Cardiovascular applications of therapeutic ultrasound.

Ultrasound (US) has gained widespread use in diagnostic cardiovascular applications. At amplitudes and frequencies typical of diagnostic use, its biomechanical effects on tissue are largely negligible. However, these parameters can be altered to harness US's thermal and non-thermal effects for therapeutic indications.

PHENOTYPIC VARIABILITY IN INDIVIDUALS WITH TYPE V OSTEOGENESIS IMPERFECTA WITH IDENTICAL IFITM5 MUTATIONS.

Background: Osteogenesis imperfecta (OI) type V is a dominantly inherited skeletal dysplasia characterized by fractures and progressive deformity of long bones. In addition, patients often present with radial head dislocation, hyperplastic callus, and calcification of the forearm interosseous membrane. Recently, a specific mutation in the gene was found to be responsible for OI type V.

Acetylation of p53 stimulates miRNA processing and determines cell survival following genotoxic stress.

It is widely accepted that different forms of stress activate a common target, p53, yet different outcomes are triggered in a stress-specific manner. For example, activation of p53 by genotoxic agents, such as camptothecin (CPT), triggers apoptosis, while non-genotoxic activation of p53 by Nutlin-3 (Nut3) leads to cell-cycle arrest without significant apoptosis. Such stimulus-specific responses are attributed to differential transcriptional activation of various promoters by p53.

mTOR inhibition specifically sensitizes colorectal cancers with KRAS or BRAF mutations to BCL-2/BCL-XL inhibition by suppressing MCL-1.

Colorectal cancers harboring KRAS or BRAF mutations are refractory to current targeted therapies. Using data from a high-throughput drug screen, we have developed a novel therapeutic strategy that targets the apoptotic machinery using the BCL-2 family inhibitor ABT-263 (navitoclax) in combination with a TORC1/2 inhibitor, AZD8055. This combination leads to efficient apoptosis specifically in KRAS- and BRAF-mutant but not wild-type (WT) colorectal cancer cells.

A phase II study of pemetrexed in patients with previously heavily treated non-squamous non-small cell lung cancer (HANSHIN Oncology Group 001).

Purpose: Pemetrexed has shown substantial activity in non-squamous non-small cell lung cancer (NSCLC) and is one of the current standard agents in second-line settings due to its efficacy and favorable tolerability profile. We conducted phase II study to evaluate the safety and efficacy of pemetrexed in Japanese patients with previously heavily treated, advanced non-squamous NSCLC.

Methods: Patients with stage IIIB or IV non-squamous NSCLC, performance status (PS) 0-2, previous two to five regimens of chemotherapy were enrolled and received pemetrexed (500 mg/m(2)) on day 1 every 21 days until disease progression.

Sex and age differences in the effect of obesity on incidence of hypertension in the Japanese population: A large historical cohort study.

Elevated risk of death from any cause and stroke associated with high body mass index (BMI) values decline with aging. However, it is not clear whether the effect of obesity on the incidence of hypertension varies by sex or age. Cox regression analyses were performed using a large historical cohort composed of 6803 men and 22,800 women.

Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations.

Background: The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation.

Contrasting quiescent G0 phase with mitotic cell cycling in the mouse immune system.

A transgenic mouse line expressing Fucci (fluorescent ubiquitination-based cell-cycle indicator) probes allows us to monitor the cell cycle in the hematopoietic system. Two populations with high and low intensities of Fucci signals for Cdt1(30/120) accumulation were identified by FACS analysis, and these correspond to quiescent G0 and cycling G1 cells, respectively. We observed the transition of immune cells between quiescent and proliferative phases in lymphoid organs during differentiation and immune responses.

Effects of rainfall events on the occurrence and detection efficiency of viruses in river water impacted by combined sewer overflows.

Rainfall events can introduce large amount of microbial contaminants including human enteric viruses into surface water by intermittent discharges from combined sewer overflows (CSOs). The present study aimed to investigate the effect of rainfall events on viral loads in surface waters impacted by CSO and the reliability of molecular methods for detection of enteric viruses. The reliability of virus detection in the samples was assessed by using process controls for virus concentration, nucleic acid extraction and reverse transcription (RT)-quantitative PCR (qPCR) steps, which allowed accurate estimation of virus detection efficiencies.

