Prognostic signature based on S100 calcium-binding protein family members for lung adenocarcinoma and its clinical significance.

The S100 family proteins (S100s) participate in multiple stages of tumorigenesis and are considered to have potential value as biomarkers for detecting and predicting various cancers. But the role of S100s in lung adenocarcinoma (LUAD) prognosis is elusive. Transcriptional data of LUAD patients were retrieved from TCGA, and relevant literature was extensively reviewed to collect S100 genes. Differential gene expression analysis was performed on the LUAD data, followed by intersection analysis between the differentially expressed genes (DEGs) and S100 genes. Unsupervised consensus clustering analysis identified two clusters. Significant variations in overall survival between the two clusters were shown by Kaplan-Meier analysis. DEGs between the two clusters were analyzed using Lasso regression and univariate/multivariate Cox regression analysis, leading to construction of an 11-gene prognostic signature. The signature exhibited stable and accurate predictive capability in TCGA and GEO datasets. Subsequently, we observed distinct immune cell infiltration, immunotherapy response, and tumor mutation characteristics in high and low-risk groups. Finally, small molecular compounds targeting prognostic genes were screened using CellMiner database, and molecular docking confirmed the binding of AMG-176, Estramustine, and TAK-632 with prognostic genes. In conclusion, we generated a prognostic signature with robust and reliable predictive ability, which may provide guidance for prognosis and treatment of LUAD.

Ferritin-mediated mitochondrial iron homeostasis is essential for the survival of hematopoietic stem cells and leukemic stem cells.

Iron metabolism plays a crucial role in cell viability, but its relationship with adult stem cells and cancer stem cells is not fully understood. The ferritin complex, responsible for intracellular iron storage, is important in this process. We report that conditional deletion of ferritin heavy chain 1 (Fth1) in the hematopoietic system reduced the number and repopulation capacity of hematopoietic stem cells (HSCs). These effects were associated with a decrease in cellular iron level, leading to impaired mitochondrial function and the initiation of apoptosis. Iron supplementation, antioxidant, and apoptosis inhibitors reversed the reduced cell viability of Fth1-deleted hematopoietic stem and progenitor cells (HSPCs). Importantly, leukemic stem cells (LSCs) derived from MLL-AF9-induced acute myeloid leukemia (AML) mice exhibited reduced Fth1 expression, rendering them more susceptible to apoptosis induced by the iron chelation compared to normal HSPCs. Modulating FTH1 expression using mono-methyl fumarate increased LSCs resistance to iron chelator-induced apoptosis. Additionally, iron supplementation, antioxidant, and apoptosis inhibitors protected LSCs from iron chelator-induced cell death. Fth1 deletion also extended the survival of AML mice. These findings unveil a novel mechanism by which ferritin-mediated iron homeostasis regulates the survival of both HSCs and LSCs, suggesting potential therapeutic strategies for blood cancer with iron dysregulation.

Identifying the prognosis implication, immunotherapy response prediction value, and potential targeted compound inhibitors of integrin subunit α3 (ITGA3) in human cancers.

The integrin subunit α3 (ITGA3) is a member of the integrin alpha chain protein family, which could promote progression, metastasis, and invasion in some cancers. Still, its function in the tumor microenvironment (TME), cancer prognosis, and immunotherapy remains unclear. A multifaceted analysis of ITGA3 in pan-cancer utilizing various databases and online web tools revealed ITGA3 was aberrantly expressed in tumor tissues and upregulated in most cancers, which may be related to ITGA3 genomic alterations and methylation modification. In addition, ITGA3 was significantly correlated with the poor or better prognosis of cancer patients, immune-related pathways in hallmark, immune infiltration, and immune checkpoints, revealing a biological function of ITGA3 in the tumor progression, tumor microenvironment, and tumor immunity. We also found that ITGA3 could predict the response to tumor immunotherapy based on cytokine-treated samples and immunotherapy cohorts. ITGA3 may participate in shaping and regulating the tumor microenvironment to affect the tumor immune response, which was a promising immunotherapy response predictive biomarker and potential therapeutic target to work synergistically with cancer immunotherapy to boost the response and efficacy. Finally, potential targeted compound inhibitors and sensitive drugs were screened using databases ConnectivityMap (CMap) and CellMiner, and AutoDock Tools was used for molecular docking.

