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Informal face-to-face communication and chance encounters encourage knowledge sharing. This Post-Occupancy Evaluation (POE) examines how well a new building of a Dutch University Institute (DI) supported interaction and perceived privacy among faculty members. The study is designed as a qualitative research project with in-depth interviews among faculty members before and after relocation into the new building. The transparent and centrally organized floor plan supported face-to-face communication but generated a lack of privacy for faculty members. Not all perceived affordances of the design were planned. Lack of visual privacy and the sense of being controlled by others were related to the hierarchical position of teachers in this Higher Education Institute (HEI) between students and the dean, which caused tension and diminished their well-being.

This paper discusses knowledge sharing through scenario development as applied in the interdisciplinary and international research project uVITAL. It focused on user-oriented upgrading of the social housing stock. The aim was to gain deeper insights into the specificities and commonalities of the four country case studies involved. Two online workshops, which included various steps for scenario development, were particularly important during the COVID-19 pandemic when face-to-face exchanges were not possible. A Miro whiteboard was very useful as a technical communication and collaboration tool. This paper outlines the benefits and challenges of scenario development to facilitate communication and collaboration between researchers from different disciplines and national and cultural backgrounds, particularly in online and hybrid settings. The well-structured process of scenario development was an important step in the project, moving from passive to active knowledge sharing. This included issues of content, geographical and cultural diversity and methodological openness. [ABSTRACT FROM AUTHOR]

With the need to increase total revenues, airports have begun to use commercial retail. A well-designed airport may provide great service to clients and consumers and increase their satisfaction and in turn their spending behaviours. Since there is suggestive evidence that there might be cultural associations of white, purple or black with different emotional loadings to these colours across cultures, the present study investigated passengers' preferences for architectural design characteristics of an airport in a new cultural setting. Discrete choice modelling was used to measure the passengers' preferences for 10 interior design characteristics of the passenger terminal using 3D renderings. Data on 435 passengers were collected at Mehrabad International Airport, which also included passengers' emotions. Passengers in the terminal hall preferred a curved and transparent ceiling, material in warm colours, cool lighting, with low width and low height, greenery and without any decorations. When compared to other studies, it may well be that passenger preferences for lighting and certain colour schemes reflect geographical or cultural differences. For other interior design characteristics, preferences relating to the shape of the ceiling and the amount of daylight, as well as the presence of greenery, may well be reflections of passengers' restorative needs. [ABSTRACT FROM AUTHOR]

Tobacco smoking is a very important preventable cause of mortality and morbidity, and this is also the case in immigrant populations. Therefore, smoking cessation interventions need to take these groups into account. Insight into the applicability of behavioral smoking cessation interventions for non-Western populations is necessary. The objective of our study is to gain insight into the beliefs of smoking cessation in Turkish and Moroccan immigrants in The Netherlands using the I-Change Model. In this model, intention and behavior are supposed to be determined by three types of (psychosocial) factors: attitudes, social influences and self-efficacy expectations. Face-to-face structured interviews among Turkish and Moroccan immigrants were conducted. Results indicate that in contrast to smokers, ex-smokers perceived fewer advantages of smoking and more advantages of smoking cessation. They also perceived less social pressure that encourages smoking (e.g. by being offered cigarettes) and a high self-efficacy of being able to quit. The I-Change Model explained 66% of the observed variance. We conclude that the basic factors identified in social cognition theories were replicated in this study. When developing smoking cessation interventions, the results show that it is important to include ethnic-specific salient beliefs, such as the subjective norms of the religious leader.

