Identification of DLL3-related genes affecting the prognosis of patients with colon adenocarcinoma.

Background: Delta-like ligand 3 (DLL3) is one of the NOTCH family of ligands, which plays a pro- or anti-carcinogenic role in some cancers. But the role of DLL3 in colon adenocarcinoma (COAD) has not been studied in depth. Materials and methods: First, we used Kaplan-Meier (K-M) curve to evaluate the effect of DLL3 on the prognosis of COAD in The Cancer Genome Atlas (TCGA), which was further validated in clinical samples for immunohistochemistry. Then we screened for differentially expressed genes (DEGs) of DLL3 by analyzing datasets of COAD samples from Gene Expression Omnibus (GEO) and TCGA. Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses, and Gene Set Enrichment Analysis (GSEA) were conducted to explore the underlying mechanisms of DLL3-related in the development and prognosis of COAD. On the basis of DLL3-related signature genes, a prognostic model and a nomogram were constructed. Finally, CIBERSORT was applied to assess the proportion of immune cell types in COAD sample. Results: Survival analysis showed a significant difference in overall survival between high- and low-expression group (p = 0.0092), with COAD patients in the high-group having poorer 5-year survival rate. Gene functional enrichment analysis revealed that DLL3-related DEGs were mainly enriched in tumor- and immunity-related signaling pathways, containing AMPK pathway and mitophagy-animal. The comparison of COAD tumor and normal, DLL3 high- and low-expression groups by GSEA found that AMPK signaling pathway and mitophagy-animal were inhibited. Nomogram constructed from DLL3-related signature genes had a good predictive effect on the prognosis of COAD. We found the highest correlation between DLL3 and interstitial dendritic cell (iDC), natural killer (NK) cell and Interstitial dendritic cell (Tem). DLL3 was also revealed to be diagnostic for COAD. In clinical sample, we identified higher DLL3 expression in colon cancer tissue than in adjacent control (p < 0.0001) and in metastasis than in primary lesion (p = 0.0056). DLL3 expression was associated with stage and high DLL3 expression was observed to predict poorer overall survival (p = 0.004). Conclusion: It suggested that DLL3 may offer prognostic value and therapeutic potential for individualized treatment of COAD, and that it may has a diagnostic role in COAD.

PD-1/PD-L1 Blockade Accelerates the Progression of Atherosclerosis in Cancer Patients.

PD-1(programed death-1)/PD-L1(programed death-1 ligand) blockade represents a major breakthrough of anti-cancer therapies, however, it may come with increased risk of cardiovascular morbidity, such as myocarditis, acute coronary syndrome, arrhythmias, etc. Although the PD-1/PD-L1-blockade-related acute coronary syndrome (ACS) is rare, it can be fatal. Previous studies have implicated a role of the PD-1/PD-L1 axis in the development of atherosclerosis. This review explores a hypothesis that PD-1/PD-L1 blockade accelerates the progression of atherosclerosis and promotes plaque rupture, by synthesizing the evidence of vascular inflammation, as well as plaque progression, destabilization and rupture via T-cell activation and effector function. In order to improve the prognosis of cancer patients and decrease the cardiotoxicity of PD-1/PD-L1 blockade therapy, early recognition of PD-1/PD-L1-blockade-related ACS is important.

Increased terrigenous input from North America to the northern Mendeleev Ridge (western Arctic Ocean) since the mid-Brunhes Event.

Mid-Brunhes Event (MBE) occurred at approximately 420 ka between Marine Isotope Stage 11 and 12, and is considered the most pronounced climatic shift during the last ~ 800 kyrs. On the other hand, it is unclear if the MBE was global, despite being observed in the high-latitude Northern Hemispheric cryosphere in terms of climate systems. A 5.35-m long gravity core ARC5-MA01 was obtained from the northern Mendeleev Ridge in the western Arctic Ocean to track the paleoenvironmental changes in terms of the terrigenous sedimentation in response to the glacial-interglacial climate changes across the MBE. Geochemical proxies (biogenic opal, total organic carbon, C/N ratio, carbon isotope of organic matter, and calcium carbonate) of MA01 suggest that the terrigenous input was generally higher during the interglacial periods. Based on a mineralogical examination, most of the terrigenous input was attributed to the abundance of dolomite and the increased kaolinite content from North America. In particular, most paleoceanographic proxies showed that the terrigenous input from North America was enhanced distinctly during the post-MBE interglacial periods. These results suggest that the MBE in the western Arctic Ocean was a global climatic shift closely linked to cryospheric development in North America during the middle Pleistocene.

ICIs-Related Cardiotoxicity in Different Types of Cancer.

Immune checkpoint inhibitors (ICIs) are rapidly developing immunotherapy cancer drugs that have prolonged patient survival. However, ICIs-related cardiotoxicity has been recognized as a rare, but fatal, consequence. Although there has been extensive research based on different types of ICIs, these studies have not indicated whether cardiotoxicity is specific to a type of cancer. Therefore, we conducted a systematic review to analyze a variety of ICIs-related cardiotoxicity, focusing on different types of cancer. We found that the incidence of ICIs-related cardiac adverse events (CAEs) and common cardiotoxic manifestations vary with cancer type. This inspired us to explore the underlying mechanisms to formulate targeted clinical strategies for maintaining the cardiovascular health of cancer patients.

Clinical significance of hypertension in patients with different types of cancer treated with antiangiogenic drugs.

Hypertension is a common comorbidity in patients receiving antiangiogenic therapy. Prior studies have reported worsening or new-onset hypertension as an adverse event of antiangiogenetic therapy, which can be managed by dose reduction or discontinuation of the culprit medication. By contrast, other studies have found that the occurrence of hypertension is a potential biomarker associated with greater efficacy of antiangiogenic therapy and predicts improved survival. At present, there is no consensus on the effects of hypertension in patients treated with antiangiogenic drugs. The present study reviewed the relationship between antiangiogenic drugs and hypertension in different types of cancer. It was demonstrated that the use of antiangiogenic drugs was associated with an increased risk of hypertension in most types of solid cancers. There was no significant difference in the incidence of hypertension between monoclonal antibody and small-molecule tyrosine kinase inhibitor treatments. Hypertension was more likely to occur in patients younger than 75 years old, female, and those with no history of bevacizumab use. Discontinuation or death caused by hypertension was rare, although previous studies have reported that hypertension was a risk factor for acute and chronic cardiovascular diseases and ischemic stroke. Of note, the early development of hypertension may serve as a potential biomarker associated with greater efficacy of antiangiogenic therapy.