ONC201 is a first-in-class small molecule discovered in a phenotypic screen for p53-independent inducers of tumor-selective pro-apoptotic pathways. Oral ONC201 is currently being evaluated at leading institutions as a new therapeutic agent in five early phase clinical trials for select advanced cancers based on pronounced efficacy in aggressive and refractory tumors and excellent safety. Here, we report the prediction and validation of selective direct molecular interactions between ONC201 and specific members of the dopamine receptor family. One initial prediction of this interaction was derived from the BANDIT drug target prediction method. BANDIT combines millions of data points from clinical, genomic, chemical and structural datasets within a Bayesian network to predict the targets of small molecules. The molecular structure of ONC201, its in vitro efficacy profile, and its publicly available bioactivity assay results were used as inputs for BANDIT and ONC201 was tested against all small molecules with known targets. Results of the BANDIT analysis indicated that ONC201 was highly correlated with other small molecules known to target DRD2, a member of the dopamine receptor family of GPCRs. Furthermore, BANDIT predicted a highly specific binding to DRD2 rather than other members of the dopamine receptor family. In parallel to these independent in silico predictions, experimental GPCR profiling indicated that ONC201 selectively antagonizes the D2-like, but not D1-like, subfamily of dopamine receptors. Reporter assays in a heterologous expression system revealed that ONC201 selectively antagonizes both short and long isoforms of DRD2 and DRD3, with weaker potency for DRD4 and no antagonism of DRD1 or DRD5. Increased secretion of prolactin is a clinical hallmark of DRD2 antagonism by several psychiatric medications that potently target this receptor. ELISA measurements in the peripheral blood of patients who were treated with ONC201 in the first-in-human trial with advanced solid tumors determined that 10/11 patients evaluated in this analysis exhibited induction of prolactin (mean of 2-fold). Using the TCGA database, we found that the D2-like subfamily of dopamine receptors, particularly DRD2, is prevalent and selectively overexpressed in several malignancies. Preclinical reports show that DRD2 inhibition imparts antitumor efficacy, without killing normal cells, via induction of ATF4/CHOP and inhibition of Akt and ERK signaling that are all attributes of ONC201. In summary, antagonizing the D2-like family of dopamine receptors appears to be a promising therapeutic target in oncology, and ONC201 is the first compound to exploit this treatment paradigm in several ongoing Phase II clinical studies. Citation Format: Neel S. Madhukar, Olivier Elemento, Cyril H. Benes, Mathew J. Garnett, Mark Stein, Joseph R. Bertino, Howard L. Kaufman, Isabel Arrillaga-Romany, Tracy T. Batchelor, Lee Schalop, Wolfgang Oster, Martin Stogniew, Michael Andreeff, Wafik S. El-Deiry, Joshua E. Allen. D2-like dopamine receptor antagonism by ONC201 identified by confluence of computational, receptor binding, and clinical studies. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-209.


Temperature characteristics of supply oil in an ultra-precision hydrostatic table are largely influenced by parameter setting in an oil cooler such as the location of reference sensor and cooling temperature. In this paper, influences of the parameter setting on the temperature variation in the hydrostatic table are experimentally analyzed to suggest the guidelines for practical application. In case of using temperature of inlet oil as a reference sensor in the oil cooler, temperature rise of the supply oil is smaller and thermal settling time is faster than that of using temperature of outlet oil as a reference sensor. The experimental results also show that temperatures of table, rail and return oil can be made almost same, and thermal settling time can be decreased by setting cooling temperature in the oil cooler to be lower than atmospheric temperature.


Based on field research conducted in a rural area of France, this article analyzes the situation of railway workers from farming families. Going against the frequent tendency to lump departure from farming together with rural exodus, this article envisages a departure from farming without a (significant) geographical move and sheds light on the interdependence between farmers and workers in the same geographical space. Analyzing the trajectories of railway workers from farming backgrounds reveals the composite facet of rural working-class socialization, which is marked by tensions between family farming legacies and forms of sociability among industrial workers. After providing a socio-historical background on the processes of mobility between agriculture and industry, the article analyzes how proximity with the farming world feeds into reputation issues and particular strategies in a workshop of the SNCF (the French national train network) and in its union, the CGT. The case study that follows aims to tease out the socialization process, as worker and as activist, of a "farmer-railway man" who joined the union.


