Enhanced ALOX12 Gene Expression Predicts Therapeutic Susceptibility to 5-Azacytidine in Patients with Myelodysplastic Syndromes.

5-azacytidine (AZA), a representative DNA-demethylating drug, has been widely used to treat myelodysplastic syndromes (MDS). However, it remains unclear whether AZA's DNA demethylation of any specific gene is correlated with clinical responses to AZA. In this study, we investigated genes that could contribute to the development of evidence-based epigenetic therapeutics with AZA.

AXL/CDCP1/SRC axis confers acquired resistance to osimertinib in lung cancer.

Osimertinib, a third-generation EGFR-TKI, has nowadays been applied to non-small cell lung cancer harboring activated EGFR mutation with or without T790M, but ultimately develop resistance to this drug. Here we report a novel mechanism of acquired resistance to osimertinib and the reversal of which could improve the clinical outcomes. In osimertinib-resistant lung cancer cell lines harboring T790M mutation that we established, expression of multiple EGFR family proteins and MET was markedly reduced, whereas expression of AXL, CDCP1 and SRC was augmented along with activation of AKT.

Reduction of leakage from insertion site during continuous femoral nerve block with catheter-through-needle versus catheter-over-needle technique for postoperative analgesia after total knee arthroplasty: a randomized controlled trial.

Background: Continuous femoral nerve block (CFNB) is a common procedure used for postoperative analgesia in total knee arthroplasty. Continuous nerve block using a conventional needle (catheter-through-needle/CTN) is complicated by leakage of the anesthetic from the catheter insertion site. A different type of needle (catheter-over-needle/ CON) is now available, which is believed to reduce leakage as the diameter of the catheter is larger than that of the needle.

NDRG1 activates VEGF-A-induced angiogenesis through PLCγ1/ERK signaling in mouse vascular endothelial cells.

Many diseases, including cancer, have been associated with impaired regulation of angiogenesis, of which vascular endothelial growth factor (VEGF)-A is a key regulator. Here, we test the contribution of N-myc downstream regulated gene 1 (NDRG1) to VEGF-A-induced angiogenesis in vascular endothelial cells (ECs). Ndrg1 mice exhibit impaired VEGF-A-induced angiogenesis in corneas.

Targeting Phosphorylation of Y-Box-Binding Protein YBX1 by TAS0612 and Everolimus in Overcoming Antiestrogen Resistance.

Nuclear expression of Y-box-binding protein (YBX1) is closely correlated with clinical poor outcomes and drug resistance in breast cancer. Nuclear translocation of YBX1 is facilitated by YBX1 phosphorylation at serine 102 by AKT, p70S6K, and p90RSK, and the phosphorylated YBX1 (pYBX1) promotes expression of genes related to drug resistance and cell growth. A forthcoming problem to be addressed is whether targeting the phosphorylation of YBX1 overcomes antiestrogen resistance by progressive breast cancer.

Bidirectional Regulation between NDRG1 and GSK3β Controls Tumor Growth and Is Targeted by Differentiation Inducing Factor-1 in Glioblastoma.

The development of potent and selective therapeutic approaches to glioblastoma (GBM), one of the most aggressive primary brain tumors, requires identification of molecular pathways that critically regulate the survival and proliferation of GBM. Previous studies have reported that deregulated expression of N-myc downstream regulated gene 1 (NDRG1) affects tumor growth and clinical outcomes of patients with various types of cancer including glioma. Here, we show that high level expression of NDRG1 in tumors significantly correlated with better prognosis of patients with GBM.

The augmented expression of the cytidine deaminase gene by 5-azacytidine predicts therapeutic efficacy in myelodysplastic syndromes.

5-Azacytidine (5AC), a hypomethylating agent, is clinically used for the treatment of patients with myelodysplastic syndromes (MDS). Cytidine deaminase (CDA) is a key enzyme in the detoxification of 5AC. We investigated whether the CDA expression could predict response to 5AC in MDS.

Y-box binding protein YBX1 and its correlated genes as biomarkers for poor outcomes in patients with breast cancer.

The enhanced expression of the Y-box binding protein YBX1 is consistently correlated with poor outcomes or reduced survival of breast cancer patients. However, the mechanism underlying the association between increased YBX1 expression and poor outcomes has yet to be revealed. We searched a database for the top 500 genes that are positively or negatively correlated with YBX1 and with ESR1 in breast cancer patients.

Copy number gain in recurrent anaplastic lymphoma kinase (ALK) rearrangement-lung adenocarcinoma in the pleural effusion.

Copy number gain (CNG), which includes both numerical and structural chromosomal abnormalities, has been investigated in many human cancers. We report a case of recurrence of anaplastic lymphoma kinase (ALK) rearrangement-positive lung adenocarcinoma with increased cellular pleomorphism and ALK copy number in pleural effusion cytology, and retrospectively compared the recurrent tumor with the primary tumor in terms of cytological features, immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The patient was a woman in her 50s who was found to have a 20 × 20 mm sized mass in the lung by chest computed tomography (CT), and was diagnosed with ALK rearrangement-positive lung adenocarcinoma.

Breast Cancer Resistance to Antiestrogens Is Enhanced by Increased ER Degradation and ERBB2 Expression.

