Fitness of cells is dependent on protein homeostasis which is maintained by cooperative activities of protein chaperones and proteolytic machinery. Upon encountering protein-damaging conditions, cells activate the heat-shock response (HSR) which involves HSF1-mediated transcriptional upregulation of a group of chaperones – the heat shock proteins (HSPs). Cancer cells experience high levels of proteotoxic stress due to the production of mutated proteins, aneuploidy-induced excess of components of multiprotein complexes, increased translation rates, and dysregulated metabolism. To cope with this chronic state of proteotoxic stress, cancers almost invariably upregulate major components of HSR, including HSF1 and individual HSPs. Some oncogenic programs show dependence or coupling with a particular HSR factor (such as frequent coamplification of HSF1 and MYC genes). Elevated levels of HSPs and HSF1 are typically associated with drug resistance and poor clinical outcomes in various malignancies. The non-oncogene dependence (“addiction”) on protein quality controls represents a pancancer target in treating human malignancies, offering a potential to enhance efficacy of standard and targeted chemotherapy and immune checkpoint inhibitors. In cancers with specific dependencies, HSR components can serve as alternative targets to poorly druggable oncogenic drivers.

Cellular homeostasis is continuously challenged by damage from reactive oxygen species (ROS) and numerous reactive electrophiles. Human cells contain various protective systems that are upregulated in response to protein damage by electrophilic or oxidative stress. In addition to the NRF2mediated antioxidant response, ROS and reactive electrophiles also activate HSF1 and HIF1 that control heat shock response and hypoxia response, respectively. Here, we review chemical and biological mechanisms of activation of these three transcription factors by ROS/reactive toxicants and the roles of their gene expression programs in antioxidant protection. We also discuss how NRF2, HSF1, and HIF1 responses establish multilayered cellular defenses consisting of largely nonoverlapping programs, which mitigates limitations of each response. Some innate immunity links in these stress responses help eliminate damaged cells, whereas others suppress deleterious inflammation in normal tissues but inhibit immunosurveillance of cancer cells in tumors.

Extracellular vesicles (EVs) are produced and released by all cells and are present in all body fluids. They exist in a variety of sizes, however, small extracellular vesicles (sEVs), the EV subset with a size range from 30 to 150 nm, are of current interest. By transporting a complex cargo that includes genetic material, proteins, lipids, and signaling molecules, sEVs can alter the state of recipient cells. The role of sEVs in mediating inflammatory processes and responses of the immune system is well-documented, and adds another layer of complexity to our understanding of frequent diseases, including chronic rhinosinusitis (CRS), asthma, chronic obstructive pulmonary disease (COPD), and upper airway infections. In these diseases, two aspects of sEV biology are of particular interest: (1) sEVs might be involved in the etiopathogenesis of inflammatory airway diseases, and might emerge as attractive therapeutic targets, and (2) sEVs might be of diagnostic or prognostic relevance. The purpose of this review is to outline the biological functions of sEVs and their capacity to both augment and attenuate inflammation and immune response in the context of pathogen invasion, CRS, asthma, and COPD.

Graves’ orbitopathy (GO) is an extrathyroidal manifestation of Graves’ disease (GD), which can be associated with corneal ulcerations or optic neuropathy in severe forms. Transnasal endoscopic orbital decompression (TEOD) is a surgical procedure performed in order to decrease the intraorbital pressure by removing part of its bony borders in cases with excessive mass in orbit. The aim of this study was to present the results and evaluate the efficacy of TEOD for GO. The retrospective study included 28 orbits (16 patients) who underwent TEOD from 2017 to 2020. Outcome was evaluated based on visual acuity improvement, clinical activity score (CAS) decrease, proptosis, and intraocular pressure (IOP) reduction. A preoperative best-corrected visual acuity (BCVA) increased from 0.69 ± 0.385 (mean ± standard deviation) to 0.74 ± 0.332 (p = 0.17) postoperatively. CAS decreased in 15 orbits postoperatively. Proptosis decreased from 22.89 ± 1.873 mm to 21.25 ± 2.053 mm (p < 0.05). IOP decreased from a preoperative 16.11 ± 3.93 mmHg to 14.40 ± 3.27 mmHg (p < 0.05) postoperatively. In addition, postoperative relief of exposure keratitis was observed. The analysis of development of iatrogenic diplopia revealed increasing in degree of diplopia. TEOD shows rare complications, but significant improvements in BCVA, CAS, proptosis, and IOP.

Mercury (Hg) is a persistent environmental pollutant that has long been associated with neurotoxic and other noncancer health effects in exposed populations. Recent large epidemiological studies using different internal indices of Hg exposure have found significantly elevated risks for skin cancers in both men and women. To understand potential carcinogenic mechanisms for Hg(II), we examined its mutagenicity and impact on processing of different types of DNA damage. In agreement with its lack of DNA reactivity, we found that Hg(II) was not mutagenic at the mammalian Hprt locus and did not change DNA incorporation of rNMPs which are the most abundant endogenous nucleotide abnormalities in the genome. We next tested the impact of Hg(II) at nontoxic or only mildly toxic concentrations on sensitivity of cells to several genotoxicants producing specific classes of DNA damage. We found that even nontoxic concentrations of Hg(II) impaired cellular resistance to topoisomerase I-mediated DNA damage in human epidermal keratinocytes. Hg(II) had no significant effect on cytotoxicity of topoisomerase II-mediated DNA lesions and examination of numerous components of DNA damage response activated by topoisomerase II-targeting drugs showed no major differences between control and Hg(II)-exposed cells. In contrast, Hg(II)-treated keratinocytes displayed a distorted DNA damage response to topoisomerase I-produced DNA damage, manifested in a misbalanced activation of ATM and ATR targets. Consistent with their lower survival, Hg(II)-treated cells accumulated higher levels of toxic DNA double-strand breaks (DSBs). Further analyses indicated that Hg(II) caused impartment of DNA repair of replication-associated DSBs. Thus, although Hg(II) is not directly genotoxic, it can increase genomic instability by interfering with accurate processing of endogenous DNA damage produced by topoisomerase I. Citation Format: Giorgiana Madalina Ursu, Anna M. Cyran, Anatoly Zhitkovich. Mercury(II)-induced abnormalities in processing of topoisomerase I-mediated DNA damage [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1218.