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Vicente Marchan, Ana Zamora, Albert Gandioso, Anna Massaguer, Silvia Buenestado, Carme Calvis, Jose Luis Hernández, Francesc Mitjans, Venancio Rodríguez, Jose Ruiz
A novel conjugate between a cyclometalated platinum(II) complex with dual anti-angiogenic and antitumor activity and a cyclic peptide containing the RGD sequence (-Arg-Gly-Asp-) has been synthesized by combining solid- and solution-phase methodologies. Although peptide conjugation rendered a non-cytotoxic compound in all tested tumor cell lines (+/- αVβ3 and αVβ5 integrin receptors), the anti-angiogenic activity of the Pt-c(RGDfK) conjugate in HUVEC cells at sub-cytotoxic concentrations opens the way to the design of a novel class of angiogenesis inhibitors through conjugation of metallodrugs with high anti-angiogenic activity to cyclic RGD-containing peptides or peptidomimetic analogues...
June 22, 2018: ChemMedChem
Charles J David, Joan Massagué
In the section 'Combinatorial ligand perception' of the original article, DMP1 was incorrectly used in place of BMP. This has now been corrected in the HTML and PDF versions of the article.
May 8, 2018: Nature Reviews. Molecular Cell Biology
Karuna Ganesh, Joan Massagué
Immune checkpoint therapy can induce durable remissions, but many tumors demonstrate resistance. In a recent issue of Nature, Mariathasan et al. (2018) and Tauriello et al. (2018) identify stromal TGF-β signaling as a determinant of immune exclusion. Combination TGF-β inhibition and immunotherapy induces complete responses in mouse models.
April 17, 2018: Immunity
María José Ojeda-Montes, Aleix Gimeno, Sarah Tomas-Hernández, Adrià Cereto-Massagué, Raúl Beltrán-Debón, Cristina Valls, Miquel Mulero, Gerard Pujadas, Santiago Garcia-Vallvé
The inhibition of dipeptidyl peptidase-IV (DPP-IV) has emerged over the last decade as one of the most effective treatments for type 2 diabetes mellitus, and consequently (a) 11 DPP-IV inhibitors have been on the market since 2006 (three in 2015), and (b) 74 noncovalent complexes involving human DPP-IV and drug-like inhibitors are available at the Protein Data Bank (PDB). The present review aims to (a) explain the most important activity cliffs for DPP-IV noncovalent inhibition according to the binding site structure of DPP-IV, (b) explain the most important selectivity cliffs for DPP-IV noncovalent inhibition in comparison with other related enzymes (i...
April 16, 2018: Medicinal Research Reviews
Charles J David, Joan Massagué
Few cell signals match the impact of the transforming growth factor-β (TGFβ) family in metazoan biology. TGFβ cytokines regulate cell fate decisions during development, tissue homeostasis and regeneration, and are major players in tumorigenesis, fibrotic disorders, immune malfunctions and various congenital diseases. The effects of the TGFβ family are mediated by a combinatorial set of ligands and receptors and by a common set of receptor-activated mothers against decapentaplegic homologue (SMAD) transcription factors, yet the effects can differ dramatically depending on the cell type and the conditions...
April 11, 2018: Nature Reviews. Molecular Cell Biology
Pau Martin-Malpartida, Marta Batet, Zuzanna Kaczmarska, Regina Freier, Tiago Gomes, Eric Aragón, Yilong Zou, Qiong Wang, Qiaoran Xi, Lidia Ruiz, Angela Vea, José A Márquez, Joan Massagué, Maria J Macias
Smad transcription factors activated by TGF-β or by BMP receptors form trimeric complexes with Smad4 to target specific genes for cell fate regulation. The CAGAC motif has been considered as the main binding element for Smad2/3/4, whereas Smad1/5/8 have been thought to preferentially bind GC-rich elements. However, chromatin immunoprecipitation analysis in embryonic stem cells showed extensive binding of Smad2/3/4 to GC-rich cis-regulatory elements. Here, we present the structural basis for specific binding of Smad3 and Smad4 to GC-rich motifs in the goosecoid promoter, a nodal-regulated differentiation gene...
December 12, 2017: Nature Communications
María José Ojeda-Montes, Andrea Ardid-Ruiz, Sarah Tomás-Hernández, Aleix Gimeno, Adrià Cereto-Massagué, Raúl Beltrán-Debón, Miquel Mulero, Santiago Garcia-Vallvé, Gerard Pujadas, Cristina Valls
AIM: Extracts from Ephedra species have been reported to be effective as antidiabetics. A previous in silico study predicted that ephedrine and five ephedrine derivatives could contribute to the described antidiabetic effect of Ephedra extracts by inhibiting dipeptidyl peptidase IV (DPP-IV). Finding selective DPP-IV inhibitors is a current therapeutic strategy for Type 2 diabetes mellitus management. Therefore, the main aim of this work is to experimentally determine whether these alkaloids are DPP-IV inhibitors...
