Hospitalization rates in patients switched from oral anti-psychotics to aripiprazole once-monthly: final efficacy analysis

Abstract Objective: To compare hospitalization rates in patients with schizophrenia treated prospectively with aripiprazole once-monthly 400 mg (AOM 400; an extended-release injectable suspension) vs the same patients\u27 retrospective rates with their prior oral anti-psychotic therapy. Research design and methods: Multi-center, open-label, mirror-image, naturalistic study in a community setting in North America. Patients who required a change in treatment and/or would benefit from long-acting injectable anti-psychotic therapy were treated prospectively for 6 months with AOM 400. Retrospective data on hospitalization rates were obtained. Clinical trial registration: ClinicalTrials.gov: NCT01432444. Main outcome measures: The proportion of patients with \u3e/=1 psychiatric inpatient hospitalization with oral anti-psychotic therapy examined retrospectively (months -4 to -1 before oral conversion) and after switching to AOM 400 (months 4-6 after initiating AOM 400). Results: Psychiatric hospitalization rates were significantly lower when patients were treated with AOM 400 compared with oral anti-psychotic therapy both in the 3-month primary efficacy sample (2.7% [n = 9/336] vs 27.1% [n = 91/336], respectively; p \u3c 0.0001) and in the total sample (6-month prospective rate: 8.8% [n = 38/433] vs 6-month retrospective rate: 38.1% [n = 165/433]; p \u3c 0.0001). Discontinuations due to adverse events (AEs) during cross-titration were lower in patients cross-titrated on oral aripiprazole for \u3e1 and(2.9% [n = 7/239]) compared with patients cross-titrated fo

Effects of aripiprazole once-monthly on domains of personal and social performance: Results from 2 multicenter, randomized, double-blind studies

Objective: To assess the effects of maintenance therapy with aripiprazole once-monthly 400 mg on personal and social functioning. Methods: Data were analyzed from 2 randomized, double-blind trials of patients with schizophrenia requiring chronic antipsychotic treatment. One study was a 52-week trial of aripiprazole once-monthly 400 mg versus placebo; the other was a 38-week trial of aripiprazole once-monthly 400 mg, oral aripiprazole (10-30 mg daily), and aripiprazole once-monthly 50 mg (subtherapeutic dose to test assay sensitivity). Functioning was assessed using the Personal and Social Performance (PSP) scale, comprising 4 domain subscales. Results: In the 52-week study, 403 patients stabilized on aripiprazole once-monthly 400 mg were randomized to receive aripiprazole once-monthly 400 mg (n=269) or placebo (n=134). In the 38-week study, 662 patients stabilized on oral aripiprazole were randomized to receive aripiprazole once-monthly 400 mg (n=265), oral aripiprazole (n=266), or aripiprazole once-monthly 50 mg (subtherapeutic dose; n=131). In the 52-week study, mean changes from baseline were significantly worsened with placebo compared with aripiprazole once-monthly 400 mg for PSP total score (

PTEN status is a crucial determinant of the functional outcome of combined MEK and mTOR inhibition in cancer

Combined MAPK/PI3K pathway inhibition represents an attractive, albeit toxic, therapeutic strategy in oncology. Since PTEN lies at the intersection of these two pathways, we investigated whether PTEN status determines the functional response to combined pathway inhibition. PTEN (gene, mRNA, and protein) status was extensively characterized in a panel of cancer cell lines and combined MEK/mTOR inhibition displayed highly synergistic pharmacologic interactions almost exclusively in PTEN-loss models. Genetic manipulation of PTEN status confirmed a mechanistic role for PTEN in determining the functional outcome of combined pathway blockade. Proteomic analysis showed greater phosphoproteomic profile modification(s) in response to combined MEK/mTOR inhibition in PTEN- loss contexts and identified JAK1/STAT3 activation as a potential mediator of synergistic interactions. Overall, our results show that PTEN-loss is a crucial determinant of synergistic interactions between MAPK and PI3K pathway inhibitors, potentially exploitable for the selection of cancer patients at the highest chance of benefit from combined therapeutic strategies

The origin of early Acheulean expansion in Europe 700 ka ago: new findings at Notarchirico (Italy)

Notarchirico (Southern Italy) has yielded the earliest evidence of Acheulean settlement in Italy and four older occupation levels have recently been unearthed, including one with bifaces, extending the roots of the Acheulean in Italy even further back in time. New 40Ar/39Ar on tephras and ESR dates on bleached quartz securely and accurately place these occupations between 695 and 670 ka (MIS 17), penecontemporaneous with the Moulin-Quignon and la Noira sites (France). These new data demonstrate a very rapid expansion of shared traditions over Western Europe during a period of highly variable climatic conditions, including interglacial and glacial episodes, between 670 and 650 (i.e., MIS17/MIS16 transition). The diversity of tools and activities observed in these three sites shows that Western Europe was populated by adaptable hominins during this time. These conclusions question the existence of refuge areas during intense glacial stages and raise questions concerning understudied migration pathways, such as the Sicilian route

The origin of early Acheulean expansion in Europe 700 ka ago: new findings at Notarchirico (Italy)

Notarchirico (Southern Italy) has yielded the earliest evidence of Acheulean settlement in Italy and four older occupation levels have recently been unearthed, including one with bifaces, extending the roots of the Acheulean in Italy even further back in time. New 40Ar/39Ar on tephras and ESR dates on bleached quartz securely and accurately place these occupations between 695 and 670 ka (MIS 17), penecontemporaneous with the Moulin-Quignon and la Noira sites (France). These new data demonstrate a very rapid expansion of shared traditions over Western Europe during a period of highly variable climatic conditions, including interglacial and glacial episodes, between 670 and 650 (i.e., MIS17/MIS16 transition). The diversity of tools and activities observed in these three sites shows that Western Europe was populated by adaptable hominins during this time. These conclusions question the existence of refuge areas during intense glacial stages and raise questions concerning understudied migration pathways, such as the Sicilian route

