Molecular subtypes of breast cancer identified by dynamically enhanced MRI radiomics: the delayed phase cannot be ignored.

OBJECTIVES: To compare the diagnostic performance of intratumoral and peritumoral features from different contrast phases of breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) by building radiomics models for differentiating molecular subtypes of breast cancer. METHODS: This retrospective study included 377 patients with pathologically confirmed breast cancer. Patients were divided into training set (n = 202), validation set (n = 87) and test set (n = 88). The intratumoral volume of interest (VOI) and peritumoral VOI were delineated on primary breast cancers at three different DCE-MRI contrast phases: early, peak, and delayed. Radiomics features were extracted from each phase. After feature standardization, the training set was filtered by variance analysis, correlation analysis, and least absolute shrinkage and selection (LASSO). Using the extracted features, a logistic regression model based on each tumor subtype (Luminal A, Luminal B, HER2-enriched, triple-negative) was established. Ten models based on intratumoral or/plus peritumoral features from three different phases were developed for each differentiation. RESULTS: Radiomics features extracted from delayed phase DCE-MRI demonstrated dominant diagnostic performance over features from other phases. However, the differences were not statistically significant. In the full fusion model for differentiating different molecular subtypes, the most frequently screened features were those from the delayed phase. According to the Shapley additive explanation (SHAP) method, the most important features were also identified from the delayed phase. CONCLUSIONS: The intratumoral and peritumoral radiomics features from the delayed phase of DCE-MRI can provide additional information for preoperative molecular typing. The delayed phase of DCE-MRI cannot be ignored. CRITICAL RELEVANCE STATEMENT: Radiomics features extracted and radiomics models constructed from the delayed phase of DCE-MRI played a crucial role in molecular subtype classification, although no significant difference was observed in the test cohort. KEY POINTS: The molecular subtype of breast cancer provides a basis for setting treatment strategy and prognosis. The delayed-phase radiomics model outperformed that of early-/peak-phases, but no differently than other phases or combinations. Both intra- and peritumoral radiomics features offer valuable insights for molecular typing.

Effect of Al2Cu constituent layer thickness discrepancy on the tensile mechanical behavior of Cu/Al2Cu/Al layered composites: a molecular dynamics simulation.

Nano-polycrystalline Cu/Al2Cu/Al layered composites with different layer thicknessesdof single-crystal Al2Cu constituent are constructed. The effects ofdon the strength and fracture modes of nano-polycrystalline Cu/Al2Cu/Al layered composites are systematically investigated by molecular dynamics simulations. The uniaxial tensile results show that the ultimate strength and fracture mode of the nano-polycrystalline Cu/Al2Cu/Al layered composites do not change monotonically with the change of single crystal Al2Cu constituent layer thicknessd, the ultimate strength peaking atd= 2.44 nm, and the toughness reaching the optimum atd= 4.88 nm. The improvement of deformation incompatibility between Cu, Al and Al2Cu components increases the ultimate strength of polycrystalline Cu/Al2Cu/Al laminated composites. Due to the high activity of Cu dislocation and the uniformity of strain distribution of single crystal Al2Cu, the fracture of nano-crystalline Cu/Al2Cu/Al layered composites changes from brittleness to toughness. This study is crucial to establish the organic connection between microstructure and macroscopic properties of Cu/Al layered composites. To provide theoretical basis and technical support for the application of Cu/Al layered composites in high-end fields, such as automotive and marine, aerospace and defense industries.

The efficacy of bone marrow mesenchymal stem cells on rat intestinal immune-function injured by ischemia/reperfusion.

Background: Transplantation of bone marrow mesenchymal stem cells (BMSCs) has a promising therapeutic efficiency for varieties of disorders caused by ischemia or reperfusion impairment. It has been shown that BMSCs can mitigate intestinal ischemia/reperfusion (I/R) injuries, but the underlying mechanism is still unclear. This study aimed at investigating the efficacy of BMSCs on the immune function of intestinal mucosal microenvironment after I/R injuries. Methods: Twenty adult Sprague-Dawley rats were randomly assigned to a treatment or a control group. All the rats underwent superior mesenteric artery clamping and unclamping. In the treatment group, BMSCs were implanted into the intestine of ten rats by direct submucosal injection whereas the other ten rats in the control group were injected with the same volume of saline. On the fourth and seventh day after BMSCs transplantation, intestinal samples were examined for the CD4 (CD4-positive T-lymphocytes)/CD8 (CD8-positive T-lymphocytes) ratio of the bowel mucosa via flow cytometry, and for the level of Interleukin-2 (IL-2), Interleukin-4 (IL-4) and Interleukin-6 (IL-6) via ELISA. Paneth cell counts and Secretory Immunoglobulin A (SIgA) level were examined via immunohistochemical (IHC) analysis. Real time PCR (RT-PCR) was used to detect the expression levels of tumor necrosis factor-α (TNF-α) and trypsinogen (Serine 2) (PRSS2) genes. White blood cell (WBC) count was measured by manual counting under the microscope. Results: The CD4/CD8 ratio in the treatment group was significantly lower compared with that in the control group. The concentration of IL-2 and IL-6 was lower in the treatment group compared with the control group, while the level of IL-4 is the reverse between the two groups. The number of Paneth cells in intestinal mucosa increased significantly, while the level of SIgA in intestinal mucosa decreased significantly, after BMSCs transplantation. The gene expression levels of TNF-α and PRSS2 in intestinal mucosa of treatment group were significantly lower than those of control group. The WBC count in the treatment group was significantly lower than that in the control group. Conclusion: We identified immune-relevant molecular changes that may explain the mechanism of BMSCs transplantation efficacy in alleviating rat intestinal immune-barrier after I/R.