Relationship Between Serum Lipid Profiles and Carotid Intraplaque Neovascularization in a High-Stroke-Risk Population: A Cross-Sectional Study in China.

Background Evidence of the association between serum lipid profiles and intraplaque neovascularization (IPN) is still limited. We aimed to study the value of a novel Doppler method, superb microvascular imaging, in correlating serum lipid profiles and evidence of IPN in a population with a high risk of stroke. Methods and Results A community-based cross-sectional study was conducted in Beijing, China. Residents (aged ≥40 years) underwent questionnaire interviews, physical examinations, and laboratory testing in 2018 and 2019. Subjects with a high risk of stroke were then selected. Standard carotid ultrasound and carotid plaque superb microvascular imaging examinations were then performed on the high-stroke-risk participants. Logistic regression was used to evaluate the relationship between serum lipid profiles and carotid plaque IPN. Overall, a total of 250 individuals (mean age, 67.20±8.12 years; 66.4% men) met the study inclusion criteria. Superb microvascular imaging revealed carotid plaque IPN in 96 subjects (38.4%). Subjects with IPN were more likely to be current smokers (34.0% versus 46.9%, P=0.046), and their identified carotid plaques were much thicker (2.35±0.63 mm versus 2.75±0.80 mm, P=0.001). Serum lipids, including total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were positively associated with the presence of IPN (4.33±1.00 mmol/L versus 4.79±1.12 mmol/L, P=0.001; 2.96±0.92 mmol/L versus 3.40±1.01 mmol/L, P=0.001; 2.18±0.76 mmol/L versus 2.46±0.80 mmol/L, P=0.005, respectively), and after adjustment for other confounders, the positive relationship remained significant. Furthermore, non-high-density lipoprotein cholesterol (odds ratio, 2.62 [95% CI, 1.35-5.06]) was significantly associated with the presence of carotid plaque IPN even after adjusting for low-density lipoprotein cholesterol. Conclusions Total cholesterol, non-high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol were positively associated with the presence of carotid IPN in a Chinese high-stroke-risk population. Further prospective studies should be conducted to better understand how much finding IPN adds to current stroke prediction tools.

Clinical and ultrasound characteristics of virilizing ovarian tumors in pre- and postmenopausal patients: a single tertiary center experience.

BACKGROUND: A virilizing ovarian tumor (VOT) is a rare cause of hyperandrogenism in pre- and postmenopausal women. Although transvaginal ultrasound is considered as the first-line imaging method for ovarian tumors, it is examiner-dependent. We aimed to summarize the clinical and ultrasound manifestations of VOTs to help establish the diagnosis with emphasis on those causing diagnostic difficulty. METHOD: We retrospectively identified 31 patients with VOTs who underwent surgery at Peking Union Medical College Hospital. RESULTS: Patients with VOTs were predominantly premenopausal. All patients showed androgenic manifestations with serum testosterone levels elevated to varying degrees. The tumor size of VOTs was significantly correlated with age (P < 0.001). The VOTs in the postmenopausal group were significantly smaller than those in the premenopausal group (median 1.8 cm [range, 1.3-4.8 cm] vs 4.5 cm [range, 0.7-11.9 cm]; P = 0.018). Twenty-seven out of 31 VOTs were successfully identified by ultrasound. On ultrasound, VOTs are mostly solid and hypoechoic masses with enhanced vascularity. Four VOTs (0.7-1.5 cm) were radiologically negative, and they were the smallest among all patients. CONCLUSION: Patients with VOTs showed androgenic manifestations with varying degrees of hyperandrogenemia. Older patients tend to have smaller VOTs. Ultrasound is an effective method for the detection of VOTs. Some VOTs can be very small and difficult to visualize radiologically, especially in postmenopausal patients. Examiners must remain vigilant about very small VOTs on the basis of endocrine symptoms.