SLC25A17 inhibits autophagy to promote triple-negative breast cancer tumorigenesis by ROS-mediated JAK2/STAT3 signaling pathway.

BACKGROUND: SLC25A17, a peroxisomal solute carrier, has been implicated in various physiological and pathological processes. However, its precise roles and underlying mechanisms in triple-negative breast cancer (TNBC) remain incompletely understood. METHODS: The expression and survival data of breast cancer were derived from TCGA and GEO databases. A variety of in vitro assays were conducted, including proliferation, apoptosis, cell cycle, migration, and invasion. Reactive oxygen species (ROS) were measured by immunofluorescence microscopy and flow cytometry. The levels of autophagy were assessed by mRFP-GFP-LC3 confocal microscopy scanning, western blotting, and electron microscopy. RESULTS: SLC25A17 was highly expressed in breast cancer tissues, which was found to be associated with unfavorable prognosis. Functional assays demonstrated that SLC25A17 knockdown suppressed proliferation, epithelial-mesenchymal transition (EMT), migration, and invasion. Moreover, it prompted apoptosis and autophagy. On the other hand, SLC25A17 knockdown promoted autophagy through triggering ROS accumulation, which was counteracted by N-acetyl-l-cysteine (NAC). Furthermore, the pro-apoptotic effect of SLC25A17 knockdown was reversed when treated with autophagy inhibitor 3-MA in TNBC cells, suggesting that SLC25A17 knockdown-induced autophagic cell death. Mechanistically, SLC25A17 performed its function through regulation JAK2/STAT3 signaling in TNBC. In a nude mice xenograft study, SLC25A17 knockdown markedly decreased breast tumor growth and metastasis. CONCLUSION: SLC25A17 up-regulation may be a critical factor driving TNBC progression by modulating ROS production and autophagy. Consequently, targeting SLC25A17 could be an effective therapeutic strategy against TNBC.

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives.

Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood-brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition.

FERMT1 contributes to the migration and invasion of nasopharyngeal carcinoma through epithelial-mesenchymal transition and cell cycle arrest.

BACKGROUND: Fermitin family member 1 (FERMT1) is significantly overexpressed in human cancers and associated with poor prognosis, but its contributions to tumorigenesis and nasopharyngeal carcinoma (NPC) progression remain unclear. METHODS: The public GEO database was examined to investigate the role of FERMT1. Immunohistochemistry (IHC) staining of FERMT1 was performed in NPC tissues to corroborate the results. Western blotting and qRT-PCR were performed to test the expression of related proteins and mRNAs. Cell counting kit-8 assay (CCK8 assay) and colony formation assays were carried out to investigate the association of FERMT1 expression with NPC cell proliferation. The wound healing assay and Transwell assay were used to detect the migration and invasion of NPC cells. Flow cytometric analysis was conducted to detect the cell cycle transition of NPC cells. Co-immunoprecipitation (Co-IP) was employed to identify the correlation of FEMRT1 and Nod-like receptor family protein 3 (NLRP3). Xenograft tumors were generated to investigate the effect of FERMT1 on the growth of NPC cells in vivo. RESULTS: Here, we found that FERMT1 was upregulated in NPC tissues and correlated with the clinicopathological characteristics of NPC patients. Moreover, knockdown of FERMT1 significantly decreased cell proliferation, migration and invasion by mediating epithelial-mesenchymal transition (EMT) and cell cycle arrest of NPC cells both in vitro and in vivo. Knockdown FERMT1 inhibited EMT through directly binding to the NLRP3 and inhibited NF-kB signaling pathway. CONCLUSION: These data indicated that FERMT1 could be a good potential therapeutic target for NPC treatment.

Identification novel prognostic signatures for Head and Neck Squamous Cell Carcinoma based on ceRNA network construction and immune infiltration analysis.

