An integrative evaluation of circadian gene TIMELESS as a pan-cancer immunological and predictive biomarker.

BACKGROUND: The gene TIMELESS, which is involved in the circadian clock and the cell cycle, has recently been linked to various human cancers. Nevertheless, the association between TIMELESS expression and the prognosis of individuals afflicted with pan-cancer remains largely unknown. OBJECTIVES: The present study aims to exhaustively scrutinize the expression patterns, functional attributes, prognostic implications, and immunological contributions of TIMELESS across diverse types of human cancer. METHODS: The expression of TIMELESS in normal and malignant tissues was examined, as well as their clinicopathologic and survival data. The characteristics of genetic alteration and molecular subtypes of cancers were also investigated. In addition, the relationship of TIMELESS with immune infiltration, tumor mutation burden (TMB), microsatellite instability (MSI), and drug sensitivity was illustrated. Immunohistochemistry (IHC) was used to validate the expression of TIMELESS in clinical patients with several types of cancer. RESULTS: In contrast to the matching normal controls, most tumor types were found to often overexpress TIMELESS. Abnormal expression of TIMELESS was significantly related to more advanced tumor stage and poorer prognosis of breast cancer, as well as infiltrating immune cells such as cancer-associated fibroblast infiltration in various tumors. Multiple cancer types exhibited abnormal expression of TIMELESS, which was also highly correlated with MSI and TMB. More crucially, TIMELESS showed promise in predicting the effectiveness of immunotherapy and medication sensitivity in cancer therapy. Moreover, cell cycle, DNA replication, circadian rhythm, and mismatch repair were involved in the functional mechanisms of TIMELESS on carcinogenesis. Furthermore, immunohistochemical results manifested that the TIMELESS expression was abnormal in some cancers. CONCLUSIONS: This study provides new insights into the link between the circadian gene TIMELESS and the development of various malignant tumors. The findings suggest that TIMELESS could be a prospective prognostic and immunological biomarker for pan-cancer.

Overlapping and segregated changes of functional hubs in melancholic depression and non-melancholic depression.

BACKGROUND: Previous research found associations between neuropsychiatric disorders and patterns of highly connected "hub" nodes, which are crucial in coordinating brain functions. Melancholic depression is considered a relatively distinct and homogenous subtype of major depressive disorder (MDD), which responds better to pharmacological treatments than placebos or psychotherapies. Accordingly, melancholic depression probably has distinct neuropathological underpinnings. This study aims to examine the overlapping and segregated changes of functional hubs in melancholic and non-melancholic MDD. METHODS: Thirty-one melancholic patients, 28 non-melancholic patients, and 32 healthy controls were included. Resting-state functional imaging data were analyzed using global functional connectivity. RESULTS: Both melancholic and non-melancholic patients had increased GFC in the bilateral insula and decreased GFC in the PCC/precuneus compared to HCs. The distinction was that melancholic patients showed increased GFC in the bilateral thalamus, right inferior parietal lobule (IPL), and left cerebellum Crus I and decreased GFC in the left temporal lobe, whereas non-melancholic patients showed increased GFC in the left superior parietal lobe. Additionally, compared with non-melancholic patients, melancholic individuals displayed significant increases of GFC in the left IPL and cerebellum. CONCLUSION: Increased GFC of the insula and decreased GFC of the PCC and precuneus are the common abnormalities of melancholic and non-melancholic MDD. Hyperconnectivity of the IPL and cerebellum might be distinctive neuropathological features of melancholic MDD.

Suppressive effect of microRNA-126 on oral squamous cell carcinoma in vitro.

MicroRNA-126 (miR-126), an endothelial-specific miRNA located within intron 7 of epidermal growth factor­like domain 7 (EGFL7), has been demonstrated to act as a tumor suppressor in various types of human cancer. However, its role in oral squamous cell carcinoma (OSCC) remains unclear. In the present study, we revealed that the expression of miR-126 was significantly decreased in OSCC tissues, when compared with that in their matched adjacent tissues, and its expression level was also reduced in Tca8113, OSCC-15 and CAL27 cell lines compared with normal tissues. The protein expression of EGFL7 was upregulated in OSCC tissues compared with their matched adjacent tissues as well as normal tissues, and Tca8113, OSCC-15 and CAL27 cells additionally demonstrated a positive expression of EGFL7. The overexpression of miR-126 significantly reduced the protein expression of EGFL7 in OSCC-15 cells, while transfection with the miR-126 inhibitor upregulated the EGFL7 protein level in OSCC-15 cells. Furthermore, transfection with an miR-126 mimic into OSCC-15 cells markedly suppressed cell proliferation, cell cycle progression, cell invasion and colony formation, while inducing cell apoptosis, which contrasted with the effects of transfection with an miR-126 inhibitor. The overexpression of miR-126 suppressed the secretion of two key regulators of angiogenesis, vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF), which was also reversed by miR-126 inhibitor transfection. In conclusion, the present study demonstrated that miR-126 acts as a tumor suppressor in OSCC cells, partially at least via the downregulation of EGFL7. Thus, miR-126 may serve as a promising candidate for the treatment of OSCC.