An Integrative Multi-Omics Analysis of The Molecular Links between Aging and Aggressiveness in Thyroid Cancers.

Aging modifies risk in all cancers, but age is used as a clinical staging criterion uniquely in thyroid cancer (TC). The molecular drivers of age-dependent TC onset and aggressiveness remain poorly understood. We applied an integrative, multi-omics data analysis approach to characterize these signatures. Our analysis reveals that aging, independent of BRAFV600E mutational status, drives a significant accumulation of aggressiveness-related markers and poorer survival outcomes, most noticeably at age 55 and over. We identified that chromosomal alterations in loci 1p/1q as aging-associated drivers of aggressiveness, and that depleted infiltration with tumor surveillant CD8+T and follicular helper T cells, dysregulation of proteostasis- and senescence-related processes, and ERK1/2 signaling cascade are key features of the aging thyroid and TC onset/progression and aggressiveness in aging patients but not in young individuals. A panel of 23 genes, including those related to cell division such as CENPF, ERCC6L, and the kinases MELK and NEK2, were identified and rigorously characterized as aging-dependent and aggressiveness-specific markers. These genes effectively stratified patients into aggressive clusters with distinct phenotypic enrichment and genomic/transcriptomic profiles. This panel also showed excellent performance in predicting metastasis stage, BRAFV600E, TERT promoter mutation, and survival outcomes and was superior to the American Thyroid Association (ATA) methodology in predicting aggressiveness risk. Our analysis established clinically relevant biomarkers for TC aggressiveness factoring in aging as an important component.

A Predictive Model of Adaptive Resistance to BRAF/MEK Inhibitors in Melanoma.

The adaptive acquisition of resistance to BRAF and MEK inhibitor-based therapy is a common feature of melanoma cells and contributes to poor patient treatment outcomes. Leveraging insights from a proteomic study and publicly available transcriptomic data, we evaluated the predictive capacity of a gene panel corresponding to proteins differentially abundant between treatment-sensitive and treatment-resistant cell lines, deciphering predictors of treatment resistance and potential resistance mechanisms to BRAF/MEK inhibitor therapy in patient biopsy samples. From our analysis, a 13-gene signature panel, in both test and validation datasets, could identify treatment-resistant or progressed melanoma cases with an accuracy and sensitivity of over 70%. The dysregulation of HMOX1, ICAM, MMP2, and SPARC defined a BRAF/MEK treatment-resistant landscape, with resistant cases showing a >2-fold risk of expression of these genes. Furthermore, we utilized a combination of functional enrichment- and gene expression-derived scores to model and identify pathways, such as HMOX1-mediated mitochondrial stress response, as potential key drivers of the emergence of a BRAF/MEK inhibitor-resistant state in melanoma cells. Overall, our results highlight the utility of these genes in predicting treatment outcomes and the underlying mechanisms that can be targeted to reduce the development of resistance to BRAF/MEK targeted therapy.

Crassocephalum rubens (Juss Ex Jacq) leaf diets ameliorate systemic oxidative stress and tissue damage in a Wistar rat model.

The capacity of Crassocephalum rubens (Juss Ex Jacq) leaf to protect against systemic oxidative stress was evaluated in N-methyl-N-nitrosourea (MNU) - intoxicated rats fed at various inclusion rates for a period of twelve (12) weeks. Major organs and tissues were then assessed for indices of lipid peroxidation and oxidative stress. Crassocephalum rubens leaf significantly (p < .05) sustained the activities of superoxide dismutase and catalase with significant decrease in lipid peroxidation in MNU-intoxicated animals, particularly at 5% and 10% inlusion rates. The dietary inclusion also prevented significant changes in hematological parameters such as neutrophil and lymphocyte counts. It also reduced the severity of histologic damages such as necrosis, epithelial degeneration, inflammatory cell infiltration and other pathological changes to major organs. These results indicate that regular consumption of C. rubens leaf, prevents the deleterious biologic effects of the damaging reactive oxidative species (ROS). PRACTICAL APPLICATIONS: Crassocephalum rubens leaf has potential for development into a nutraceutical or functional food for chemoprevention and management of neurodegenerative diseases and other diseases associated with systemic oxidative stress, This is because its inclusion in the diet has attenuated lipid peroxidation, sustained the activity of antioxidant enzymes and mitigated deleterious changes in blood composition and tissue architecture resulting from exposure to a chemical carcinogen.

Evaluation of the preventive potential of graded dietary inclusion of Hyphaene thebaica (Linn) fruit in rat model of colon carcinogenesis.

The preventive effect of Hyphaene thebaica fruit in colon carcinogenesis was evaluated in Wistar rats at 0, 2.5, 5 and 10% inclusion rates for twelve weeks with concomitant 72-h intra-rectal N-methyl-N-nitrosourea (MNU) instillations. Indices of antioxidant status and carcinogenesis were analyzed using spectrophotometric, ELISA, histological and immunohistochemical techniques. The fruit protected against lipid peroxidation and level of early biomarkers of colon carcinogenesis, accompanied by decrease in some endogenous antioxidant enzymes functionality. It also prevented colon tissues against MNU-induced severe inflammations and damage to the mutL-homolog 1 (MLH1) gene. There was significant negative correlation between endogenous antioxidant enzyme activities and carcinoembryonic antigen (CEA) as well as lipid peroxidation, but relationship between total polyphenols and percentage expression of MLH1 proteins as well as endogenous antioxidant enzyme activities was positive. These results validate the folkloric use of H. thebaica fruit in the management of colorectal disorders. PRACTICAL APPLICATIONS: Hyphaene thebaica fruit which is widely consumed in northern Nigeria and other countries of sub-Saharan Africa is rich in fiber and antioxidant polyphenols. These two classes of compounds have demonstrated capacity to prevent colorectal cancer and cancer of other sites. Therefore, the validated protective Hyphaene thebaica fruit suggests that it can be processed for inclusion in beverages/diets as functional foods for prevention and management of colorectal disorders.