Metal-free organocatalysts for high hydrolytic stability single component polyurethane adhesives and their application in decorative insulation facades manufacturing

We focused on developing polyurethane (PU) adhesives with superior ambient thermal and hydrolytic stability, a crucial factor for industrial productivity. Our approach involved creating PU prepolymers that can withstand varying temperatures in ambient conditions. These prepolymers consist of conventional isocyanate-terminated polyurethane and metal-free acid:base organic catalysts, with the stability of the adhesive relying on the organocatalyst employed. We tested a series of 11 latent organocatalysts derived from the reaction between 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) and various acids. Among these, the catalyst based on 1-naphthoic acid exhibited exceptional stability, lasting at least 3 h at 60 ◦C and an average relative humidity of 65% under vigorous stirring. We assessed this stability using a fan-based stirrer and analyzed the curing conditions kinetically through DSC. Furthermore, our adhesive formulation is environmentally friendly as it is free of metals, specifically tin (typically present in catalysts such as dibutyltin dilaurate). This quality enhances its sustainability. To validate the practical applicability of the adhesives, we conducted tests using decorative facade models composed of siliciclastic sandstone extracted from a quarry in Vilviestre del Pinar (Burgos, Spain. Latitude: 41.951024◦N, longitude: 3.078283◦W) and extruded polystyrene (XPS). The results demonstrated the excellent hydrolytic and thermal stability of the adhesives, highlighting their significant potential for panel manufacturing in this context.This work was supported by the Regional Government of Castilla y León (Junta de Castilla y León) and by the Ministry of Science and Innovation MICIN and the European Union NextGeneration EU PRTR. Author José Miguel García received grant PID2020-113264RB-I00 funded by MCIN/AEI/ 10.13039/501100011033 and by “ERDF A way of making Europe”. Author Miriam Trigo-López received grant PID2019-108583RJ-I00 funded by MCIN/AEI/10.13039/501100011033. Author Saul Vallejos received grant BG22/00086 funded by Spanish Ministerio de Universidades

YES1 drives lung cancer growth and progression and predicts sensitivity to dasatinib

Rationale: The characterization of new genetic alterations is essential to assign effective personalized therapies in non–small cell lung cancer (NSCLC). Furthermore, finding stratification biomarkers is essential for successful personalized therapies. Molecular alterations of YES1, a member of the SRC (proto-oncogene tyrosine-protein kinase Src) family kinases (SFKs), can be found in a significant subset of patients with lung cancer. Objectives: To evaluate YES1 (v-YES-1 Yamaguchi sarcoma viral oncogene homolog 1) genetic alteration as a therapeutic target and predictive biomarker of response to dasatinib in NSCLC. Methods: Functional significance was evaluated by in vivo models of NSCLC and metastasis and patient-derived xenografts. The efficacy of pharmacological and genetic (CRISPR [clustered regularly interspaced short palindromic repeats]/Cas9 [CRISPR-associated protein 9]) YES1 abrogation was also evaluated. In vitro functional assays for signaling, survival, and invasion were also performed. The association between YES1 alterations and prognosis was evaluated in clinical samples. Measurements and Main Results: We demonstrated that YES1 is essential for NSCLC carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology significantly reduced tumor growth and metastasis. YES1 effects were mainly driven by mTOR (mammalian target of rapamycin) signaling. Interestingly, cell lines and patient-derived xenograft models with YES1 gene amplifications presented a high sensitivity to dasatinib, an SFK inhibitor, pointing out YES1 status as a stratification biomarker for dasatinib response. Moreover, high YES1 protein expression was an independent predictor for poor prognosis in patients with lung cancer. Conclusions: YES1 is a promising therapeutic target in lung cancer. Our results provide support for the clinical evaluation of dasatinib treatment in a selected subset of patients using YES1 status as predictive biomarker for therapy

Combinatorial Nanomedicine Made of Squalenoyl-Gemcitabine and Edelfosine for the Treatment of Osteosarcoma

International audienceDue to chemoresistance and a high propensity to form lung metastasis, survival rates in pediatric osteosarcoma (OS) are poor. With the aim to improve anticancer activity in pediatric OS, a multidrug nanomedicine was designed using the alkyl-lysophospholipid edelfosine (EF) co-assembled with squalenoyl–gemcitabine (SQ–Gem) to form nanoassemblies (NAs) of 50 nm. SQ–Gem/EF NAs modified the total Gem pool exposure in the blood stream in comparison with SQ–Gem NAs, which correlated with a better tolerability and a lower toxicity profile after multiple intravenous administrations in mice. For in vivo preclinical assessment in an orthotopic OS tumor model, P1.15 OS cells were intratibially injected in athymic nude mice. SQ–Gem/EF NAs considerably decreased the primary tumor growth kinetics and reduced the number of lung metastases. Our findings support the candidature of this anticancer nanomedicine as a potential pediatric OS therapy

"Ich bin ein Sachse, protestiere aber nicht, wenn mich ein bodenständiger Deutscher für einen Rumänen hält." : das (inter-)kulturelle Portrait Paul Schusters