Background: Head and neck squamous cell carcinoma (HNSCC) is a common malignancy with high mortality and morbidity worldwide, but the underlying biological mechanisms of molecules and tumor infiltrating-immune cells (TIICs) are still unknown. Methods and Results: We obtained mRNAs, lncRNAs, and miRNAs expression profiles of 546 HNSCC from The Cancer Genome Atlas (TCGA) database to develop a ceRNA network. CIBERSORT was employed to estimate the fraction of 22 types of TIICs in HNSCC. Univariate and multivariate Cox regression and lasso regression analyses were used to develop prognostic signatures. Then, two novel risk signatures were constructed respectively based on six ceRNAs (ANLN, KIT, PRKAA2, NFIA, PTX3 and has-miR-148a-3p) and three immune cells (naïve B cells, regulatory T cells and Neutrophils). Kaplan-Meier (K-M) analysis and Cox regression analysis further proved that these two signatures were significant prognostic factors independent of multiple clinicopathological characteristics. Two nomograms were built based on ceRNAs-riskScore and TIICs-riskScore that could be used to predict the prognosis of HNSCC. Co-expression analysis showed significant correlations between miR-148a-3p and naive B cells, naive B cells and plasmas cells. Conclusion: Through construction of the ceRNA network and estimation of TIICs, we established two risk signatures and their nomograms with excellent utility, which indicated the potential molecular and cellular mechanisms, and predicted the prognosis of HNSCC.

Pulsed terahertz spectroscopy combined with hybrid machine learning approaches for structural health monitoring of multilayer thermal barrier coatings.

Structural health monitoring of multilayer thermal barrier coatings (TBCs) is very vital to ensure the structural integrity and service performance of the hot-section components of the aero-engine. In this paper, we theoretically and numerically demonstrated that the terahertz time domain spectrum and the terahertz reflectance spectrum could be adopted to estimate the structure parameters, based on the finite difference time domain (FDTD) algorithm, 64 samples which were imported with three kinds of 64 sets structure parameters had been calculated to obtain the time domain and terahertz reflectance signals. To mimic the actual test signals, the original FDTD simulation signals were processed by adding the Gaussian white noise and wavelet noise reduction. To reduce the data dimension and improve the calculation efficiency during modeling, the principal component analysis (PCA) algorithm was adopted to reduce the dimensions of time-domain data and reflectance data. Finally, these data after multiple signal processing and PCA feature extraction were used to train the extreme learning machine (ELM), combining the genetic algorithm (GA) could optimize the PCA-ELM model and further improve the prediction performance of the hybrid model. Our proposed novel and efficient terahertz nondestructive technology combined with the hybrid machine learning approaches provides great potential applications on the multilayer TBCs structural integrity evaluation.

Assessment of high sensitivity C-reactive protein and coronary plaque characteristics by computed tomography in patients with and without diabetes mellitus.

BACKGROUND: To evaluate the coronary plaque characteristics of coronary arteries using computed tomography angiography (CTA) in order to assess the risk of coronary artery disease and the relevance of high sensitivity C reactive protein (hs-CRP) in patients with Diabetes Mellitus (DM). METHODS: The clinical data of 400 DM patients and 400 non-DM patients from January 2017 to December 2019 were collected, including the results of coronaryCTA. The plasma hs-CRP level of the two groups were divided into three groups: CRP ≤ 1, 1 < CRP ≤ 2, CRP > 2. The correlation of the degree of stenosis, the number of plaques, the nature of plaques and hs-CRP value between the two groups was evaluated. RESULTS: Compared with non-DM patients, the incidence of coronary artery plaques and lumen stenosis in DM patients was more higher than that in non-DM patients. DM patients were more likely to have more diseased vessels, especially diffuse vascular disease (12.00% vs 1.75%; P < 0.001). Subjects with high hs-CRP levels were more likely to have any plaque compared with individuals showing normal hs-CRP levels (p<0.01). There was no statistical significance in non calcified plaque with high level of hs-CRP, but the occurrence of plaque types in DM group was statistically significant compared with other hs-CRP levels in non DM group. Subjects with high hs-CRP were observed to be at increased risk for the presence of calcified plaque and severe narrowing in the unadjusted values. CONCLUSIONS: Coronary CTA combined with hs-CRP can accurately detect the characteristics of coronary artery stenosis and plaque in DM patients, which has an important clinical value in the risk assessment of coronary heart disease in DM patients.

