CBX4 counteracts cellular senescence to desensitize gastric cancer cells to chemotherapy by inducing YAP1 SUMOylation.

AIMS: As our comprehension of the intricate relationship between cellular senescence and tumor biology continues to evolve, the therapeutic potential of cellular senescence is gaining increasing recognition. Here, we identify chromobox 4 (CBX4), a Small Ubiquitin-related Modifier (SUMO) E3 ligase, as an antagonist of cellular senescence and elucidate a novel mechanism by which CBX4 promotes drug resistance and malignant progression of gastric cancer (GC). METHODS: In vitro and in vivo models were conducted to investigate the manifestation and impact of CBX4 on cellular senescence and chemoresistance. High-throughput sequencing, chromatin immunoprecipitation, and co-immunoprecipitation techniques were utilized to identify the upstream regulators and downstream effectors associated with CBX4, revealing its intricate regulatory network. RESULTS: CBX4 diminishes the sensitivity of GC cells to cellular senescence, facilitating chemoresistance and GC development by deactivating the senescence-related Hippo pathway. Mechanistically, low-dose cisplatin transcriptionally downregulates CBX4 through CEBPB. In addition, CBX4 preserves the stability and cytoplasm-nuclear transport of YAP1, the key player of Hippo pathway, by inducing SUMO1 modification at K97 and K280, which competitively inhibits YAP1-S127 phosphorylation. CONCLUSIONS: Our study highlights the anti-senescence role of CBX4 and suggests that CBX4 inhibition in combination with low-dose cisplatin has the potential to overcome chemoresistance and effectively restrict GC progression.

Naples Prognostic Score: A Novel Predictor of Survival in Patients with Triple-Negative Breast Cancer.

Purpose: This study investigated the correlation between the Naples prognostic score (NPS), clinicopathological traits, and the postoperative prognoses of patients with triple-negative breast cancer (TNBC). Based on NPS, a predictive nomogram was developed to estimate the long-term survival probabilities of patients with TNBC post-surgery. Patients and Methods: We retrospectively examined the clinical records of 223 women with TNBC treated at Ningbo Medical Center, Lihuili Hospital between January 1, 2016 and December 31, 2020. Blood tests and biochemical analyses were conducted before surgery. The prognostic nutritional index (PNI), controlling nutritional status (CONUT), neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and NPS were determined based on blood-related markers. A Kaplan-Meier survival analysis assessed the association between NPS, PNI, CONUT score, overall survival (OS), and breast cancer-specific survival (BCSS). Predictive accuracy was evaluated using the area under the receiver operating characteristic curve (AUC) and C index. The patients were randomly divided into the training and the validation group (6:4 ratio). A nomogram prediction model was developed and evaluated using the R Software for Statistical Computing (RMS) package. Results: NPS outperformed other scores in predicting inflammation outcomes. Patients with an elevated NPS had a poorer prognosis (P<0.001). Lymph node ratio (LNR), surgical method, postoperative chemotherapy, and NPS independently predicted OS, whereas M stage, LNR, and NPS independently predicted BCSS outcome. The OS and BCSS predicted by the nomogram model aligned well with the actual OS and BCSS. The decision curve analysis showed significant clinical utility for the nomogram model. Conclusion: In this study, NPS was an important prognostic indicator for patients with TNBC. The nomogram prognostic model based on NPS outperformed other prognostic scores for predicting patient prognosis. The model demonstrated a clear stratification ability for patient prognosis, which emphasized the potential benefits of early intervention for high-risk patients.

In this study, we aimed to understand how the Naples prognostic score (NPS) scoring system could predict the prognosis for patients with triple-negative breast cancer (TNBC). TNBC is a type of breast cancer that can be difficult to treat. Medical records of 223 women with TNBC were retrospectively analyzed. These women had their blood tested before surgery to check for certain markers related to nutrition and inflammation. NPS was used along with other scores to determine their accuracy in predicting survival. NPS was better at predicting outcomes than the other scores. The patients with higher NPS scores tended to have poorer outcomes. We also created a visual tool called a nomogram to help doctors predict patient outcomes based on the NPS scores. NPS can be a valuable tool for doctors treating patients with TNBC because it can help them predict how well a patient might do after surgery. This information could be used to tailor treatment plans for these patients. The nomogram provides a user-friendly way for doctors to use NPS in their practice. Overall, this study showed that NPS is a powerful tool for predicting outcomes for patients with TNBC, which could lead to better treatment decisions and improved outcomes for these patients.

