Patients' and physicians' preferences for type 2 diabetes mellitus treatments in Spain and Portugal: a discrete choice experiment

Objective To assess Spanish and Portuguese patients’ and physicians’ preferences regarding type 2 diabetes mellitus (T2DM) treatments and the monthly willingness to pay (WTP) to gain benefits or avoid side effects. Methods An observational, multicenter, exploratory study focused on routine clinical practice in Spain and Portugal. Physicians were recruited from multiple hospitals and outpatient clinics, while patients were recruited from eleven centers operating in the public health care system in different autonomous communities in Spain and Portugal. Preferences were measured via a discrete choice experiment by rating multiple T2DM medication attributes. Data were analyzed using the conditional logit model. Results Three-hundred and thirty (n=330) patients (49.7% female; mean age 62.4 [SD: 10.3] years, mean T2DM duration 13.9 [8.2] years, mean body mass index 32.5 [6.8] kg/m2, 41.8% received oral + injected medication, 40.3% received oral, and 17.6% injected treatments) and 221 physicians from Spain and Portugal (62% female; mean age 41.9 [SD: 10.5] years, 33.5% endocrinologists, 66.5% primary-care doctors) participated. Patients valued avoiding a gain in bodyweight of 3 kg/6 months (WTP: €68.14 [95% confidence interval: 54.55–85.08]) the most, followed by avoiding one hypoglycemic event/month (WTP: €54.80 [23.29–82.26]). Physicians valued avoiding one hypoglycemia/week (WTP: €287.18 [95% confidence interval: 160.31–1,387.21]) the most, followed by avoiding a 3 kg/6 months gain in bodyweight and decreasing cardiovascular risk (WTP: €166.87 [88.63–843.09] and €154.30 [98.13–434.19], respectively). Physicians and patients were willing to pay €125.92 (73.30–622.75) and €24.28 (18.41–30.31), respectively, to avoid a 1% increase in glycated hemoglobin, and €143.30 (73.39–543.62) and €42.74 (23.89–61.77) to avoid nausea. Conclusion Both patients and physicians in Spain and Portugal are willing to pay for the health benefits associated with improved diabetes treatment, the most important being to avoid hypoglycemia and gaining weight. Decreased cardiovascular risk and weight reduction became the third most valued attributes for physicians and patients, respectively

The MNT transcription factor autoregulates its expression and supports proliferation in MYC-associated factor X (MAX)-deficient cells

The MAX network transcriptional repressor (MNT) is an MXD family transcription factor of the basic helix-loop-helix (bHLH) family. MNT dimerizes with another transcriptional regulator, MYC-associated factor X (MAX), and down-regulates genes by binding to E-boxes. MAX also dimerizes with MYC, an oncogenic bHLH transcription factor. Upon E-box binding, the MYC-MAX dimer activates gene expression. MNT also binds to the MAX dimerization protein MLX (MLX), and MNT-MLX and MNT-MAX dimers co-exist. However, all MNT functions have been attributed to MNT-MAX dimers, and no functions of the MNT-MLX dimer have been described. MNT's biological role has been linked to its function as a MYC oncogene modulator, but little is known about its regulation. We show here that MNT localizes to the nucleus of MAX-expressing cells and that MNT-MAX dimers bind and repress the MNT promoter, an effect that depends on one of the two E-boxes on this promoter. In MAX-deficient cells, MNT was overexpressed and redistributed to the cytoplasm. Interestingly, MNT was required for cell proliferation even in the absence of MAX. We show that in MAX-deficient cells, MNT binds to MLX, but also forms homodimers. RNA-sequencing experiments revealed that MNT regulates the expression of several genes even in the absence of MAX, with many of these genes being involved in cell cycle regulation and DNA repair. Of note, MNT-MNT homodimers regulated the transcription of some genes involved in cell proliferation. The tight regulation of MNT and its functionality even without MAX suggest a major role for MNT in cell proliferation.This work was supported by Grant SAF2017-88026-R from Agencia Estatal de Investigación, Spanish Government (to J. L. and M. D. D.), funded in part by FEDER Program from the European Union, National Institutes of Health Grant CA57138/CA from NCI (to R. N. E.), and grants from Shriners Hospitals for Children (to P. J. H.). The authors declare that they have no conflicts of interest with the contents of this article. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health

