An Interim Report on the Development of the Psychological Trauma and Resources Scales

The William S. Hall Psychiatric Institute Psychological Trauma and Psychological Resources Scales is a preliminary measure for the assessment of psychological trauma and psychological health from a developmental perspective. This three-part article (1) discusses the various rationales leading to the development of the scales, (2) provides a factor-analysis of responses of 336 college students, and (3) addresses current ( N=37) and planned efforts to establish reliability and validity of a more refined version

Design and synthesis of novel selective anaplastic lymphoma kinase inhibitors

Anaplastic lymphoma kinase (ALK) is a receptor tyrosine kinase belonging to the insulin receptor superfamily. Expression of ALK in normal human tissues is only found in a subset of neural cells, however it is involved in the genesis of several cancers through genetic aberrations involving translocation of the kinase domain with multiple fusion partners (e.g., NPM-ALK in anaplastic large cell lymphoma ALCL or EML4-ALK in non-small cell lung cancer) or activating mutations in the full-length receptor resulting in ligand-independent constitutive activation (e.g., neuroblastoma). Here we are reporting the discovery of novel and selective anaplastic lymphoma kinase inhibitors from specific modifications of the 2,4-diaminopyridine core present in TAE684 and LDK378. Synthesis, structure activity relationships (SAR), absorption, distribution, metabolism, and excretion (ADME) profile, and in vivo efficacy in a mouse xenograft model of anaplastic large cell lymphoma are described

(R)-2-Phenylpyrrolidine substituted imidazopyridazines: A new class of potent and selective pan-TRK inhibitors

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (R)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (R)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs

[1,2,4]Triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: Antagonists of the Wnt Pathway That Inhibit Tankyrases 1 and 2 via Novel Adenosine Pocket Binding

The Wnt signaling pathway is critical to the regulation of key cellular processes. When deregulated, it has been shown to play a crucial role in the growth and progression of multiple human cancers. The identification of small molecule modulators of Wnt signaling has proven challenging, largely due to the relative paucity of druggable nodes in this pathway. Several recent publications have identified small molecule inhibitors of the Wnt pathway, and tankyrase (TNKS) inhibition has been demonstrated to antagonize Wnt signaling via axin stabilization. Herein, we report the early hit assessment of a series of compounds previously reported to antagonize Wnt signaling. We report the biophysical, computational characterization, structure–activity relationship, and physicochemical properties of a novel series of [1,2,4]­triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]­oxadiazole inhibitors of TNKS1 and 2. Furthermore, a cocrystal structure of compound <b>24</b> complexed to TNKS1 demonstrates an alternate binding mode for PARP family member proteins that does not involve interactions with the nicotinamide binding pocket

Discovery of GNF-5837, a Selective TRK Inhibitor with Efficacy in Rodent Cancer Tumor Models

Neurotrophins and their receptors (TRKs) play key roles in the development of the nervous system and the maintenance of the neural network. Accumulating evidence points to their role in malignant transformations, chemotaxis, metastasis, and survival signaling and may contribute to the pathogenesis of a variety of tumors of both neural and non-neural origin. By screening the GNF kinase collection, a series of novel oxindole inhibitors of TRKs were identified. Optimization led to the identification of GNF-5837 (<b>22</b>), a potent, selective, and orally bioavailable pan-TRK inhibitor that inhibited tumor growth in a mouse xenograft model derived from RIE cells expressing both TRKA and NGF. The properties of <b>22</b> make it a good tool for the elucidation of TRK biology in cancer and other nononcology indications

Microfiltration applied to dairy streams: removal of bacteria

[EN] Microfiltration applied in the dairy industry for bacteria removal is an important technology for extending the shelf life of milk while maintaining or even improving its organoleptic and nutritional properties. This article reviews the evolution of this technique over recent years and the advances currently being made in the field. The cited literature indicates the strategies used to overcome the main drawbacks of this type of operation, the most common operating conditions employed and the reduction degree of bacteria obtained. (C) 2012 Society of Chemical IndustryFernandez García, L.; Alvarez Blanco, S.; Riera Rodriguez, FA. (2013). Microfiltration applied to dairy streams: removal of bacteria. Journal of the Science of Food and Agriculture. 93(2):187-196. doi:10.1002/jsfa.5935S18719693