Potential Antihuman Epidermal Growth Factor Receptor 2 Target Therapy Beneficiaries: The Role of MRI-Based Radiomics in Distinguishing Human Epidermal Growth Factor Receptor 2-Low Status of Breast Cancer.

BACKGROUND: Multiparametric MRI radiomics could distinguish human epidermal growth factor receptor 2 (HER2)-positive from HER2-negative breast cancers. However, its value for further distinguishing HER2-low from HER2-negative breast cancers has not been investigated. PURPOSE: To investigate whether multiparametric MRI-based radiomics can distinguish HER2-positive from HER2-negative breast cancers (task 1) and HER2-low from HER2-negative breast cancers (task 2). STUDY TYPE: Retrospective. POPULATION: Task 1: 310 operable breast cancer patients from center 1 (97 HER2-positive and 213 HER2-negative); task 2: 213 HER2-negative patients (108 HER2-low and 105 HER2-zero); 59 patients from center 2 (16 HER2-positive, 27 HER2-low and 16 HER2-zero) for external validation. FIELD STRENGTH/SEQUENCE: A 3.0 T/T1-weighted contrast-enhanced imaging (T1CE), diffusion-weighted imaging (DWI)-derived apparent diffusion coefficient (ADC). ASSESSMENT: Patients in center 1 were assigned to a training and internal validation cohort at a 2:1 ratio. Intratumoral and peritumoral features were extracted from T1CE and ADC. After dimensionality reduction, the radiomics signatures (RS) of two tasks were developed using features from T1CE (RS-T1CE), ADC (RS-ADC) alone and T1CE + ADC combination (RS-Com). STATISTICAL TESTS: Mann-Whitney U tests, the least absolute shrinkage and selection operator, receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA). RESULTS: For task 1, RS-ADC yielded higher area under the ROC curve (AUC) in the training, internal, and external validation of 0.767/0.725/0.746 than RS-T1CE (AUC = 0.733/0.674/0.641). For task 2, RS-T1CE yielded higher AUC of 0.765/0.755/0.678 than RS-ADC (AUC = 0.706/0.608/0.630). For both of task 1 and task 2, RS-Com achieved the best performance with AUC of 0.793/0.778/0.760 and 0.820/0.776/0.711, respectively, and obtained higher clinical benefit in DCA compared with RS-T1CE and RS-ADC. The calibration curves of all RS demonstrated a good fitness. DATA CONCLUSION: Multiparametric MRI radiomics could noninvasively and robustly distinguish HER2-positive from HER2-negative breast cancers and further distinguish HER2-low from HER2-negative breast cancers. EVIDENCE LEVEL: 3. TECHNICAL EFFICACY: Stage 2.

Cuproptosis regulator-mediated patterns associated with immune infiltration features and construction of cuproptosis-related signatures to guide immunotherapy.

Background: Liver hepatocellular carcinoma (HCC) is a prevalent cancer that lacks a sufficiently efficient approach to guide immunotherapy. Additionally, cuproptosis is a recently identified regulated cell death program that is triggered by copper ionophores. However, its possible significance in tumor immune cell infiltration is still unclear. Methods: Cuproptosis subtypes in HCC were identified using unsupervised consensus cluster analysis based on 10 cuproptosis regulators expressions, and a cuproptosis-related risk signature was generated using univariate and LASSO Cox regression and validated using the ICGC data. Moreover, the relationship between signature and tumor immune microenvironment (TME) was studied through tumor immunotherapy responsiveness, immune cell infiltration, and tumor stem cell analysis. Finally, clinical specimens were analyzed using immunohistochemistry to verify the expression of the three genes in the signature. Results: Two subtypes of cuproptosis regulation were observed in HCC, with different immune cell infiltration features. Genes expressed differentially between the two cuproptosis clusters in the TCGA were determined and used to construct a risk signature that was validated using the ICGC cohort. Greater immune and stromal cell infiltration were observed in the high-risk group and were associated with unfavorable prognosis. Elevated risk scores were linked with higher RNA stemness scores (RNAss) and tumor mutational burden (TMB), together with a greater likelihood of benefitting from immunotherapy. Conclusion: It was found that cuproptosis regulatory patterns may play important roles in the heterogeneity of immune cell infiltration. The risk signature associated with cuproptosis can assess each patient's risk score, leading to more individualized and effective immunotherapy.