Femtocells are small, low-cost and low-power cellular base stations optimized for providing wireless voice and broadband services to customers in a relatively small area.
Femtocells are considered to be one of the most promising solutions for future wireless communication with all the advantages that they bring, such as better indoor coverage,
higher spectrum efficiency and lower energy consumption to name but a few.
However time synchronization for femtocells is very challenging. Femtocells are expected to be equipped with cheap and less accurate crystal oscillators, which cannot satisfy the femtocell synchronization requirements. Moreover, femtocells are deployed in a variety of scenarios with different synchronization requirements and so different synchronization solutions are needed. Existing solutions for some of the femtocell synchronization
scenarios either are unsuitable for that particular scenario or suffer serious performance degradation. Therefore, this thesis is focused on investigating the time synchronization problem for femtocells and proposing novel synchronization schemes.
This thesis mainly investigated two femtocell synchronization methods: synchronization via backhaul and synchronization via neighbouring cells listening. Femtocell synchronization using the IEEE 1588 protocol, which is seen as the major solution for femtocell synchronization via backhaul, suffers from both asymmetric and random delay problems.
An 'improved IEEE 1588' scheme is firstly proposed, which utilizes additional packets with different sizes in every IEEE 1588 synchronization process to solve both of these problems. Although the simulation results show that the 'improved IEEE 1588' scheme successfully overcomes both aforementioned limitations and yields much better
synchronization accuracy than the conventional scheme, it also brings an additional undesirable overhead. Therefore, this thesis also presented a 'variable-length IEEE 1588'
scheme, where the length of transmitted packets varies periodically. Simulation results show that the synchronization accuracy of the 'variable-length IEEE 1588' scheme is similar to the 'improved IEEE 1588' scheme but with the advantage of a significantly reduced number of transmitted messages.
For femtocell synchronization via neighbouring cells listening, listening to other synchronized femtocells is an important approach, especially for femtocells in SOHO (Small
Office and Home Office) area where the femtocells overlap with each other and then form a wireless femtocell network. This thesis carefully examines the time synchronization in
wireless femtocell networks. First, the receiver-receiver synchronization (RRS), which has proved efficient in WSNs (wireless sensor networks), is applied in wireless femtocell
networks. Two new RRS based synchronization schemes are proposed for different scenarios to ensure better availability. Second, a hybrid synchronization scheme based
on wireless IEEE 1588 and RRS is proposed for wireless femtocell networks. The synchronization accuracy and robustness of this hybrid scheme are then evaluated through
simulations.
Finally, the synchronization scenario where the femtocell is connected to more than one synchronization sources is studied. The basic solution for this scenario is to simply
select the best synchronization source when it is available. A two-step weighted multiple linear regression (WMLR) based synchronization scheme is proposed for this case, and it is proved via simulations that it provides better synchronization accuracy and better stability than the basic solution, especially when the two synchronization sources are comparable.


The incidence of vomiting before the administration of analgesics was studied in 109 patients admitted to hospital as emergencies with prolonged ischaemic cardiac pain. In transmural myocardial infarction (58 patients) the incidence was 43% (anterior infarction 58%, inferior infarction 41%). Of the 23 patients with myocardial necrosis but without transmural infarction (that is, those with diffuse or subendocardial necrosis) and the 28 with coronary insufficiency but no necrosis, only one patient in each group experienced vomiting. When vomiting occurs early in association with cardiac pain transmural infarction may be expected in 90% of patients.


Tamoxifen is a nonsteroidal antiestrogen whose mode of action is, as yet, unclear. The purpose of this report is to investigate the effects of Tamoxifen on endometrial adenocarcinoma ultrastructurally. Five patients with endometrial adenocarcinoma, 3 cases well differentiated and the others undifferentiated, were treated with 20mg Tamoxifen per os a day for 7 days, and the following changes were observed: The cells became roundish and slightly swollen. Development of cytoplasmic organelles was observed. In the cytoplasm, glycogen granules did not increase. These results suggest that an anti-cancer effect is brought about by the induction of the tissue toward functional differentiation as well as inhibition of glycogen metabolism in tumor cells.


