135 research outputs found
Targeting molecular addictions in cancer
No full textCancer cells depend on a finite number of critical signals for their survival. Oncogene addiction, that is, the acquired dependence of a cancer cell on the activity of a single oncogenic gene product, has been the basis for the targeted therapy paradigm, and operationally defines such signals. Additionally, cancer cells have altered metabolic requirements that create addictions to specific nutrients such as glucose and glutamine. In this review, I will discuss the therapeutic opportunities that these two types of molecular addictions offer, focusing on lessons learned from targeting members of the epidermal growth factor receptor family of kinases, and components of MAPK pathway. I will also discuss the challenges in simultaneously harnessing two types of molecular addictions for therapeutic benefit, and the importance of understanding not only the effects of oncogenic signal transduction on metabolism, but also the impact of metabolic states on signal transduction
Mathematical modeling identifies optimum lapatinib dosing schedules for the treatment of glioblastoma patients.
No full textHuman primary glioblastomas (GBM) often harbor mutations within the epidermal growth factor receptor (EGFR). Treatment of EGFR-mutant GBM cell lines with the EGFR/HER2 tyrosine kinase inhibitor lapatinib can effectively induce cell death in these models. However, EGFR inhibitors have shown little efficacy in the clinic, partly because of inappropriate dosing. Here, we developed a computational approach to model the in vitro cellular dynamics of the EGFR-mutant cell line SF268 in response to different lapatinib concentrations and dosing schedules. We then used this approach to identify an effective treatment strategy within the clinical toxicity limits of lapatinib, and developed a partial differential equation modeling approach to study the in vivo GBM treatment response by taking into account the heterogeneous and diffusive nature of the disease. Despite the inability of lapatinib to induce tumor regressions with a continuous daily schedule, our modeling approach consistently predicts that continuous dosing remains the best clinically feasible strategy for slowing down tumor growth and lowering overall tumor burden, compared to pulsatile schedules currently known to be tolerated, even when considering drug resistance, reduced lapatinib tumor concentrations due to the blood brain barrier, and the phenotypic switch from proliferative to migratory cell phenotypes that occurs in hypoxic microenvironments. Our mathematical modeling and statistical analysis platform provides a rational method for comparing treatment schedules in search for optimal dosing strategies for glioblastoma and other cancer types
Inhibitors in AKTion: ATP-competitive vs allosteric.
No full textAberrant activation of the PI3K pathway is one of the commonest oncogenic events in human cancer. AKT is a key mediator of PI3K oncogenic function, and thus has been intensely pursued as a therapeutic target. Multiple AKT inhibitors, broadly classified as either ATP-competitive or allosteric, are currently in various stages of clinical development. Herein, we review the evidence for AKT dependence in human tumours and focus on its therapeutic targeting by the two drug classes. We highlight the future prospects for the development and implementation of more effective context-specific AKT inhibitors aided by our increasing knowledge of both its regulation and some previously unrecognised non-canonical functions
Figure 5—source data 1. Contains source data for Figure 5.
No full textThe serine–threonine kinase AKT regulates proliferation and survival by phosphorylating a network of protein substrates. In this study, we describe a kinase-independent function of AKT. In cancer cells harboring gain-of-function alterations in MET, HER2, or Phosphatidyl-Inositol-3-Kinase (PI3K), catalytically inactive AKT (K179M) protected from drug induced cell death in a PH-domain dependent manner. An AKT kinase domain mutant found in human melanoma (G161V) lacked enzymatic activity in vitro and in AKT1/AKT2 double knockout cells, but promoted growth factor independent survival of primary human melanocytes. ATP-competitive AKT inhibitors failed to block the kinase-independent function of AKT, a liability that limits their effectiveness compared to allosteric AKT inhibitors. Our results broaden the current view of AKT function and have important implications for the development of AKT inhibitors for cancer.National Institutes of Health (1R01NS080944–01, U54CA143798, F32 GM096558), the James S McDonnell Foundation, and National Brain Tumor Society Defeat GBM initiativ
Replication Data for: "Justice as Checks and Balances: Indigenous Claims in the Courts of Colonial Mexico"
No full textThe centralization of conflict resolution and the administration of justice, two crucial elements of state formation, are often ignored by the state-building literature. This article studies the monopolization of justice administration, using the historical example of the General Indian Court (GIC) of colonial Mexico. The author argues that this court's development and decision-making process can show us how the rule of law develops in highly authoritarian contexts. Centralized courts could be used strategically to solve an agency problem, limiting local elites' power and monitoring state agents. To curb these actors' power, the Spanish Crown allowed the indigenous population to raise claims and access property rights. But this access remained limited and subject to the Crown’s strategic considerations. The author’s theory predicts that a favorable ruling for the indigenous population was more likely in cases that threatened to increase the local elites’ power. This article shows the conditions under which the rule of law can emerge in a context where a powerful ruler is interested in imposing limits on local powers—and on their potential predation of the general population. It also highlights the endogenous factors behind the creation of colonial institutions and the importance of judicial systems in colonial governance
A systematic molecular and pharmacologic evaluation of AKT inhibitors reveals new insight into their biological activity