Using 3D design models, this study aims to better involve patients in the design of hospitals by investigating what physical environmental characteristics in hospital patient rooms are valued by patients. There is a plea for shared-decision-making and collaborative design processes with representatives from healthcare and the construction sector based on evidence and end users' perspectives. Existing research is hampered by poor conceptualization of environmental design factors, as these are differently operationalized between medical and technological sciences. Architects communicate through visuals, whereas medical professionals and researchers tend to communicate in words. By using 3D-modeling to research the relationship between health and well-being on the one hand, and the affordances the built environment offers, this knowledge gap can be better addressed. Two hundred four respondents, 60% patients and 40% medical professionals, engaged in discrete choice experiments visualizing a single patient room. A main finding is that patients and medical professionals consistently choose for hospital rooms with the highest amount of daylight access. What this study adds is that the orientation of the windows matters as well. Horizontal windows, allowing for a panoramic view, were twice as much chosen than were vertical windows. Another important finding concerns patients' preferences for an open door, suggesting patients prefer to stay "connected" to the outside world. This study is important as it shows, empirically, that patients may make different choices if in research the rooms are better conceptualized and thus visualized and if multiple design features are assessed as configuration rather than using a sequential, "one-design-characteristic-after-another" approach. [ABSTRACT FROM AUTHOR]

Background: The study was designed to examine the relative contributions of genetic and nongenetic factors to structural brain abnormalities in schizophrenia and subjects at risk to develop the disorder. Methods: The brains of 15 monozygotic and 14 same-sex dizygotic twins discordant for schizophrenia (patients) and 29 healthy twins pair-wise matched for zygosity, sex, age, and birth order were studied using high-resolution magnetic resonance imaging scans. Results: Intracranial and whole-brain corrected frontal lobe volumes were smaller (4.6% and 2.7%, respectively) in discordant monozygotic twins as compared with healthy monozygotic twins. Irrespective of zygosity, discordant twins had smaller whole-brain (2%), parahippocampal (9%), and hippocampal (8%) volumes than healthy twins. Moreover, patients had smaller whole-brain volumes (2.2%). than their nonschizophrenic cotwins, who in turn had smaller brains (1%) than healthy twins. Lateral and third-ventricle volumes were increased in discordant dizygotic twins as compared with healthy dizygotic twins (60.6% and 56.6%, respectively). Finally, within discordant twins, lateral ventricles were larger (14.4%) in patients than in their nonschizophrenic cotwins. Conclusions: Smaller intracranial volumes in the monozygotic patients and their cotwins suggest that increased genetic risk to develop schizophrenia is related to reduced brain growth early in life. The additional reduction in whole-brain volume found in the patients suggests that the manifestation of the disorder is related to (neurodegenerative) processes that are most likely non-genetic in origin. [ABSTRACT FROM AUTHOR]

KRAS is the most frequently mutated oncogene in human cancer and facilitates uncontrolled growth through hyperactivation of the receptor tyrosine kinase (RTK)/mitogen-activated protein kinase (MAPK) pathway. The Son of Sevenless homolog 1 (SOS1) protein functions as a guanine nucleotide exchange factor (GEF) for the RAS subfamily of small GTPases and represents a druggable target in the pathway. Using a structure-based drug discovery approach, MRTX0902 was identified as a selective and potent SOS1 inhibitor that disrupts the KRAS:SOS1 protein-protein interaction to prevent SOS1-mediated nucleotide exchange on KRAS and translates into an anti-proliferative effect in cancer cell lines with genetic alterations of the KRAS-MAPK pathway. MRTX0902 augmented the antitumor activity of the KRAS G12C inhibitor adagrasib when dosed in combination in eight out of 12 KRAS G12C-mutant human non-small cell lung cancer and colorectal cancer xenograft models. Pharmacogenomic profiling in preclinical models identified cell cycle genes and the SOS2 homolog as genetic co-dependencies and implicated tumor suppressor genes (NF1 and PTEN) in resistance following combination treatment. Lastly, combined vertical inhibition of RTK/MAPK pathway signaling by MRTX0902 with inhibitors of EGFR or RAF/MEK led to greater downregulation of pathway signaling and improved antitumor responses in KRAS-MAPK pathway-mutant models. These studies demonstrate the potential clinical application of dual inhibition of SOS1 and KRAS G12C and additional SOS1 combination strategies that will aide in the understanding of SOS1 and RTK/MAPK biology in targeted cancer therapy., (©2024 The Authors; Published by the American Association for Cancer Research.)

