ANO4 Expression Is a Potential Prognostic Biomarker in Non-Metastasized Clear Cell Renal Cell Carcinoma

Background: Over the past decade, transcriptome profiling has elucidated many pivotal pathways involved in oncogenesis. However, a detailed comprehensive map of tumorigenesis remains an enigma to solve. Propelled research has been devoted to investigating the molecular drivers of clear cell renal cell carcinoma (ccRCC). To add another piece to the puzzle, we evaluated the role of anoctamin 4 (ANO4) expression as a potential prognostic biomarker in non-metastasized ccRCC. Methods: A total of 422 ccRCC patients with the corresponding ANO4 expression and clinicopathological data were obtained from The Cancer Genome Atlas Program (TCGA). Differential expression across several clinicopathological variables was performed. The Kaplan–Meier method was used to assess the impact of ANO4 expression on the overall survival (OS), progression-free interval (PFI), disease-free interval (DFI), and disease-specific survival (DSS). Univariate and multivariate Cox logistic regression analyses were conducted to identify independent factors modulating the aforementioned outcomes. Gene set enrichment analysis (GSEA) was used to discern a set of molecular mechanisms involved in the prognostic signature. Tumor immune microenvironment was estimated using xCell. Results: ANO4 expression was upregulated in tumor samples compared to normal kidney tissue. Albeit the latter finding, low ANO4 expression is associated with advanced clinicopathological variables such as tumor grade, stage, and pT. In addition, low ANO4 expression is linked to shorter OS, PFI, and DSS. Multivariate Cox logistic regression analysis identified ANO4 expression as an independent prognostic variable in OS (HR: 1.686, 95% CI: 1.120–2.540, p = 0.012), PFI (HR: 1.727, 95% CI: 1.103–2.704, p = 0.017), and DSS (HR: 2.688, 95% CI: 1.465–4.934, p = 0.001). GSEA identified the following pathways to be enriched within the low ANO4 expression group: epithelial–mesenchymal transition, G2-M checkpoint, E2F targets, estrogen response, apical junction, glycolysis, hypoxia, coagulation, KRAS, complement, p53, myogenesis, and TNF-α signaling via NF-κB pathways. ANO4 expression correlates significantly with monocyte (ρ = −0.1429, p = 0.0033) and mast cell (ρ = 0.1598, p = 0.001) infiltration. Conclusions: In the presented work, low ANO4 expression is portrayed as a potential poor prognostic factor in non-metastasized ccRCC. Further experimental studies should be directed to shed new light on the exact molecular mechanisms involved.The article processing charges were funded jointly by Qatar National Library and Qatar University

Cyclin dependent kinase inhibitor 3 (CDKN3) upregulation is associated with unfavorable prognosis in clear cell renal cell carcinoma and shapes tumor immune microenvironment: A bioinformatics analysis

Cell cycle regulatory proteins plays a pivotal role in the development and progression of many human malignancies. Identification of their biological functions as well as their prognostic utility presents an active field of research. As a continuation of the ongoing efforts to elucidate the molecular characteristics of clear cell renal cell carcinoma (ccRCC); we present a comprehensive bioinformatics study targeting the prognostic and mechanistic role of cyclin-dependent kinase inhibitor 3 (CDKN3) in ccRCC. The ccRCC cohort from the Cancer Genome Atlas Program was accessed through the UCSC Xena browser to obtain CDKN3 mRNA expression data and their corresponding clinicopathological variables. The independent prognostic signature of CDKN3 was evaluated using univariate and multivariate Cox logistic regression analysis. Gene set enrichment analysis and co-expression gene functional annotations were used to discern CDKN3-related altered molecular pathways. The tumor immune microenvironment was evaluated using TIMER 2.0 and gene expression profiling interactive analysis. CDKN3 upregulation is associated with shortened overall survival (hazard ratio [HR] = 2.325, 95% confident interval [CI]: 1.703–3.173, P < .0001) in the Cancer Genome Atlas Program ccRCC cohort. Univariate (HR: 0.426, 95% CI: 0.316–0.576, P < .001) and multivariate (HR: 0.560, 95% CI: 0.409–0.766, P < .001) Cox logistic regression analyses indicate that CDKN3 is an independent prognostic variable of the overall survival. High CDKN3 expression is associated with enrichment within the following pathways including allograph rejection, epithelial–mesenchymal transition, mitotic spindle, inflammatory response, IL-6/JAK/STAT3 signaling, spermatogenesis, TNF-α signaling via NF-kB pathway, complement activation, KRAS signaling, and INF-γ signaling. CDKN3 is also associated with significant infiltration of a wide spectrum of immune cells and correlates remarkably with immune-related genes. CDKN3 is a poor prognostic biomarker in ccRCC that alters many molecular pathways and impacts the tumor immune microenvironment.Scopu

The Prognostic Utility of Lymphocyte-Based Measures and Ratios in Chemotherapy-Induced Febrile Neutropenia Patients following Granulocyte Colony-Stimulating Factor Therapy

Background and Objectives: Chemotherapy-induced febrile neutropenia is the most widespread oncologic emergency with high morbidity and mortality rates. Herein we present a retrospective risk factor identification study to evaluate the prognostic role of lymphocyte-based measures and ratios in a cohort of chemotherapy-induced febrile neutropenia patients following granulocyte colony-stimulating factor (G-CSF) therapy. Materials and Methods: The electronic medical records at our center were utilized to identify patients with a first attack of chemotherapy-induced febrile neutropenia and were treated accordingly with G-CSF between January 2010 to December 2020. Patients&rsquo; demographics and disease characteristics along with laboratory tests data were extracted. Prognosis-related indicators were the absolute neutrophil count (ANC) at admission and the following 6 days besides the length of stay and mortality rate. Results: A total of 80 patients were enrolled, which were divided according to the absolute lymphocyte count at admission into two groups, the first includes lymphopenia patients (n = 55) and the other is the non-lymphopenia group (n = 25) with a cutoff point of 700&thinsp;lymphocytes/&mu;L. Demographics and baseline characteristics were generally insignificant among the two groups but the white blood cell count was higher in the non-lymphopenia group. ANC, neutrophils percentage and ANC difference in reference to admission among the two study groups were totally insignificant. The same insignificant pattern was observed in the length of stay and the mortality rate. Univariate analysis utilizing the ANC difference compared to the admission day as the dependent variable, revealed no predictability role in the first three days of follow up for any of the variables included. However, during the fourth day of follow up, both WBC (OR = 0.261; 95% CI: 0.075, 0.908; p = 0.035) and lymphocyte percentage (OR = 1.074; 95% CI: 1.012, 1.141; p = 0.019) were marginally significant, in which increasing WBC was associated with a reduction in the likelihood of ANC count increase, compared to the lymphocyte percentage which exhibited an increase in the likelihood. In comparison, sequential ANC difference models demonstrated lymphocyte percentage (OR = 0.961; 95% CI: 0.932, 0.991; p = 0.011) and monocyte-to-lymphocyte ratio (OR = 7.436; 95% CI: 1.024, 54.020; p = 0.047) reduction and increment in the enhancement of ANC levels, respectively. The fifth day had WBC (OR = 0.790; 95% CI: 0.675, 0.925; p = 0.003) to be significantly decreasing the likelihood of ANC increment. Conclusions: we were unable to determine any concrete prognostic role of lymphocyte-related measures and ratios. It is plausible that several limitations could have influenced the results obtained, but as far as our analysis is concerned ALC role as a predictive factor for ANC changes remains questionable