Oxygen and nutrient deprivation are common features of solid tumors. Although abnormal alternative splicing (AS) has been found to be an important driving force in tumor pathogenesis and progression, the regulatory mechanisms of AS that underly the adaptation of cancer cells to harsh microenvironments remain unclear. Here, we found that hypoxia- and nutrient deprivation–induced asparagine endopeptidase (AEP) specifically cleaved DDX3X in a HIF1A-dependent manner. This cleavage yields truncated carboxyl-terminal DDX3X (tDDX3X-C), which translocates and aggregates in the nucleus. Unlike intact DDX3X, nuclear tDDX3X-C complexes with an array of splicing factors and induces AS events of many pre-mRNAs; for example, enhanced exon skipping (ES) in exon 2 of the classic tumor suppressor PRDM2 leads to a frameshift mutation of PRDM2. Intriguingly, the isoform ARRB1-Δexon 13 binds to glycolytic enzymes and regulates glycolysis. By utilizing in vitro assays, glioblastoma organoids, and animal models, we revealed that AEP/tDDX3X-C promoted tumor malignancy via these isoforms. More importantly, high AEP/tDDX3X-C/ARRB1-Δexon 13 in cancerous tissues was tightly associated with poor patient prognosis. Overall, our discovery of the effect of AEP-cleaved DDX3X switching on alternative RNA splicing events identifies a mechanism in which cancer cells adapt to oxygen and nutrient shortages and provides potential diagnostic and/or therapeutic targets.

Lacking quantitative evaluations of clinicopathological features and the risk factors for loco-regional recurrence (LRR) in gastric cancer after D2 gastrectomy, we aimed to develop a competing risk nomogram to identify the risk predictors for initial LRR. We retrospectively analysed 1105 patients who underwent radical gastrectomy with D2 resection for stage I-III gastric cancer. A nomogram predicting initial LRR of gastric cancer was conducted based on Fine and Grey’s competing risk analysis. The predictive accuracy and discriminative ability of the model were determined using the concordance index (C-index) and calibration curve. Decision tree analysis was performed for patient grouping. At a median follow-up of 28.4 months, 274 patients developed 373 first recurrence events (local, regional, and distant disease). The median recurrence-free survival (RFS) was 16.7 months. Multivariate competing risk analysis showed that age (SHR, 1.72; 95% CI, 1.10–2.83, p = 0.031), CEA (SHR, 1.94; 95% CI, 1.09–3.46, p = 0.024), pT4 (SHR, 2.77; 95% CI, 1.01–7.57, p = 0.047), lymph node metastasis (SHR 1.92, 95% CI: 1.09–3.38, p = 0.024) and LVI (SHR, 1.84; 95% CI, 1.06–3.20, p = 0.028) were independent risk factors for LRR (all p < 0.05). The nomogram incorporating these factors achieved good agreement between prediction and actual observation with a concordance index of 0.738 (95% CI, 0.767 to 0.709). In a subgroup analysis of node-positive patients, pN3b was associated with increased peritoneal and distant metastasis (p = 0.048). The para-aortic lymph nodes were the most frequent sites (n = 71) of LRR, and among them, the 16a2 and 16b1 nodes exhibited even more prevalence (90.1 and 81.7%). Adjuvant radiotherapy might be recommended in gastric cancer patients ≥65 years old or those with pN+, pT4, LVI, or increased CEA levels, particularly in high-risk or pN1-3a patients. The competing risk nomograms may be considered as convenient and individualized predictive tools for LRR in gastric cancer after D2 gastrectomy. It is also recommended that the clinical target volume (CTV) include 16a2 and 16b1 regions of para-aortic lymph nodes.

To explore the risk factors for breast cancer-related lymphedema (BCRL) and upper extremity dysfunction (UED) in patients with early breast cancer after modern comprehensive treatment and to compare the toxicity of different treatment strategies. From 2017 to 2020, a total of 1369 female patients with pT1-3N0-1M0 breast cancer who underwent adjuvant radiotherapy in our centre were retrospectively reviewed. BCRL and UED were identified by the Norman and QuickDASH questionnaires. The incidence, severity and risk factors for BCRL and UED were evaluated. After a median follow-up of 25 months, a total of 249 patients developed BCRL; axillary lymph node dissection (ALND), increased number of dissected nodes, right-sided and hypofractionated radiotherapy containing RNI were found to be significant risk factors (all p values < 0.05). The sentinel lymph node biopsy (SLNB)+ regional nodal irradiation (RNI) group had a significantly lower BCRL risk than the ALND + RNI group (10.8% vs. 32.5%, HR = 0.426, p = 0.020), while there was no significant difference between ALND vs. ALND + RNI or SLNB vs. SLNB + RNI. A total of 193 patients developed UED, and ALND (p = 0.02) was the only significant risk factor. The SLNB + RNI group had a significantly decreased risk of UED compared with the ALND + RNI group (7.5% vs. 23.9%, HR = 0.260, p = 0.001), and there was no significant difference between SLNB vs. SLNB + RNI or ALND vs. ALND + RNI. Aggressive ALND remains the primary risk factor for BCRL and UED while RNI does not. Thus, replacing ALND with tailored radiotherapy would be an effective preventive strategy in early breast cancer patients.

Background: Recently, there has been a growing focus on the prognostic significance of nutrition-related biomarkers. We attempted to explore the association between a novel albumin-related nutrition marker called “lymphocyte × albumin (LA)” and disease-free survival (DFS) in breast cancer patients undergoing neoadjuvant chemotherapy (NAC). Methods: In total, 711 non-metastatic breast cancer patients who underwent NAC at two medical centers were retrospectively analyzed. We performed least absolute shrinkage and selection operator (LASSO) Cox regression analysis as well as multivariate Cox regression analyses to identify the variables associated with DFS and to establish a predictive nomogram. Results: The nomogram incorporated four variables based on the multivariate analysis of DFS in the training cohort: LA, ypN stage, ypT stage, and hormone receptor status. In comparison with the traditional TNM staging system, the nomogram demonstrated superior discrimination, calibration ability, and clinical usefulness in both the training set and internal and external validation sets. Furthermore, patients stratified into different risk groups resulted in significant differences in DFS. Conclusions: LA is an independent prognostic biomarker, and LA-based prognostic nomogram offers a more precise assessment of DFS for breast cancer patients treated with NAC, potentially serving as a valuable tool for personalized prognostic predictions.