FOSL1 promotes cholangiocarcinoma via transcriptional effectors that could be therapeutically targeted

Understanding the molecular mechanisms involved in cholangiocarcinoma (bile duct cancer) development and progression stands as a critical step for the development of novel therapies. Through an inter-species approach, this study provides evidence of the clinical and functional role of the transcription factor FOSL1 in cholangiocarcinoma. Moreover, we report that downstream effectors of FOSL1 are susceptible to pharmacological inhibition, thus providing new opportunities for therapeutic intervention

Signature-driven repurposing of Midostaurin for combination with MEK1/2 and KRASG12C inhibitors in lung cancer

Drug combinations are key to circumvent resistance mechanisms compromising response to single anti-cancer targeted therapies. The implementation of combinatorial approaches involving MEK1/2 or KRASG12C inhibitors in the context of KRAS-mutated lung cancers focuses fundamentally on targeting KRAS proximal activators or effectors. However, the antitumor effect is highly determined by compensatory mechanisms arising in defined cell types or tumor subgroups. A potential strategy to find drug combinations targeting a larger fraction of KRAS-mutated lung cancers may capitalize on the common, distal gene expression output elicited by oncogenic KRAS. By integrating a signature-driven drug repurposing approach with a pairwise pharmacological screen, here we show synergistic drug combinations consisting of multi-tyrosine kinase PKC inhibitors together with MEK1/2 or KRASG12C inhibitors. Such combinations elicit a cytotoxic response in both in vitro and in vivo models, which in part involves inhibition of the PKC inhibitor target AURKB. Proteome profiling links dysregulation of MYC expression to the effect of both PKC inhibitor-based drug combinations. Furthermore, MYC overexpression appears as a resistance mechanism to MEK1/2 and KRASG12C inhibitors. Our study provides a rational framework for selecting drugs entering combinatorial strategies and unveils MEK1/2- and KRASG12C-based therapies for lung cancer.M.R. was supported by a fellowship from MICIU (FPU15/00173), R.E. by a donation from Mauge Burgos de la Iglesia’s family. The Proteomics Platforms of Navarrabiomed led by E.S. and J.F.-I. is a member of Proteored, PRB3 and is supported by grant PT17/0019 of the PE I + D + i 2013–2016, funded by ISCIII and ERDF. E.J.-L. was supported by Foundation of Spanish Association Against Cancer (PROYE18012ROSE), by Centro de Investigación Biomédica en Red (CIBERONC; CB16-12-00350), and by Generalitat Valenciana (AICO/2021/333). F.L. was funded by the Gobierno de Navarra (Ref. 34/2021), the Cancer Research Thematic Network of the Instituto de Salud Carlos III (RTICC RD12/0036/0066), PID2021-122638OB-I00 MCIN/AEI/10.13039/501100011033/ FEDER, UE and by FEDER “Una manera de hacer Europa”. I.F. was funded by FIS PI19/00320 and by the Miguel Servet Program CP21/00052. S.V. was supported by Ministerio de Ciencia, Innovación y Universidades, Convocatoria 2019 para incentivar la Incorporación Estable de Doctores (IED2019-001007-I), by FEDER /Ministerio de Ciencia, Innovación y Universidades - Agencia Estatal de Investigación (SAF2017-89944-R and PID2020‐116344‐RB‐100/MCIN/AEI/10.13039/501100011033, by a Leonardo Grant for Researchers and Cultural Creators 2018 from BBVA Foundation, by a seed grant at the I Convocatoria Proyectos Prueba de Concepto from PRB3-Proteored (Institute of Health Carlos III-ISCIII), by Fundació La Marató de TV3 (474/C/2019), and by Foundation of Spanish Association Against Cancer - Strategic Projects 2020 (PROYE20029VICE). M.P.-S. and S.V. were also funded by Fundación Alberto Palatchi. None of the funding sources were involved in the decision to submit the article for publication.Peer reviewe

Entrepreneurial intention among University students in Malaysia: integrating self-determination theory and the theory of planned behavior

The present study endeavors to develop a deeper understanding of the motivational processes involved in intentional entrepreneurial behavior. For this purpose, it integrates the social cognitive approach of the theory of planned behavior (TPB) and the organismic theory of motivation of self-determination theory (SDT). More specifically, it tests the role of basic psychological needs of autonomy, competence and relatedness as defined in SDT in shaping university students’ attitudes and intentions toward entrepreneurship. The sample of this study consisted of 438 (Males = 166, Females =272) 3rd and4th year university students from four Malaysian Public Universities. The results of the study show that the model strongly explains about 71% of the variance in entrepreneurial intention. Basic psychological needs of autonomy, competence and relatedness have a strong indirect impact on entrepreneurial intention via their attitudinal antecedents: attitude,subjective norm, and perceived behavioral control. This indicates a full-mediational model,where the attitudinal factors operated as transmitters of effects from the distal constructs ofSDT on entrepreneurial intention. These findings confirm that both SDT and the TPB provide complementary explanations of the motivational processes of entrepreneurial behavior. The study contributes to the existing knowledge by providing a theory-based understanding of the role of motivations in the formation of entrepreneurial intentions. It opens the way for future research to analyze how alternative motivations may affect new venture creation, survival and success

Current Status of Langmuir Monolayer Degradation of Polymeric Biomaterials

Langmuir monolayer degradation (LMD) experiments with polymers possessing outstanding biomedical application potential yield information regarding the kinetics of their hydrolytic or enzymatic chain scission under well-defined and adjustable degradation conditions. A brief review is given of LMD investigations, including the author's own work on 2-dimensional (2D) polymer systems, providing chain scission data, which are not disturbed by simultaneously occurring transport phenomena, such as water penetration into the sample or transport of scission fragments out of the sample. A knowledge-based approach for the description and simulation of polymer hydrolytic and enzymatic degradation based on a combination of fast LMD experiments and computer simulation of the water penetration is briefly introduced. Finally, the advantages and disadvantages of this approach are discussed

Entrepreneurial orientation and the performance of service business

Entrepreneurial orientation, Entrepreneurship, Service business, Performance, Culture, Japanese restaurant,