Comprehensive data mining reveals RTK/RAS signaling pathway as a promoter of prostate cancer lineage plasticity through transcription factors and CNV.

Prostate cancer lineage plasticity is a key driver in the transition to neuroendocrine prostate cancer (NEPC), and the RTK/RAS signaling pathway is a well-established cancer pathway. Nevertheless, the comprehensive link between the RTK/RAS signaling pathway and lineage plasticity has received limited investigation. In particular, the intricate regulatory network governing the interplay between RTK/RAS and lineage plasticity remains largely unexplored. The multi-omics data were clustered with the coefficient of argument and neighbor joining algorithm. Subsequently, the clustered results were analyzed utilizing the GSEA, gene sets related to stemness, multi-lineage state datasets, and canonical cancer pathway gene sets. Finally, a comprehensive exploration of the data based on the ssGSEA, WGCNA, GSEA, VIPER, prostate cancer scRNA-seq data, and the GPSAdb database was conducted. Among the six modules in the clustering results, there are 300 overlapping genes, including 3 previously unreported prostate cancer genes that were validated to be upregulated in prostate cancer through RT-qPCR. Function Module 6 shows a positive correlation with prostate cancer cell stemness, multi-lineage states, and the RTK/RAS signaling pathway. Additionally, the 19 leading-edge genes of the RTK/RAS signaling pathway promote prostate cancer lineage plasticity through a complex network of transcriptional regulation and copy number variations. In the transcriptional regulation network, TP63 and FOXO1 act as suppressors of prostate cancer lineage plasticity, whereas RORC exerts a promoting effect. This study provides a comprehensive perspective on the role of the RTK/RAS pathway in prostate cancer lineage plasticity and offers new clues for the treatment of NEPC.

Etoposide-induced SENP8 confers a feed-back drug resistance on acute lymphoblastic leukemia cells.

Chemotherapy is the most common treatment for acute lymphoblastic leukemia (ALL). However, many ALL patients eventually develop relapse and treating relapsed ALL has always been challenging. Therefore, exploring the resistance mechanism of chemotherapeutic drugs and proposing feasible intervention strategies are of great significance for ALL treatment. Here, we show that SENP8, whose coding protein is an important deNEDDylase targeting the substrate for deNEDDylation, is highly expressed in relapsed ALL specimens. Interestingly, overexpressing SENP8 specifically reduces the chemosensitivity of ALL cells to etoposide (VP-16) and significantly alleviates the proapoptotic effect of VP-16 on ALL cells. By contrast, NEDDylation inhibition reduces the chemosensitivity of ALL cells to VP-16. Furthermore, VP-16 induces SENP8 accumulation and the instability of MDM2 as well as the stabilization of p53 in ALL cells, and SENP8 knockdown can sensitize ALL cells to VP-16. Our study reveals a novel function of SENP8 in ALL and that VP-16-induced SENP8 confers a feed-back drug resistance on ALL cells, suggesting a possibility of overcoming the chemotherapeutic resistance to VP-16 via targeting SENP8.

Effective Response to Hospital Congestion Scenarios: Simulation-Based Evaluation of Decongestion Interventions.

Hospital overcrowding is becoming a major concern in the modern era due to the increasing demand for hospital services. This study seeks to identify effective and efficient ways to resolve the serious problem of congestion in hospitals by testing a range of decongestion strategies with simulated scenarios. In order to determine more efficient solutions, interventions with smaller changes were consistently tested at the beginning through a simulation platform. In addition, the implementation patterns were investigated, which are important to hospital managers with respect to the decisions made to control hospital congestion. The results indicated that diverting a small number of ambulances seems to be more effective and efficient in congestion reduction compared to other approaches. Furthermore, instead of implementing an isolated approach continuously, combining one approach with other strategies is recommended as a method for dealing with hospital overcrowding.

A virtual evaluation of options for managing risk of hospital congestion with minimum intervention.

Hospital congestion is a common problem for the healthcare sector. However, existing approaches including hospital resource optimization and process improvement might lead to huge cost of human and physical structure changes. This study evaluated less disruptive interventions based on a hospital simulation model and offer objective reasoning to support hospital management decisions. This study tested a congestion prevention method that estimates hospital congestion risk level (R), and activates minimum intervention when R is above certain threshold, using a virtual hospital created by simulation modelling. The results indicated that applying a less disruptive intervention is often enough, and more cost effective, to reduce the risk level of hospital congestion. Moreover, the virtual implementation approach enabled testing of the method at a more detailed level, thereby revealed interesting findings difficult to achieve theoretically, such as discharging extra two medical inpatients, rather than surgical inpatients, a day earlier on days when R is above the threshold, would bring more benefits in terms of congestion reduction for the hospital.

Antileukemic effects of topoisomerase I inhibitors mediated by de-SUMOylase SENP1.

