Farnesyltransferase inhibitors and human malignant pleural mesothelioma: a first-step comparative translational study.

It is known that the potential clinical use of farnesyltransferase inhibitors (FTI) could be expanded to include cancers harboring activated receptor tyrosine kinases. Approximately 70% of malignant pleural mesotheliomas (MPM) overexpress epidermal growth factor receptors (EGFR) and a subset express both EGFR and transforming growth factor A (TGF-A), suggesting an autocrine role for EGFR in MPM. We checked on MPM cells (10 human cell lines, 11 primary cultures obtained by human biopsies, and 7 short-term normal mesothelial cell cultures) concerning the following: (a) the relative overexpression of EGFR (Western blotting, flow cytometry, immunohistochemistry), (b) the relative expression of EGFR ligands (EGF, amphiregulin, TGF-A, ELISA), (c) the relative increase of the activated form of Ras (Ras-bound GTP) after EGF stimulation (Ras activation assay), (d) the efficacy of five different FTIs (HDJ2 prenylation, cell cytotoxicity, and apoptosis using ApopTag and gel ladder). EGFR was overexpressed in MPM cells compared with normal pleural mesothelial cells in equivalent levels as in non\u2013small cell lung cancer cells A549. MPM cells constitutively expressed EGFR ligands; however, Ras activation was attenuated at high EGF concentrations (100 ng/mL). Growth of MPM cells was substantially not affected by treatment with different FTIs (SCH66336, BMS- 214662, R115777, RPR-115135, and Manumycin). Among these, BMS-214662 was the only one moderately active. BMS-214662 triggered apoptosis in a small fraction of cells (not higher than 30%) that was paralleled by a slight decrease in the levels of TGF-A secreted by treated MPM cells. Our data highlighted the concept that the same signaling pathway can be regulated in different ways and these regulations can differ between different cells of different origin

The Anxiety of Recognition: The Search for Legibility of Mayan Identities in Yucatán, Mexico and San Francisco, California

This dissertation tracks the mobilization of Yucatec Maya culture and identity across Yucatán, Mexico and San Francisco, California. Moving within a circulating discourse pertaining to a crisis of culture loss, I pause at three distinct sites to explore how culture is deployed for recognition in national and transnational spaces. I focus on Tuch Mukuy, a 17-member community theater troupe in Oxkutzcab, Yucatán; U Najil Xook, a one-member NGO dedicated to Mayan language preservation; and Alianza del Pueblo Maya, an NGO formed by the members of the Yucatec Maya migrant community in San Francisco to represent their interests and provide for their needs. I explore the efforts of Tuch Mukuy, U Najil Xook, and Alianza del Pueblo Maya to position themselves to be seen as Maya or indigenous by state and non-state actors across shifting fields of power and authority in Mexico and the United States. I examine the ways in which the space of the nation forecloses certain mobilizations of culture and cultural identity, while the space of the transnational open up possibilities for alternative visions and mobilizations of culture and identity. Within Yucatán, the space of the national, Tuch Mukuy and U Najil Xook are trapped into particular configurations of culture that will always be past-oriented. In Mexico, claims for rights and recognition are made to the nation-state based upon a history of marginalization and state-sponsored cultural assimilationist programs. Maya culture becomes framed, necessarily, through terms of revitalization and preservation, and packaged in the tangible and intangible forms of that which can be saved--such as, language, dress, and traditional practices, and knowledge entailed therein. This past-orientation renders claims to Mayaness as always under the impossible scrutiny of authenticity. In San Francisco, the space of the transnational, Alianza del Pueblo Maya becomes untethered from the future anterior temporality characteristic of recognition claims within the Mexican nation-state. In a city saturated with civil society organizations dedicated the rights of a range of politicized identities situated in race, ethnicity, gender, sexuality, culture, and nation, Alianza must rely on a combination of strategies and alliances to become culturally recognized, but also politically and economically addressed. Coalition, not culture, becomes the space through which claims of recognition are made

A Study of the Radiative Ke3 Decay and Search for Direct Photon Emission with the KLOE Detector

We present a measurement of the ratio R = \Gamma(\keg;\Estar>30\mev,\qstar>20^\circ)$/$\Gamma(\kegf)$and a first measurement of the direct emission contribution in KL semileptonic decays. The measurement is done at the DAFNE phi-factory selecting phi->KL KS decays with the KLOE detector. We use 328 pb^{-1}$ of data corresponding to about 3.5 million Ke3(g) events and about 9000 radiative events. Our result is R=(924 +/- 23(stat) +/-16(syst)10^{-5} for the branching ratio and X=-2.3 +/- 1.3(stat) +/- 1.4(syst) for the parameter describing direct emission.Comment: 8 pages, 7 figure

Author Correction: A consensus-based transparency checklist.