This article is dedicated to the intercultural aspects of Paul Schuster’s stories (1930-2004), a German writer, born in Sibiu, regarded by German literary historians and criticists as one of the most talented prose writers descending from the small German cultural enclave of Transylvania. His work is thematically focused on events of the past century; The German minority he belongs to plays a decisive role, but also its cohabitation with different ethnic groups in Romania as well as the interethnic relations between them. Interculturality in Paul Schuster's stories is revealed on several levels: cultural exchanges between different ethnic groups, aspects of interethnic collaboration, imagology, linguistic interferences and translations from Romanian authors

Additional file 8: Figure S7. of EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth

Cell growth kinetics of APC-stimulated breast cancer cell lines. A. MTS proliferation assay of cells stimulated with increasing doses of APC. Data were normalized with absorbance values from day 0. Each dot represents mean ± SD of six replicates. B. Percentage of cells in each phase of the cell cycle in control and 50 nM APC-stimulated cells for 24 and 48 h, in serum-free and 4% serum medium. C. Percentage of apoptotic cells in basal and staurosporine-induced conditions, measured by annexin-V binding flow cytometry assay. Cell lines are MDA-MB-231,1833, BT-549, and ANV5, from the left to the right, in all figure sections. (PPTX 325 kb

Additional file 4: Figure S3. of EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth

Immunohistochemical analysis of several markers in control and EPCR-silenced size-matched mammary tumors resected at different time points. A. Representative images showing H&E staining (×2.5 magnification) and the immunohistochemical staining of Ki67, cleaved caspase-3, CD31, and F4/80 (×20 magnification) in formaldehyde-fixed tumors. Scale bars 80 μm (H&E) and 10 μm (Ki67, caspase-3, CD31, and F4/80). T. mass, tumor mass. T. border, tumor border. B. Quantification of the percentage of immunoreactive cells. Each dot represents one tumor. Data are mean ± SEM. ns means non-statistical significance. (PPTX 2780 kb

Additional file 3: Figure S2. of EPCR promotes breast cancer progression by altering SPOCK1/testican 1-mediated 3D growth

Effects of EPCR silencing in vitro and in vivo tumor growth in an orthotopic model. A. Western blot analysis of EPCR protein levels in human BT-549 (top) and murine ANV5 (bottom) cells transduced with a scramble shRNA (shControl) and shRNAs targeting human (shEPCR#1 and shEPCR#2 in BT-549) and murine (shEPCR#3 in ANV5) EPCR. β-tubulin was used as loading control. White line indicates that the membrane was cut. B. MTS in vitro proliferation assay of BT-549 (top) and ANV5 (bottom) cells. Data were normalized with absorbance values from day 0 and represent mean ± SD of six replicates. C. Percentage of BT549 (top) and ANV5 (bottom) cells in each phase of the cell cycle after maintaining cells in culture for 24 and 48 h. Sta, staurosporine. D. Percentage of apoptotic BT-549 (top) and ANV5 (bottom) cells in basal and staurosporine-induced conditions, measured by annexin-V binding flow cytometry assay. E. Quantification of spheres grown in 3D matrigel cultures. Data are mean ± SD of 8 replicates. Representative images at ×4 magnification. Scale bar 0.5 mm. F. Outline of the in vivo orthotopic experiment (n = 8 per group). G. Quantification of tumor volume at day 15 post-injection. H. Kaplan–Meier curves of resection-free survival. (PPTX 9850 kb

Lamc2 Regulates Key Transcriptional and Targetable Effectors to Support Pancreatic Cancer Growth

Purpose: The identification of PDAC dysregulated genes may unveil novel molecular targets entering inhibitory strategies. Laminins are emerging as potential targets in PDAC given their role as diagnostic and prognostic markers. Here we investigated the cellular, functional and clinical relevance of LAMC2 and its regulated network, with the ultimate goal of identifying potential therapies. Experimental design: LAMC2 expression was analyzed in PDAC tissues, a panel of human and mouse cell lines, and a genetically engineered mouse model. Genetic perturbation in 2D, 3D, and in vivo allograft and xenograft models was done. Expression profiling of a LAMC2 network was performed by RNA sequencing, and publicly available gene expression datasets from experimental and clinical studies queried for human relevance. Dual inhibition of pharmacologically targetable LAMC2-regulated effectors was investigated. Results: LAMC2 was upregulated in human and mouse experimental models as well as in human PDAC specimens, and associated with tumor grade and survival. LAMC2 inhibition impaired cell cycle, induced apoptosis, and sensitized PDAC to MEK1/2 inhibitors. A LAMC2-regulated network was featured in PDAC including classical and quasi-mesenchymal subtypes, and contained downstream effectors transcriptionally shared by the KRAS signaling pathway. LAMC2 regulated a functional FOSL1-AXL axis via AKT phosphorylation. Furthermore, genetic LAMC2 or pharmacological AXL inhibition elicited a synergistic antiproliferative effect in combination with MEK1/2 inhibitors that was consistent across 2D and 3D human and mouse PDAC models, including primary patient-derived organoids. Conclusions: LAMC2 is a molecular target in PDAC which regulates a transcriptional network that unveils a dual drug combination for cancer treatment