In-situ evaluation of porosity in thermal barrier coatings based on the broadening of terahertz time-domain pulses: simulation and experimental investigations.

Porosity is one of the most important indicators for the characterization of the comprehensive performance of thermal barrier coatings (TBCs). Herein, we explored a fast, nondestructive porosity evaluation method based on the terahertz time-domain broadening effect. Different preparation process parameters were used to deposit the ceramic coatings, and the porosity ranged from 9.09% to 21.68%. Monte Carlo simulations were conducted to reveal the transitive relation between porosity and the terahertz time-domain broadening at different extinction coefficients and transmission distances. A transmission mode with an incidence angle of 0° was used to estimate the terahertz dielectric properties of ceramic coatings and the relative broadening ratio of terahertz pulses at different porosities. As a result, the Monte Carlo simulations showed that the time-domain broadening effect was enhanced when the extinction coefficient and transmission distances increased. As the porosity increased, the refractive index decreased and the extinction coefficient increased. The latter was more sensitive to minor porosity changes as demonstrated by linear fitting comparisons. Meanwhile, the relative broadening ratio increased when the porosity increased, and reserved the sensitivity of the extinction coefficient to porosity changes. The effect was more obvious on the relative broadening ratio which experienced multiple transmissions and reflections. Moreover, the relative broadening ratio could be obtained faster and in an easier manner compared to the dielectric parameters in both the transmission and reflection modes, based on single-step tests with the use of actual terahertz wave inspection. Finally, this study proposed a novel, convenient, online, nondestructive, and noncontact porosity evaluation method that could be potentially utilized to evaluate the integrity of TBCs in gas turbine blades.

CT pulmonary angiogram for assessing the treatment outcome of acute pulmonary embolism.

OBJECTIVE: To discuss the value of CT pulmonary angiogram (CTPA) for assessing the treatment outcome of acute pulmonary embolism (APE). MATERIALS AND METHODS: CT pulmonary angiogram data and other clinical data were collected for 28 cases diagnosed as APE and analyzed retrospectively. The number and positions of emboli in the pulmonary artery, pulmonary artery obstruction index, right ventricular/left ventricular diameter ratio, main pulmonary artery/ascending aorta diameter ratio and blood oxygen saturation, and pulmonary arterial pressure were compared before and after treatment. RESULTS: Of 28 cases, emboli in the pulmonary artery completely or partially disappeared in 16 and 12 cases, respectively. CPTA indicated that the pulmonary arterial pressure decreased dramatically and the blood oxygen saturation increased after treatment in 26 cases. There were significant differences in the number and positions of pulmonary emboli and in pulmonary artery obstruction index before and after treatment in 28 cases (P < .05). However, no significant differences were found in the right ventricular/left ventricular diameter ratio or main pulmonary artery/ascending aorta diameter ratio (P > .05). CONCLUSION: CT pulmonary angiogram proved reliable for assessing the treatment efficacy of APE, providing more clinical information on the patients' status.

[Grading standard of processed Curcumae Radix].

As one of the three pillars of Chinese medicine industry, traditional Chinese medicines prepared in ready-to-use forms are important raw materials for clinical medication and production of Chinese patent drugs. By considering the literature of Curcumae Radix, a multi-source Chinese herb and the situation of market investigation, the modern evaluation method based on traditional grading was introduced for comprehensive evaluation of the processed Curcumae Radix. The correlation between traditional grading method and modern evaluation index was explored to establish the grading standard of Curcumae Radix. According to the comprehensive evaluation, Curcumae Radix was divided into four grades: superior, first, second and third grades under the guidance of the theory of traditional Chinese medicine. This study provides a new idea for the grading of multi-source processed Chinese medicine, achieving high quality and good price, which is helpful to improve the clinical efficacy.

