Phase I/II Study of Erlotinib to Determine the Optimal Dose in Patients With Non-Small Cell Lung Cancer Harboring Only EGFR Mutations.

The recommended daily dose of erlotinib was determined for patients with all types of non-small cell lung cancer (NSCLC). We determined the optimal dose (OD) in patients with NSCLC harboring only epidermal growth factor receptor (EGFR) sensitizing mutations. EGFR-tyrosine kinase inhibitor-naïve patients with sensitizing mutations were eligible.

Minocycline prevents and repairs the skin disorder associated with afatinib, one of the epidermal growth factor receptor-tyrosine kinase inhibitors for non-small cell lung cancer.

Background: While epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) exert a breakthrough effect, the incidence of skin disorders as a side effect has significantly reduced patients' quality of life. This study aimed to develop a treatment for inflammatory ulcers as one of the side effects of afatinib (Giotrif®), a second-generation EGFR-TKI, and established a skin disorder mouse model to investigate the protective effect of minocycline.

Methods: First, under inhalation anesthesia with isoflurane, the back of a male ddy mouse was shaved, and afatinib petrolatum was applied alone or in combination with minocycline to observe the state of the skin and measure transepidermal water transpiration (TEWL).

Impact of Q141K on the Transport of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors by ABCG2.

The ATP-binding cassette transporter ABCG2 is expressed in various organs, such as the small intestine, liver, and kidney, and influences the pharmacokinetics of drugs that are its substrates. ABCG2 is also expressed by cancer cells and mediates resistance to anticancer agents by promoting the efflux of these drugs. In the present study, we investigated the interactions between epidermal growth factor receptor tyrosine kinase inhibitors and ABCG2 by MTT assay, intracellular drug accumulation assay, and FACS.

Effect of Radiological Countermeasures on Subjective Well-Being and Radiation Anxiety after the 2011 Disaster: The Fukushima Health Management Survey.

After the Fukushima Daiichi Nuclear Power Station accident in 2011, concerns about radiation exposure and decline in subjective well-being have been reported. To tackle these problems, various countermeasures in relation to radiation have been implemented. In this study, we comprehensively evaluated the effects of radiological countermeasures on subjective well-being (e.

Investigation of Bioequivalence Between Brand-name and Generic Irinotecan Products.

Background/aim: To investigate bioequivalence among generic and brand-name irinotecan products.

Materials And Methods: Products of Yakult and Daiichi-Sankyo (brand-name products), Sandoz, Nippon Kayaku, Taiho, and Sawai were compared with respect to their composition and antitumor activity.

Results: High-performance liquid chromatography demonstrated that related substances were within the acceptable range.

Pharmacokinetic parameters of gefitinib predict efficacy and toxicity in patients with advanced non-small cell lung cancer harboring EGFR mutations.

Purpose: The relationship between plasma concentration and antitumor activity of gefitinib was assessed in patients with advanced non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations.

Patients And Methods: Plasma trough levels of gefitinib were measured on days 2 (D2) and 8 (D8) by high-performance liquid chromatography in 31 patients. Plasma concentrations of gefitinib were also measured 10 h after the first administration in 21 of these patients to calculate the elimination half-life of gefitinib.

Gefitinib enhances the antitumor activity of CPT-11 in vitro and in vivo by inhibiting ABCG2 but not ABCB1: a new clue to circumvent gastrointestinal toxicity risk.

Background: Despite the potent antitumor activity of CPT-11, late-onset diarrhea owing to enterohepatic circulation of SN-38 is a critical issue.

Methods: We aimed to evaluate the inhibitory potency of gefitinib against the ABCB1- or ABCG2-mediated excretion of CPT-11 and its active metabolite SN-38 in vitro and in vivo.

Results: Gefitinib dose-dependently enhanced the antiproliferation activity of SN-38 in vitro by inhibiting ABCG2.

[Drunkenness caused by isoniazid in a tuberculosis patient with extrapulmonary lesions on hemodialysis: a case report].

The patient was a 55-year-old man who had been on hemodialysis for 6 years for diabetic nephropathy. He was clinically diagnosed with pulmonary tuberculosis with extrapulmonary lesion after 3 years of chronic fever. His fever subsided immediately after the beginning of antituberculosis drug therapy and the antituberculosis drugs were discontinued 3 days after the initiation of the therapy.

Phase II trial of erlotinib in patients with advanced non‑small‑cell lung cancer harboring epidermal growth factor receptor mutations: additive analysis of pharmacokinetics.

