IGF-1R inhibition sensitizes breast cancer cells to ATM-Related Kinase (ATR) inhibitor and cisplatin

The complexity of the IGF-1 signalling axis is clearly a roadblock in targeting this receptor in cancer therapy. Here, we sought to identify mediators of resistance, and potential co-targets for IGF-1R inhibition. By using an siRNA functional screen with the IGF-1R tyrosine kinase inhibitor (TKI) BMS-754807 in MCF-7 cells we identified several genes encoding components of the DNA damage response (DDR) pathways as mediators of resistance to IGF-1R kinase inhibition. These included ATM and Ataxia Telangiectasia and RAD3-related kinase (ATR). We also observed a clear induction of DDR in cells that were exposed to IGF-1R TKIs (BMS-754807 and OSI-906) as indicated by accumulation of γ-H2AX, and phosphorylated Chk1. Combination of the IGF-1R/IR TKIs with an ATR kinase inhibitor VE-821 resulted in additive to synergistic cytotoxicity compared to either drug alone. In MCF-7 cells with stably acquired resistance to the IGF-1R TKI (MCF-7-R), DNA damage was also observed, and again, dual inhibition of the ATR kinase and IGF-1R/IR kinase resulted in synergistic cytotoxicity. Interestingly, dual inhibition of ATR and IGF-1R was more effective in MCF-7-R cells than parental cells. IGF-1R TKIs also potentiated the effects of cisplatin in a panel of breast cancer cell lines. Overall, our findings identify induction of DDR by IGF-1R kinase inhibition as a rationale for co-targeting the IGF-1R with ATR kinase inhibitors or cisplatin, particularly in cells with acquired resistance to TKIs.

Síndrome de boca ardente

A Síndrome de Boca Ardente (SBA) é uma condição caracterizada por uma sensação descrita pelo paciente como ardência e que afeta a mucosa oral. Tem sido referida como dor orofacial crónica, sem lesões na mucosa oral ou outros sinais clínicos evidentes. Afeta predominantemente mulheres no período pós-menopáusico. A sua etiologia foi considerada multifatorial, contudo foram sugeridos como fatores etiológicos os seguintes fatores: locais, sistémico, psicológicos, neuropáticos e idiopático. O seu diagnóstico é complexo e essencialmente por exclusão. De forma a compreender quais são os fatores etiológicos implicados nesta síndrome, como é realizado o seu diagnóstico e quais são os tratamentos utilizados de forma eficaz, foi realizada uma revisão bibliográfica nas bases de dados “PubMed”e “B-On”. O tratamento geralmente tem como objetivo o alívio sintomático de forma a melhorar a qualidade de vida das pessoas afetadas por SBA, as modalidades de tratamento podem variar desde farmacológicos até aos não farmacológicos. Ainda não existe um consenso relativamente aos critérios de diagnósticos que devem ser utilizados e nem do mais eficaz. Há necessidade de realização de mais estudos de forma a criar algoritmos específicos para esta condição.

