2): e0443822

  Abstract

  Human endogenous retroviruses (HERVs) comprise about 8.3% of the human genome and are capable of producing RNA molecules that can be sensed by pattern recognition receptors, leading to the activation of innate immune response pathways. The HERV-K (HML-2) subgroup is the youngest HERV clade with the highest degree of coding competence. Its expression is associated with inflammation-related diseases. However, the precise HML-2 loci, stimuli, and signaling pathways involved in these associations are not well understood or defined. To elucidate HML-2 expression on a locus-specific level, we used the retroelement sequencing tools TEcount and Telescope to analyze publicly available transcriptome sequencing (RNA-seq) and chromatin immunoprecipitation (ChIP) sequencing data sets of macrophages treated with a wide range of agonists. We found that macrophage polarization significantly correlates with modulation of the expression of specific HML-2 proviral loci. Further analysis demonstrated that the provirus HERV-K102, located in an intergenic region of locus 1q22, constituted the majority of the HML-2 derived transcripts following pro-inflammatory (M1) polarization and was upregulated explicitly in response to interferon gamma (IFN-γ) signaling. We found that signal transducer and activator of transcription 1 and interferon regulatory factor 1 interact with a solo long terminal repeat (LTR) located upstream of HERV-K102, termed LTR12F, following IFN-γ signaling. Using reporter constructs, we demonstrated that LTR12F is critical for HERV-K102 upregulation by IFN-γ. In THP1-derived macrophages, knockdown of HML-2 or knockout of MAVS, an adaptor of RNA-sensing pathways, significantly downregulated genes containing interferon-stimulated response elements (ISREs) in their promoters, suggesting an intermediate role of HERV-K102 in the switch from IFN-γ signaling to the activation of type I interferon expression and, therefore, in a positive feedback loop to enhance pro-inflammatory signaling. IMPORTANCE The human endogenous retrovirus group K subgroup, HML-2, is known to be elevated in a long list of inflammation-associated diseases. However, a clear mechanism for HML-2 upregulation in response to inflammation has not been defined. In this study, we identify a provirus of the HML-2 subgroup, HERV-K102, which is significantly upregulated and constitutes the majority of the HML-2 derived transcripts in response to pro-inflammatory activation of macrophages. Moreover, we identify the mechanism of HERV-K102 upregulation and demonstrate that HML-2 expression enhances interferon-stimulated response element activation. We also demonstrate that this provirus is elevated in vivo and correlates with interferon gamma signaling activity in cutaneous leishmaniasis patients. This study provides key insights into the HML-2 subgroup and suggests that it may participate in enhancing pro-inflammatory signaling in macrophages and probably other immune cells.

  View details for DOI 10.1128/spectrum.04438-22

  View details for PubMedID 36861980

  View details for PubMedCentralID PMC10100713

• Endogenous Retroviruses as Modulators of Innate Immunity. Pathogens (Basel, Switzerland) Russ, E., Iordanskiy, S. 2023; 12 (2)

  Abstract

  Endogenous retroviruses (ERVs), or LTR retrotransposons, are a class of transposable elements that are highly represented in mammalian genomes. Human ERVs (HERVs) make up roughly 8.3% of the genome and over the course of evolution, HERV elements underwent positive selection and accrued mutations that rendered them non-infectious; thereby, the genome could co-opt them into constructive roles with important biological functions. In the past two decades, with the help of advances in sequencing technology, ERVs are increasingly considered to be important components of the innate immune response. While typically silenced, expression of HERVs can be induced in response to traumatic, toxic, or infection-related stress, leading to a buildup of viral transcripts and under certain circumstances, proteins, including functionally active reverse transcriptase and viral envelopes. The biological activity of HERVs in the context of the innate immune response can be based on the functional effect of four major viral components: (1) HERV LTRs, (2) HERV-derived RNAs, (3) HERV-derived RNA:DNA duplexes and cDNA, and (4) HERV-derived proteins and ribonucleoprotein complexes. In this review, we will discuss the implications of HERVs in all four contexts in relation to innate immunity and their association with various pathological disease states.