Background: We conducted a phase II trial of erlotinib in patients with advanced non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations and evaluated the relationship between plasma concentration and efficacy of erlotinib.

Methods: Patients who were previously treated but naive to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs), with advanced NSCLC harboring EGFR mutations, were enrolled. Erlotinib was given at 150 mg once daily until disease progression.

Evolutionary relations of Hexanchiformes deep-sea sharks elucidated by whole mitochondrial genome sequences.

Hexanchiformes is regarded as a monophyletic taxon, but the morphological and genetic relationships between the five extant species within the order are still uncertain. In this study, we determined the whole mitochondrial DNA (mtDNA) sequences of seven sharks including representatives of the five Hexanchiformes, one squaliform, and one carcharhiniform and inferred the phylogenetic relationships among those species and 12 other Chondrichthyes (cartilaginous fishes) species for which the complete mitogenome is available. The monophyly of Hexanchiformes and its close relation with all other Squaliformes sharks were strongly supported by likelihood and Bayesian phylogenetic analysis of 13,749 aligned nucleotides of 13 protein coding genes and two rRNA genes that were derived from the whole mDNA sequences of the 19 species.

Pharmacokinetics of rifabutin in Japanese HIV-infected patients with or without antiretroviral therapy.

Objective: Based on drug-drug interaction, dose reduction of rifabutin is recommended when co-administered with HIV protease inhibitors for human immunodeficiency virus (HIV)-associated mycobacterial infection. The aim of this study was to compare the pharmacokinetics of rifabutin administered at 300 mg/day alone to that at 150 mg every other day combined with lopinavir-ritonavir in Japanese patients with HIV/mycobacterium co-infection.

Methods: Plasma concentrations of rifabutin and its biologically active metabolite, 25-O-desacetyl rifabutin were measured in 16 cases with HIV-mycobacterial coinfection.

The pharmacokinetics and long-term therapeutic effects of gefitinib in patients with lung adenocarcinoma harboring the epidermal growth factor receptor(EGFR)mutation.

Introduction: The relationship between the pharmacokinetics and long-term antitumor activity of gefitinib in patients with epidermal growth factor receptor(EGFR)mutation-positive lung adenocarcinoma has not yet been clarified in clinical practice. The present study assessed the correlation between the pharmacokinetics and long-term therapeutic effects of gefitinib in patients with lung adenocarcinoma harboring the EGFR-activating mutation.

Methods: Fifteen patients with lung adenocarcinoma harboring the EGFR mutation were administered 250 mg of gefitinib daily.

OryzaExpress: an integrated database of gene expression networks and omics annotations in rice.

Similarity of gene expression profiles provides important clues for understanding the biological functions of genes, biological processes and metabolic pathways related to genes. A gene expression network (GEN) is an ideal choice to grasp such expression profile similarities among genes simultaneously. For GEN construction, the Pearson correlation coefficient (PCC) has been widely used as an index to evaluate the similarities of expression profiles for gene pairs.

Mesenchymal mode of migration participates in pulmonary metastasis of mouse osteosarcoma LM8.

The outcomes of osteosarcoma patients still remain poor because of intractable pulmonary metastasis. We previously established a highly metastatic osteosarcoma cell line, LM8 from Dunn mouse osteosarcoma by in vivo selection. We herein aimed to clarify the characteristic biological features related with high metastatic potential and new target molecules to suppress pulmonary metastasis of osteosarcoma, using this syngeneic spontaneous metastatic model.

Pharmacokinetics of gefitinib predicts antitumor activity for advanced non-small cell lung cancer.

Introduction: We assessed the relationship between the plasma concentration of gefitinib and its efficacy in Japanese patients with advanced non-small cell lung cancer (NSCLC).

Methods: Plasma trough levels of gefitinib were measured on days 3 (D3) and 8 (D8) by high-performance liquid chromatography in 44 patients with advanced NSCLC treated with 250 mg gefitinib daily. Eligibility criteria included performance status < or =3, age < or = 80 years, and stages IIIB-IV cancer.

[A case of lung adenocarcinoma successfully treated with dose-reescalated gefitinib after resistance was acquired].

Gefitinib is a selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, and it shows favorable antitumor activity against chemorefractory non-small cell lung cancer (NSCLC), especially with EGFR gene mutations. On the other hand, patients with NSCLC have few treatment options available if they acquire resistance to gefitinib or severe adverse events occur. We report a 73-year-old small woman diagnosed with NSCLC who was treated with gefitinib (250 mg/day) every other day or by 7-days-on followed by 7-days-off therapy dose schedule after severe paronychia appeared.