Business model evolution and firm performance of entrepreneurial companies

This research explores the business model (BM) evolution process of entrepreneurial companies and investigates the relationship between BM evolution and firm performance. Recently, it has been increasingly recognised that the innovative design (and re-design) of BMs is crucial to the performance of entrepreneurial firms, as BM can be associated with superior value creation and competitive advantage. However, there has been limited theoretical and empirical evidence in relation to the micro-mechanisms behind the BM evolution process and the entrepreneurial outcomes of BM evolution. This research seeks to fill this gap by opening up the ‘black box’ of the BM evolution process, exploring the micro-patterns that facilitate the continuous shaping, changing, and renewing of BMs and examining how BM evolutions create and capture value in a dynamic manner. Drawing together the BM and strategic entrepreneurship literature, this research seeks to understand: (1) how and why companies introduce BM innovations and imitations; (2) how BM innovations and imitations interplay as patterns in the BM evolution process; and (3) how BM evolution patterns affect firm performances. This research adopts a longitudinal multiple case study design that focuses on the emerging phenomenon of BM evolution. Twelve entrepreneurial firms in the Chinese Online Group Buying (OGB) industry were selected for their continuous and intensive developments of BMs and their varying success rates in this highly competitive market. Two rounds of data collection were carried out between 2013 and 2014, which generates 31 interviews with founders/co-founders and in total 5,034 pages of data. Following a three-stage research framework, the data analysis begins by mapping the BM evolution process of the twelve companies and classifying the changes in the BMs into innovations and imitations. The second stage focuses down to the BM level, which addresses the BM evolution as a dynamic process by exploring how BM innovations and imitations unfold and interplay over time. The final stage focuses on the firm level, providing theoretical explanations as to the effects of BM evolution patterns on firm performance. This research provides new insights into the nature of BM evolution by elaborating on the missing link between BM dynamics and firm performance. The findings identify four patterns of BM evolution that have different effects on a firm’s short- and long-term performance. This research contributes to the BM literature by presenting what the BM evolution process actually looks like. Moreover, it takes a step towards the process theory of the interplay between BM innovations and imitations, which addresses the role of companies’ actions, and more importantly, reactions to the competitors. Insights are also given into how entrepreneurial companies achieve and sustain value creation and capture by successfully combining the BM evolution patterns. Finally, the findings on BM evolution contributes to the strategic entrepreneurship literature by increasing the understanding of how companies compete in a more dynamic and complex environment. It reveals that, the achievement of superior firm performance is more than a simple question of whether to innovate or imitate, but rather an integration of innovation and imitation strategies over time. This study concludes with a discussion of the findings and their implications for theory and practice.

Étude du rôle de la membrane basale spécialisée dans la maturation de l'émail

Les cellules épithéliales qui produisent l’émail, les améloblastes, sont séparées de l'émail au niveau de la zone de maturation par une membrane basale spécialisée (MBS) enrichie en laminine 332 (LM-332). Cette protéine hétérotrimérique (composée des chaînes α3, ß3 et γ2) assure l'intégrité structurelle des membranes basales (MB) et influence divers processus cellulaires épithéliaux tels que l'adhésion et la différenciation cellulaire. Des modèles de souris « knockout » (KO), où les gènes codant pour LM-332 ont été supprimés, meurent peu après la naissance. Néanmoins, ce phénotype létal peut être contourné en substituant chez la souris le gène produisant la chaîne γ2 de la laminine (LAMC2) par sa forme humaine, sous le contrôle de l’expression du promoteur-rtTA, de la cytokératine 14, inductible par la prise de doxycycline (Dox) - (Tet-on). Le but de ce projet est d’examiner si l’utilisation de cette protéine humaine chez la souris a un effet sur la structuration de la MBS ainsi que sur la maturation de l'émail. La phase de maturation de l’organe de l’émail chez la souris transgénique a été sévèrement altérée par rapport à une souris normale (WT). La MBS n’est plus visible, une matrice dystrophique s’est formée dans la couche d'émail dans la phase de maturation, et la présence d’une matrice résiduelle de l'émail est observée durant la phase tardive de maturation. Des micro-analyses tomographiques ont révélé une usure excessive des surfaces occlusales des molaires, un écroulement de l'émail sur les pointes des incisives et une hypominéralisation de l'émail. Cependant, aucune altération structurale due à cette recombinaison transgénique n’a été observée dans d'autres sites épithéliaux, tels que la peau, le palais et la langue. Ces résultats indiquent que, bien que ce modèle de souris humanisée soit capable de rétablir ses fonctions dans divers tissus épithéliaux, il est incapable de soutenir la structuration d'une MBS à l'interface entre les améloblastes et l’émail en maturation. Cet échec peut être lié à la composition spécifique de la MBS dans la phase de maturation et supporte l’hypothèse que la MBS est essentielle pour la maturation adéquate de l'émail.