The H1047R mutation of PIK3CA is highly prevalent in breast cancers and other solid tumors. Selectively targeting PI3Kα H1047R over PI3Kα WT is crucial due to the role that PI3Kα WT plays in normal cellular processes, including glucose homeostasis. Currently, only one PI3Kα H1047R -selective inhibitor has progressed into clinical trials, while three pan mutant (H1047R, H1047L, H1047Y, E542K, and E545K) selective PI3Kα inhibitors have also reached the clinical stage. Herein, we report the design and discovery of a series of pyridopyrimidinones that inhibit PI3Kα H1047R with high selectivity over PI3Kα WT , resulting in the discovery of compound 17 . When dosed in the HCC1954 tumor model in mice, 17 provided tumor regressions and a clear pharmacodynamic response. X-ray cocrystal structures from several PI3Kα inhibitors were obtained, revealing three distinct binding modes within PI3Kα H1047R including a previously reported cryptic pocket in the C-terminus of the kinase domain wherein we observe a ligand-induced interaction with Arg1047.

The PRMT5•MTA complex has recently emerged as a new synthetically lethal drug target for the treatment of MTAP -deleted cancers. Here, we report the discovery of development candidate MRTX1719 . MRTX1719 is a potent and selective binder to the PRMT5•MTA complex and selectively inhibits PRMT5 activity in MTAP -deleted cells compared to MTAP -wild-type cells. Daily oral administration of MRTX1719 to tumor xenograft-bearing mice demonstrated dose-dependent inhibition of PRMT5-dependent symmetric dimethylarginine protein modification in MTAP -deleted tumors that correlated with antitumor activity. A 4-(aminomethyl)phthalazin-1(2 H )-one hit was identified through a fragment-based screen, followed by X-ray crystallography, to confirm binding to the PRMT5•MTA complex. Fragment growth supported by structural insights from X-ray crystallography coupled with optimization of pharmacokinetic properties aided the discovery of development candidate MRTX1719 .

Flavaglines such as silvestrol (1) and rocaglamide (2) constitute an interesting class of natural products with promising anticancer activities. Their mode of action is based on inhibition of eukaryotic initiation factor 4A (eIF4A) dependent translation through formation of a stable ternary complex with eIF4A and mRNA, thus blocking ribosome scanning. Herein we describe initial SAR studies in a novel series of 1-aminomethyl substituted flavagline-inspired eIF4A inhibitors. We discovered that a variety of N-substitutions at the 1-aminomethyl group are tolerated, making this position pertinent for property and ADME profile tuning. The findings presented herein are relevant to future drug design efforts towards novel eIF4A inhibitors with drug-like properties., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

The PI3K/AKT/mTOR pathway is often activated in lymphoma through alterations in PI3K, PTEN, and B-cell receptor signaling, leading to dysregulation of eIF4A (through its regulators, eIF4B, eIF4G, and PDCD4) and the eIF4F complex. Activation of eIF4F has a direct role in tumorigenesis due to increased synthesis of oncogenes that are dependent on enhanced eIF4A RNA helicase activity for translation. eFT226, which inhibits translation of specific mRNAs by promoting eIF4A1 binding to 5'-untranslated regions (UTR) containing polypurine and/or G-quadruplex recognition motifs, shows potent antiproliferative activity and significant in vivo efficacy against a panel of diffuse large B-cell lymphoma (DLBCL), and Burkitt lymphoma models with ≤1 mg/kg/week intravenous administration. Evaluation of predictive markers of sensitivity or resistance has shown that activation of eIF4A, mediated by mTOR signaling, correlated with eFT226 sensitivity in in vivo xenograft models. Mutation of PTEN is associated with reduced apoptosis in vitro and diminished efficacy in vivo in response to eFT226. In models evaluated with PTEN loss, AKT was stimulated without a corresponding increase in mTOR activation. AKT activation leads to the degradation of PDCD4, which can alter eIF4F complex formation. The association of eFT226 activity with PTEN/PI3K/mTOR pathway regulation of mRNA translation provides a means to identify patient subsets during clinical development., (©2020 American Association for Cancer Research.)

