5'-Methylthioadenosine phosphorylase (MTAP) is a key enzyme in the methionine salvage pathway and has been reported to suppress tumorigenesis. The MTAP gene is located at 9p21, a chromosome region often deleted in breast cancer (BC). However, the clinical and biological significance of MTAP in BC is still unclear. Here, we reported that MTAP was frequently downregulated in 41% (35/85) of primary BCs and 89% (8/9) of BC cell lines. Low expression of MTAP was significantly correlated with a poor survival of BC patients (P=0.0334). Functional studies showed that MTAP was able to suppress both in vitro and in vivo tumorigenic ability of BC cells, including migration, invasion, angiogenesis, tumor growth and metastasis in nude mice with orthotopic xenograft tumor of BC. Mechanistically, we found that downregulation of MTAP could increase the polyamine levels by activating ornithine decarboxylase (ODC). By treating the MTAP-repressing BC cells with specific ODC inhibitor Difluoromethylornithine (DFMO) or treating the MTAP-overexpressing BC cells with additional putrescine, metastasis-promoting or -suppressing phenotype of these MTAP-manipulated cells was significantly reversed, respectively. Taken together, our data suggested that MTAP has a critical metastasis-suppressive role by tightly regulating ODC activity in BC cells, which may serve as a prominent novel therapeutic target for advanced breast cancer treatment.
To explore the short-term efficacy and tolerability of paroxetine in the treatment of panic disorder in adults.Multiple electronic databases were searched to find randomized controlled trials (RCTs) on paroxetine and panic disorder. The primary efficacy outcomes were: the mean change compared to the baseline in the total number of full panic attacks, Clinical Global Impression-Severity of Illness (CGI-S) score, and the proportion of participants with zero full panic attacks and with a 50% or greater reduction in the number of full panic attacks. The tolerability outcomes included withdrawal rate and the incidence of adverse events (AEs).13RCTs were included. The pooled analyses showed patients who received paroxetine experienced greater improvements in the number of full panic attacks (total: MD=-1.96, 95%CI -3.45 to -0.47, P=0.010; ≥50% reduction: OR=1.66, 95%CI 1.08 to 2.55, P=0.02; zero full panic attacks: OR=1.70, 95%CI 1.42 to 2.03, P < 0.00001) and CGI-S (MD=-0.37, 95%CI -0.74 to -0.01, P=0.05) than placebo. There was no evident difference in the total withdrawal rate (OR=0.91, 95%CI 0.76 to 1.08, P=0.26) and withdrawal rate due to AEs (OR=1.29, 95%CI 0.97 to 1.72, P=0.07) between the two groups. Withdrawal rate due to lack of efficacy or relapse (OR=0.44, 95%CI 0.31 to 0.63, P < 0.00001) and the incidence of serious AEs (OR=0.42, 95%CI 0.23 to 0.79, P=0.007) in the paroxetine group was lower than the placebo group. Meanwhile, the incidence of any treatment-emergent adverse events (TEAEs) (OR=1.32, 95%CI 1.05 to 1.64, P=0.02) in the paroxetine group was higher in comparison with the placebo.Paroxetine is an effective and well-tolerated short-term treatment for adults with panic disorder.
Protein disulfide isomerase (PDI), a family of thiol‐disulfide oxidoreductases, is one of the most abundant soluble proteins in the endoplasmic reticulum (ER) and is responsible for protein folding. Increasing evidence suggests that PDI is overexpressed in multiple types of cancer, positioning it as a promising target for tumor therapy. We have designed and synthesized a series of gallium complex‐based proteolysis targeting chimeras (PROTACs), which exhibited effective targeting and degradation of PDI in vitro. After analyzing the relationship between structure and function, we have identified M‐2 as the compound that most efficiently degrades PDI. Our research shows that M‐2‐induced degradation of PDI can trigger the unfolded protein response, leading to cell autophagy and initiating immunogenic cell death (ICD), as demonstrated in mouse models. This study suggests a potential opportunity for combining PDI targeting and immunotherapy.
Endoplasmic-reticulum-associated protein degradation
Gastrointestinal (GI) cancer, a common malignant tumor with a high incidence in China, is showing a trend of rising incidence and is afflicting increasingly younger patients. Meanwhile, there have been constant development and innovations in new therapeutic technologies, among which, immunotherapy is now leading in a new era in the treatment of GI cancer. However, the complexity and diversity of immunosuppressive tumor microenvironment (TME) bring many obstacles to the immunotherapy of solid tumors in the GI tract. In this paper, focusing on solid tumors in the GI tract, we reviewed the main factors affecting the formation of immunosuppressive TME, and summarized strategies for targeted immunosuppressive TME-based therapies. Moreover, we analyzed the synergistic mechanism of various combination immunotherapies and reported on the latest progress in and future direction of immunotherapy for GI cancer, intending to provide new perspectives for treating solid tumors in the GI tract with immumotherapy.
To ensure the stable operation of a smart grid, it is necessary to monitor fault information and release timely warnings.In this paper, a monitoring algorithm based on a convolutional neural network (CNN) was designed using the deep learning method to determine the fault category of transformers and monitor them.An improved particle swarm optimizationlong short-term memory (IPSO-LSTM) model was established to realize early warning of faults based on the prediction of dissolved gas concentration in oil.Experiments were conducted on the data of a power company.It was found that the CNN model had higher fault monitoring accuracy than the support vector machine (SVM) model and other methods; compared with the LSTM model, the IPSO-LSTM model had a smaller error in gas concentration prediction.Taking H2 as an example, the root-mean-square error (RMSE), mean absolute error (MAE), and mean absolute percentage error (MAPE) of the IPSO-LSTM model was 0.0412, 0.0432, and 6.2145%, superior to the LSTM model, so the IPSO-LSTM model could achieve the early warning of faults.The experimental results prove the effectiveness of the proposed method.The method can be further applied to the actual smart grid.
Abstract Gastric cancer (GC) is characterized by its vigorous chemoresistance to current therapies, which is attributed to the highly heterogeneous and immature phenotype of cancer stem cells (CSCs) during tumor initiation and propagation. The secretory WNT2 ligand regulates multiple cancer pathways and has been demonstrated to be a potential therapeutic target for gastrointestinal tumors; however, its role involved in gastric CSCs (GCSCs) remains unclear. Here, we found that WNT2 was overexpressed in GCSCs and positively regulated by its transcription factor SOX4. SOX4 was in turn upregulated by the canonical WNT2/FZD8/β-catenin signaling pathway to form an auto-regulatory positive feedback loop, resulting in the maintenance of GCSC self-renewal and tumorigenicity. Furthermore, blocking WNT2 using a specific monoclonal antibody significantly disrupted the WNT2–SOX4 positive feedback loop in GCSCs and enhanced the chemotherapeutic efficacy when synergized with the chemo-drugs 5-fluorouracil and oxaliplatin in a GCSC-derived mouse xenograft model. Overall, this study identified a novel WNT2–SOX4 positive feedback loop as a mechanism for GCSC-induced chemo-drugs resistance and suggested that the WNT2–SOX4 axis may be a potential therapeutic target for gastric cancer treatment.
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