Triple-negative breast cancer survival prediction: population-based research using the SEER database and an external validation cohort.

Introduction: Triple-negative breast cancer (TNBC) is linked to a poorer outlook, heightened aggressiveness relative to other breast cancer variants, and limited treatment choices. The absence of conventional treatment methods makes TNBC patients susceptible to metastasis. The objective of this research was to assess the clinical and pathological traits of TNBC patients, predict the influence of risk elements on their outlook, and create a prediction model to assist doctors in treating TNBC patients and enhancing their prognosis. Methods: We included 23,394 individuals with complete baseline clinical data and survival information who were diagnosed with primary TNBC between 2010 and 2015 based on the SEER database. External validation utilised a group from The Affiliated Lihuili Hospital of Ningbo University. Independent risk factors linked to TNBC prognosis were identified through univariate, multivariate, and least absolute shrinkage and selection operator regression methods. These characteristics were chosen as parameters to develop 3- and 5-year overall survival (OS) and breast cancer-specific survival (BCSS) nomogram models. Model accuracy was assessed using calibration curves, consistency indices (C-indices), receiver operating characteristic curves (ROCs), and decision curve analyses (DCAs). Finally, TNBC patients were divided into groups of high, medium, and low risk, employing the nomogram model for conducting a Kaplan-Meier survival analysis. Results: In the training cohort, variables such as age at diagnosis, marital status, grade, T stage, N stage, M stage, surgery, radiation, and chemotherapy were linked to OS and BCSS. For the nomogram, the C-indices stood at 0.762, 0.747, and 0.764 in forecasting OS across the training, internal validation, and external validation groups, respectively. Additionally, the C-index values for the training, internal validation, and external validation groups in BCSS prediction stood at 0.793, 0.755, and 0.811, in that order. The findings revealed that the calibration of our nomogram model was successful, and the time-variant ROC curves highlighted its effectiveness in clinical settings. Ultimately, the clinical DCA showcased the prospective clinical advantages of the suggested model. Furthermore, the online version was simple to use, and nomogram classification may enhance the differentiation of TNBC prognosis and distinguish risk groups more accurately. Conclusion: These nomograms are precise tools for assessing risk in patients with TNBC and forecasting survival. They can help doctors identify prognostic markers and create more effective treatment plans for patients with TNBC, providing more accurate assessments of their 3- and 5-year OS and BCSS.

Efficacy of first-line chemotherapy based on primary site of tumor versus etoposide-platinum in advanced gastroenteropancreatic neuroendocrine carcinoma.

Background: Gastroenteropancreatic neuroendocrine carcinomas (GEP-NECs) constitute a rare and aggressive group of malignancies usually with widespread disease. There are limited studies on GEP-NECs, and therefore, we aim to acquire more information on the clinical features, treatment regimens, and prognosis. Methods: Data from advanced GEP-NECs patients who had not previously received systemic treatment for advanced disease at The First Affiliated Hospital of Nanjing Medical University from 2010 to 2022 were retrospectively collected. Relationships between clinical-pathological features, treatment regimens, and prognosis were investigated using Kaplan-Meier curves and cox regression models. Results: A total of fifty-four patients were enrolled in the study. The median age was 65.5 years and 79.6% were male. At diagnosis, 51.9% and 3.7% of patients developed liver and brain metastasis respectively. Sixteen (29.6%) patients received chemotherapy according to primary site of tumor (PST), while thirty-eight (70.4%) were treated with etoposide-platinum (EP) regimen, which based on the first-line treatment of advanced small cell lung cancer (SCLC). No significant differences on progression-free survival (PFS) and response rate were observed between these two groups. Univariate survival analysis showed that liver metastasis, elevated baseline serum carcinoembryonic antigen, elevated baseline serum neuron-specific enolase, elevated baseline serum lactate dehydrogenase, and elevated baseline serum neutrophil-to-lymphocyte ratio (NLR) were associated with shorter PFS. After multivariate analysis, elevated NLR was the only factor that remained significantly associated with shorter PFS (P=0.01). Conclusions: GEP-NECs are aggressive neoplasms, of which elevated NLR is proven to be an independent negative predictor. Treatment regimens based on PST are not inferior to regiments based on SCLC (EP) for GEP-NECs patients. Large-scale, prospective randomized controlled trials are required to establish the standard of care.