AlGaN/GaN HEMTs are the most promising high power switching devices. The material properties of III-nitrides are exceptionally better than that of Si and GaAs. GaN-based devices have been recorded to have higher operating temperatures and higher breakdown field due to the wide bandgap. AlGaN/GaN heterostructures forms 2DEG without doping due to the spontaneous polarization. The performance and reliability of AlGaN/GaN HEMTs are dependent on the structure of the AlGaN/GaN heterostructures.Surface passivation has been proven to improve the 2DEG conductivity and device performance. 20 nm of plasma-enhanced chemical vapor deposition (PECVD) SiN was deposited on AlGaN/GaN HEMTs, and the PECVD SiN passivated sample demonstrated higher carrier concentration of 9.88 ? 1012 cm-2 compared to the un-passivated sample, 8.08 ? 1012 cm-2. High temperature annealing is an important processing step in the fabrication of the devices, and the effects have shown to improve the DC and RF performance. High temperature annealing may affect the structure and the 2DEG conductivity. The annealing effects modifies the AlGaN layer and the AlGaN/GaN interface. Herein, we present the a study on the thermal stability of the PECVD SiN passivation layer on AlGaN/GaN HEMT structures at high temperature anneals. High-resolution x-ray diffraction (HRXRD) measurements were used to investigate the strain of AlGaN layer, and Hall measurements were used to investigate the 2DEG conductivity. PECVD SiN passivated and un-passivated AGaN/GaN HEMTs structure underwent high temperature thermal anneals for 30 minutes in N2. The starting temperature of the annealing is 400?C with step of 50?C until degradation. Degradation was determined through Hall sheet resistivity and mobility measurements. The ending annealed temperature is 1000 ?C and 700 ?C for passivated and control samples, respectively. From no anneal to degradation temperature, the 2DEG conductivity dropped by 15% and 34% for passivated and un-passivated samples, respectively. The HRXRD measurements found the change in-plane strain of the AlGaN layer after high temperature anneals. Higher in-plane strain showed higher 2DEG conductivity. In-plane strain from no anneal to degradation temperature dropped from 2% and 7% for passivated and un-passivated samples, respectively. Therefore, the passivated sample demonstrated to be more stable at high temperatures. The SiN passivation layer adds tensile stress to the AlGaN layer thus increased the piezoelectric effect and 2DEG conductivity.


The S100A1 protein in humans is a calcium-binding protein. Upon Ca2+ binding to S100A1 EF-hand motifs, the conformation of S100A1 changes and promotes interactions with target proteins. RAGE consists of three domains: the cytoplasmic, transmembrane, and extracellular domains. The extracellular domain consists of C1, C2, and V domains. V domains are the primary receptors for the S100 protein. It was reported several years ago that S100A1 and RAGE V domains interact in a pathway involving S100A1-RAGE signaling, whereby S100A1 binds to the V domain, resulting in RAGE dimerization. The autophosphorylation of the cytoplasmic domain initiates a signaling cascade that regulates cell proliferation, cell growth, and tumor formation. In this study, we used pentamidine and a newly synthesized pentamidine analog (WLC-4059) to inhibit the S100A1-RAGE V interaction. 1H-15N HSQC NMR titration was carried out to characterize the interaction between mS100A1 (mutant S100A1, C86S) and pentamidine analogs. We found that pentamidine analogs interact with S100A1 via 1H-15N HSQC NMR spectroscopy. Based on the results, we utilized the HADDOCK program to generate structures of the mS100A1–WLC-4059 binary complex. Interestingly, the binary complex overlapped with the complex crystal structure of the mS100A1–RAGE-V domain, proving that WLC-4059 blocks interaction sites between S100A1 and RAGE-V. A WST-1 cell proliferation assay also supported these results. We conclude that pentamidine analogs could potentially enhance therapeutic approaches against cancers.