An amendment to this paper has been published and can be accessed via a link at the top of the paper

Design, development and deployment of a hand/wrist exoskeleton for home-based rehabilitation after stroke - SCRIPT project

YesChanges in world-wide population trends have provided new demands for new technologies in areas such as care and rehabilitation. Recent developments in the the field of robotics for neurorehabilitation have shown a range of evidence regarding usefulness of these technologies as a tool to augment traditional physiotherapy. Part of the appeal for these technologies is the possibility to place a rehabilitative tool in one’s home, providing a chance for more frequent and accessible technologies for empowering individuals to be in charge of their therapy. Objective: this manuscript introduces the Supervised Care and Rehabilitation Involving Personal Tele-robotics (SCRIPT) project. The main goal is to demonstrate design and development steps involved in a complex intervention, while examining feasibility of using an instrumented orthotic device for home-based rehabilitation after stroke. Methods: the project uses a user-centred design methodology to develop a hand/wrist rehabilitation device for home-based therapy after stroke. The patient benefits from a dedicated user interface that allows them to receive feedback on exercise as well as communicating with the health-care professional. The health-care professional is able to use a dedicated interface to send/receive communications and remote-manage patient’s exercise routine using provided performance benchmarks. Patients were involved in a feasibility study (n=23) and were instructed to use the device and its interactive games for 180 min per week, around 30 min per day, for a period of 6 weeks, with a 2-months follow up. At the time of this study, only 12 of these patients have finished their 6 weeks trial plus 2 months follow up evaluation. Results: with the “use feasibility” as objective, our results indicate 2 patients dropping out due to technical difficulty or lack of personal interests to continue. Our frequency of use results indicate that on average, patients used the SCRIPT1 device around 14 min of self-administered therapy a day. The group average for the system usability scale was around 69% supporting system usability. Conclusions: based on the preliminary results, it is evident that stroke patients were able to use the system in their homes. An average of 14 min a day engagement mediated via three interactive games is promising, given the chronic stage of stroke. During the 2nd year of the project, 6 additional games with more functional relevance in their interaction have been designed to allow for a more variant context for interaction with the system, thus hoping to positively influence the exercise duration. The system usability was tested and provided supporting evidence for this parameter. Additional improvements to the system are planned based on formative feedback throughout the project and during the evaluations. These include a new orthosis that allows a more active control of the amount of assistance and resistance provided, thus aiming to provide a more challenging interaction.This work has been partially funded under Grant FP7-ICT-288698(SCRIPT) of the European Community Seventh Framework Programme

Determination of η→π+π−π0\eta\to\pi^+\pi^-\pi^0 Dalitz plot slopes and asymmetries with the KLOE detector

We have studied, with the KLOE detector at the DA$\Phi$NE $\Phi$-Factory, the dynamics of the decay $\eta\to\pi^+\pi^-\pi^0$ using $\eta$ mesons from the decay $\phi\to\eta\gamma$ for an integrated luminosity ${\mathcal L}$ = 450 pb$^{-1}$. From a fit to the Dalitz plot density distribution we obtain a precise measurement of the slope parameters. An alternative parametrization relates the $\pi^+\pi^-\pi^0$ slopes to that for $\eta\to 3\pi^0$ showing the consistency of KLOE results for both channels. We also obtain the best confirmation of the $C$-invariance in the $\eta\to\pi^+\pi^-\pi^0$ decay.Comment: 15 pages, 7 figure

Statistical Modeling of Single Target Cell Encapsulation

High throughput drop-on-demand systems for separation and encapsulation of individual target cells from heterogeneous mixtures of multiple cell types is an emerging method in biotechnology that has broad applications in tissue engineering and regenerative medicine, genomics, and cryobiology. However, cell encapsulation in droplets is a random process that is hard to control. Statistical models can provide an understanding of the underlying processes and estimation of the relevant parameters, and enable reliable and repeatable control over the encapsulation of cells in droplets during the isolation process with high confidence level. We have modeled and experimentally verified a microdroplet-based cell encapsulation process for various combinations of cell loading and target cell concentrations. Here, we explain theoretically and validate experimentally a model to isolate and pattern single target cells from heterogeneous mixtures without using complex peripheral systems.Wallace H. Coulter Foundation (Young Investigator in Bioengineering Award)National Institutes of Health (U.S.) (Grant R01AI081534)National Institutes of Health (U.S.) (Grant R21AI087107

Non-genomic effects of nuclear receptors: insights from the anucleate platelet

Nuclear receptors have the ability to elicit two different kinds of responses, genomic and non-genomic. While genomic responses control gene expression by influencing the rate of transcription, non-genomic effects occur rapidly and independently of transcriptional regulation. Due to their anucleate nature and mechanistically well-characterised and rapid responses, platelets provide a model system for the study of any non-genomic effects of the nuclear receptors. Several nuclear receptors have been found to be expressed in human platelets, and multiple nuclear receptor agonists have been shown to elicit anti-platelet effects by a variety of mechanisms. The non-genomic functions of NRs vary, including the regulation of kinase and phosphatase activity, ion channel function, intracellular calcium levels and production of second messengers. Recently, the characterisation of mechanisms and identification of novel binding partners of nuclear receptors have further strengthened the prospects of developing their ligands into potential therapeutics that offer cardio-protective properties in addition to their other defined genomic effects