Objective: To provide higher level evidence on the benefits of a Chinese patent medicine (CPM) (Fufang E’jiao Syrup, FFEJS) for alleviating cancer-related fatigue (CRF), this article describes a protocol for a randomized controlled trial. Methods/design: We designed a double-blind, placebo-controlled stratified permuted block randomization clinical trial on CRF among 3 types of cancer in China. Participants will be equally allocated to FFEJS group or placebo group according to the randomization sequence and the hospitals they were enrolled at. Each patient will receive 20 ml of either the study formula FFEJS or a placebo formula, 3 times a day for 6 weeks. The follow-up period will be another 4 weeks for safety evaluation. The primary outcome is the difference in improvement of fatigue as measured with the Revised Piper Fatigue Scale-Chinese Version (RPFS-CV). Secondary outcomes include change in fatigue (measured by routine blood panel and hormones in peripheral blood) and QoL (measured by Edmonton symptom assessment scale and Functional Assessment of Cancer Therapy). Patient safety will be measured by liver, renal or cardiac damage, and the risk of FFEJS having a tumor promotion and progression effect will be monitored throughout this study. Cost-effectiveness will also be evaluated mainly by incremental cost per each quality-adjusted life year gained. Discussion: This article describes the study design of a CPM for CRF in patients with advanced cancer through exploring the effectiveness, safety, and cost-effectiveness of FFEJS. Trial registration: ClinicalTrials.gov, NCT04147312. Registered on 1 Sep 2019.

Introduction: Given insulin resistance’s (IR) critical role in metabolic pathophysiology, this study aims to identify optimal coffee consumption patterns by timing and dose to improve population health. Material and methods: Multivariate logistic regression and restricted cubic splines assessed associations between coffee timing, dosage, and IR (measured by estimated glucose disposal rate) from NHANES data (1999–2018). Interaction and subgroup analyses explored variations across population segments. Results: We analysed 21,138 participants, of whom 46.79% were non-consumers. Among consumers, 76% primarily drank coffee in the morning. Morning consumption at the lowest quartile (Q1) showed significant improvement in IR (odds ratio [OR] = 1.37, 95% confidence interval [CI]: 1.16–1.62), although this benefit diminished with higher consumption levels (p < 0.05). While the “all-day” pattern overall showed a non-significant trend toward improved insulin resistance (OR = 1.20, 95% CI: 0.83–1.73), higher consumption within this pattern (Q3: OR = 1.46, 95% CI: 1.13–1.89; Q4: OR = 1.34, 95% CI: 1.11–1.63) proved significantly more beneficial than lower intake. Comparative analysis revealed that morning consumption tended to be more advantageous for low-to-moderate intake (Q1-Q2), whereas all-day distribution showed potential benefits at higher consumption levels (Q3-Q4). The observed benefits were primarily associated with caffeinated coffee, attenuated by sugar addition, and varied across subgroups based on age, sex, and comorbidities. Conclusions: Both morning and all-day coffee intake improve IR. For moderate consumption (1–2 cups/day), morning intake provides optimal improvement in insulin sensitivity. For higher intake (≥ 3 cups/day), distributed consumption is more effective. These findings support chrono-nutrition principles for optimising metabolic health through coffee consumption.

The glioma tumor microenvironment (TME) exhibits profound heterogeneity that drives tumor progression and therapy resistance. By integrating single-cell RNA sequencing (eleven samples) and spatial transcriptomics (two samples), the cellular components of the glioma microenvironment were deconvoluted, revealing tumor-associated foam cells (TAFCs) as the most abundant and centrally connected subtype. The high expression of two prognostic candidate genes, growth differentiation factor 8 (GDF-8, also known as myostatin, MSTN) and transcription factor 12 (TCF12), in TAFCs was found to be correlated with poor overall survival. These two genes were associated with M2 macrophage infiltration, altered cholesterol homeostasis, and immunosuppressive signaling. Regulatory network and pathway analyses, based on computational motif enrichment and co-expression analysis, linked them to ribosome, Notch signaling, DNA repair, and cell-cycle pathways. Pseudotime trajectories revealed dynamic expression during differentiation. Additionally, drug sensitivity prediction analysis demonstrated that MSTN expression was significantly associated with sensitivity to paclitaxel and VE-822, while TCF12 expression showed potential associations with sensitivity to cytarabine, olaparib, Wee1 inhibitor, paclitaxel, and VE-822. Logistic regression analysis combining clinical parameters with MSTN and TCF12 expression effectively achieved risk stratification for glioma, with higher composite scores predicting worse 2- and 3-year survival outcomes. Calibration curves demonstrated high consistency between nomogram-predicted overall survival probabilities and actual observed outcomes. Immunofluorescence confirmed upregulated expression of MSTN and TCF12 in glioma tissues and their co-localization with macrophages. In conclusion, this study identified TAFCs as the central cells in the glioma microenvironment, with their signature genes MSTN and TCF12 representing candidate immunometabolic signatures associated with macrophage-mediated immunosuppression and metabolic reprogramming in glioma, suggesting their potential as biomarkers for patient stratification and as targets for immunometabolic therapies.