This paper presents a study protocol for an effectiveness evaluation of antiandrogenic (NAM) medications (i.e. abiraterone acetate and enzalutamide) against standard of care in patients suffering from metastatic castrate resistant prostate cancer. The study protocol takes stock in the Rubin Causal Model for observational data in using historical comparisons for the analysis on three outcomes: mortality, pain and skeleton related events. We restrict the evaluation to 1,285 NAM patients with a prostate cancer diagnosis after June 2012 and find the comparisons in the group of men that had a prostate cancer diagnosis between June 2008 and June 2010. The rich registry data and the lack of NAMs as an option for the comparisons provide support for the validity of the design. However, while the design yields balance on the observed covariates, one cannot discard the possibility that unobserved confounders are not balanced. Thus, sensitivity analyses are suggested.


ABSTRACT During their doctoral studies, students undergo an emotionally and intellectually intensive process involving a wide range of positive and negative experiences. This article analyses PhD students' perceptions of the most positive and negative experiences related to doctoral study conditions. Previous researchers have primarily focused on analysing experiences that negatively affect doctoral work and have related these experiences to institutional, social and individual variables. However, little is known regarding positive experiences and how both positive and negative experiences are interpreted and related to variables connected with doctoral study, such as discipline, funding, enrolment type, and the stage of the doctoral process. In total, 1173 doctoral students from 56 Spanish universities completed an open-ended online survey. The findings indicate that opportunities for PhD students to communicate their scientific advances, receive expert feedback and interact with other researchers have a high positive influence on their doctoral journey. However, funding difficulties, particularly for students in the social sciences, and relationships with the research community, principally with the supervisor, were perceived as the main negative challenges. Experiences related to research design, data collection and analysis were perceived either negatively – primarily for mid-level students – or positively. These results should be considered in future doctoral programme policies to determine when, how and why to provide specific support during the doctoral process.


There has recently been increased interest in carbon-based resistive random-access (RRAM) memory. Carbon-based RRAM has the potential to scale to atomic dimensions, resulting in ultra-high-density and low-power memory. Here we report reversible unipolar resistance switching in hydrogenated amorphous carbon. The devices used in this study are fabricated using e-beam lithography with built-in series resistors. A thorough analysis of the electrical transport and the resistance switching mechanism is presented.


We report a case of ureterocolic fistula secondary to urolithiasis in a 70-year-old female imaged with both CT and an antegrade nephrostogram. The ureterocolic fistula was managed with insertion of an antegrade ureteral stent.


A multistage stochastic optimization model is presented to address the scheduling of supply chains with embedded multipurpose batch chemical plants under demand uncertainty. In order to overcome the numerical difficulties associated with the resulting large-scale stochastic mixed-integer-linear-programming (MILP) problem, an approximation strategy comprising two steps, and based on the resolution of a set of deterministic and two-stage stochastic models is presented. The performance of the proposed strategy regarding computation time and optimality gap is studied through comparison with other traditional approaches that address optimization under uncertainty. Results indicate that the proposed strategy provides better solutions than stand-alone two-stage stochastic programming and two-stage shrinking-horizon algorithms for similar computational efforts and incurs much lower computation times than the rigorous multistage stochastic model. © 2006 American Institute of Chemical Engineers AIChE J, 2006


Following the growing interest towards the role of the knowledge in the modern economies the economic literature has focused many studies on the role of the sources of new knowledge, e.g. universities and public research institutions. The relations between these bodies and the firms, the contributions of the technological spillovers at the local level, the creation of new technology based firms, the challenge between fundamental research and applied research are some of the arguments of the present debate. This paper represents a short survey of the international literature with a focus on the studies concerning Italy, and an analysis of the relations of some Italian research institutes with users of knowledge and technology (such as firms, etc.). The results show a common evidence even if in some areas the Italian situation is quite underdeveloped with large areas for future research policy implications.