  View details for DOI 10.3390/pathogens12020162

  View details for PubMedID 36839434

  View details for PubMedCentralID PMC9963469

• Comparison of the Medical Uses and Cellular Effects of High and Low Linear Energy Transfer Radiation. Toxics Russ, E., Davis, C. M., Slaven, J. E., Bradfield, D. T., Selwyn, R. G., Day, R. M. 2022; 10 (10)

  Abstract

  Exposure to ionizing radiation can occur during medical treatments, from naturally occurring sources in the environment, or as the result of a nuclear accident or thermonuclear war. The severity of cellular damage from ionizing radiation exposure is dependent upon a number of factors including the absorbed radiation dose of the exposure (energy absorbed per unit mass of the exposure), dose rate, area and volume of tissue exposed, type of radiation (e.g., X-rays, high-energy gamma rays, protons, or neutrons) and linear energy transfer. While the dose, the dose rate, and dose distribution in tissue are aspects of a radiation exposure that can be varied experimentally or in medical treatments, the LET and eV are inherent characteristics of the type of radiation. High-LET radiation deposits a higher concentration of energy in a shorter distance when traversing tissue compared with low-LET radiation. The different biological effects of high and low LET with similar energies have been documented in vivo in animal models and in cultured cells. High-LET results in intense macromolecular damage and more cell death. Findings indicate that while both low- and high-LET radiation activate non-homologous end-joining DNA repair activity, efficient repair of high-LET radiation requires the homologous recombination repair pathway. Low- and high-LET radiation activate p53 transcription factor activity in most cells, but high LET activates NF-kB transcription factor at lower radiation doses than low-LET radiation. Here we review the development, uses, and current understanding of the cellular effects of low- and high-LET radiation exposure.

  View details for DOI 10.3390/toxics10100628

  View details for PubMedID 36287908

  View details for PubMedCentralID PMC9609561

• Circulating Cell-free DNA in Serum as a Marker for the Early Detection of Tumor Recurrence in Breast Cancer Patients. Cancer diagnosis & prognosis Bera, A., Russ, E., Karaian, J., Landa, A., Radhakrishnan, S., Subramanian, M., Hueman, M., Pollard, H. B., Hu, H., Shriver, C. D., Srivastava, M. 2022; 2 (3): 285-292

  Abstract

  Circulating cell-free DNA (cfDNA) isolated from serum by noninvasive procedures can serve as a potential biomarker for the early detection of many cancers. The aim of this study was to implement a simple, yet effective quantitative method for measuring the cfDNA in serum and to investigate the relationship between cfDNA and the occurrence of recurrence in breast cancer (BrCa) patients.A total of 240 cases were selected, which comprised different subtypes of BrCa patients and control individuals. We selected 20 serum samples from patients which showed recurrence after 4-7 years of disease-free survival. SYBR green was used as a reporter molecule to estimate the amount of cfDNA in these serum samples.A global Wilcoxon analysis was performed to compare the cfDNA abundance between non-recurrent and recurrent patients. The amount of cfDNA was higher in recurrent patients (recurrent vs. non-recurrent ratio=1.3; p=0.03; AUC=0.76) compared to non-recurrent patients. The data between normal/healthy controls and non-recurrent patients indicated no significant differences (n=20 in each group, healthy to non-recurrent ratio=1.03; p=0.20; AUC=0.61).We implemented a straightforward one-step technique to measure the amount of cfDNA in serum, which can translate into a clinical diagnostic tool in the near future. The high levels of cfDNA in the serum of recurrent BrCa patients compared to non-recurrent BrCa patients indicates a possible uncovered role for circulating genetic information, which either contributes to the cancer recurrence phenomenon or at the very least, serves as an identifier for the potential of recurrence.