December 2017: Future Medicinal Chemistry
Oriol López-Massaguer, Kevin Pinto-Gil, Ferran Sanz, Alexander Amberg, Lennart T Anger, Manuela Stolte, Carlo Ravagli, Philippe Marc, Manuel Pastor
Over the past decades, pharmaceutical companies have conducted a large number of high-quality in vivo repeat-dose toxicity (RDT) studies for regulatory purposes. As part of the eTOX project, a high number of these studies have been compiled and integrated into a database. This valuable resource can be queried directly, but it can be further exploited to build predictive models. As the studies were originally conducted to investigate the properties of individual compounds, the experimental conditions across the studies are highly heterogeneous...
March 1, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Jose M Baldasano, Jordi Massagué
Air quality trends and patterns in the coastal city of Santa Cruz de Tenerife (Canary Islands, Spain) for the period 2011-2015 were analyzed. The orographic and meteorological characteristics, the proximity to the African continent, and the influence of the Azores anticyclone in combination with the anthropogenic (oil refinery, road/maritime traffic) and natural emissions create specific dispersion conditions. SO2 , NO2 , PM10 , PM2.5 , and O3 pollutants were assessed. The refinery was the primary source of SO2 ; EU hourly and daily average limit values were exceeded during 2011 and alert thresholds were reached in 2011 and 2012...
2017: Air Quality, Atmosphere, & Health
Ma Ángeles Martínez, M Pilar Carranza, Anna Massaguer, Lucia Santos, Juan A Organero, Cristina Aliende, Rafael de Llorens, Iteng Ng-Choi, Lidia Feliu, Marta Planas, Ana M Rodríguez, Blanca R Manzano, Gustavo Espino, Félix A Jalón
The synthesis and characterization of Pt(II) (1 and 2) and Ru(II) arene (3 and 4) or polypyridine (5 and 6) complexes is described. With the aim of having a functional group to form bioconjugates, one uncoordinated carboxyl group has been introduced in all complexes. Some of the complexes were selected for their potential in photodynamic therapy (PDT). The molecular structures of complexes 2 and 5, as well as that of the sodium salt of the 4'-(4-carboxyphenyl)-2,2':6',2″-terpyridine ligand (cptpy), were determined by X-ray diffraction...
November 20, 2017: Inorganic Chemistry
Oriol López-Massaguer, Ferran Sanz, Manuel Pastor
Summary: We describe an application (Collector) for obtaining series of compounds annotated with bioactivity data, ready to be used for the development of quantitative structure-activity relationships (QSAR) models. The tool extracts data from the 'Open Pharmacological Space' (OPS) developed by the Open PHACTS project, using as input a valid name of the biological target. Collector uses the OPS ontologies for expanding the query using all known target synonyms and extracts compounds with bioactivity data against the target from multiple sources...
January 1, 2018: Bioinformatics
Qing Chen, Adrienne Boire, Xin Jin, Manuel Valiente, Ekrem Emrah Er, Alejandro Lopez-Soto, Leni S Jacob, Ruzeen Patwa, Hardik Shah, Ke Xu, Justin R Cross, Joan Massagué
No abstract text is available yet for this article.
April 6, 2017: Nature
Adrienne Boire, Yilong Zou, Jason Shieh, Danilo G Macalinao, Elena Pentsova, Joan Massagué
We molecularly dissected leptomeningeal metastasis, or spread of cancer to the cerebrospinal fluid (CSF), which is a frequent and fatal condition mediated by unknown mechanisms. We selected lung and breast cancer cell lines for the ability to infiltrate and grow in CSF, a remarkably acellular, mitogen-poor metastasis microenvironment. Complement component 3 (C3) was upregulated in four leptomeningeal metastatic models and proved necessary for cancer growth within the leptomeningeal space. In human disease, cancer cells within the CSF produced C3 in correlation with clinical course...
March 9, 2017: Cell
Albert Gandioso, Anna Massaguer, Núria Villegas, Cándida Salvans, Dani Sánchez, Isabelle Brun-Heath, Vicente Marchán, Modesto Orozco, Montserrat Terrazas
Despite the broad applicability of the Huisgen cycloaddition reaction, the click functionalization of RNAs with peptides still remains a challenge. Here we describe a straightforward method for the click functionalization of siRNAs with peptides of different sizes and complexities. Among them, a promising peptide carrier for the selective siRNA delivery into HER2+ breast cancer cell lines has been reported.
