The aging process is driven by multiple mechanisms that lead to changes in energy production, oxidative stress, homeostatic dysregulation and eventually to loss of functionality and increased disease susceptibility. Most aged individuals develop chronic low-grade inflammation, which is an important risk factor for morbidity, physical and cognitive impairment, frailty, and death. At any age, chronic inflammatory diseases are major causes of morbimortality, affecting up to 5–8% of the population of industrialized countries. Several environmental factors can play an important role for modifying the inflammatory state. Genetics accounts for only a small fraction of chronic-inflammatory diseases, whereas environmental factors appear to participate, either with a causative or a promotional role in 50% to 75% of patients. Several of those changes depend on epigenetic changes that will further modify the individual response to additional stimuli. The interaction between inflammation and the environment offers important insights on aging and health. These conditions, often depending on the individual’s sex, appear to lead to decreased longevity and physical and cognitive decline. In addition to biological factors, the environment is also involved in the generation of psychological and social context leading to stress. Poor psychological environments and other sources of stress also result in increased inflammation. However, the mechanisms underlying the role of environmental and psychosocial factors and nutrition on the regulation of inflammation, and how the response elicited for those factors interact among them, are poorly understood. Whereas certain deleterious environmental factors result in the generation of oxidative stress driven by an increased production of reactive oxygen and nitrogen species, endoplasmic reticulum stress, and inflammation, other factors, including nutrition (polyunsaturated fatty acids) and behavioral factors (exercise) confer protection against inflammation, oxidative and endoplasmic reticulum stress, and thus ameliorate their deleterious effect. Here, we discuss processes and mechanisms of inflammation associated with environmental factors and behavior, their links to sex and gender, and their overall impact on aging.

The tumor microenvironment (TME) corresponds to a complex and dynamic interconnection between the extracellular matrix and malignant cells and their surrounding stroma composed of immune and mesenchymal cells. The TME has constant cellular communication through cytokines that sustain an inflammatory profile, which favors tumor progression, angiogenesis, cell invasion, and metastasis. Although the epithelial-mesenchymal transition (EMT) represents a relevant metastasis-initiating event that promotes an invasive phenotype in malignant epithelial cells, its relationship with the inflammatory profile of the TME is poorly understood. Previous evidence strongly suggests that cyclooxygenase-2 (COX-2) overexpression, a pro-inflammatory enzyme related to chronic unresolved inflammation, is associated with common EMT-signaling pathways. This review article summarizes how COX-2 overexpression, within the context of the TME, orchestrates the EMT process and promotes initial metastatic-related events.

Muscle and bone are tightly integrated through mechanical and biochemical signals. Osteoclasts are cells mostly related to pathological bone loss; however, they also start physiological bone remodeling. Therefore, osteoclast signals released during bone remodeling could improve both bone and skeletal muscle mass. Extracellular ATP is an autocrine/paracrine signaling molecule released by bone and muscle cells. Then, in the present work, it was hypothesized that ATP is a paracrine mediator released by osteoclasts and leads to skeletal muscle protein synthesis. RAW264.7-derived osteoclasts were co-cultured in Transwell® chambers with flexor digitorum brevis (FDB) muscle isolated from adult BalbC mice. The osteoclasts at the upper chamber were mechanically stimulated by controlled culture medium perturbation, resulting in a two-fold increase in protein synthesis in FDB muscle at the lower chamber. Osteoclasts released ATP to the extracellular medium in response to mechanical stimulation, proportional to the magnitude of the stimulus and partly dependent on the P2X7 receptor. On the other hand, exogenous ATP promoted Akt phosphorylation (S473) in isolated FDB muscle in a time- and concentration-dependent manner. ATP also induced phosphorylation of proteins downstream Akt: mTOR (S2448), p70S6K (T389) and 4E-BP1 (T37/46). Exogenous ATP increased the protein synthesis rate in FDB muscle 2.2-fold; this effect was blocked by Suramin (general P2X/P2Y antagonist), LY294002 (phosphatidylinositol 3 kinase inhibitor) and Rapamycin (mTOR inhibitor). These blockers, as well as apyrase (ATP metabolizing enzyme), also abolished the induction of FDB protein synthesis evoked by mechanical stimulation of osteoclasts in the co-culture model. Therefore, the present findings suggest that mechanically stimulated osteoclasts release ATP, leading to protein synthesis in isolated FDB muscle, by activating the P2-PI3K-Akt-mTOR pathway. These results open a new area for research and clinical interest in bone-to-muscle crosstalk in adaptive processes related to muscle use/disuse or in musculoskeletal pathologies.

