Public assistance and survival equality in patients with EGFR mutation-positive lung cancer.

Background: Disparities in public assistance or the urbanization level of a residential region can affect cancer treatment outcomes. This study aimed to investigate whether these factors affect the overall survival (OS) of patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) using Tokushukai REAL World Data.

Methods: We analyzed the clinical data of consecutive patients with NSCLC receiving EGFR-tyrosine kinase inhibitors between April 2010 and March 2020 at 46 Tokushukai Medical Group hospitals in Japan.

Association of tumour burden with the efficacy of programmed cell death-1/programmed cell death ligand-1 inhibitors for treatment-naïve advanced non-small-cell lung cancer.

Background: Tumour burden (TB) is implicated in resistance to programmed cell death-1/PD-L1 inhibitor (immune checkpoint inhibitor [ICI]) therapy. However, whether TB contributes to such resistance in non-small-cell lung cancer (NSCLC) has remained unknown.

Methods: A total of 260 treatment-naïve patients with advanced NSCLC who started ICI monotherapy (ICI cohort), platinum-doublet therapy (Chemo cohort) or ICI and platinum-doublet therapy (ICI+Chemo cohort) as first-line treatment were consecutively included.

Production of functional eggs and sperm from in vitro-expanded type A spermatogonia in rainbow trout.

Combining cryopreservation of germline stem cells (GSCs) with their subsequent transplantation into recipient fish is a powerful tool for long-term preservation of genetic resources of endangered fishes. However, application of this technique has been limited because endangered species sometimes have small gonads and do not supply enough GSCs to be used for transplantation. This limitation could be overcome by expanding GSCs in vitro, though this has been difficult due to the complexity of reconstructing the gonadal microenvironment that surrounds GSCs.

Porous diaphragm syndrome with recurrent thymoma.

Porous diaphragm syndrome describes a defect in the diaphragm in which substances pass from the peritoneal cavity to the pleural space. Defects may be congenital or acquired. Acquired defects are caused by the thinning and eventual splitting of collagen fibres in the tendinous part of the diaphragm.

B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity.

Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non-small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting.

Phase I trial of 5-FU, docetaxel, and nedaplatin (UDON) combination therapy for recurrent or metastatic esophageal cancer.

Purpose: The aims of this dose-escalating phase I study were to determine the maximum tolerable dose (MTD) and recommended dose (RD) of 5-fluorouracil (5-FU), docetaxel, and nedaplatin (UDON) combination therapy for future phase II studies, and to evaluate the safety and efficacy of this regimen in patients with untreated recurrent or metastatic esophageal cancer.

Methods: Patients were administered 5-FU on days 1-5, docetaxel on days 1 and 15, and nedaplatin on day 1 at 4-week intervals. The dose levels of 5-FU/docetaxel/nedaplatin were escalated as follows (mg/m(2)): level 1, 800/30/80; level 2, 800/30/90; and level 3, 800/35/90.

Tyrosine phosphoproteomics identifies both codrivers and cotargeting strategies for T790M-related EGFR-TKI resistance in non-small cell lung cancer.

Purpose: Irreversible EGFR-tyrosine kinase inhibitors (TKI) are thought to be one strategy to overcome EGFR-TKI resistance induced by T790M gatekeeper mutations in non-small cell lung cancer (NSCLC), yet they display limited clinical efficacy. We hypothesized that additional resistance mechanisms that cooperate with T790M could be identified by profiling tyrosine phosphorylation in NSCLC cells with acquired resistance to reversible EGFR-TKI and harboring T790M.

Experimental Design: We profiled PC9 cells with TKI-sensitive EGFR mutation and paired EGFR-TKI-resistant PC9GR (gefitinib-resistant) cells with T790M using immunoaffinity purification of tyrosine-phosphorylated peptides and mass spectrometry-based identification/quantification.

A phase 1 study of linifanib in combination with carboplatin/paclitaxel as first-line treatment of Japanese patients with advanced or metastatic non-small cell lung cancer (NSCLC).