Phosphorylation in the C-terminal domain of Aquaporin-4 is required for Golgi transition in primary cultured astrocytes.

Aquaporin-4 (AQP4) is expressed in the perivascular and subpial astrocytes end-feet in mammalian brain, and plays a critical component of an integrated water and potassium homeostasis. Here we examine whether AQP4 is phosphorylated in primary cultured mouse astrocytes. Astrocytes were metabolically labeled with [(32)P]phosphoric acid, then AQP4 was immunoprecipitated with anti-AQP4 antibody.

Gefitinib increases serum concentrations of oral irinotecan and SN-38 without increasing the biliary concentration of SN-38 in rats.

Background: Gefitinib competes with topoisomerase I inhibitors at drug efflux pumps in vitro. We evaluated the effects of oral gefitinib on pharmacokinetic parameters of orally coadministered irinotecan.

Methods: We measured the serum pharmacokinetic parameters and biliary excretion of irinotecan, SN-38 and its glucuronide after irinotecan (50 or 100 mg/kg) was orally administered with or without gefitinib 100 mg/kg to rats.

Rapid evolution of major histocompatibility complex class I genes in primates generates new disease alleles in humans via hitchhiking diversity.

A plausible explanation for many MHC-linked diseases is lacking. Sequencing of the MHC class I region (coding units or full contigs) in several human and nonhuman primate haplotypes allowed an analysis of single nucleotide variations (SNV) across this entire segment. This diversity was not evenly distributed.

Transport mechanism-based drug molecular design: novel camptothecin analogues to circumvent ABCG2-associated drug resistance of human tumor cells.

Acquired and intrinsic drug resistance in cancer is the major obstacle to long-term, sustained patient response to chemotherapy. Irinotecan (CPT-11) is a widely-used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I). However, overexpression of ABCG2 (BCRP/MXR/ABCP) reportedly confers cancer cells resistance to SN-38, the active form of CPT-11.

Genomic evolution of MHC class I region in primates.

To elucidate the origins of the MHC-B-MHC-C pair and the MHC class I chain-related molecule (MIC)A-MICB pair, we sequenced an MHC class I genomic region of humans, chimpanzees, and rhesus monkeys and analyzed the regions from an evolutionary stand-point, focusing first on LINE sequences that are paralogous within each of the first two species and orthologous between them. Because all the long interspersed nuclear element (LINE) sequences were fragmented and nonfunctional, they were suitable for conducting phylogenetic study and, in particular, for estimating evolutionary time. Our study has revealed that MHC-B and MHC-C duplicated 22.

Beta-adrenergic blocking agents and intermittent claudication: systematic review.

To clarify contradictions in past reports and the package inserts for beta-adrenergic blocking agents (beta-blockers) for patients with intermittent claudication (IC), we investigated the effects of beta-blockers in patients with IC using the systematic review technique. Data sources were randomized, controlled trials that investigated the effects of beta-blockers compared with the placebo or untreated group (controls) in patients with IC. Primary endpoints were walking distance and walking time, and secondary endpoints were ankle-brachial index (ABI) and calf blood flow.

Transport of SN-38 by the wild type of human ABC transporter ABCG2 and its inhibition by quercetin, a natural flavonoid.

Irinotecan (CPT-11) is a widely-used potent anticancer drug that inhibits mammalian DNA topoisomerase I, however overexpression of the ATP-binding cassette transporter ABCG2 can confer cancer cells resistance to SN-38, the active form of CPT-11. In the present study, we have examined the contribution of three variant forms of ABCG2 to SN-38 resistance. Exogenous expression of the Arg482 (wild type), Gly482, and Thr482 variants of ABCG2 conferred HEK293 cells resistance to SN-38 by 15.

Novel camptothecin analogues that circumvent ABCG2-associated drug resistance in human tumor cells.

Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxycamptothecin; CPT-11) is a widely used potent antitumor drug that inhibits mammalian DNA topoisomerase I (Topo I); however, overexpression of ABCG2 (BCRP/MXR/ABCP) can confer cancer cell resistance to SN-38, the active form of CPT-11. We have recently demonstrated that plasma membrane vesicles prepared from ABCG2-overexpressing PC-6/SN2-5H cells transported SN-38 and its glucuronide conjugate in an ATP-dependent manner (Nakatomi et al., Biochem Biophys Res Commun 2001;288:827-32).