Matching microscopic and macroscopic responses in glasses

Primero reproducimos en las computadoras Janus y Janus II un experimento importante que mide la longitud de la coherencia de los hilados de vidrio a través de la reducción de las barreras de energía libre inducidas por el efecto Zeeman. En segundo lugar, determinamos el comportamiento de escala que permite un análisis cuantitativo de un nuevo experimento informado en la Carta complementaria [S. Guchhait y R. Orbach, Phys. Rev. Lett. 118, 157203 (2017)]. El valor de la longitud de coherencia estimada a través del análisis de las funciones de correlación microscópicas resulta ser cuantitativamente consistente con su medición a través de las funciones de respuesta macroscópica. Además, las susceptibilidades no lineales, recientemente medidas en líquidos formadores de vidrio, se escalan como potencias de la misma longitud microscópica.We first reproduce on the Janus and Janus II computers a milestone experiment that measures the spin glass coherence length through the lowering of free-energy barriers induced by the Zeeman effect. Secondly, we determine the scaling behavior that allows a quantitative analysis of a new experiment reported in the companion Letter [S. Guchhait and R. Orbach, Phys. Rev. Lett. 118, 157203 (2017)]. The value of the coherence length estimated through the analysis of microscopic correlation functions turns out to be quantitatively consistent with its measurement through macroscopic response functions. Further, nonlinear susceptibilities, recently measured in glass-forming liquids, scale as powers of the same microscopic length.• European Research Council. Beca No. NPRGGLASS. Ayuda para Marco Baity Jesi • Unión Europea. Marie Skłodowska- Curie. Beca No. 654971 • Consejo Europeo de Investigación (ERC). Subvención 694925 • University of Syracuse. Beca No. NSF-DMR-305184, para David Yllanes Mosquera • Ministerio de Economía y Competitividad. No. FIS2012-35719-C02, No. FIS2013-42840-P (I+D+i), No. FIS2015-65078-C2, No. FIS2016-76359-P (I+D+i), y No. TEC2016-78358-R • Junta de Extremadura y Fondos FEDER. Contrato parcial GRU10158 • Dipùtación General de Aragón y Fondos Social Europeo. AyudapeerReviewe

New biological functions of MXD1 and MNT, proteins of the MYC-MAX-MXD network

RESUMEN: En esta Tesis Doctoral se estudian funciones biológicas de las proteínas MXD1 y MNT. MXD1 y MNT son dos proteínas pertenecientes a la familia de factores de transcripción MXD. Las proteínas MXD a su vez, forman parte de la red MYC-MAX-MXD compuesta por las familias de factores de transcripción MYC, MAX y MXD. Esta red se encarga de regular la expresión génica de genes implicados en multitud de funciones biológicas como son la proliferación celular, el crecimiento celular, el metabolismo, la apoptosis o la diferenciación celular. Las proteínas MYC heterodimerizan con MAX para activar la transcripción génica de estos genes, mientras que las proteínas MXD heterodimerizan con MAX para reprimirla. Recientemente se han descubierto mutaciones inactivadoras de función de las proteínas MAX en paragangliomas, feocromocitomas o cáncer de pulmón de células pequeñas sugiriendo que un desequilibrio de la red MYC-MAX-MXD podría contribuir al desarrollo de estos tumores. En esta Tesis se describen nuevas funciones de las proteínas MXD1 y MNT independientes de su heterodimerización con MAX que ayudan a la entender el comportamiento de esta red en ausencia de MAX.ABSTRACT: In this Thesis new biological functions of the MXD1 and MNT proteins are described. MXD1 and MNT are two proteins belonging to the MXD family of transcription factors. The MXD proteins take part in the MYC-MAX-MXD network composed of the family of transcription factors MYC, MAX and MXD. This network regulates the transcription of genes involved in multiple biological functions such as proliferation, cell growth, metabolism, apoptosis and differentiation. The MYC proteins heterodimerize with MAX to activate the transcription of these genes meanwhile the MXD proteins heterodimerize with MAX to repress it. Recently, it has been described inactivating mutations in the MAX gene in paranganglyomas, pheochromocytomas and small cell lung cancer tumors suggesting that a disequilibrium of the MYC-MAX-MXD network can contribute to the development of these tumors. In this Thesis new MAX- independent functions of MXD1 and MNT are described that help to understand the behavior of the network in the absence of MAX

