MSCT-UNET: multi-scale contrastive transformer within U-shaped network for medical image segmentation.

Objective.Automatic mutli-organ segmentation from anotomical images is essential in disease diagnosis and treatment planning. The U-shaped neural network with encoder-decoder has achieved great success in various segmentation tasks. However, a pure convolutional neural network (CNN) is not suitable for modeling long-range relations due to limited receptive fields, and a pure transformer is not good at capturing pixel-level features.Approach.We propose a new hybrid network named MSCT-UNET which fuses CNN features with transformer features at multi-scale and introduces multi-task contrastive learning to improve the segmentation performance. Specifically, the multi-scale low-level features extracted from CNN are further encoded through several transformers to build hierarchical global contexts. Then the cross fusion block fuses the low-level and high-level features in different directions. The deep-fused features are flowed back to the CNN and transformer branch for the next scale fusion. We introduce multi-task contrastive learning including a self-supervised global contrast learning and a supervised local contrast learning into MSCT-UNET. We also make the decoder stronger by using a transformer to better restore the segmentation map.Results.Evaluation results on ACDC, Synapase and BraTS datasets demonstrate the improved performance over other methods compared. Ablation study results prove the effectiveness of our major innovations.Significance.The hybrid encoder of MSCT-UNET can capture multi-scale long-range dependencies and fine-grained detail features at the same time. The cross fusion block can fuse these features deeply. The multi-task contrastive learning of MSCT-UNET can strengthen the representation ability of the encoder and jointly optimize the networks. The source code is publicly available at:https://github.com/msctunet/MSCT_UNET.git.

The antiferroptotic role of TRIM7: Molecular mechanism and synergistic effect with temozolomide.

Nuclear receptor coactivator 4 (NCOA4) protein is a selective cargo receptor that plays a crucial role in ferritinophagy by targeting and delivering the ferritin iron storage protein to lysosomes for degradation and releasing iron. TRIM7 overexpression inhibits ferroptosis in glioblastoma cells by ubiquitinating NCOA4 protein.

Targeting the ferroptosis crosstalk: novel alternative strategies for the treatment of major depressive disorder.

Depression is a major contributor to poor global health and disability, with a recently increasing incidence. Although drug therapy is commonly used to treat depression, conventional antidepressant drugs have several disadvantages, including slow onset, low response rates and severe adverse effects. Therefore, developing effective therapies for depression remains challenging. Although various aetiological theories of depression exist, the underlying mechanisms of depression are complex, and further research is crucial. Moreover, oxidative stress (OS)-induced lipid peroxidation has been demonstrated to trigger ferroptosis. Both OS and ferroptosis are pivotal mechanisms implicated in the pathogenesis of neurological disorders, and investigation of the mediators involved in these processes has emerged as a prominent and active research direction. One previous study revealed that regulatory proteins involved in ferroptosis are implicated in the pathogenesis of depression, and antidepressant drugs could reverse depressive symptoms by inhibiting ferroptosis in vivo, suggesting an important role of ferroptosis in the pathogenesis of depression. Hence, our current comprehensive review offers an up-to-date perspective on the intricate mechanisms involved, specifically concerning ferroptosis and OS in the context of depression, along with promising prospects for using molecular mediators to target ferroptosis. We delineate the key targets of molecular mediators involved in OS and ferroptosis implicated in depression, most notably reactive oxygen species and iron overload. Considering the pivotal role of OS-induced ferroptosis in the pathogenesis of neurological disorders, delving deeper into the underlying subsequent mechanisms will contribute significantly to the identification of novel therapeutic targets for depression.

Transcription factor CASZ1 increases an oncogenic transcriptional process in tumorigenesis and progression of glioma cells.

As a transcription factor, the role of CASZ1 in different entities is inconsistent. Glioma is one of the leading causes of cancer death worldwide. Its prognostic relevance and biological functions in glioma remain obscure. We focused on the role, mechanism, and prognostic value of CASZ1 in glioma cells. Herein, CASZ1 was identified as a novel potential oncogene in glioma tissues from GEO and TCGA datasets. CASZ1 was highly expressed in glioma tissues, predicting poor prognosis in glioma patients. Knockdown of CASZ1 inhibited proliferation and invasion in vitro, whereas upregulation of CASZ1 presented opposite results. Overexpression of CASZ1 increased transcriptional process of target gene p75NTR. CASZ1 was the potential transcriptional regulators for p75NTR. In addition, the p75NTR expression is essential for CASZ1 to exert its function as an oncogene. Our findings indicate that highly expressed CASZ1 in glioma cells acts as a pro-oncogene factor in gliomas via regulating transcriptional process of target gene p75NTR, which was identified as an unfavorable prognostic marker in patients with gliomas. CASZ1 is expected to become a novel target for the treatment of gliomas.

An integrated analysis of C5AR2 related to malignant properties and immune infiltration of gliomas.