Selenocysteine-containing cyclic 8-mer peptides, which were designed to mimic the plausible catalytic tetrad of glutathione peroxidase, were successfully synthesized in one pot via tandem N-to-S acyl migration of N-alkylcysteine (NAC)-containing selenopeptides and intramolecular selenocysteine-mediated native chemical ligation (Sec-NCL) of the generated thioesters.


The objective of this research program is to develop a novel, noninvasive, low-cost infrared (8–12?m spectral range) imaging technique that would improve upon current methods using nanostructured core/shell magnetic/noble metal-based imaging and therapies. The biocompatible magnetic nanoparticles are able to produce heat under AC magnetic field. This thermal radiation propagates along the tissue by thermal conduction reaching the medium's (tissue's) surface. The surface temperature distribution is acquired by a thermal camera and can be analyzed to retrieve and reconstruct nanoparticles' temperature and location within the tissue. The technique may function as a diagnostic tool thanks to the ability of specific bioconjugation of these nanoparticles to tumor's outer surface markers. Hence, by applying a magnetic field, we could cause a selective elevation of temperature of the targeted nanoparticles up to , which detects the tumor. Furthermore, elevating the temperature over and up to stimulates a thermo ablating interaction which causes a localized irreversible damage to the cancerous site with no harm to the surrounding tissue. While functioning as a diagnostic tool, this procedure may serve as a targeted therapeutic tool under thermal feedback control as well.


An important aspect of structural change in the U.S. hog industry has been the adoption of breeding technology. The adoption of each of four breeding technologies, weekly farrowing, intensive breeding, terminal crossbreeding, and artificial insemination, in U.S. hog production is analyzed using multivariate probit analysis. Results suggest that diversification, whether the producer raised breeding stock, debt and asset levels, and producer's education influence adoption rate. Larger, more risk-averse producers were more likely to adopt technology. Producers who rated the quality of labor available as higher were more likely to adopt management-intensive technologies.


doi: https://doi.org/10.1557/jmr.2017.88 Published by Materials Research Society with Cambridge University Press, 16 March 2017 After publication of Lu et al.^1, the authors requested an additional author be added, thanks to their contributions in calculating the thermoelectric transport of crystal Bi and proposing some valuable suggestions. The additional author's information is as follows: Chun Kong School of Energy and Engineering, Henan Polytechnic University, Jiaozuo 454000, China The original article has since been updated to reflect the addition.


Let $A$ be an algebra over a commutative ring $k$. We compute the center of the category of $A$-bimodules. There are six isomorphic descriptions: the center equals the weak center, and can be described as categories of noncommutative descent data, comodules over the Sweedler canonical $A$-coring, Yetter-Drinfeld type modules or modules with a flat connection from noncommutative differential geometry. All six isomorphic categories are braided monoidal categories: in particular, the category of comodules over the Sweedler canonical $A$-coring $A \ot A$ is braided monoidal. We provide several applications: for instance, if $A$ is finitely generated projective over $k$ then the category of left End_k(A)$-modules is braided monoidal and we give an explicit description of the braiding in terms of the finite dual basis of $A$. As another application, new families of solutions for the quantum Yang-Baxter equation are constructed: they are canonical maps $\Omega$ associated to any right comodule over the Sweedler canonical coring $A \ot A$ and satisfy the condition $\Omega^3 = \Omega$. Explicit examples are provided.


In the last two decades knowledge on volunteering has significantly expanded, but a thorough understanding of the organizational socialization of volunteers is still lacking: the process through which one learns the job, internalizes organizational values and goals, and becomes an effective and involved volunteer. By performing an ethnographic study with Israeli volunteers working for at-risk youth, the organizational process was portrayed. The Volunteering Stages and Transitions Model (VSTM) presented in this article indicates five different phases in volunteers' socialization (nominee, newcomer, emotional involvement, established volunteering and retiring). The importance of the model lies in the way it explains transitions between the phases and details the process, experiences, and emotions involved in each phase. The transformation is reflected in different aspects related to volunteer work: activity and training; emotions and perceptions; attitudes and behavior; perceived benefits and costs; and relationships with the organization, peers and recipients.