Multislice spiral CT angiography for evaluation of acute aortic syndrome.

OBJECTIVE: To discuss the diagnostic value of multislice CT angiography (MSCTA) in acute aortic syndrome (AAS). MATERIALS AND METHODS: The clinical and imaging data of 36 cases diagnosed as AAS by MSCTA were collected. The manifestations of the MSCTA images were reviewed retrospectively, and the average x-ray dose was calculated. RESULTS: Among 36 AAS cases, 16 cases had aortic dissection (AD), 8 cases had penetrating atherosclerotic ulcer (PAU), 7 cases had intramural hematoma (IMH), and 5 cases had unstable thoracic aneurysm (UTA). Of 16 cases with AD, type A and type B accounted for 43.7% (7/16) and 56.3% (9/16), respectively. Of 7 cases with IMH, type A and type B accounted for 42.9% (3/7) and 57.1% (4/7), respectively. CONCLUSION: In spite of the x-ray radiation, MSCTA proves to be a rapid and noninvasive imaging technique for the diagnosis of AAS.

ECG-gated pulmonary artery CTA for evaluation of right ventricular function in patients with acute pulmonary embolism.

OBJECTIVE: To evaluate right ventricular function in patients with acute pulmonary embolism (APE) using electrocardiogram-gated CTA and to discuss the clinical value of pulmonary artery CTA PATIENTS AND METHODS: Based on death risk evaluation, 86 APE patients were divided into high-risk group (n=46) and non-high-risk group (n=40). The CT pulmonary embolism (PE) index and parameters of right ventricular function were analyzed from the CTPA images and compared between the two groups. Potential correlation between the two was also discussed. RESULT: CT PE index (median 24.69%) of the high-risk group was obviously higher than that of the non-high-risk group (median 8.58%) (P<.05). Except the diameter of superior vena cava, all other parameters of right ventricular function were significantly different between the two groups (P<.05). CT PE index was correlated with the parameters of right ventricular function. CONCLUSION: ECG-gated pulmonary artery CTA is suitable for assessing the severity of APE and right ventricular function.

[Transcatheter aortic valve implantation: Present and development trend].

Currently, although surgical aortic valve replacement (SAVR) is still the golden standard in treatment of severe aortic stenosis according to the guideline, transcatheter aortic valve implantation (TAVI) is gradually becoming a common treatment for patients who are prohibitive or in high risk for SAVR. Recently, the valve manufacturers, including medical companies in China, are making their utmost to develop valve device, leading remarkable results achieved by TAVI. With the complications being controlled, TAVI displays promising future. It is likely that TAVI is expected to become a substitute for SAVR to treat patients with aortic stenosis or even aortic regurgitation.

Evaluation of image quality in carotid and cerebrovascular disease: a comparative study between subtraction and routine computed tomography angiography.

OBJECTIVE: Few data exist comparing the image quality and diagnostic accuracy of subtraction computed tomography (CT) angiography (SCTA) in carotid and cerebrovascular arteries with routine CT angiography (RCTA). PATIENTS AND METHODS: In this study, 56 patients underwent 128-row CT angiography of these vessels with review by two radiologists using routine, nonsubtracted, and SCTA protocols. Comparisons were made using a 4-point subjective rating scale in all patients. Eighteen patients were examined with both SCTA and invasive digital subtraction angiography (DSA). The accuracy of SCTA and routine CTA reformations was assessed and compared by both patient-based and vessel-based analyses of intracranial aneurysms and intracranial and extracranial arterial stenotic lesions using DSA results as the reference standard. RESULTS: Diagnostic accuracy in the adjacent skull base portion of the internal carotid artery (ICA) and reading time for cerebral aneurysms and vessel stenoses were obviously improved with SCTA protocol, but the accuracy in vertebro-basilar arteries was no different. The diagnostic accuracy in general was slightly increased compared with routine CTA. CONCLUSION: Review of SCTA images is an effective means to remove bone close to vessels as seen on routine CTA and has good image quality and diagnostic accuracy. SCTA is superior to routine CTA in the visualization and diagnostic accuracy of adjacent skull base part of the ICA and decreases reading time for carotid and cerebrovascular arterial imaging.