Role of microRNAs in lung development and pulmonary diseases.

MicroRNAs (miRNAs) are a class of small noncoding RNA which exert post-transcriptional gene regulation activity by targeting messenger RNAs. miRNAs have been found to be involved in various fundamental biological processes and deregulation of miRNAs is known to result in pathological conditions. In this review, we provide an overview of recent discoveries on the role played by this class of molecules in lung development and in pulmonary diseases, such as asthma, cystic fibrosis, chronic obstructive pulmonary disease, and pulmonary artery hypertension.

TORC1 suppression predicts responsiveness to RAF and MEK inhibition in BRAF-mutant melanoma.

RAF and MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase) inhibitors are effective in treating patients with BRAF-mutant melanoma. However, most responses are partial and short-lived, and many patients fail to respond at all. We found that suppression of TORC1 activity in response to RAF or MEK inhibitors, as measured by decreased phosphorylation of ribosomal protein S6 (P-S6), effectively predicted induction of cell death by the inhibitor in BRAF-mutant melanoma cell lines.

Atrial natriuretic peptide is negatively regulated by microRNA-425.

Numerous common genetic variants have been linked to blood pressure, but no underlying mechanism has been elucidated. Population studies have revealed that the variant rs5068 (A/G) in the 3' untranslated region of NPPA, the gene encoding atrial natriuretic peptide (ANP), is associated with blood pressure. We selected individuals on the basis of rs5068 genotype (AG vs.

Magnesium intake decreases Type 2 diabetes risk through the improvement of insulin resistance and inflammation: the Hisayama Study.

Aims: Early studies have shown that magnesium intake decreases the risk of Type 2 diabetes, but the results are still inconsistent. We prospectively examined the association between magnesium intake and incidence of Type 2 diabetes in a general Japanese population.

Methods: A total of 1999 subjects without diabetes aged 40-79 years who underwent a 75-g oral glucose tolerance test were followed up prospectively for a mean of 15.

A peptide microarray fabricated on a non-fouling phosphatidylcholine-polymer-coated surface for a high-fidelity analysis of a cellular kinome.

Phosphatidylcholine-polymer-coated plastic slides were utilized for the fabrication of peptide microarrays for cellular kinome analysis. According to the non-fouling features of the surface, the signal-to-noise ratio of the detection of phosphorylated peptides improved by about 100-fold from that of a peptide microarray fabricated on a glass slide blocked by a commercial BSA-based reagent. When the phosphatidylcholine-polymer-coated peptide microarray was applied to the analysis of the kinome of HCC827 cells, hyperactivation of c-Src and EGFR were successfully detected.

BMI mediates the association between low educational level and higher blood pressure during pregnancy in Japan.

Background: Research investigating the association between socioeconomic status (SES) and blood pressure (BP) during pregnancy is limited and its underlying pathway is unknown. The aim of this study was to investigate the mediators of the association between educational level as an indicator of the SES and BP in early and mid-pregnancy among Japanese women.

Methods: Nine hundred and twenty-three pregnant women in whom BP was measured before 16 weeks and at 20 weeks of gestation were enrolled in this study.

Development of a reverse transcription-quantitative PCR system for detection and genotyping of aichi viruses in clinical and environmental samples.

Aichi viruses (AiVs) have been proposed as a causative agent of human gastroenteritis potentially transmitted by fecal-oral routes through contaminated food or water. In the present study, we developed a TaqMan minor groove binder (MGB)-based reverse transcription-quantitative PCR (RT-qPCR) system that is able to quantify AiVs and differentiate between genotypes A and B. This system consists of two assays, an AiV universal assay utilizing a universal primer pair and a universal probe and a duplex genotype-specific assay utilizing the same primer pair and two genotype-specific probes.

Safety, humoral and cell-mediated immune responses to herpes zoster vaccine in subjects with diabetes mellitus.

Objective: To evaluate varicella zoster virus-specific cell-mediated immunity and humoral immunogenicity against the herpes zoster vaccine, which is licensed as the Live Varicella Vaccine (Oka Strain) in Japan, in elderly people with or without diabetes mellitus.