Dysregulation of protein translation is a key driver for the pathogenesis of many cancers. Eukaryotic initiation factor 4A (eIF4A), an ATP-dependent DEAD-box RNA helicase, is a critical component of the eIF4F complex, which regulates cap-dependent protein synthesis. The flavagline class of natural products ( i.e. , rocaglamide A) has been shown to inhibit protein synthesis by stabilizing a translation-incompetent complex for select messenger RNAs (mRNAs) with eIF4A. Despite showing promising anticancer phenotypes, the development of flavagline derivatives as therapeutic agents has been hampered because of poor drug-like properties as well as synthetic complexity. A focused effort was undertaken utilizing a ligand-based design strategy to identify a chemotype with optimized physicochemical properties. Also, detailed mechanistic studies were undertaken to further elucidate mRNA sequence selectivity, key regulated target genes, and the associated antitumor phenotype. This work led to the design of eFT226 (Zotatifin), a compound with excellent physicochemical properties and significant antitumor activity that supports clinical development.

Transient-receptor-potential melastatin 8 (TRPM8), the predominant mammalian cold-temperature thermosensor, is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system, including nerve circuitry implicated in migraine pathogenesis: the trigeminal and pterygopalatine ganglia. Genomewide association studies have identified an association between TRPM8 and reduced risk of migraine. This disclosure focuses on medicinal-chemistry efforts to improve the druglike properties of initial leads, particularly removal of CYP3A4-induction liability and improvement of pharmacokinetic properties. A novel series of biarylmethanamide TRPM8 antagonists was developed, and a subset of leads were evaluated in preclinical toxicology studies to identify a clinical candidate with an acceptable preclinical safety profile leading to clinical candidate AMG 333, a potent and highly selective antagonist of TRPM8 that was evaluated in human clinical trials.

Dysregulated translation of mRNA plays a major role in tumorigenesis. Mitogen-activated protein kinase interacting kinases (MNK)1/2 are key regulators of mRNA translation integrating signals from oncogenic and immune signaling pathways through phosphorylation of eIF4E and other mRNA binding proteins. Modulation of these key effector proteins regulates mRNA, which controls tumor/stromal cell signaling. Compound 23 (eFT508), an exquisitely selective, potent dual MNK1/2 inhibitor, was designed to assess the potential for control of oncogene signaling at the level of mRNA translation. The crystal structure-guided design leverages stereoelectronic interactions unique to MNK culminating in a novel pyridone-aminal structure described for the first time in the kinase literature. Compound 23 has potent in vivo antitumor activity in models of diffuse large cell B-cell lymphoma and solid tumors, suggesting that controlling dysregulated translation has real therapeutic potential. Compound 23 is currently being evaluated in Phase 2 clinical trials in solid tumors and lymphoma. Compound 23 is the first highly selective dual MNK inhibitor targeting dysregulated translation being assessed clinically.

Transient receptor potential melastatin 8 (TRPM8) is a nonselective cation channel expressed in a subpopulation of sensory neurons in the peripheral nervous system. TRPM8 is the predominant mammalian cold temperature thermosensor and is activated by cold temperatures ranging from 8 to 25 °C and cooling compounds such as menthol or icilin. TRPM8 antagonists are being pursued as potential therapeutics for treatment of pain and bladder disorders. This manuscript outlines new developments in the SAR of a lead series of 1,2,3,4-tetrahydroisoquinoline derivatives with emphasis on strategies to improve pharmacokinetic properties and potency. Selected compounds were profiled in two TRPM8 target-specific in vivo coverage models in rats (the icilin-induced wet dog shake model and the cold pressor test). Compound 45 demonstrated robust efficacy in both pharmacodynamic models with ED90 values <3 mg/kg.

The discovery of a series of novel and orally efficacious type II calcimimetics, developed from the lead compound 1, is described herein. Compound 22 suppressed plasma PTH levels relative to vehicle when dosed orally in a rat pharmacodynamic model., (Copyright (c) 2010 Elsevier Ltd. All rights reserved.)