A comprehensive investigation on the receptor BSG expression reveals the potential risk of healthy individuals and cancer patients to 2019-nCoV infection.

BACKGROUND: Coronavirus disease-2019 (COVID-19) pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a newly emerging coronavirus. BSG (basigin) is involved in the tumorigenesis of multiple tumors and recently emerged as a novel viral entry receptor for SARS-CoV-2. However, its expression profile in normal individuals and cancer patients are still unclear. METHODS: We performed a comprehensive analysis of the expression and distribution of BSG in normal tissues, tumor tissues, and cell lines via bioinformatics analysis and experimental verification. In addition, we investigated the expression of BSG and its isoforms in multiple malignancies and adjacent normal tissues, and explored the prognostic values across pan-cancers. Finally, we conducted function analysis for co-expressed genes with BSG. RESULTS: We found BSG was highly conserved in different species, and was ubiquitously expressed in almost all normal tissues and significantly increased in some types of cancer tissues. Moreover, BSG at mRNA expression level was higher than ACE2 in normal lung tissues, and lung cancer tissues. High expression of BSG indicated shorter overall survival (OS) in multiple tumors. The Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses indicated that BSG is mostly enriched in genes for mitochondria electron transport, oxidoreduction-driven active transmembrane transporter activity, mitochondrial inner membrane, oxidative phosphorylation, and genes involving COVID-19. CONCLUSIONS: Our present work emphasized the value of targeting BSG in the treatment of COVID-19 and cancer, and also provided several novel insights for understanding the SARS-CoV-2 pandemic.

Progress and Innovative Combination Therapies in Trop-2-Targeted ADCs.

Precise targeting has become the main direction of anti-cancer drug development. Trophoblast cell surface antigen 2 (Trop-2) is highly expressed in different solid tumors but rarely in normal tissues, rendering it an attractive target. Trop-2-targeted antibody-drug conjugates (ADCs) have displayed promising efficacy in treating diverse solid tumors, especially breast cancer and urothelial carcinoma. However, their clinical application is still limited by insufficient efficacy, excessive toxicity, and the lack of biological markers related to effectiveness. This review summarizes the clinical trials and combination therapy strategies for Trop-2-targeted ADCs, discusses the current challenges, and provides new insights for future advancements.

Pharmacological modulation of gp130 signalling enhances Achilles tendon repair by regulating tenocyte migration and collagen synthesis via SHP2-mediated crosstalk of the ERK/AKT pathway.

Tendon injuries typically display limited reparative capacity, often resulting in suboptimal outcomes and an elevated risk of recurrence or rupture. While cytokines of the IL-6 family are primarily recognised for their inflammatory properties, they also have multifaceted roles in tissue regeneration and repair. Despite this, studies examining the association between IL-6 family cytokines and tendon repair remained scarce. gp130, a type of glycoprotein, functions as a co-receptor for all cytokines in the IL-6 family. Its role is to assist in the transmission of signals following the binding of ligands to receptors. RCGD423 is a gp130 modulator. Phosphorylation of residue Y759 of gp130 recruits SHP2 and SOCS3 and inhibits activation of the STAT3 pathway. In our study, RCGD423 stimulated the formation of homologous dimers of gp130 and the phosphorylation of Y759 residues without the involvement of IL-6 and IL-6R. Subsequently, the phosphorylated residues recruited SHP2 kinase, activating the downstream ERK and AKT pathways. These mechanisms ultimately promoted the migration ability of tenocytes and matrix synthesis, especially collagen I. Moreover, RCGD423 also demonstrated significant improvements in collagen content, alignment of collagen fibres, and biological and biomechanical function in a rat Achilles tendon injury model. In summary, we demonstrated a promising gp130 modulator (RCGD423) that could potentially enhance tendon injury repair by redirecting downstream signalling of IL-6, suggesting its potential therapeutic application for tendon injuries.

