1,720,962 research outputs found
Progettazione e sintesi di nuovi agenti modulatori della proteina p53 per l'immuno-oncologia mirata
No full textLa tesi descrive lo sviluppo di nuove terapie immuno-oncologiche mirate a migliorare la selettività e l'efficacia delle terapie anti-tumorali, riducendone al minimo gli effetti collaterali. Il lavoro è suddiviso in cinque capitoli, ciascuno dei quali affronta specifici progressi nella scoperta di farmaci per la terapia oncologica mirata: nel Capitolo 1 viene descritto l'uso della sequenza isoDGR come unità di targeting per la sintesi di coniugati di piccole molecole (SMDC), mirati specificamente per l’integrina αVβ3, un recettore sovraespresso nei tumori. Questa strategia è volta a migliorare la selettività degli agenti citotossici per le cellule tumorali, migliorandone gli effetti terapeutici e riducendone gli effetti collaterali. Nel Capitolo 2 viene descritta una strategia a doppio target, che modula sia l'integrina α5β1 sia la proteina p53, regolatori chiave della sopravvivenza e proliferazione delle cellule tumorali. Mirando a questi due bersagli biologici, la strategia punta a potenziare la risposta immunitaria contro i tumori, interrompendo il crosstalk negativo tra p53 e α5β1 e riattivando così le funzioni onco-soppressorie di p53. A tal fine, sono stati progettati, sintetizzati e sottoposti a valutazione preliminare in vitro nuovi SMDCs. Nel Capitolo 3 viene presentata la progettazione e sintesi di nuovi agenti β-carbolinici in grado di riattivare p53, dotati di un sito di coniugazione adatto all'approccio terapeutico mirato. Vengono quindi riportati e discussi gli studi computazionali e ADME in silico, insieme alla sintesi ed una prima valutazione biologica dei derivati per ripristinare l'attività di p53 in differenti linee cellulari tumorali. Nel Capitolo 4 viene proposta la progettazione e sintesi di nuovi peptidomimetici come potenziali farmaci per stabilizzare la proteina p53. Vengono inoltre discusse sintesi, indagini preliminari biofisiche e attività biologica. Le procedure sperimentali sono descritte nella Sezione Sperimentale (Capitolo 5), insieme ai dati spettroscopici e analitici dei nuovi prodotti.The thesis focuses on the development of novel immuno-oncological therapies aimed at enhancing the selectivity and efficacy of cancer treatments, while minimizing side effects. The work is divided into five chapters, each addressing specific advancements in drug discovery for targeted cancer therapy: in Chapter 1 is described the use of isoDGR as targeting moiety for the synthesis of small molecule drug conjugates, specifically targeting the αVβ3 integrin, an overexpressed receptor in tumors. This strategy aims at enhancing the delivery of cytotoxic agents directly to cancer cells, improving therapeutic outcomes by reducing off-target effects. In Chapter 2 is described a dual-targeted approach, modulating both α5β1 integrin and p53 protein, key regulators in cancer cell survival and proliferation. By targeting these two pathways, the strategy aim at enhancing the immune response against tumors, while disrupting the p53- α5β1 negative crosstalk and, thereby reactivating the tumor-suppressive functions of p53. For this purpose, novel SMDCs were designed, synthetized and subjected to preliminary in vitro evaluation. In Chapter 3 is presented the design and synthesis of novel β-carboline p53-reactivating agent, bearing a site of conjugations suitable for targeted therapy approach. Docking and in silico physio pharmacological studies are presented and discussed, along with initial biological evaluation of the β-carboline derivatives to restore p53 activity in cancer cells. In Chapter 4 is proposed the design and synthesis of novel peptidomimetics as potential drug candidates for stabilizing p53 protein. Hence, preliminary biological and aggregational investigation are presented. The experimental procedures are detailed in the Experimental Section (Chapter 5), together with the spectroscopic and analytical data of the new products
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Valuable compounds from pollutants: converting PET into enantiopure alanine