Étude du rôle de la membrane basale spécialisée dans la maturation de l'émail

Les cellules épithéliales qui produisent l’émail, les améloblastes, sont séparées de l'émail au niveau de la zone de maturation par une membrane basale spécialisée (MBS) enrichie en laminine 332 (LM-332). Cette protéine hétérotrimérique (composée des chaînes α3, ß3 et γ2) assure l'intégrité structurelle des membranes basales (MB) et influence divers processus cellulaires épithéliaux tels que l'adhésion et la différenciation cellulaire. Des modèles de souris « knockout » (KO), où les gènes codant pour LM-332 ont été supprimés, meurent peu après la naissance. Néanmoins, ce phénotype létal peut être contourné en substituant chez la souris le gène produisant la chaîne γ2 de la laminine (LAMC2) par sa forme humaine, sous le contrôle de l’expression du promoteur-rtTA, de la cytokératine 14, inductible par la prise de doxycycline (Dox) - (Tet-on). Le but de ce projet est d’examiner si l’utilisation de cette protéine humaine chez la souris a un effet sur la structuration de la MBS ainsi que sur la maturation de l'émail. La phase de maturation de l’organe de l’émail chez la souris transgénique a été sévèrement altérée par rapport à une souris normale (WT). La MBS n’est plus visible, une matrice dystrophique s’est formée dans la couche d'émail dans la phase de maturation, et la présence d’une matrice résiduelle de l'émail est observée durant la phase tardive de maturation. Des micro-analyses tomographiques ont révélé une usure excessive des surfaces occlusales des molaires, un écroulement de l'émail sur les pointes des incisives et une hypominéralisation de l'émail. Cependant, aucune altération structurale due à cette recombinaison transgénique n’a été observée dans d'autres sites épithéliaux, tels que la peau, le palais et la langue. Ces résultats indiquent que, bien que ce modèle de souris humanisée soit capable de rétablir ses fonctions dans divers tissus épithéliaux, il est incapable de soutenir la structuration d'une MBS à l'interface entre les améloblastes et l’émail en maturation. Cet échec peut être lié à la composition spécifique de la MBS dans la phase de maturation et supporte l’hypothèse que la MBS est essentielle pour la maturation adéquate de l'émail.

A NOVEL MODELING AND STATE OF CHARGE ESTIMATION SCHEME FOR LITHIUM-ION BATTERIES

Lithium Ion (Li-Ion) batteries have got attention in recent decades because of their undisputable advantages over other types of batteries. They are used in so many our devices which we need in our daily life such as cell phones, lap top computers, cameras, and so many electronic devices. They also are being used in smart grids technology, stand-alone wind and solar systems, Hybrid Electric Vehicles (HEV), and Plug in Hybrid Electric Vehicles (PHEV). Despite the rapid increase in the use of Lit-ion batteries, the existence of limited battery models also inadequate and very complex models developed by chemists is the lack of useful models a significant matter. A battery management system (BMS) aims to optimize the use of the battery, making the whole system more reliable, durable and cost effective. Perhaps the most important function of the BMS is to provide an estimate of the State of Charge (SOC). SOC is the ratio of available ampere-hour (Ah) in the battery to the total Ah of a fully charged battery. The Open Circuit Voltage (OCV) of a fully relaxed battery has an approximate one-to-one relationship with the SOC. Therefore, if this voltage is known, the SOC can be found. However, the relaxed OCV can only be measured when the battery is relaxed and the internal battery chemistry has reached equilibrium. This thesis focuses on Li-ion battery cell modelling and SOC estimation. In particular, the thesis, introduces a simple but comprehensive model for the battery and a novel on-line, accurate and fast SOC estimation algorithm for the primary purpose of use in electric and hybrid-electric vehicles, and microgrid systems. The thesis aims to (i) form a baseline characterization for dynamic modeling; (ii) provide a tool for use in state-of-charge estimation. The proposed modelling and SOC estimation schemes are validated through comprehensive simulation and experimental results.

