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Another independent Gene Expression Omnibus (GEO) contained specimens from 109 GC patients was designed as an external validation. Our works suggested that the 9-gene-signature prediction model, which was derived from TMB, MSI, and SCNA, was a promising predictive tool for clinical outcomes in GC patients. This novel methodology may help clinicians uncover the underlying mechanisms and guide future treatment strategies.Copper is an essential metal micronutrient with biological roles ranging from energy metabolism to cell signaling. Recent studies have shown that copper regulation is altered by fat accumulation in both rodent and cell models with phenotypes consistent with copper deficiency, including the elevated expression of the copper transporter, ATP7B. This study examines the changes in the copper trafficking mechanisms of liver cells exposed to excess fatty acids. Fatty acid uptake was induced in liver hepatocarcinoma cells, HepG2, by treatment with the saturated fatty acid, palmitic acid. Changes in chaperones, transporters, and chelators demonstrate an initial state of copper overload in the cell that over time shifts to a state of copper deficiency. This deficiency is due to sequestration of copper both into the membrane-bound copper protein, hephaestin, and lysosomal units. These changes are independent of changes in copper concentration, supporting perturbations in copper localization at the subcellular level. We hypothesize that fat accumulation triggers an initial copper miscompartmentalization within the cell, due to disruptions in mitochondrial copper balance, which induces a homeostatic response to cytosolic copper overload. This leads the cell to activate copper export and sequestering mechanisms that in turn induces a condition of cytosolic copper deficiency. Taken together, this work provides molecular insights into the previously observed phenotypes in clinical and rodent models linking copper-deficient states to obesity-associated disorders.Hybrid epithelial/mesenchymal cells (E/M) are key players in aggressive cancer metastasis. It remains a challenge to understand how these cell states, which are mostly non-existent in healthy tissue, become stable phenotypes participating in collective cancer migration. The transcription factor Nrf2, which is associated with tumor progression and resistance to therapy, appears to be central to this process. Here, using a combination of immunocytochemistry, single cell biosensors, and computational modeling, we show that Nrf2 functions as a phenotypic stability factor for hybrid E/M cells by inhibiting a complete epithelial-mesenchymal transition (EMT) during collective cancer migration. We also demonstrate that Nrf2 and EMT signaling are spatially coordinated near the leading edge. In particular, computational analysis of an Nrf2-EMT-Notch network and experimental modulation of Nrf2 by pharmacological treatment or CRISPR/Cas9 gene editing reveal that Nrf2 stabilizes a hybrid E/M phenotype which is maximally observed in the interior region immediately behind the leading edge. [https://www.selleckchem.com/products/gsk2982772.html selleck kinase inhibitor] We further demonstrate that the Nrf2-EMT-Notch network enhances Dll4 and Jagged1 expression at the leading edge, which correlates with the formation of leader cells and protruding tips. Altogether, our results provide direct evidence that Nrf2 acts as a phenotypic stability factor in restricting complete EMT and plays an important role in coordinating collective cancer migration.<br /><br /> The concept of coproduction shows great promise for meaningful partnerships between patients and health professionals. This is particularly relevant for immigrant patients who are less inclined to take an active role in consultations. The present study described health professionals' practices and experiences of coproducing healthcare service with immigrant and refugee patients in clinical encounters.<br /><br /> We conducted a three-phase qualitative study with immigrant and refugee patients and health professionals at an interdisciplinary outpatient clinic for immigrants and refugees with complex long-standing health problems at a Danish university hospital. First, we conducted 25 observations of consultations between seven professionals (three doctors, three nurses, one social worker) and 24 patients with varied backgrounds and health problems. Findings were discussed in a focus group and individual interviews with the migrant clinic's staff. Finally, the themes were discussed with co-researchers and revised in a of doing what makes sense to form a positive partnership with the patient allows health professionals to act autonomously, flexibly, and creatively. Using communication tools designed around patient needs, create optimal conditions for coproduction as health professionals empathically validate and integrate patient experiences. Professionals need advanced listening and relational skills and tolerance of ambiguity and insecurity. Relational continuity facilitates long-term coproduction but also bears risks of emotional dependency.Cervical cancer commonly caused by Human Papillomavirus (HPV) imposes a significant burden in Asia. This study examined the awareness and knowledge of HPV, cervical cancer, and its early detection methods among South Asian immigrant women in Australia to determine factors associated with knowledge deficits. A cross-sectional internet-based survey was completed by a convenience sample of women (n=148), with South-Asian background, residing in Queensland during May-October 2019. Main outcome variables were awareness of HPV, cervical cancer, cervical screening test (Pap test and HPV test) and HPV test self-sampling availability (Yes/No). HPV and cervical cancer knowledge were assessed via 16-item and 20 item aggregated scales respectively, (higher scores indicating better knowledge). Five individual items queried knowledge of the Pap and HPV test, and one item actual cervical screening uptake. One-way ANOVA was used to study differences in HPV and cervical cancer knowledge among sociodemographic groups. Of 148 participating women, 55% (n=86) had heard of HPV, 77% (n=114) of cervical cancer and 81.8% (n=121) of Pap tests. Only one third of participants (n=49) were aware that now an HPV test is used for cervical screening and 10% (n=15) of its self-sampling availability, whereas 55.4% (n=82) reported participation in screening previously. The mean HPV knowledge score was 5.3 (S.D 5.7) and mean cervical cancer knowledge score 9.8 (S.D 6.5) with zero being the most common score on both scales. Higher knowledge scores were significantly associated with higher educational level, English language proficiency, discussion with a GP on the topic and previous participation in screening. The majority of participants lacked detailed knowledge about the available screening tests. This study identified key target groups for future interventions.Atherosclerotic vascular disease (ASVD) is the leading cause of death worldwide. Hyperuricemia is the fourth risk factor for atherosclerosis after hypertension, diabetes, and hyperlipidemia. The mechanism of hyperuricemia affecting the occurrence and development of atherosclerosis has not been fully elucidated. Mononuclear macrophages play critical roles in all stages of atherosclerosis. Studies have confirmed that both hyperuricemia and ferroptosis promote atherosclerosis, but whether high level of uric acid (HUA) promotes atherosclerosis by regulating ferroptosis in macrophages remains unclear. We found that HUA significantly promoted the development of atherosclerotic plaque and downregulated the protein level of the NRF2/SLC7A11/GPX4 signaling pathway in ApoE-/- mice. Next, we evaluated the effect of HUA and ferroptosis inhibitor ferrostatin-1 (Fer-1) treatment on the formation of macrophage-derived foam cells. HUA promoted the formation of foam cells, decreased cell viability, and increased iron accumulation and lipid peroxidation in macrophages treated with oxidized low-density lipoprotein (oxLDL); these effects were reversed by Fer-1 treatment. Mechanistically, HUA significantly inhibited autophagy and the protein level of the NRF2/SLC7A11/GPX4 signaling pathway. Fer-1 activated autophagy and upregulated the level of ferroptosis-associated proteins. Moreover, an NRF2 inducer (tertbutyl hydroquinone (TBHQ)) and autophagy activator (rapamycin (RAPA)) could reverse the inhibitory effect of HUA on foam cell survival. Our results suggest that HUA-induced ferroptosis of macrophages is involved in the formation of atherosclerotic plaques. More importantly, enhancing autophagy and inhibiting ferroptosis by activating NRF2 may alleviate HUA-induced atherosclerosis. These findings might contribute to a deeper understanding of the role of HUA in the pathogenesis of atherosclerosis and provide a therapeutic target for ASVD associated with hyperuricemia.Intervertebral disc degeneration (IDD), being the predominant root cause of lower back pain, has led to an enormous socioeconomic burden in the world. Ferroptosis is an iron-dependent nonapoptotic and nonpyroptotic programmed cell death associated with an increase in reactive oxygen species (ROS), which has been implicated in the pathogenesis of IDD. Activation transcription factor 3 (ATF3) is widely reported to promote ferroptosis and apoptosis in multiple diseases, but its roles and underlying regulatory mechanism in IDD have not been identified. FAoptosis is defined as a mixed cell death consisting of ferroptosis and apoptosis. The loss- and gain-of-function experiments demonstrated that ATF3 positively regulated tert-butyl hydroperoxide- (TBHP-) induced nucleus pulposus cell (NPC) FAoptosis, ROS production, inflammatory response, and extracellular matrix (ECM) degradation. Furthermore, silencing ATF3 ameliorated the progression of IDD in vivo, whereas its overexpression showed the opposite phenotype. Bioinformatics analysis and molecular experiments corroborated that ATF3 is a direct target of miR-874-3p, suggesting that the upregulation of ATF3 in IDD might be caused at least in part due to the downregulation of miR-874-3p in IDD, thereby relieving the inhibition of ATF3 by miR-874-3p. The findings revealed that ATF3 has the potential to be used as a promising therapeutic target against IDD.Age-related cataract (ARC) is the leading cause of vision impairment globally. It has been widely accepted that excessive reactive oxygen species (ROS) accumulation in lens epithelial cells (LECs) is a critical risk factor for ARC formation. Biliverdin (BV)/bilirubin (BR) redox pair is the active by-product of heme degradation with robust antioxidative stress and antiapoptotic effects. Thus, we purpose that BV and BR may have a therapeutic effect on ARC. In the present study, we determine the expression levels of enzymes regulating BV and BR generation in human lens anterior capsule samples. The therapeutic effect of BV/BR redox pair on ARC was assessed in hydrogen peroxide (H2O2)-damaged mouse LECs in vitro. The NF-κB/inducible nitric oxide synthase (iNOS) and nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) signaling pathways were evaluated to illustrate the molecular mechanism. The results revealed that the mRNA expressions of Nrf2, HO-1, and biliverdin reductase A (BVRA) were all decreased in human samples of age-related nuclear cataract.