Background: C5AR2 is recognized as a proinflammatory molecule and activates the inflammatory response in multiple disorders. However, little has been reported on C5AR2 in glioma. This study sought to explore its expression, biological function, and association with clinical pathological indicators, prognosis, and immune infiltration levels in glioma through glioma cohorts. Methods: A cohort of 657 patients was screened from the Chinese Glioma Genome Atlas (CGGA). χ 2 test was performed to calculate the difference of classified variables. Cox proportional hazard regression modeling was used to identify independent prognostic indicators of glioma patients. A survival plot was generated by the Kaplan-Meier method. The immune cell infiltration score of glioma patients was calculated by TIMER algorithm. Results: We observed that high expression of C5AR2 was strongly associated with malignant clinical indicators in 657 patients with glioma, and patients with high C5AR2 expression had worse prognoses. Multivariate Cox analysis showed that C5AR2 could be a new independent prognostic indicator for glioma patients. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis revealed that C5AR2 overexpression correlated with multiple inflammatory and immune biological processes. Additionally, high C5AR2 expression was strongly associated with higher abundance and marker gene expression of multiple tumor immune cells in low-grade glioma. Finally, a model was constructed to improve the prognostic evaluation of glioma patients. Conclusions: The C5AR2 gene is highly expressed in gliomas and is significantly associated with clinical indicators of malignant progression in glioma patients. In glioma, patients with high C5AR2 expression displayed a worse outcome. In glioma tissues, the expression level of C5AR2 highly correlated with the abundance of tumor immune cell infiltration. Additionally, GO and KEGG enrichment analysis revealed that C5AR2 expression may be involved in a variety of immune and inflammatory biological processes.

Enrichment and detection method for the prognostic value of circulating tumor cells in ovarian cancer: A meta-analysis.

OBJECTIVES: Recent studies have revealed that circulating tumor cells (CTCs) might predict bad prognosis, but the results were conflicting. Sampling time, treatment, enrichment method and detection method also varied. We aimed to evaluate whether patients with CTCs in peripheral blood have bad survival outcomes with consideration of the above four aspects. METHODS: Relevant studies were searched on Pubmed, Embase and the Cochrane Library. Studies of CTCs involving survival data available were identified for a systematic review and meta-analysis. HRs and 95% CIs for PFS and OS were extracted directly or from the Kaplan-Meier survival curves by the Engauge Digitizer v4.1. Subgroup analyses were performed to evaluate the effect of sampling time, treatment, enrichment method and detection method. RESULTS: Two clinical trials and thirteen retrospective studies with a total of 1285 patients were included. CTCs significantly correlated with OS (HR = 1.77, 95%CI:1.42-2.21, p < 0.00001 and PFS (HR = 1.53, 95%CI:1.26-1.86, p < 0.0001). Subgroup analyses showed that CTCs were significant associated with OS in the "Pre-therapy" subgroup (HR = 1.79, 95%CI:1.43-2.24, p < 0.00001), the "Surgery" group (HR = 1.82, 95%CI:1.42-2.33, p < 0.00001), and the "RT-PCR"subgroup (HR = 2.29, 95%CI:1.53-3.42, p < 0.0001). While for enrichment method, CTCs significantly correlated with OS in the"Physical method" subgroup (HR = 1.94, 95%CI:1.21-3.09, p = 0.006) and the "Immunological method" subgroup (HR = 1.84, 95%CI:1.37-2.48, p < 0.0001). CONCLUSIONS: The presence of CTCs prior to the treatment indicated worse OS and PFS and CTCs might be predictive biomarker for ovarian cancer patients . CTCs detected using RT-PCR seem to be associated with poorer OS and PFS in patients with ovarian cancer.

Activation of the reverse transsulfuration pathway through NRF2/CBS confers erastin-induced ferroptosis resistance.

BACKGROUND: Ferroptosis is an iron-dependent, lipid peroxide-mediated cell death that may be exploited to selective elimination of damaged and malignant cells. Recent studies have identified that small-molecule erastin specifically inhibits transmembrane cystine-glutamate antiporter system xc-, prevents extracellular cystine import and ultimately causes ferroptosis in certain cancer cells. In this study, we aimed to investigate the molecular mechanism underlying erastin-induced ferroptosis resistance in ovarian cancer cells. METHODS: We treated ovarian cancer cells with erastin and examined cell viability, cellular ROS and metabolites of the transsulfuration pathway. We also depleted cystathionine ß-synthase (CBS) and NRF2 to investigate the CBS and NRF2 dependency in erastin-resistant cells. RESULTS: We found that prolonged erastin treatment induced ferroptosis resistance. Upon exposure to erastin, cells gradually adapted to cystine deprivation via sustained activation of the reverse transsulfuration pathway, allowing the cells to bypass erastin insult. CBS, the biosynthetic enzyme for cysteine, was constantly upregulated and was critical for the resistance. Knockdown of CBS by RNAi in erastin-resistant cells caused ferroptotic cell death, while CBS overexpression conferred ferroptosis resistance. We determined that the antioxidant transcriptional factor, NRF2 was constitutively activated in erastin-resistant cells and NRF2 transcriptionally upregulated CBS. Genetically repression of NRF2 enhanced ferroptosis susceptibility. CONCLUSIONS: Based on these results, we concluded that constitutive activation of NRF2/CBS signalling confers erastin-induced ferroptosis resistance. This study demonstrates a new mechanism underlying ferroptosis resistance, and has implications for the therapeutic response to erastin-induced ferroptosis.