Regulation of Nucleolar Activity by MYC

The nucleolus harbors the machinery necessary to produce new ribosomes which are critical for protein synthesis. Nucleolar size, shape, and density are highly dynamic and can be adjusted to accommodate ribosome biogenesis according to the needs for protein synthesis. In cancer, cells undergo continuous proliferation; therefore, nucleolar activity is elevated due to their high demand for protein synthesis. The transcription factor and universal oncogene MYC promotes nucleolar activity by enhancing the transcription of ribosomal DNA (rDNA) and ribosomal proteins. This review summarizes the importance of nucleolar activity in mammalian cells, MYC’s role in nucleolar regulation in cancer, and discusses how a better understanding (and the potential inhibition) of aberrant nucleolar activity in cancer cells could lead to novel therapeutics

Pequeños grandes artistas

Seleccionado en la convocatoria: Ayudas a la innovación e investigación educativa en centros docentes de niveles no universitarios, Gobierno de Aragón 2010-11Proyecto del CP Miguel Artigas para promover el espíritu creativo e incentivar un aprendizaje significativo y reflexivo a través de pintores de Aragón, España y Europa. Se realizan diversas actividades basadas en los materiales, técnicas y composiciones de los cuadros de Francisco de Goya, Salvador Dalí y Matisse. Los alumnos aprenden el lenguaje artístico, interpretan obras de diferentes autores y reconocen, respetan y disfrutan tradiciones culturales y folklore de diferentes sitios.Gobierno de Aragón. Departamento de Educación, Cultura y DeporteAragónDirección General de Política Educativa; Avda. Gómez Laguna, 25, planta 2; 50009 Zaragoza; Tel. +34976715416; Fax +34976715496ES

NUMB inactivation confers resistance to imatinib in chronic myeloid leukemia cells.

Chronic myeloid leukemia (CML) progresses from a chronic to a blastic phase, where the leukemic cells are proliferative and undifferentiated. The CML is nowadays successfully treated with BCR-ABL kinase inhibitors as imatinib and its derivatives. NUMB is an evolutionary well-conserved protein initially described as a functional antagonist of NOTCH function. NUMB is an endocytic protein associated with receptor internalization, involved in multiple cellular functions. It has been reported that MSI2 protein, a NUMB inhibitor, is upregulated in CML blast crisis, whereas NUMB itself is downregulated. This suggest that NUMB plays a role in the malignant progression of CML. Here we have generated K562 cells (derived from CML in blast crisis) constitutively expressing a dominant negative form of NUMB (dnNUMB). We show that dnNUMB expression confers a high proliferative phenotype to the cells. Importantly, dnNUMB triggers a partial resistance to imatinib in these cells, antagonizing the apoptosis mediated by the drug. Interestingly, imatinib resistance is not linked to p53 status or NOTCH signaling, as K562 lack p53 and imatinib resistance is reproduced in the presence of NOTCH inhibitors. Taken together, our data support the hypothesis that NUMB activation could be a new therapeutic target in CML.The work was supported by grants SAF2014-53526 (to JL), BFU2007-67476 and BFU2010-21634 (to MC) from Spanish Ministry of Economy and Competitiveness (MINECO), and RD12/0036/ 0033 (to JL), RD12/0036/0054 (to AB) and RD12/0019/0006 and PI12/01097 (to FM) from Instituto Carlos III, and grant PI-57069 from CICE, FEDER/Fondo de Cohesion Europeo (FSE) de Andalucía 2007–2013 (to FM). The funding from MINECO and Instituto Carlos III was co-sponsored by the European Union FEDER program. EGA was supported with a JAE-doc contract form CSIC, MCL-N was supported by the FPU program from MINECO and LG-