The Side Population in Human Lung Cancer Cell Line NCI-H460 Is Enriched in Stem-Like Cancer Cells

Lung cancer is among the most lethal malignancies with a high metastasis and recurrence rate. Recent studies indicate that tumors contain a subset of stem-like cancer cells that possess certain stem cell properties. Herein, we used Hoechst 33342 dye efflux assay and flow cytometry to isolate and characterize the side population (SP) cells from human lung cancer cell line NCI-H460 (H460). We show that the H460 SP cells harbor stem-like cells as they can readily form anchorage-independent floating spheres, possess great proliferative potential, and exhibit enhanced tumorigenicity. Importantly, the H460 SP cells were able to self-renew both in vitro and in vivo. Finally, we show that the H460 SP cells preferentially express ABCG2 as well as SMO, a critical mediator of the Hedgehog (HH) signaling, which seems to play an important role in H460 lung cancer cells as its blockage using Cyclopamine greatly inhibits cell-cycle progression. Collectively, our results lend further support to the existence of lung cancer stem cells and also implicate HH signaling in regulating large-cell lung cancer (stem) cells

Skeletal muscle NOX4 is required for adaptive responses that prevent insulin resistance

Reactive oxygen species (ROS) generated during exercise are considered integral for the health-promoting effects of exercise. However, the precise mechanisms by which exercise and ROS promote metabolic health remain unclear. Here, we demonstrate that skeletal muscle NADPH oxidase 4 (NOX4), which is induced after exercise, facilitates ROS-mediated adaptive responses that promote muscle function, maintain redox balance, and prevent the development of insulin resistance. Conversely, reductions in skeletal muscle NOX4 in aging and obesity contribute to the development of insulin resistance. NOX4 deletion in skeletal muscle compromised exercise capacity and antioxidant defense and promoted oxidative stress and insulin resistance in aging and obesity. The abrogated adaptive mechanisms, oxidative stress, and insulin resistance could be corrected by deleting the H2O2-detoxifying enzyme GPX-1 or by treating mice with an agonist of NFE2L2, the master regulator of antioxidant defense. These findings causally link NOX4-derived ROS in skeletal muscle with adaptive responses that promote muscle function and insulin sensitivity

Colon Cancer Stem Cells Dictate Tumor Growth and Resist Cell Death by Production of Interleukin-4

A novel paradigm in tumor biology suggests that cancer growth is driven by stem-like cells within a tumor. Here, we describe the identification and characterization of such cells from colon carcinomas using the stem cell marker CD133 that accounts around 2% of the cells in human colon cancer. The CD133+ cells grow in vitro as undifferentiated tumor spheroids, and they are both necessary and sufficient to initiate tumor growth in immunodeficient mice. Xenografts resemble the original human tumor maintaining the rare subpopulation of tumorigenic CD133+ cells. Further analysis revealed that the CD133+ cells produce and utilize IL-4 to protect themselves from apoptosis. Consistently, treatment with IL-4Rα antagonist or anti-IL-4 neutralizing antibody strongly enhances the antitumor efficacy of standard chemotherapeutic drugs through selective sensitization of CD133+ cells. Our data suggest that colon tumor growth is dictated by stem-like cells that are treatment resistant due to the autocrine production of IL-4

Incremental Reconfiguration of Product Specific Use Case Models for Evolving Configuration Decisions

[Context and motivation] Product Line Engineering (PLE) is increasingly common practice in industry to develop complex systems for multiple customers with varying needs. In many business contexts, use cases are central development artifacts for requirements engineering and system testing. In such contexts, use case configurators can play a significant role to capture variable and common requirements in Product Line (PL) use case models and to generate Product Specific (PS) use case models for each new customer in a product family. [Question/Problem] Although considerable research has been devoted to use case configurators, little attention has been paid to supporting the incremental reconfiguration of use case models with evolving configuration decisions. [Principal ideas/results] We propose, apply, and assess an incremental reconfiguration approach to support evolving configuration decisions in PL use case models. PS use case models are incrementally reconfigured by focusing only on the changed decisions and their side effects. In our prior work, we proposed and applied Product line Use case modeling Method (PUM) to support variability modeling in PL use case diagrams and specifications. We also developed a use case configurator, PUMConf, which interactively collects configuration decisions from analysts to generate PS use case models from PL models. Our approach is built on top of PUM and PUMConf. [Contributions] We provide fully automated tool support for incremental configuration as an extension of PUMConf. Our approach has been evaluated in an industrial case study in the automotive domain, which provided evidence it is practical and beneficial

Topoisomerase II\u3b2 mediates the resistance of glioblastoma stem cells to replication stress-inducing drugs

The mesenchymal state in cancer is usually associated with poor prognosis due to the metastatic predisposition and the hyper-activated metabolism. Exploiting cell glucose metabolism we propose a new method to detect mesenchymal-like cancer cells. We demonstrate that the uptake of glucose-coated magnetic nanoparticles (MNPs) by mesenchymal-like cells remains constant when the glucose in the medium is increased from low (5.5 mM) to high (25 mM) concentration, while the MNPs uptake by epithelial-like cells is significantly reduced. These findings reveal that the glucose-shell of MNPs plays a major role in recognition of cells with high-metabolic activity. By selectively blocking the glucose transporter 1 channels we showed its involvement in the internalization process of glucose-coated MNPs. Our results suggest that glucose-coated MNPs can be used for metabolic-based assays aimed at detecting cancer cells and that can be used to selectively target cancer cells taking advantage, for instance, of the magnetic-thermotherapy