No full textBACKGROUND: AKT, a critical effector of the phosphoinositide 3-kinase (PI3K) signalling cascade, is an intensely pursued therapeutic target in oncology. Two distinct classes of AKT inhibitors have been in clinical development, ATP-competitive and allosteric. Class-specific differences in drug activity are likely the result of differential structural and conformational requirements governing efficient target binding, which ultimately determine isoform-specific potency, selectivity profiles and activity against clinically relevant AKT mutant variants. METHODS: We have carried out a systematic evaluation of clinical AKT inhibitors using in vitro pharmacology, molecular profiling and biochemical assays together with structural modelling to better understand the context of drug-specific and drug-class-specific cell-killing activity. RESULTS: Our data demonstrate clear differences between ATP-competitive and allosteric AKT inhibitors, including differential effects on non-catalytic activity as measured by a novel functional readout. Surprisingly, we found that some mutations can cause drug resistance in an isoform-selective manner despite high structural conservation across AKT isoforms. Finally, we have derived drug-class-specific phosphoproteomic signatures and used them to identify effective drug combinations. CONCLUSIONS: These findings illustrate the utility of individual AKT inhibitors, both as drugs and as chemical probes, and the benefit of AKT inhibitor pharmacological diversity in providing a repertoire of context-specific therapeutic options
Análisis del humor en las obras de María Fernanda Heredia: Amigo se escribe con H y Foto Estudio Corazón
No full textEl análisis del humor en las obras Amigo se escribe con H y Foto Estudio Corazón de María Fernanda Heredia, permite adentrarnos en el maravilloso mundo de la narrativa literaria. Poder relacionar el recurso humorístico con el estilo de escritura de esta talentosa literata, conduce a conocer dos valores fundamentales en la vida de los niños y jóvenes, como es el amor y la amistad, temas característicos en las obras de esta autora, ya que como ella manifiesta “no concibe la vida sin amor y sin humor” Con una gran habilidad literaria y un exquisito humor en la redacción, la autora encarna en cada uno de los personajes ficcionales, aspectos y cualidades tan humanas y reales, logrando que los lectores se sientan identificados con ellos. La lectura de sus obras, a más de producir goce y disfrute, conduce a la reflexión, porque la autora ha logrado plasmar en sus obras temas de la vida real; y, aunque estos a veces suelen ser duros y conflictivos, una dosis de humor los suaviza, haciendo que su lectura sea más divertida y amena.Analysis of humor in the works "Friend writes with H" and "Heart Photo studio" Maria Fernanda Heredia, can get into the wonderful world of literary narrative. To relate resource humorous writing style of this talented literate, it leads to meet two fundamental values in the lives of children and youth, such as love and mistad, characteristic themes in the works of the author, because as she says "can not conceive of life without humor
and without love" With great literary skill and exquisite humor in the writing, the author embodied in each of
fictional characters, aspects and qualities as human and real, making readers feel identified with them. Reading his works, apart from producing enjoyment leads to reflection, because the author has managed to capture in his works real life issues; and although these sometimes harsh and often conflicting, a dose of humor smooths, making reading more fun and enjoyable
EGFR feedback-inhibition by Ran-binding protein 6 is disrupted in cancer
No full textTransport of macromolecules through the nuclear pore by importins and exportins plays a critical role in the spatial regulation of protein activity. How cancer cells co-opt this process to promote tumorigenesis remains unclear. The epidermal growth factor receptor (EGFR) plays a critical role in normal development and in human cancer. Here we describe a mechanism of EGFR regulation through the importin β family member RAN-binding protein 6 (RanBP6), a protein of hitherto unknown functions. We show that RanBP6 silencing impairs nuclear translocation of signal transducer and activator of transcription 3 (STAT3), reduces STAT3 binding to the EGFR promoter, results in transcriptional derepression of EGFR, and increased EGFR pathway output. Focal deletions of the RanBP6 locus on chromosome 9p were found in a subset of glioblastoma (GBM) and silencing of RanBP6 promoted glioma growth in vivo. Our results provide an example of EGFR deregulation in cancer through silencing of components of the nuclear import pathway.This research was supported by the National Brain Tumor Society (I.K.M.), the National Institutes of Health grants 1R01NS080944-01 (I.K.M.), 1 R35 NS105109 01 (I.K.M.), and P30CA008748 (MSKCC Core Grant), the Geoffrey Beene Cancer Research Foundation (I.K.M.), the Cycle of Survival (I.K.M.), and the Seve Ballesteros Foundation (M.S.). B.O. was supported by an American–Italian Cancer Foundation fellowship and a MSKCC Brain Tumor Center grant. W.-Y.H. is the recipient of a FY15 Horizon Award from the U.S. Department of Defense (W81XWH-15-PRCRP-HA). A.C.-G. is the recipient of the Severo-Ochoa PhD fellowship. Further support was provided by the Sontag Foundation (B.S.T.). We thank all members of the Mellinghoff laboratory for helpful suggestions. We thank Dr. Fiona Ginty (Diagnostic Imaging and Biomedical Technologies, GE Global Research Center, Niskayuna, New York, USA) for assistance with multiplexed immunofluorescence. We thank A.J. Schuhmacher and C.S. Clemente-Troncone for assistance with the in vivo experiments, M. Kaufmann for assistance in the luciferase assays and N. Yannuzzi for assistance in cloning.S
"Autoinstrucción" Percepciones de los participantes del Área de Ortodoncia y Ortodoncia Dento-Maxilar de la Facultad de Odontología Universidad de Chile en el año 2016
No full textTrabajo de Investigación Requisito para optar al Título de Cirujano DentistaIntroducción: El sistema de educación chileno ha estado bajo constantes
modificaciones a lo largo de su historia, durante la cual la Universidad de Chile ha ido
generando instancias de innovación en el campo de la educación en sus diferentes
niveles. Se han desarrollado nuevos propósitos formativos y metodologías para
ayudar en el proceso de enseñanza aprendizaje como son por ejemplo la confección
de manuales de autoinstrucción. El presente trabajo se centra en las percepciones de
académicos y estudiantes del curso de Ortodoncia de pregrado del año 2016 para ver
cómo influyen éstos manuales en el proceso de enseñanza aprendizaje.