Methods: A pilot study was conducted between May 2010 and November 2010 at Kitano Hospital, a general hospital in the city of Osaka in Japan. A varicella skin test, interferon-gamma enzyme-linked immunospot assay and immunoadherence hemagglutination tests were performed 0, 3, and 6 months after vaccination.

Cytokeratin 19 fragment predicts the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitor in non-small-cell lung cancer harboring EGFR mutation.

Background: EGFR gene mutation is independently associated with a favorable response in non-small-cell lung cancer (NSCLC) patients receiving epidermal growth factor receptor -tyrosine kinase inhibitors (EGFR-TKIs), regardless of sex or smoking history. Squamous cell carcinoma patients harboring EGFR mutations show a significantly worse response to EGFR-TKIs compared with adenocarcinoma patients. We hypothesized that the serum cytokeratin 19 fragment (CYFRA 21-1) is associated with the efficacy of EGFR-TKIs in EGFR-mutated NSCLC patients.

Functional variants in the thromboxane A2 receptor gene are associated with lung function in childhood-onset asthma.

Background: The thromboxane A2 receptor (TBXA2R) gene is associated with asthma, but no functional genetic variations are known to associate with the disease or its related phenotypes.

Objective: To investigate the association of TBXA2R polymorphisms with asthma susceptibility and related phenotypes and to identify functionally relevant polymorphisms.

Methods: We performed comprehensive sequencing of the TBXA2R gene in 48 Japanese control subjects and found a set of variants (SNP1 G>T rs2238634, SNP2 T>G rs2238633, SNP3 C>T rs2238632 and SNP4 G>A rs2238631) in intron 1 in linkage disequilibrium with c.

Prognostic value of brain injury biomarkers in acute encephalitis/encephalopathy.

Background: Acute encephalitis/encephalopathy (AEE) is a devastating cause of severe neurodevelopmental sequelae or death in children. Assessing ongoing brain injury and predicting outcomes using bedside point-of-care testing is expected to be extremely valuable.

Methods: For this study, three brain injury markers, S-100B, glial fibrillary acidic protein (GFAP), and tau protein, were measured in early cerebrospinal fluid samples of children with AEE.

Dose reduction or intermittent administration of erlotinib: which is better for patients suffering from intolerable toxicities?

Erlotinib is an epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor that is widely used in the treatment of non-small cell lung cancer. Skin rashes and diarrhea are frequent side effects of erlotinib therapy. When these toxicities become intolerable, dose reduction is commonly performed.

Preexisting interstitial lung disease is inversely correlated to tumor epidermal growth factor receptor mutation in patients with lung adenocarcinoma.

Introduction: Interstitial lung disease (ILD), especially idiopathic pulmonary fibrosis, has been shown to be associated with lung carcinogenesis. However, an association between epidermal growth factor receptor (EGFR) mutation status and preexisting ILD in patients with lung adenocarcinoma is unknown.

Methods: Between January 2008 and April 2012, we analyzed 602 patients with lung adenocarcinoma.

Regulation of miRNA biogenesis as an integrated component of growth factor signaling.

Transcriptional control of microRNAs (miRNA) by cell signaling pathways, especially in the context of growth factor regulation, is a widely recognized phenomenon with broad-reaching implications. However, several recent studies indicate that not just transcription, but also processing of miRNAs is subject to regulation as part of an integrated physiological response to various stimuli and environmental changes. The canonical miRNA biogenesis pathway; sequential steps of nucleolytic cleavage by the RNase III enzymes Drosha and Dicer, are emerging regulatory hubs for the modulation of miRNA expression as part of both physiological and pathological responses.

Early infantile growth and cardiovascular risks in adolescent Japanese women.

Objective: Early life events connected with the risk of later disease can occur not only in utero, but also in infancy. In study of the developmental origins of health and disease, the relationship between infantile growth patterns and adolescent body mass index and blood pressure is one of the most important issues to verify.

Materials And Methods: We analyzed the correlation of current body mass index and systolic blood pressure of 168 female college students with their growth patterns in utero and in infancy.