SUMO-specific proteases (SENPs) play pivotal roles in maintaining the balance of SUMOylation/de-SUMOylation and in SUMO recycling. Deregulation of SENPs leads to cellular dysfunction and corresponding diseases. As a key member of the SENP family, SENP1 is highly correlated with various cancers. However, the potential role of SENP1 in leukemia, especially in acute lymphoblastic leukemia (ALL), is not clear. This study shows that ALL cells knocking down SENP1 display compromised growth rather than significant alterations in chemosensitivity, although ALL relapse samples have a relatively higher expression of SENP1 than the paired diagnosis samples. Camptothecin derivatives 7-ethylcamptothecin (7E-CPT, a monomer compound) and topotecan (TPT, an approved clinical drug) induce specific SENP1 reduction and severe apoptosis of ALL cells, showing strong anticancer effects against ALL. Conversely, SENP1 could attenuate this inhibitory effect by targeting DNA topoisomerase I (TOP1) for de-SUMOylation, indicating that specific reduction in SENP1 induced by 7E-CPT and/or topotecan inhibits the proliferation of ALL cells.

Acute effects of air pollution on lupus nephritis in patients with systemic lupus erythematosus: A multicenter panel study in China.

Air pollution may trigger systemic lupus erythematosus (SLE). However, few studies have investigated the associations between air pollution and complications of SLE, such as lupus nephritis (LN). In this study, multicenter longitudinal data from 13 hospitals in China, including 8552 SLE patients with 24,762 visits, were used. Based on the generalized estimating equation (GEE) model, we assessed the associations of LN occurrence with short-term exposures to different air pollutants including particulate matter with an aerodynamic diameter < 2.5 µm (PM2.5), sulfur dioxide (SO2), nitrogen dioxide (NO2), carbon monoxide (CO), and ozone (O3). We identified 2672 LN patients, and about half of them were from east China. Our results based on the entire data set showed that PM2.5 and NO2 were risk factors for LN within one month after exposure, with odds ratio of 1.16 (95% confidence interval (CI), 1.08-1.19) at lag 18 day and 1.19 (95% CI, 1.12-1.26) at lag 16 day relative to an interquartile range (IQR) increase in PM2.5 and NO2, respectively. This positive association between LN and NO2 was also observed for south, west, and east China. In addition, we found that the short term exposure to CO and O3 was not generally associated with LN. Finally, the negative associations of LN with SO2 were found for the entire region and east China. Our results implied that SLE patients may gain the health benefits of air quality improvement in China. Our work also provided evidence that short-term variations in air pollution may trigger LN, and further studies are needed to confirm these findings and the potential pathogenic mechanisms should be explored.

[Treatment of Radical Resected NSCLC by Chinese Medicine Combined with Adjuvant Chemother- apy: a Clinical Study].

OBJECTIVE: To evaluate the efficacy of Chinese medicine (CM) combined adjuvant chemotherapy in postponing relapse and metastasis of radical resected Ib-IIIa stage non-small cell lung cancer (NSCLC) patients, and to explore its effect in improving their quality of life (QOL) and clinical symptoms. METHODS: We designed a cohort study of 336 radical resected Ib-IIIa NSCLC patients by analyzing disease free survival (DFS) using Log-rank test. They were randomly assigned to the control group (155 cases, treated by adjuvant chemotherapy group) and the test group (181 cases, treated by adjuvant chemotherapy combined CM). By using controlled method, 60 radical resected NSCLC patients undergoing NP/NC program in 2012 (vinorelbine 25 mg/m2, combined with cisplatin 75 mg/m2 on day 1 and day 8/on day 1 or on day 1, 2, and 3; or carboplatin AUC = 5 on day 1) were assigned to the control group (29 cases) and the test group (31 cases). QOL scores (using EORTC QLQ-LC43 questionnaire) and TCM symptoms scores were compared between the two groups before chemotherapy, peri-chemotherapy (one day before the 2nd course of chemotherapy) , and after chemotherapy (20 days after ending the 4th course of chemotherapy). RESULTS: (1) The median DFS was longer in the test group than in the control group, but with no statistical difference between the two groups (42.73 months vs 35.57 months , P = 0.179). In the subgroup analysis, there was statistical difference in IIIa stage DFS. The median IIIa stage DFS of was longer in the test group than in the control group with statistical difference (27.87 months vs 19. 93 months, P = 0.047). (2) In the control study, repeated measured data indicated there was significant difference in physical functions between the two groups (P < 0.05). Total scores for health states decreased more in the test group than in the control group, but with no statistical difference (P > 0.05). Scores for constipation and CM syndrome scores were higher in the test group than in the control group (P < 0.05). CONCLUSIONS: CM had advantages in postponing DFS of radical resected NSCLC patients, especially in IIIa stage. CM could improve their QOL and clinical symptoms during adjuvant chemotherapy.