Endocrine therapies effectively improve the outcomes of patients with estrogen receptor (ER)-positive breast cancer. However, the emergence of drug-resistant tumors creates a core clinical challenge. In breast cancer cells rendered resistant to the antiestrogen fulvestrant, we defined causative mechanistic roles for the transcription factor YBX1 and the levels of ER and the ERBB2 receptor.

Phosphorylation of mTOR Ser2481 is a key target limiting the efficacy of rapalogs for treating hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Although recent studies facilitate the identification of crucial genes and relevant regulatory pathways, therapeutic approaches against advanced HCC are insufficiently effective. Therefore, we aimed here to develop potent therapeutics to provide a reliable biomarker for the therapeutic efficacy in patients with HCC.

Overcoming drug resistance to receptor tyrosine kinase inhibitors: Learning from lung cancer.

There are various receptor tyrosine kinase (TK)-targeted drugs that are currently used in the treatment of patients with non-small cell lung cancer (NSCLC). Among them, the epidermal growth factor receptor (EGFR) TK inhibitors (TKIs) are the most extensively studied. Receptor TKIs including EGFR TKIs have shown dramatic therapeutic efficacies in malignant tumors, which harbor activating mutations in the EGFR gene.

[Pulmonary Nocardiosis due to Nocardia asiatica in a Patient with ANCA-associated Vasculitis].

Nocardia asiatica is a rare causative organism responsible for opportunistic infection, and was first reported by Kageyama et al. in 2004. We report herein on a very rare case of N.

[Severe fever with thrombocytopenia syndrome mimicking intravascular lymphoma].

A 63-year-old woman was admitted to our hospital, because of a high fever and general malaise which had persisted for several days. Laboratory findings showed leucopenia, thrombocytopenia, and abnormal liver functions. A bone marrow smear revealed hemophagocytosis.

CpG hypermethylation contributes to decreased expression of PTEN during acquired resistance to gefitinib in human lung cancer cell lines.

Objectives: We have previously reported that decreased expression of PTEN in lung cancer PC9 cells harboring an EGFR-activating mutation (del E746-A750) results in acquisition of resistance to EGFR-TKIs, gefitinib and erlotinib, accompanied by enhanced phosphorylation of Akt and decreased nuclear translocation of a transcription factor EGR-1 [8]. In the present study, PTEN promoter methylation accounted for the decreased expression of PTEN in our gefitinib-resistant mutant.

Material And Methods: DNA methylation status of the PTEN promoter in PC9 and gefitinib-resistant cells were examined using methylation-specific PCR.

Tumor-derived interleukin-1 promotes lymphangiogenesis and lymph node metastasis through M2-type macrophages.

Tumors formed by a highly metastatic human lung cancer cell line are characterized by activated signaling via vascular endothelial growth factor (VEGF)-C through its receptor (VEGFR-3) and aggressive lymph node metastasis. In this study, we examined how these highly metastatic cancers acquired aggressive lymph node metastasis. Compared with their lower metastatic counterparts, the highly metastatic tumors formed by this cell line expressed higher amounts of interleukin (IL)-1α, with similarly augmented expression of IL-1α and IL-1β by tumor stromal cells and of VEGF-A and VEGF-C by tumor-associated macrophages.

Fixation effect of SurePath preservative fluids using epidermal growth factor receptor mutation-specific antibodies for immunocytochemistry.

Background: Cytological diagnosis of respiratory disease has become important, not only for histological typing using immunocytochemistry (ICC) but also for molecular DNA analysis of cytological material. The aim of this study was to investigate the fixation effect of SurePath preservative fluids.

Methods: Human lung cancer PC9 and 11-18 cell lines, and lung adenocarcinoma cells in pleural effusion, were fixed in CytoRich Blue, CytoRich Red, 15% neutral-buffered formalin, and 95% ethanol, respectively.

Erlotinib resistance in lung cancer cells mediated by integrin β1/Src/Akt-driven bypass signaling.

EGF receptor (EGFR) kinase inhibitors, including gefitinib and erlotinib, exert potent therapeutic efficacy in non-small cell lung cancers harboring EGFR-activating mutations. However, most patients ultimately develop resistance to these drugs. Here, we report a novel mechanism of acquired resistance to EGFR tyrosine kinase inhibitors and the reversal of which could improve clinical outcomes.

N-myc downstream-regulated gene 1 promotes tumor inflammatory angiogenesis through JNK activation and autocrine loop of interleukin-1α by human gastric cancer cells.

The expression of N-myc downstream-regulated gene 1 (NDRG1) was significantly correlated with tumor angiogenesis and malignant progression together with poor prognosis in gastric cancer. However, the underlying mechanism for the role of NDRG1 in the malignant progression of gastric cancer remains unknown. Here we examined whether and how NDRG1 could modulate tumor angiogenesis by human gastric cancer cells.

Y-box binding protein-1 contributes to both HER2/ErbB2 expression and lapatinib sensitivity in human gastric cancer cells.

Gene amplification of HER2/ErbB2 occurs in gastric cancer and the therapeutic efficacy of the HER2-targeted antibody, trastuzumab, has recently been improved against HER2-positive advanced stomach cancer. Here, we examined whether Y-box-binding protein-1 (YB-1) could selectively control HER2 gene expression and cellular sensitivity to EGF receptor (EGFR) family protein-targeted drugs in human gastric cancer cells. HER2 expression was specifically downregulated by YB-1 silencing using its cognate siRNA, whereas there was less change in the expression of EGFR and HER3.