Molecular markers that predict response to combined radiotherapy and immunotherapy in patients with lung adenocarcinoma: a bioinformatics analysis.

Background: Immunotherapy has had a high success rate in treating lung adenocarcinoma (LUAD) for several decades. However, many patients do not benefit from immunotherapy alone. Recent studies revealed that a combination of immunotherapy and radiotherapy (RT) stimulates a good systemic immune response to LUAD. However, clinical and experimental evidence suggest that RT may give rise to primary immunodeficiency, facilitating tumor immunity escape. Little is known about the molecular mechanisms whereby RT and stereotactic body radiotherapy (SBRT) influence tumor immunogenicity and the effectiveness of immunotherapy in patients with LUAD. Methods: We investigated molecular markers that predict response to combination of immunotherapy and SBRT in the treatment of LUAD using bioinformatics. Results: SBRT significantly upregulated the expression of PTPRC, LILRB2, TLR8, CCR5, and PLEK and significantly downregulated the expression of CXCL13, CD19, and LTA. Among these genes, the expression of PTPRC, TLR8, and CCR5 was associated with responsiveness to immunotherapy after SBRT. However, only TLR8 and CCR5 expression were associated with an improved prognosis. Further analysis revealed that TLR8 and CCR5 expression increased responsiveness to immunotherapy by promoting M0 macrophage and memory B cell infiltration of LUAD tissues. Conclusions: In patients with LUAD, TLR8 and CCR5 expression are potential markers of a favorable response to combined immunotherapy and RT.

Association between systemic immune-inflammation index and diabetes: a population-based study from the NHANES.

Background: Systemic Immune-Inflammation Index (SII) has been reported to be associated with diabetes. We aimed to assess possible links between SII and diabetes. Methods: Data were obtained from the 2017-2020 National Health and Nutrition Examination Survey (NHANES) database. After removing missing data for SII and diabetes, we examined patients older than 20 years. Simultaneously, the relationship between SII and diabetes was examined using weighted multivariate regression analysis, subgroup analysis, and smooth curve fitting. Results: There were 7877 subjects in this study, the average SII was 524.91 ± 358.90, and the prevalence of diabetes was 16.07%. Weighted multivariate regression analysis found that SII was positively associated with diabetes, and in model 3, this positive association remained stable (OR = 1.04; 95% CI: 1.02-1.06; p = 0.0006), indicating that each additional unit of SII, the possibility of having diabetes increased by 4%. Gender, age, BMI, regular exercise, high blood pressure, and smoking did not significantly affect this positive link, according to the interaction test (p for trend>0.05). Discussion: Additional prospective studies are required to examine the precise connection between higher SII levels and diabetes, which may be associated with higher SII levels.

Identification of MTHFD2 as a prognostic biomarker and ferroptosis regulator in triple-negative breast cancer.