March 2, 2017: Chemical Communications: Chem Comm
Tapas R Nayak, Chrysafis Andreou, Anton Oseledchyk, Warren D Marcus, Hing C Wong, Joan Massagué, Moritz F Kircher
Here we demonstrate a novel application of 'surface enhanced resonance Raman scattering nanoparticles' (SERRS NPs) for imaging breast cancer lung metastases with much higher precision than currently feasible. A breast cancer lung metastasis mouse model was established by intravenous injection of LM2 cells. These mice were intravenously administered SERRS NPs conjugated with ALT-836, an anti-tissue factor (TF) monoclonal antibody, and subjected to Raman imaging to visualize the expression of TF both in vivo and ex vivo...
January 19, 2017: Nanoscale
Albert Gandioso, Marc Cano, Anna Massaguer, Vicente Marchán
We describe for the first time the synthesis and photochemical properties of a coumarin-caged cyclic RGD peptide and demonstrate that uncaging can be efficiently performed with biologically compatible green light. This was accomplished by using a new dicyanocoumarin derivative (DEAdcCE) for the protection of the carboxyl function at the side chain of the aspartic acid residue, which was selected on the basis of Fmoc-tBu SPPS compatibility and photolysis efficiency. The shielding effect of a methyl group incorporated in the coumarin derivative near the ester bond linking both moieties in combination with the use of acidic additives such as HOBt or Oxyma during the basic Fmoc-removal treatment were found to be very effective for minimizing aspartimide-related side reactions...
December 2, 2016: Journal of Organic Chemistry
Qiong Wang, Yilong Zou, Sonja Nowotschin, Sang Yong Kim, Qing V Li, Chew-Li Soh, Jie Su, Chao Zhang, Weiping Shu, Qiaoran Xi, Danwei Huangfu, Anna-Katerina Hadjantonakis, Joan Massagué
In this study, we outline a regulatory network that involves the p53 tumor suppressor family and the Wnt pathway acting together with the TGF-β pathway in mesendodermal differentiation of mouse and human embryonic stem cells. Knockout of all three members, p53, p63, and p73, shows that the p53 family is essential for mesendoderm specification during exit from pluripotency in embryos and in culture. Wnt3 and its receptor Fzd1 are direct p53 family target genes in this context, and induction of Wnt signaling by p53 is critical for activation of mesendodermal differentiation genes...
January 5, 2017: Cell Stem Cell
Bernardo Queralt, Elisabet Cuyàs, Joaquim Bosch-Barrera, Anna Massaguer, Rafael de Llorens, Begoña Martin-Castillo, Joan Brunet, Ramon Salazar, Javier A Menendez
KRAS mutations are an established predictor of lack of response to EGFR-targeted therapies in patients with metastatic colorectal cancer (mCRC). However, little is known about the role of the rarer NRAS mutations as a mechanism of primary resistance to the anti-EGFR monoclonal antibody cetuximab in wild-type KRAS mCRC. Using isogenic mCRC cells with a heterozygous knock-in of the NRAS activating mutation Q61K, we aimed to elucidate the mechanism(s) by which mutant NRAS blocks cetuximab from inhibiting mCRC growth...
December 13, 2016: Oncotarget
Helena Pomares, Claudia M Palmeri, Daniel Iglesias-Serret, Cristina Moncunill-Massaguer, José Saura-Esteller, Sonia Núñez-Vázquez, Enric Gamundi, Montserrat Arnan, Sara Preciado, Fernando Albericio, Rodolfo Lavilla, Gabriel Pons, Eva M González-Barca, Ana M Cosialls, Joan Gil
Fluorizoline is a new synthetic molecule that induces apoptosis by selectively targeting prohibitins (PHBs). In this study, the pro-apoptotic effect of fluorizoline was assessed in two cell lines and 21 primary samples from patients with debut of acute myeloid leukemia (AML). Fluorizoline induced apoptosis in AML cells at concentrations in the low micromolar range. All primary samples were sensitive to fluorizoline irrespectively of patients' clinical or genetic features. In addition, fluorizoline inhibited the clonogenic capacity and induced differentiation of AML cells...
October 4, 2016: Oncotarget
Qing Chen, Adrienne Boire, Xin Jin, Manuel Valiente, Ekrem Emrah Er, Alejandro Lopez-Soto, Leni Jacob, Ruzeen Patwa, Hardik Shah, Ke Xu, Justin R Cross, Joan Massagué
Brain metastasis represents a substantial source of morbidity and mortality in various cancers, and is characterized by high resistance to chemotherapy. Here we define the role of the most abundant cell type in the brain, the astrocyte, in promoting brain metastasis. We show that human and mouse breast and lung cancer cells express protocadherin 7 (PCDH7), which promotes the assembly of carcinoma-astrocyte gap junctions composed of connexin 43 (Cx43). Once engaged with the astrocyte gap-junctional network, brain metastatic cancer cells use these channels to transfer the second messenger cGAMP to astrocytes, activating the STING pathway and production of inflammatory cytokines such as interferon-α (IFNα) and tumour necrosis factor (TNF)...
May 26, 2016: Nature
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