  View details for DOI 10.21873/cdp.10106

  View details for PubMedID 35530653

  View details for PubMedCentralID PMC9066529

• High mRNA expression of LY6 gene family is associated with overall survival outcome in pancreatic ductal adenocarcinoma. Oncotarget Russ, E., Bhuvaneshwar, K., Wang, G., Jin, B., Gage, M. M., Madhavan, S., Gusev, Y., Upadhyay, G. 2021; 12 (3): 145-159

  Abstract

  Pancreatic cancer ranks one of the worst in overall survival outcome with a 5 year survival rate being less than 10%. Pancreatic cancer faces unique challenges in its diagnosis and treatment, such as the lack of clinically validated biomarkers and the immensely immunosuppressive tumor microenvironment. Recently, the LY6 gene family has received increasing attention for its multi-faceted roles in cancer development, stem cell maintenance, immunomodulation, and association with more aggressive and hard-to-treat cancers. A detailed study of mRNA expression of LY6 gene family and its association with overall survival (OS) outcome in pancreatic cancers is lacking. We used publicly available clinical datasets to analyze the mRNA expression of a set of LY6 genes and its effect on OS outcome in the context of the tumor microenvironment and immunomodulation. We used web-based tools Kaplan-Meier Plotter, cBioPortal, Oncomine and R-programming to analyze copy number alterations, mRNA expression and its association with OS outcome in pancreatic cancer. These analyses demonstrated that high expression of LY6 genes is associated with OS and disease free survival (DFS) outcome. High expression of LY6 genes and their association with OS outcome is dependent on the composition of tumor microenvironment. Considering that LY6 proteins are anchored to the outer cell membrane or secreted, making them readily accessible, these findings highlight the potential of LY6 family members in the future of pancreatic cancer diagnosis and treatment.

  View details for DOI 10.18632/oncotarget.27880

  View details for PubMedID 33613843

  View details for PubMedCentralID PMC7869573

• A randomized, phase 1, placebo-controlled trial of APG-157 in oral cancer demonstrates systemic absorption and an inhibitory effect on cytokines and tumor-associated microbes. Cancer Basak, S. K., Bera, A., Yoon, A. J., Morselli, M., Jeong, C., Tosevska, A., Dong, T. S., Eklund, M., Russ, E., Nasser, H., Lagishetty, V., Guo, R., Sajed, D., Mudgal, S., Mehta, P., Avila, L., Srivastava, M., Faull, K., Jacobs, J., Pellegrini, M., Shin, D. S., Srivatsan, E. S., Wang, M. B. 2020; 126 (8): 1668-1682

  Abstract

  Although curcumin's effect on head and neck cancer has been studied in vitro and in vivo, to the authors' knowledge its efficacy is limited by poor systemic absorption from oral administration. APG-157 is a botanical drug containing multiple polyphenols, including curcumin, developed under the US Food and Drug Administration's Botanical Drug Development, that delivers the active components to oromucosal tissues near the tumor target.A double-blind, randomized, placebo-controlled, phase 1 clinical trial was conducted with APG-157 in 13 normal subjects and 12 patients with oral cancer. Two doses, 100 mg or 200 mg, were delivered transorally every hour for 3 hours. Blood and saliva were collected before and 1 hour, 2 hours, 3 hours, and 24 hours after treatment. Electrocardiograms and blood tests did not demonstrate any toxicity.Treatment with APG-157 resulted in circulating concentrations of curcumin and analogs peaking at 3 hours with reduced IL-1β, IL-6, and IL-8 concentrations in the salivary supernatant fluid of patients with cancer. Salivary microbial flora analysis showed a reduction in Bacteroidetes species in cancer subjects. RNA and immunofluorescence analyses of tumor tissues of a subject demonstrated increased expression of genes associated with differentiation and T-cell recruitment to the tumor microenvironment.The results of the current study suggested that APG-157 could serve as a therapeutic drug in combination with immunotherapy.Curcumin has been shown to suppress tumor cells because of its antioxidant and anti-inflammatory properties. However, its effectiveness has been limited by poor absorption when delivered orally. Subjects with oral cancer were given oral APG-157, a botanical drug containing multiple polyphenols, including curcumin. Curcumin was found in the blood and in tumor tissues. Inflammatory markers and Bacteroides species were found to be decreased in the saliva, and immune T cells were increased in the tumor tissue. APG-157 is absorbed well, reduces inflammation, and attracts T cells to the tumor, suggesting its potential use in combination with immunotherapy drugs.