Introduction: Linifanib is a potent, orally active, and selective inhibitor of vascular endothelial growth factor and platelet-derived growth factor receptor kinase activities with clinical efficacy in non-small cell lung cancer (NSCLC). This phase 1 dose-escalation study evaluated the pharmacokinetics, safety, and efficacy of linifanib in combination with carboplatin/paclitaxel in Japanese patients with advanced NSCLC.

Methods: Carboplatin (AUC = 6 mg/mL/min) and paclitaxel (200 mg/m²) were administered on day 1 of each 21-day cycle up to a maximum of six cycles.

Cetuximab response of lung cancer-derived EGF receptor mutants is associated with asymmetric dimerization.

Kinase domain mutations of the EGF receptor (EGFR) are common oncogenic events in lung adenocarcinoma. Here, we explore the dependency upon asymmetric dimerization of the kinase domain for activation of lung cancer-derived EGFR mutants. We show that whereas wild-type EGFR and the L858R mutant require dimerization for activation and oncogenic transformation, the exon 19 deletion, exon 20 insertion, and L858R/T790M EGFR mutants do not require dimerization.

Phase I trial of OTS11101, an anti-angiogenic vaccine targeting vascular endothelial growth factor receptor 1 in solid tumor.

OTS11101 is a novel peptide vaccine that acts as an angiogenesis inhibitor by inducing cytotoxic T lymphocyte (CTL) cells that specifically target vascular endothelial cells expressing vascular endothelial growth factor (VEGF) receptor 1. We conducted a phase I study to evaluate the safety, tolerability, maximum tolerated dose, and pharmacodynamic biomarker status of this vaccine. Nine patients with advanced solid tumors received 1.

Activation of HER family signaling as a mechanism of acquired resistance to ALK inhibitors in EML4-ALK-positive non-small cell lung cancer.

Purpose: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown.

Experimental Design: We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay.

Effect of Peucedanum japonicum Thunb extract on high-fat diet-induced obesity and gene expression in mice.

Supplementation of the diet with Peucedanum japonicum Thunb (PJT) powder inhibits high-fat diet-induced obesity in mice. Either the fiber component or other bioactive components in the PJT powder may inhibit obesity. This study, therefore, was an attempt to identify the components, fiber or other phytochemicals of PJT that were responsible for the anti-obesity activity, and also studied the modulation of obesity-related gene expression in C57BL/6 mice.

Effect of Peucedanum japonicum Thunb on the expression of obesity-related genes in mice on a high-fat diet.

The present study describes the effect of Peucedanum japonicum Thunb (PJT) intake on the expression of obesity-related genes in mice fed a high-fat diet. To explore the mechanism underlying the effect of PJT, This study focused on the expression of genes, especially those related to obesity and metabolism syndrome, in the liver and adipose tissues. In agreement with our previous observations, intake of 10 % PJT for 4 weeks significantly reduced serum triglyceride (TG), leptin, abdominal fat, and adipocyte size.

Activation of ERBB2 signaling causes resistance to the EGFR-directed therapeutic antibody cetuximab.

Cetuximab, an antibody directed against the epidermal growth factor receptor, is an effective clinical therapy for patients with colorectal, head and neck, and non-small cell lung cancer, particularly for those with KRAS and BRAF wild-type cancers. Treatment in all patients is limited eventually by the development of acquired resistance, but little is known about the underlying mechanism. Here, we show that activation of ERBB2 signaling in cell lines, either through ERBB2 amplification or through heregulin up-regulation, leads to persistent extracellular signal-regulated kinase 1/2 signaling and consequently to cetuximab resistance.

Peucedanum japonicum Thunb inhibits high-fat diet induced obesity in mice.

This study examined the antiobese activity of Peucedanum japonicum Thunb (PJT) in mice. In the first experiment, 4-week-old C57BL/6 mice were fed seven different diets containing 15% corn oil and 0-20% PJT powder for 4 weeks. Feeding the 10% and 20% PJT diet suppressed the body weight gain and the accumulation of abdominal and subcutaneous fats.

Comparative study of the effect of basal diet formulation, dietary fat and cholesterol levels on the development of aortic atherosclerotic lesions in B6.KOR-Apoeshl mice.