Fat mass and obesity-associated protein (FTO) mediated m6A modification of circFAM192A promoted gastric cancer proliferation by suppressing SLC7A5 decay.

Gastric cancer (GC) is a common malignant tumor worldwide, especially in East Asia, with high incidence and mortality rate. Epigenetic modifications have been reported to participate in the progression of gastric cancer, among which m6A is the most abundant and important chemical modification in RNAs. Fat mass and obesity-associated protein (FTO) is the first identified RNA demethylase but little is known about its role in gastric cancer. In our study, data from TCGA and clinical samples showed that FTO was highly expressed in gastric cancer tissues. Kaplan-Meier plotter suggested that patients with the high level of FTO had a poor prognosis. In vitro and in vivo experiments confirmed the role of FTO in promoting gastric cancer cell proliferation. Mechanistically, we found that FTO bound to circFAM192A at the specific site and removed the m6A modification in circFAM192A, protecting it from degradation. CircFAM192A subsequently interacted with the leucine transporter solute carrier family 7 member 5 (SLC7A5) and enhancing its stability. As a result, an increased amount of SLC7A5 was on the membrane, which facilitated leucine uptake and activated the mTOR signaling pathway. Therefore, our study demonstrated that FTO promoted gastric cancer proliferation through the circFAM192A/SLC7A5 axis in the m6A-dependent manner. Our study shed new light on the role of FTO in gastric cancer progression.

Phthalate Acid Esters (PAEs) in Indoor Dust from Decoration Material Stores: Occurrence, Sources, and Health Risks.

Phthalate acid esters (PAEs) are one of the most widely used plasticizers globally, extensively employed in various decoration materials. However, studies on the impact of these materials on indoor environmental PAE pollution and their effects on human health are limited. In this study, forty dust samples were collected from four types of stores specializing in decoration materials (flooring, furniture boards, wall coverings, and household articles). The levels, sources, exposure doses, and potential health risks of PAEs in dust from decoration material stores were assessed. The total concentrations of Σ9PAE (the sum of nine PAEs) in dust from all decoration-material stores ranged from 46,100 ng/g to 695,000 ng/g, with a median concentration of 146,000 ng/g. DMP, DEP, DBP, and DEHP were identified as the predominant components. Among all stores, furniture board stores exhibited the highest Σ9PAE (159,000 ng/g, median value), while flooring stores exhibited the lowest (95,300 ng/g). Principal component analysis (PCA) showed that decoration materials are important sources of PAEs in the indoor environment. The estimated daily intakes of PAEs through non-dietary dust ingestion and dermal-absorption pathways among staff in various decoration-material stores were 60.0 and 0.470 ng/kg-bw/day (flooring stores), 113 and 0.780 ng/kg-bw/day (furniture board stores), 102 and 0.510 ng/kg-bw/day (wall covering stores), and 114 and 0.710 ng/kg-bw/day (household article stores). Particularly, staff in wall-covering and furniture-board stores exhibited relatively higher exposure doses of DEHP. Risk assessment indicated that although certain PAEs posed potential health risks, the exposure levels for staff in decoration material stores were within acceptable limits. However, staff in wall covering stores exhibited relatively higher risks, necessitating targeted risk-management strategies. This study provides new insights into understanding the risk associated with PAEs in indoor environments.