Background: Methylenetetrahydrofolate dehydrogenase 2 (MTHFD2) is a mitochondrial bifunctional enzyme encoded in the nucleus. It plays a significant role in the regulation of glucose, nucleic acid, and folate metabolism, and maintains redox balance in the cells. The present study aimed at elucidating the potential function and mechanisms of MTHFD2 and explored the correlation between ferroptosis and MTHFD2 in triple-negative breast cancer. Methods: MTHFD2 expression, survival analysis, and clinical correlation were performed using data from various online databases including TCGA, GEO, HPA, GTEX, Kaplan-Meier Plotter, PrognoScan, and UALCAN databases. Genomic alterations and CNV analysis were performed using the cBioPortal and GSCA databases. Potential functions and mechanisms were explored by enrichment analysis. The tumor microenvironment was identified by the TIMER database. In vitro, RT-qPCR and western blot assays were utilized to identify the MTHFD2 expression and the knockdown effects in breast cancer. CCK8, cell wound healing, transwell, and flow cytometry assays were used to identify the potential function of MTHFD2 in TNBC cells. MDA, GSH detection, and flow cytometry assays were performed to identify ferroptosis. Western blot assays were performed to measure the protein expression of all target genes. Results: MTHFD2 expression levels were up-regulated in the majority of cancers and particularly in TNBC, in which higher expression levels indicated a poorer prognosis. Enrichment analyses showed that MTHFD2 is involved in various tumor-related biological processes. MTHFD2 expression was found to strongly correlate with multiple immune cell infiltration. In vitro, the knockdown of MTHFD2 suppresses the proliferation, apoptosis, migration, and invasion in TNBC cells. In addition, the MTHFD2 knockdown significantly enhanced intracellular ROS and lipid peroxidation and decreased intracellular GSH. The expressions of SLC7A11, GPX4, and NRF2 were down-regulated by the MTHFD2 knockdown. Conclusion: MTHFD2 could be a crucial molecular biomarker for predicting patient prognosis and a novel therapeutic target in TNBC. In addition, MTHFD2 is a potential ferroptosis regulatory gene in TNBC.

Diagnostic and prognostic role of circRNAs in pancreatic cancer: a meta-analysis.

Background: Circular RNAs (circRNAs) are types of endogenous noncoding RNAs produced by selective splicing that are expressed highly specifically in various organisms and tissues and have numerous clinical implications in the regulation of cancer development and progression. Since circRNA is resistant to digestion by ribonucleases and has a long half-life, there is increasing evidence that circRNA can be used as an ideal candidate biomarker for the early diagnosis and prognosis of tumors. In this study, we aimed to reveal the diagnostic and prognostic value of circRNA in human pancreatic cancer (PC). Methods: A systematic search for publications from inception to 22 July 2022 was conducted on Embase, PubMed, Web of Science (WOS), and the Cochrane Library databases. Available studies that correlated circRNA expression in tissue or serum with the clinicopathological, diagnostic, and prognostic values of PC patients were enrolled. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were used to evaluate clinical pathological characteristics. Area under the curve (AUC), sensitivity, and specificity were adopted to assess diagnostic value. Hazard ratios (HRs) were utilized to assess disease-free survival (DFS) and overall survival (OS). Results: This meta-analysis enrolled 32 eligible studies, including six on diagnosis and 21 on prognosis, which accounted for 2,396 cases from 245 references. For clinical parameters, high expression of carcinogenic circRNA was significantly associated with degree of differentiation (OR = 1.85, 95% CI = 1.47-2.34), TNM stage (OR = 0.46, 95% CI = 0.35-0.62), lymph node metastasis (OR = 0.39, 95% CI = 0.32-0.48), and distant metastasis (OR = 0.26, 95% CI = 0.13-0.51). As for clinical diagnostic utility, circRNA could discriminate patients with pancreatic cancer from controls, with an AUC of 0.86 (95% CI: 0.82-0.88), a relatively high sensitivity of 84%, and a specificity of 80% in tissue. In terms of prognostic significance, carcinogenic circRNA was correlated with poor OS (HR = 2.00, 95% CI: 1.76-2.26) and DFS (HR = 1.96, 95% CI: 1.47-2.62). Conclusion: In summary, this study demonstrated that circRNA may act as a significant diagnostic and prognostic biomarker for pancreatic cancer.