Background Cyclooxygenase‐2 protein is a critically important mediator in inflammation that influences proliferation, apoptosis, angiogenesis and metastasis. Previous works showed a relationship between cyclooxygenase‐2 and tumourigenesis in humans and animal models. In epithelial odontogenic tumours and cysts, increased cell proliferation and survival have been linked to its pathogenesis and tumour development. The aim of the present study was to analyse the immunohistochemical expression of cyclooxygenase‐2 in solid ameloblastoma and odontogenic keratocyst and its association with proteins related to cell proliferation and apoptosis. Methods This study was conducted on 40 cases from the Pathological Anatomy Service, University of Chile. The cases were diagnosed as solid ameloblastoma (n = 21) and odontogenic keratocyst (n = 19) according to WHO 2017. Slides prepared from paraffin‐embedded sections were immunohistochemically stained for cyclooxygenase‐2, cyclin D1, Ki‐67, p63 and Bcl‐2. Statistical evaluation was performed by the Shapiro–Wilk test, ANOVA Mann–Whitney test and Spearman's correlation coefficient (p < 0.05). Results There were significant differences in the immunoexpression of cyclin D1, Ki‐67 and Bcl‐2 between solid ameloblastoma and odontogenic keratocyst. Likewise, there was a significant difference in the immunoexpression of p63 between follicular and plexiform histological types/subtypes of solid ameloblastoma. Lastly, there were statistical associations between cyclooxygenase‐2 and Ki‐67 for solid ameloblastoma and between cyclooxygenase‐2 and p63 for odontogenic keratocyst. Conclusion A high level of cyclooxygenase‐2 is related to increased cell survival and proliferative activity in solid ameloblastoma and odontogenic keratocyst. This event might contribute to tumoural progression and local invasiveness in these lesions.

Our objective was to evaluate the impact of body composition (BC), beyond body mass index (BMI), and lipid metabolism disorders on therapeutic responses and outcomes in high-grade serous ovarian cancer (HGSOC).Methods: 123 and 415 patients with advanced HGSOC from two cohorts (PUC and TCGA) were analyzed. Databases containing clinical/genomic variables were built-up. BC was estimated using the measurement of adiposity (e.g., Whole body Adipose Tissue [WBAT]) and muscle mass (Lumbar muscle area to vertebral body at L4-level, [PLVI]) by CT-scan. A list of 425 genes linked to obesity and lipid metabolism was used to identify clusters using non-negative matrix factorization. GSEA, Gene Ontology, KEGG pathways enrichment, and Ecotyper analyzes were also made. Survival curves and Cox-regression models were also built-up. Results: We identified four BC types and two clusters that, unlike BMI, effectively correlate with survival regardless of achieving optimal debulking or complete response. Mention deserves central sarcopenia, which was associated with worse survival in any condition. So also, that recovering a normal BC and adding medications to correct metabolism disorders (e.g., statins) could have a positive impact on outcomes. Along with this, we showed that micro-environments depleted of immune cells predominate in HGSOC, something more evident in the BC type (High WBAT/Low PLVI) and cluster (Obesity/Lipid Metabolism Type I) with worse prognosis. Conclusions: Here, we demonstrate the relevance of BC and lipid metabolism disorders in determining therapeutic responses and long-term outcomes. Also, the importance of incorporating corrective measures addressing these disorders to obtain better results. (Research supported by Fondecyt 1201083) Citation Format: Mauricio A. Cuello-Fredes, Fernan Gomez, Ignacio Wichmann, Felipe Suarez, Sumie Kato, Jorge Brañes, Elisa Orlandini, Carolina Ibañez. Body composition and metabolic dysfunction really matter for the achievement of better outcomes in high-grade serous ovarian cancer [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 922.

Although obesity-associated metabolic disorders have a negative impact on various cancers, such evidence remains controversial for ovarian cancer. Here, we aimed to evaluate the impact of body composition (BC) and metabolism disorders on outcomes in high-grade serous ovarian cancer (HGSOC). Methods: We analyzed clinical/genomic data from two cohorts (PUC n = 123/TCGA-OV n = 415). BC was estimated using the measurement of adiposity/muscle mass by a CT scan. A list of 425 genes linked to obesity/lipid metabolism was used to cluster patients using non-negative matrix factorization. Differential expression, gene set enrichment analyses, and Ecotyper were performed. Survival curves and Cox-regression models were also built-up. Results: We identified four BC types and two clusters that, unlike BMI, effectively correlate with survival. High adiposity and sarcopenia were associated with worse outcomes. We also found that recovery of a normal BC and drug interventions to correct metabolism disorders had a positive impact on outcomes. Additionally, we showed that immune-cell-depleted microenvironments predominate in HGSOC, which was more evident among the BC types and the obesity/lipid metabolism cluster with worse prognosis. Conclusions: We have demonstrated the relevance of BC and metabolism disorders as determinants of outcomes in HGSOC. We have shone a spotlight on the relevance of incorporating corrective measures addressing these disorders to obtain better results.

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