Ferroptosis-related gene NOX4, CHAC1 and HIF1A are valid biomarkers for stomach adenocarcinoma.

Ferroptosis is a regulated cell death nexus linking metabolism, redox biology and diseases including cancer. The aim of the present study was to identify a ferroptosis-related gene prognostic signature for stomach adenocarcinoma (STAD) by systematic analysis of transcriptional profiles from The Cancer Genome Atlas (TCGA), GEO and a clinical cohort from our centre. We developed a predictive model based on three ferroptosis-related genes (CHAC1, NOX4 and HIF1A), gene expression data and corresponding clinical outcomes were obtained from the TCGA database, and the reliability of this model was verified with GSE15459 and 51 queues in our centre. ROC curve showed better predictive ability using the risk score. Immune cell enrichment analysis demonstrated that the types of immune cells and their expression levels in the high-risk group were significantly different from those in the low-risk group. The experimental results confirmed that NOX4 was upregulated and CHAC1 was downregulated in the STAD tissues compared with the normal stomach mucosal tissues (p < 0.05). In sum, the ferroptosis-related gene signature can accurately predict the outcomes of patients with STAD, providing valuable insights for personalized treatment. As the signature also has relevance to the immune characteristics, it may help improve the efficacy of personalized immunotherapy.

[Effects of Bosutinib on cerebral ischemia/reperfusion injury in rats].

Objective: To investigate the effects of bosutinib on the early stage of cerebral ischemia-reperfusion injury in rats. Methods: Forty Sprague-Dawley rats were randomly divided into four groups (random number method), 10 rats in each group; sham group (control group): only neck vessels were isolated without other treatments; MCAO (model group): the rat brain ischemia/reperfusion injury model was made by a modified wire bolus method,ischemia for 2 h followed by reperfusion for 24 h; DMSO group (solvent group): DMSO ( 0.752 ml/kg) was injected into the tail vein one day before the experiment, brain ischemia 2 h reperfusion for 24 h; Bosutinib group (intervention group): one day before the experiment, the tail vein was injected with Bosutinib (4 mg/kg), brain ischemia 2 h reperfusion for 24 h. After 24 h of ischemia reperfusion, neurological function score was performed; brain infarct area was calculated after staining with TTC; SIK2 was detected by Western blot; the contents of TNF-α and IL-6 in brain tissue were detected by ELISA. Results: Compared with the sham group, the neurological function scores, the infarct volume percentages and the levels of inflammatory factors IL-6 and TNF-α of the MCAO and DMSO groups were increased significantly (P＜0.05 or P＜0.01). Compared with the MCAO and DMSO groups, the above mentioned indexes of the bosutinib group were all decreased significantly (P＜0.05 or P＜ 0.01). Compared with sham group, the expression levels of SIK2 protein in MCAO and DMSO groups had no significant changes(P＞ 0.05); compared with the MCAO and DMSO group, the expression level of SIK2 protein in the bosutinib group was decreased significantly (P＜0.05). Conclusion: Bosutinib reduces cerebral ischemia-reperfusion-induced injury, and its possible mechanism is related to the decreased expression of SIK2 protein and inflammatory factors.

The pattern of alternative splicing in lung adenocarcinoma shows novel events correlated with tumorigenesis and immune microenvironment.

Lung adenocarcinoma (LUAD) is the leading cause of cancer deaths worldwide due to the lack of early diagnostic markers and specific drugs. Previous studies have shown the association of LUAD growth with aberrant alternative splicing (AS). Herein, clinical data of 535 tumor tissues and 59 normal tissues were extracted from The Cancer Genome Atlas (TCGA) database. Each sample was analyzed using the ESTIMATE algorithm; a comparison between higher and lower score groups (stromal or immune) was made to determine the overall- and progression-free survival-related differentially expressed AS (DEAS) events. We then performed unsupervised clustering of these DEASs, followed by determining their relationship with survival rate, immune cells, and the tumor microenvironment (TME). Next, two prognostic signatures were developed using bioinformatics tools to explore the prognosis of cases with LUAD. Five OS- and six PFS-associated DEAS events were implemented to establish a prognostic risk score model. When compared to the high-risk group (HRG), the PFS and OS of the low-risk group (LRG) were found to be considerable. Additionally, a better prognosis was found considerably associated with the ESTIMATE score of the patients as well as immune cells infiltration. Our analysis of AS events in LUAD not only helps to clarify the tumorigenesis mechanism of AS but also provides ideas for revealing potential prognostic biomarkers and therapeutic targets.