To optimize the adequate atherogenic diet composition for nutritional atherosclerosis studies utilizing B6.KOR-Apoe(shl) mice, we investigated the effect of dietary cholesterol, AIN formula, and dietary fats on the development of atherosclerosis. Cholesterol supplementation (0.

Down-regulation of lipids transporter ABCA1 increases the cytotoxicity of nitidine.

Purpose: Nitidine (NTD) cytotoxicity is highly specific for A549 human lung adenocarcinoma cells. We hypothesized that this cytotoxicity involved the accumulation of NTD in intracellular organelles. However, there have been no reports of NTD transporting factors.

Tumor-selective cytotoxicity of benzo[c]phenanthridine derivatives from Toddalia asiatica Lam.

Purpose: To develop a novel anti-cancer drug of low side effect against lung adenocarcinoma, the authors screened the bioresources of Okinawa Island, Japan. The medicinal plant Toddalia asiatica Lam. contained three benzo[c]phenanthridine derivatives: dihydronitidine (DHN), nitidine (NTD) and demethylnitidine (DMN).

Addition of S-1 to the epidermal growth factor receptor inhibitor gefitinib overcomes gefitinib resistance in non-small cell lung cancer cell lines with MET amplification.

Purpose: Most non-small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib, but they almost invariably develop resistance to these drugs. A secondary mutation in EGFR (T790M) and amplification of the MET proto-oncogene have been identified as mechanisms of such acquired resistance to EGFR-TKIs. We have now investigated whether addition of the oral fluoropyrimidine derivative S-1 to gefitinib might overcome gefitinib resistance in NSCLC cell lines.

Tumor specific cytotoxicity of beta-glucosylceramide: structure-cytotoxicity relationship and anti-tumor activity in vivo.

This study describes the structure-cytotoxicity relationship of beta-glucosylceramide (beta-GluCer) and its antitumor activity in vivo. Unglycosylated ceramide had no selective cytotoxicity which demonstrated that the sugar moiety plays a critical role for the expression of selective cytotoxicity by beta-GluCer. beta-Galactosylceramide also showed tumor specific cytotoxicity suggesting that the chemical structure of sugar group is not a factor for the selective toxicity.

Antiatherosclerotic function of Kokuto, Okinawan noncentrifugal cane sugar.

In the present study, we investigated the effect of phenolic compounds (PCs) and policosanol of Kokuto, Okinawan noncentrifugal cane sugar, on the development of atherosclerosis. A total of 67 male Japanese quail were divided into eight dietary groups in trial 1. The dietary groups were fed the atherosclerotic diet (AD) containing 5% corn oil, 2% cholesterol, and 30% sucrose or seven different types of Kokuto.

Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase.

Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the therapeutic response to EGFR tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC). The response rate to these drugs remains low, however, in NSCLC patients with wild-type EGFR alleles. Combination therapies with EGFR-TKIs and cytotoxic agents are considered a therapeutic option for patients with NSCLC expressing wild-type EGFR.

Matuzumab and cetuximab activate the epidermal growth factor receptor but fail to trigger downstream signaling by Akt or Erk.

Molecular inhibition of the epidermal growth factor receptor (EGFR) is a promising anticancer strategy, and monoclonal antibodies (mAbs) to EGFR are undergoing extensive evaluation in preclinical and clinical trials. However, the effects of anti-EGFR mAbs on EGFR signaling have remained unclear. We have now examined the effects of 2 anti-EGFR mAbs, matuzumab (EMD72000) and cetuximab (Erbitux), both of which are currently under assessment for treatment of various cancers, on EGFR signal transduction and cell survival in nonsmall cell lung cancer cell lines.

Differential constitutive activation of the epidermal growth factor receptor in non-small cell lung cancer cells bearing EGFR gene mutation and amplification.

The identification of somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in patients with non-small cell lung cancer (NSCLC) and the association of such mutations with the clinical response to EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, have had a substantial effect on the treatment of this disease. EGFR gene amplification has also been associated with an increased therapeutic response to EGFR-TKIs. The effects of these two types of EGFR alteration on EGFR function have remained unclear, however.