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Wnts are secreted ligands that consist of 19 members in humans, regulate cell proliferation, differentiation, motility and fate in many stages including the embryonic stage and tumorigenesis. Wnts bind to cell surface receptors named Frizzleds and LRPs, and transduce their signals through β‐catenin‐dependent and ‐independent intracellular pathways. Gliomas are one of the most common intracranial tumors. Gliomas exhibit a progression associated with widespread infiltration into surrounding neuronal tissues. However, the molecular mechanisms that stimulate the invasion of glioma cells are not fully understood. We established two cell lines from human glioma cases and analyzed the expression of all Wnt and Frizzled members in these cell lines and other well‐known glioma cell lines by real‐time PCR study. The mRNA of Wnt‐5a and ‐7b and Frizzled‐2, ‐6 and ‐7 were overexpressed in glioma cells. The elevation of Wnt‐5a expression was most remarkable. Although Wnt‐5a is reported to have oncogenic and antioncogenic activity in several cancers, the role of Wnt‐5a signaling in human glioma cells remains unclear. Immunohistochemical study also revealed high expression of Wnt‐5a in 26 (79%) of 33 human glioma cases. The positivity of Wnt‐5a expression was correlated with the clinical grade. Knockdown of Wnt‐5a expression suppressed migration, invasion and expression of matrix metalloproteinase‐2 of glioma cells. Reciprocally, treatment with purified Wnt‐5a ligand resulted in stimulation of cell migration and invasion. MMP‐2 inhibitor suppressed the Wnt‐5a‐dependent invasion of U251 cells. These results suggested that Wnt‐5a is not only a prognostic factor but also a therapeutic target molecule in gliomas for preventing tumor cell infiltration. (Cancer Sci 2011; 102: 540–548)

Mitochondria‐eating protein (Mieap), encoded by a p53‐target gene, plays an important role in mitochondrial quality control (MQC). Mieap has been reported to have a critical role in tumor suppression in colorectal cancer. Here, we investigated its role as a tumor suppressor in breast cancer. The enforced expression of exogenous Mieap in breast cancer cells induced caspase‐dependent apoptosis, with activation of both caspase‐3/7 and caspase‐9. Immunohistochemistry revealed endogenous Mieap in the cytoplasm in 24/75 (32%) invasive ductal carcinomas (IDC), 15/27 (55.6%) cases of ductal carcinoma in situ (DCIS) and 16/18 (88.9%) fibroadenomas (FA) (IDC vs DCIS; P = 0.0389, DCIS vs FA; P = 0.0234, IDC vs FA; P < 0.0001). In IDC, the Mieap promoter was methylated in 6/46 (13%) cases, whereas p53 was mutated in 6/46 (13%) cases. Therefore, the p53/Mieap‐regulated MQC pathway was inactivated in 12/46 IDC (26.1%). Interestingly, all tumors derived from the 12 patients with Mieap promoter methylation or p53 mutations pathologically exhibited more aggressive and malignant breast cancer phenotypes. Impairment of p53/Mieap‐regulated MQC pathway resulted in significantly shorter disease‐free survival (DFS) (P = 0.021), although p53 status is more prognostic in DFS than Mieap promoter methylation. These results indicate that p53/Mieap‐regulated MQC has a critical role in tumor suppression in breast cancer, possibly in part through mitochondrial apoptotic pathway. We demonstrated that enforced Mieap overexpression induced caspase‐dependent apoptosis in breast cancer cells. The expression level of Mieap in invasive ductal carcinoma (IDC) was significantly lower than that in ductal carcinoma in situ (DCIS) and benign tumours in vivo. The p53/Mieap/NIX/BNIP3‐regulated MQC pathway was inactivated in IDC, which resulted in significantly shortened disease‐free survival.

Background To develop and validate a prediction model for severe bronchopulmonary dysplasia (BPD) that integrates the respiratory severity (RS) score with early postnatal risk factors. Methods This retrospective cohort study included preterm infants born at less than 32 weeks gestation or with a birth weight of less than 1500 g, from Aichi Prefecture (training dataset) and Saitama Medical University (validation dataset) from April 1, 2016, to March 31, 2020. The primary outcome was severe BPD, defined as the use of home oxygen therapy or death due to BPD. We used classification and regression tree (CART) analysis to explore the relationship between outcomes and BPD risk factors in the training dataset. Results The incidence of severe BPD was 149 out of 2026 (7.3%) in the training dataset and 35 out of 387 (8.9%) in the validation dataset. CART analysis identified gestational age and the RS score as significant predictors of outcome in the day 7 and day 14 models, with C-statistics of 0.789 and 0.779, respectively. When applied to the validation dataset, these models achieved C-statistics of 0.753 and 0.827, respectively. Conclusion Our prediction models demonstrated the ability to predict severe BPD, with the RS score being a crucial predictor. Impact Many existing prediction models for bronchopulmonary dysplasia (BPD) use multiple predictors, and do not provide specific cutoff values, which complicates their clinical application. To address this issue, we developed a prediction model for severe BPD based on a score derived from mean airway pressure and inhaled oxygen concentration at 1–2 weeks of age. This user-friendly model can be easily integrated into clinical practice, facilitating treatment decisions based on predicted probabilities.

The increasing prevalence of diabetes mellitus (DM) worldwide has underscored the urgency of developing an efficient therapeutic agent. Recently, Zn complexes have been attracting attention due to their antidiabetic activity. In this study, we designed and synthesized a new Zn complex, Zn-3,4-heptanedione-bis(N ⁴-methylthiosemicarbazonato) (Zn-HTSM), characterized its physicochemical properties, and examined its antidiabetic activity in KK-Aʸ type 2 DM model mice. It was demonstrated that Zn-HTSM has adequate lipophilicity for the cellular permeability, shows potent hypoglycemic activity, and improves glucose intolerance in KK-Aʸ mice. We also analyzed the levels of serum adipokines after continuous oral administration of Zn-HTSM. The level of serum leptin of KK-Aʸ mice is significantly reduced by the treatment of Zn-HTSM. Nevertheless, the levels of serum insulin and adiponectin were not improved. These data suggested that the Zn-HTSM acts on the leptin metabolism. Our present studies indicate that Zn-HTSM is a candidate oral antidiabetic agent for the treatment of type 2 DM.

A 0.5%-iron-containing fiducial marker, Gold Anchor  (Naslund Medical AB, Huddinge, Sweden), has been recently developed. Herein, we report our initial experiences with the clinical use of the Gold Anchor (GA) in radiotherapy for liver tumors. Data of four consecutive patients with liver tumors, including two liver metastases and two hepatocellular carcinomas, were retrospectively analyzed. The GA was percutaneously placed under local anesthesia, close to the tumor. Gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid-enhanced magnetic resonance imaging (MRI) was performed after the placement of the GA. Radiotherapy was designed using the volumetric modulated arc therapy technique. All procedures for placement of the GA were successfully performed with no complications. The GA exhibited various forms in the liver in the four patients. All of the GAs were well-detected on MRI, planned computed tomography (CT), and cone-beam CT. Additionally, the tadpole-like shape of the GA showed better detectability than the uptake of lipiodol emulsion and could be used for three-dimensional correlation during setup in daily image-guided radiotherapy. GA was a useful tool in image registration of radiotherapy with a high applicability. Additionally, the tadpole-like shape can be recommended for liver radiotherapy. Our findings suggest that the GA will indeed be useful in clinical practice.