We have designed, synthesized, and evaluated using physical, chemical and biochemical assays various oligonucleotide N3'-->P5' phosphoramidates, as potential telomerase inhibitors. Among the prepared compounds were 2'-deoxy, 2'-hydroxy, 2'-methoxy, 2'-ribo-fluoro, and 2'-arabino-fluoro oligonucleotide phosphoramidates, as well as novel N3'-->P5' thio-phosphoramidates. The compounds demonstrated sequence specific and dose dependent activity with IC50 values in the sub-nM to pM concentration range.

BackgroundThe toxicokinetics of nanomaterials are an important factor in toxicity, which may be affected by slow clearance and/or distribution in the body.MethodsFour types of nickel oxide (NiO) nanoparticles were single-administered intratracheally to male F344 rats at three doses of 0.67–6.0 mg/kg body weight. The rats were sacrificed under anesthesia and the lung, thoracic lymph nodes, bronchoalveolar lavage fluid, liver, and other organs were sampled for Ni burden measurement 3, 28, and 91 days post-administration; Ni excretion was measured 6 and 24 h after administration. Solubility of NiO nanoparticles was determined using artificial lysosomal fluid, artificial interstitial fluid, hydrogen peroxide solution, pure water, and saline. In addition, macrophage migration to trachea and phagosome-lysosome-fusion rate constants were estimated using pulmonary clearance and dissolution rate constants.ResultsThe wire-like NiO nanoparticles were 100% dissolved by 24 h when mixed with artificial lysosomal fluid (dissolution rate coefficient: 0.18/h); spherical NiO nanoparticles were 12% and 35% dissolved after 216 h when mixed with artificial lysosomal fluid (1.4 × 10−3 and 4.9 × 10−3/h). The largest irregular-shaped NiO nanoparticles hardly dissolved in any solution, including artificial lysosomal fluid (7.8 × 10−5/h). Pulmonary clearance rate constants, estimated using a one-compartment model, were much higher for the NiO nanoparticles with a wire-shape (0.069–0.078/day) than for the spherical and irregular-shaped NiO nanoparticles (0–0.012/day). Pulmonary clearance rate constants of the largest irregular-shaped NiO nanoparticles showed an inverse correlation with dose. Translocation of NiO from the lungs to the thoracic lymph nodes increased in a time- and dose-dependent manner for three spherical and irregular-shaped NiO nanoparticles, but not for the wire-like NiO nanoparticles. Thirty-five percent of the wire-like NiO nanoparticles were excreted in the first 24 h after administration; excretion was 0.33–3.6% in that time frame for the spherical and irregular-shaped NiO nanoparticles.ConclusionThese findings suggest that nanomaterial solubility differences can result in variations in their pulmonary clearance. Nanoparticles with moderate lysosomal solubility may induce persistent pulmonary inflammation.Electronic supplementary materialThe online version of this article (10.1186/s12989-017-0229-x) contains supplementary material, which is available to authorized users.

SMPVrPD without SV reconstruction can be safely conducted. Additionally, preservation of these two confluences may reduce the risk of LSPH.

Since bisphenol F (4,4'-dihydroxydiphenylmethane) has been reported to exhibit estrogen agonistic properties in the uterotrophic assay, we performed a 28-day repeated-dose toxicity study (enhanced OECD test guideline No. 407) on bisphenol F based on the OECD draft protocols to determine whether it has endocrine-mediated properties. Bisphenol F was orally administered at doses 0, 20, 100 and 500 mg/kg per day for at least 28 days, but no clear endocrine-mediated changes were detected, and it was concluded to have no endocrine-mediated effects in young adult rats. On the other hand, the main effect of bisphenol F was concluded to be liver toxicity based on clinical biochemical parameters and liver weight, but without histopathological changes. The no-observed-effect level for bisphenol F is concluded to be under 20 mg/kg per day since decreased body weight accompanied by decreased serum total cholesterol, glucose, and albumin values were observed in the female rats given 20 mg/kg per day or higher doses of bisphenol F.