Effects of hook and bait on targeted and bycatch fishes in an equatorial atlantic pelagic longline fishery

We examined the effects of different hook style and bait type combinations on the catches of targeted, bycatch, and discarded fishes in equatorial Atlantic waters. In total, 221 longline sets (>305,000 hooks) were deployed from Portuguese pelagic longline vessels (SELECT -PAL Project) during the February–October fishing season. Three different hook styles and two bait types were tested: the traditional J-hook was compared to two circle hooks (one non-offset and one with 10° offset), and squid bait was compared to mackerel. Catch per unit effort (CPU Es) were calculated and compared between the different hook style and bait type combinations, which indicated that the effects of hook style and bait on the CPU Es were species-specific. For example, swordfish CPU Es were higher with J-hooks baited with squid, while for targeted tunas and blue shark only the bait effect was significant, but with opposite effect (i.e., higher catches of tuna with squid bait and higher catches of blue shark with mackerel bait). For the discarded species, at-haulback mortality was also species-specific. Proportions of alive vs dead specimens at time of fishing gear retrieval did not vary significantly by hook style or bait type combinations. The total retained catch was analyzed in value per unit effort (VPU E), and indicated losses in fishery revenue when mackerel was used instead of squid, but not when circle hooks were used instead of J-hooks.

Effect of nitrogen fertilization on soil microbial biomass in an Oxisol cultivated with irrigated barley in the Brazilian Cerrado.

Abstract:The aim of this study was to evaluate the effect of different nitrogen doses and five period of sample collection, on soil microbial biomass - nitrogen (SMB-N), total nitrogen (total N) and percentual ratio of the microbial biomass and total N (SMB-N/total N) in a Oxisol cultivated with barley (Hordeum vulgare L.). The experiment was installed in June, 2005, in an area located at Embrapa Cerrados, Federal District. The experimental design was a randomized block, with three replicates. The plots received doses of nitrogen: 20 - 40 - 80 kg ha-1 N and a control without it and the subplots were period of soil sample. Three applications of N were realized: 10 kg ha-1 on the 5th day (06/14) after sowing; the rest of N was parceled in two applications with fertigation, on tillage, on the 27th (07/08) DAP, e no 43rd (07/22) DAP. Soil samples layer (0 - 10 cm deep) were collected for (SMB-N) determination and total N in six periods: 02 days before of the first fertigation; 02 days after of the first fertigation; 04 days before of the last fertigation and 04 days after of the last fertigation; on flowering stage and after harvesting. There was effect of the doses of N and the period of soil collection on the SMB-N, total N and in the ratio SMB-N/total N. The average values of total N revealed steadier in short-term (cycle of the culture) and this was not a good parameter to evaluate the behavior and N transformations in the soil-plant system. Resumen: El objetivo de este estudio fue evaluar el efecto de diferentes dosis de nitrógeno y cinco período de muestreo en la biomasa microbiana del complejo suelo - nitrogeno (BMS-N), nitrógeno total (N total) y la relación porcentual de la biomasa microbiana y N total (BMS-N/N total) en un Oxisol cultivado con cebada (Hordeum vulgare L.). El estudio se inició en junio de 2005 en la estación experimental de la Empresa de Pesquisa Agropecuaria (Embrapa-Cerrados), Distrito Federal, Brazil. El experimento se dispuso en bloques al azar con tres repeticiones. Las parcelas recibieron dosis de nitrógeno: 20 - 40 - 80 kg/ha de N más un control sin N, y las subparcelas fueron el periodo de muestro. Las aplicaciones de N se realizaron de la forma siguiente: cinco días después de la siembra (dds) se aplicaron 10 kg/ha y el resto de la dosis se aplicó con fertirrigación en dos dosis 27 y 43 dds. Las muestras de suelo (0-10 cm de profundidad) para determinar BMS-N y N total fueron tomadas, 2 días antes e igual número de días después de la primera fertirrigación y 4 días antes y después de la última, en floración y después de la cosecha. No se encontró efecto de las dosis de N y el período de muestreo en el BMS-N, N total y en la relación BMS-N/N total. Los valores medios de N total fueron más estable en el corto plazo (ciclo de la cultivo) lo que indica que éste no es un buen parámetro para evaluar la dinámica del N y sus transformaciones en el sistema suelo-planta.