  View details for DOI 10.1002/cncr.32644

  View details for PubMedID 32022261

• Liver Function Enzymes are Potential Predictive Markers for Kidney Allograft Dysfunction. Advancements in journal of urology and nephrology Bera, A., Russ, E., Jindal, R. M., Watson, M. A., Nee, R., Eidelman, O., Karaian, J., Pollard, H. B., Srivastava, M. 2020; 2 (1): 27-36

  Abstract

  Biopsy of the allograft is the gold standard for assessing kidney allograft dysfunction. The aim of our pilot study was to identify serum biomarkers that could obviate the need for biopsy.We conducted a study to identify the biomarkers in the serum from different groups of chronic kidney disease (CKD) patients and kidney transplanted patients vs. healthy individuals. The four groups (n=25 in each group) were as follows: 1) Patients with unstable kidney allograft transplants requiring biopsy for cause, 2) Patients with stable kidney allograft transplants, 3) Patients with CKD not on immunosuppressive therapy and, 4) healthy subjects. We measured the activity and level of serum alkaline phosphatase (ALP) and other liver enzymes (alanine transaminase (ALT) and aspartate transaminase (AST)) as potential serum biomarkers in acute allograft dysfunction.We found that ALP correlated with allograft biopsy findings, liver function, and clinical outcomes and possibly graft survival. Additionally, AST and ALT were higher in patients with graft rejection compared to non-rejected and stable kidney transplants. Moreover, the low Pearson correlations (r- values) between ALP level with age (r=0.179), gender, body mass index (r=0.236), creatinine (r=0.044) or estimated glomerular filtration rate (r=0.048) suggest that ALP may be an independent biomarker which is relatively unaffected by other individual-level variables.ALP may be a putative biomarker to predict kidney allograft function and rejection. Data also indicated that liver function plays an important role for the overall success of kidney transplantation.

  View details for DOI 10.33140/ajun.02.01.07

  View details for PubMedID 33083794

  View details for PubMedCentralID PMC7571418

• Proteomic Analysis of Inflammatory Biomarkers Associated With Breast Cancer Recurrence. Military medicine Bera, A., Russ, E., Manoharan, M. S., Eidelman, O., Eklund, M., Hueman, M., Pollard, H. B., Hu, H., Shriver, C. D., Srivastava, M. 2020; 185 (Suppl 1): 669-675

  Abstract

  Breast cancer is the most frequent cancer detected for women, and while our ability to treat breast cancer has improved substantially over the years, recurrence remains a major obstacle. Standard screening for new and recurrent breast cancer involves clinical breast imaging. However, there is no clinically approved noninvasive body fluid test for the early detection of recurrent breast cancer. Materials and Method: In this study, we analyzed serum samples from both recurrent and nonrecurrent breast cancer patients by different proteomics methods to identify biomarkers in patients with recurrence of disease.Comparative data analysis identified several histone deacetylase (HDAC) proteins, which were found at significantly higher levels in the serum of recurrent breast cancer patients: HDAC9 (C-term) (P = 0.0035), HDAC5 (C-term) (P = 0.013), small ubiquitin-like modifier 1 (N-term) (P = 0.017), embryonic stem cell-expressed Ras (inter) (P = 0.018), and HDAC7 (C-term) (P = 0.020). Chronic inflammation plays a critical role in the development of the breast cancer recurrence, and we identified several proinflammatory cytokines that were present at elevated levels only in recurrent breast cancer patient serum.Our data indicated that the epigenetic regulation of inflammatory processes plays a critical role in breast cancer recurrence. The identified proteins could lay the groundwork for the development of a serum-based breast cancer recurrence assay.

  View details for DOI 10.1093/milmed/usz254

  View details for PubMedID 32074342