Background: Myelolipoma is an uncommon tumor comprising adipose tissue and normal hematopoietic cells and mainly occurs in the adrenal cortex. Mediastinal myelolipoma is very rare; we report a case of posterior mediastinal myelolipoma that required surgical resection. Case Presentation: A 56-year-old male was diagnosed with a posterior mediastinal tumor by computed tomography. The tumor was originally noted in 2005, and during follow-up in March 2014, it was found to have increased in size. During consultation at our hospital, on magnetic resonance imaging (MRI), we considered the possibility that the tumor was malignant. Consequently, we resected the tumor by video-assisted thoracic surgery (VATS). The histopathological findings revealed that the tumor had undergone intrathoracic extramedullary hematopoiesis. However, after considering the patient's background and histopathological findings, we diagnosed the tumor as a thoracic extra-adrenal myelolipoma. Conclusions: Pathological analysis was instrumental in clarifying the diagnosis. We recommend surgery as a treatment option for posterior mediastinal tumors.

These results suggest that lapatinib has antitumor activity against the Tmab-resistant gastric cancer cell lines, and that these cell lines are useful for understanding the mechanism of Tmab resistance and for developing a new molecular therapy for Tmab-resistant HER2-positive gastric cancers.

Anchorage dependence of cell growth and survival is a critical trait that distinguishes nontransformed cells from transformed cells. We demonstrate that anchorage dependence is determined by anchorage-dependent nuclear retention of cyclin D1, which is regulated by the focal adhesion protein, Hic-5, whose CRM1-dependent nuclear export counteracts that of cyclin D1. An adaptor protein, PINCH, interacts with cyclin D1 and Hic-5 and potentially serves as an interface for the competition between cyclin D1 and Hic-5 for CRM1. In nonadherent cells, the nuclear export of Hic-5, which is redox-sensitive, was interrupted due to elevated production of reactive oxygen species, and cyclin D1 was exported from the nucleus. When an Hic-5 mutant that was continuously exported in a reactive oxygen species-insensitive manner was introduced into the cells, cyclin D1 was retained in the nucleus under nonadherent conditions, and a significant population of cells escaped from growth arrest or apoptosis. Interestingly, activated ras achieved predominant cyclin D1 nuclear localization and thus, growth in nonadherent cells. We report a failsafe system for anchorage dependence of cell growth and survival. INTRODUCTIONAnchorage dependence of cell growth is the phenomenon whereby nontransformed cells adhere to the substratum for cell cycle progression from G1 to S phase. Numerous studies have defined the roles of adhesion signals mediated by the integrin-extracellular matrix (ECM) interaction in cell cycle progression. Basically, integrin-ECM-mediated signaling potentiates and prolongs the growth factor receptor-mediated mitogenic signaling and is required from mid-to late-G1 phase in various events associated with cell cycle progression, such as up-regulation of G1-phase CDK activity, Cip/Kips down-regulation, association of cyclin E with CDK2, pRb phosphorylation, and cyclin A expression (Fang et al., 1996;Zhu et al., 1996;Assoian, 1997;Schwartz and Assoian, 2001). As a result, loss of adhesion generally causes complete G1-phase cell cycle arrest in nontransformed cells; moreover, in susceptible cells, it leads to anoikis, a specific type of apoptosis caused by the detachment of a cell from its supportive matrix, which was first described in epithelial and endothelial cells (Frisch and Screaton, 2001;Reddig and Juliano, 2005).In contrast, transformed cells usually circumvent the anchorage requirement in cell cycle progression. Their anchorage-independent survival and growth is well known as a hallmark of cellular transformation and correlates with tumorigenicity in vivo (Freedman and Shin, 1974). Mechanistically, the anchorage-independent growth is considered to be based on an abnormal activation of the G1-phase cyclincyclin-dependent kinases (CDKs) uncoupled from anchorage. In general, an oncogenic pathway activates a robust and/or constitutive mitogenic signal, which is presumed to reduce the requirement for integrin-ECM-mediated signaling and its importance as a booster of growth factor receptor-mediated mitogenic signaling in the tra...

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