Material y métodos: Basado en el marco del paradigma interpretativo a través de
la metodología cualitativa, se abordó a los sujetos de estudio desde la interpretación
de la realidad del proceso enseñanza-aprendizaje, mediante la percepción de los
individuos.El universo en estudio comprendió 30 individuos, 6 académicos y 24
estudiantes del área, con los cuales se efectuaron sesiones de entrevista y 5 grupos
focales respectivamente, de 40 minutos de duración. Los grupos focales fueron
realizados en el horario del curso de Ortodoncia y Ortopedia Dentomaxilar II.
Mediante grabaciones de video y audio se recaudó la información y se analizó en el
programa para investigación cualitativa AQUAD 6.0.
Resultados: Para el estamento docente como para estudiantes, el uso de manuales
genera autonomía en el proceso de enseñanza, facilita la entrega de información,
genera independencia al momento de preparar los contenidos, esto permite llegar
mejor preparado a clases. Consideran que debe existir una retroalimentación de los
contenidos y una evaluación para sacar el máximo rendimiento a los manuales. Crear
y validar los manuales se ve como la principal dificultad para su desarrollo.
Conclusiones: Los hallazgos de este estudio sugieren que los manuales de
autoinstrucción son un aporte al proceso de enseñanza aprendizaje. No pueden ser el
único medio para la entrega de información. Deben existir clases presenciales y
evaluaciones para reforzar los contenidos.Adscrito a Proyecto PRI-ODO 15/005 "Cómo influye el uso de diferentes metodologías de enseñanza activo participativas en el proceso de enseñanza-aprendizaje del Área de Ortodoncia y Ortopedia Dentomaxilar en los años 2015 y 2016. Estudio Cualitativo
Selección de levaduras Saccharomyces y no Saccharomyces de la colección del ICVV en medio aeróbico para reducir el grado alcohólico del vino
No full textTrabajo fin de máster presentado en la Universidad del País Vasco, Máster en Enología Innovadora.--2021-09-24El presente trabajo tenía como objetivo seleccionar cepas apropiadas para obtener vinos con menor graduación alcohólica por respiración, dando continuidad al proceso de investigación iniciado por algunos integrantes del Microwine lab. Para ello, se realizó un análisis inicial de 115 cepas de levaduras de 6 especies diferentes de la colección del ICVV, en condiciones aeróbicas, buscando principalmente identificar aquellas que lograsen consumir la mayor cantidad de azúcar, produjeran un grado de alcohol suficiente para ser considerado ¿vino¿ y que mantuviesen los niveles de acético bajos, manteniendo durante los 6 primeros experimentos como cepa control a la levadura comercial PR 1280 (S. cerevisiae). Dichas cepas fueron
sometidas a un screening inicial y con base en los datos obtenidos de esta serie de experimentos, no solo se seleccionó 16 cepas para analizar en un siguiente nivel en condiciones controladas dentro del biorreactor, si no, que se consiguió determinar que una de las cepas se encontraba incorrectamente caracterizada. Los resultados finales permitieron llegar a la conclusión de que S. uvarum, es la especie que consiguió los mejores resultados al tener bajos niveles de acético
y conseguir casi 10 %V/V, aunque, los resultados de L. thermotolerans también fueron atractivos principalmente por la baja producción de acético. Sin embargo, en el caso contrario S. cerevisiae alertó en tanto que tuvo demasiadas fluctuaciones en sus resultados y además sus niveles de acético generado fueron con gran diferencia los más elevados del estudio
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