Automatización y control regulatorio de una columna de destilación extractiva a nivel planta piloto para la producción de etanol anhidro

La destilación extractiva es una de las principales tecnologías empleadas para la deshidratación de etanol y así usarlo como carburante. Entre los solventes que se pueden utilizar la glicerina presenta un alto potencial en cuanto al consumo energético de la operación. Por otra parte no existe una única metodología o algoritmo para seleccionar la estrategia de control de una columna de destilación puesto que cada sistema opera a diferentes condiciones y se presentan diferentes objetivos de control. Este trabajo aborda el estudio de dicho sistema a un nivel de simulación en estado estacionario para encontrar los parámetros de operación del proceso así como en estado dinámico para determinar la operabilidad y controlabilidad del sistema para finalmente seleccionar la estrategia de control a implementar en una columna real. Dicha estrategia de control se implemento en una columna de destilación a escala planta piloto para lo cual fue necesario realizar la instrumentación, automatización y configuración de 11 lazos de control en la columna. Finalmente, se ejecutan corridas experimentales para observar la dinámica del sistema, parámetros de operación reales y seleccionar una metodología de arranque y operación del sistema. / Abstract. Extractive distillation is one of the main technologies used for dehydration of ethanol and so use it as fuel. Among the solvents that can be used glycerol has a high potential in terms of energy consumption in the operation. Moreover there is no single methodology or algorithm to select the control strategy of a distillation column because each system operates at different conditions and have different control objectives. This paper deals with the study of this system to a level of steady-state simulation to find the process operating parameters as well as dynamic conditions to determine the operability and controllability of the system to finally select the control strategy to implement in a real column. This control strategy was implemented in a distillation column pilot scale for which it was necessary instrumentation, automation and configuration of 11 control loops in the column. Finally, experimental runs were performed to observe the dynamics of the system, actual operating parameters and select a startup and operation methodology.Maestrí

Discovery and SAR of [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazoles: Antagonists of the Wnt pathway that inhibit tankyrase 1&2

The Wnt signaling pathway is critical to the regulation of key cellular processes. When deregulated, it has been shown to play a crucial role in the growth and progression of multiple human cancers. The identification of small molecule modulators of Wnt signaling has proven challenging, largely due to the relative paucity of druggable nodes in this pathway. Several recent publications have identified small molecule inhibitors of the Wnt pathway and tankyrase (TNKS) inhibition has been demonstrated to antagonize Wnt signaling via axin stabilization. Herein we report the early hit assessment of a series of compounds previously reported to antagonize Wnt signaling. We report the biophysical, computational characterization, structure activity relationship and physicochemical properties of a novel series of [1,2,4]triazol-3-ylsulfanylmethyl)-3-phenyl-[1,2,4]oxadiazole inhibitors of TNKS1 and 2. Furthermore, a co-crystal structure of compound 24 complexed to TNKS1 demonstrates an alternate binding mode for PARP family member proteins that does not involve interactions with the nicotinamide binding pocket

(<i>R</i>)‑2-Phenylpyrrolidine Substituted Imidazopyridazines: A New Class of Potent and Selective Pan-TRK Inhibitors

Deregulated kinase activities of tropomyosin receptor kinase (TRK) family members have been shown to be associated with tumorigenesis and poor prognosis in a variety of cancer types. In particular, several chromosomal rearrangements involving TRKA have been reported in colorectal, papillary thyroid, glioblastoma, melanoma, and lung tissue that are believed to be the key oncogenic driver in these tumors. By screening the Novartis compound collection, a novel imidazopyridazine TRK inhibitor was identified that served as a launching point for drug optimization. Structure guided drug design led to the identification of (<i>R</i>)-2-phenylpyrrolidine substituted imidazopyridazines as a series of potent, selective, orally bioavailable pan-TRK inhibitors achieving tumor regression in rats bearing KM12 xenografts. From this work the (<i>R</i>)-2-phenylpyrrolidine has emerged as an ideal moiety to incorporate in bicyclic TRK inhibitors by virtue of its shape complementarity to the hydrophobic pocket of TRKs