Full text linkThe enzymatic depolymerization of single-use plastic products, primarily made from poly(ethylene terephthalate) (PET), is now a reality. Herein, we report the development of an innovative tandem system process that uses engineered enzymes and Escherichia coli strains to depolymerize PET and convert the resulting products into enantiomers of alanine, useful amino acids, and starting point for further valorization processes. A biosynthetic pathway has been generated, consisting of twelve enzymes derived from four different microorganisms. This pathway has been optimized using recombinant proteins and whole-cells that harbor different modules of the pathway. Specifically, the S101N/F243T-ΔLCC variant was selected to degrade PET into terephthalic acid (TPA) and ethylene glycol also at 37 °C, a temperature compatible with the E. coli RARE strain. A recombinant E. coli strain catalyzed the subsequent conversion of TPA into 2-pyrone-4,6-dicarboxylic acid, which is then transformed into pyruvate by recombinant enzymes to prevent depletion of pyruvate due to cellular catabolism. Finally, pyruvate is enzymatically aminated to enantiopure d- or l-alanine. We successfully converted postconsumer PET waste into d- and l-alanine, with an overall yield of 50 mg/170 mg PET, demonstrating that the bioconversion of selected plastics into valuable biomolecules via an eco-friendly process is feasible
Design, Synthesis and Preliminary In‐Vitro Activity of 6‐Hydroxyalkyl β‐Carboline Derivatives for the Development of Drug Conjugates Targeting MDM2
Full text linkThe mouse-double-minute-2 (MDM2) protein, the main downregulator of the tumor suppressor p53 protein, represents a promising target for the development of novel anticancer therapies. However, the lack of selectivity and poor effectiveness in tumors bearing mutated-p53 impaired the approval of several MDM2 inhibitors for the market. In this context, the possibility of generating drug-conjugates within a MDM2 inhibitor is a growing research area aimed to overcome these drawbacks. Considering the promising MDM2 inhibition by the β-carboline-based 1, in this work we explored the introduction of a new functionalization on it for a future conjugation while preserving its anticancer properties. Based on preliminary docking studies, we synthesized derivatives 2 a–d having linear hydroxyalkyl chains with different lengths at the 6-position of the β-carboline core, which effectively preserved the submicromolar IC50 on wild-type-p53-U87MG glioblastoma cell line observed with 1. Candidates 2 a, d showed the functionalization was tolerated with respect of bioactivity also on mutated-p53-U138MG glioblastoma cell line, and their hydroxyl groups proved to be easily accessible when coupled to 4-pentynoic-N,N’-dimethylethylenediamine affording derivatives 10 a, d with high yields. In summary, our results led to generating novel 6-hydroxyalkyl-β-carboline compounds displaying a suitable hydroxyl-site useful to improve the efficacy and/or the tumor specificity of 1 through conjugation strategies
Comparative Enzymatic and Stability Assays Reveal GPLG as an Effective Cathepsin B Cleavable Linker for Tumor-Targeting Drug Conjugates
Full text linkIn the past decade, targeted drug delivery systems have significantly advanced cancer therapy. A key component of these constructs is the chemical linker that covalently connects a targeting unit to a potent cytotoxic payload. Among approved and investigational antibody-drug conjugates (ADCs) and small molecule-drug conjugates (SMDCs), lysosomal-cleavable peptide sequences such as Val-Cit (VCit), Val-Ala (VA), and Gly-Phe-Leu-Gly (GFLG) are widely used for tumor-specific drug release. However, premature drug release and instability often cause off-target toxicity and poor selectivity. Since lysosomal proteases are still considered optimal for the drug release within the tumor site, the quest for new and more stable lysosomal-sensitive peptide sequences is currently an ongoing challenge. This work investigates the enzymatic susceptibility, cleavage kinetics, and metabolic stability of the peptide sequence Gly-Pro-Leu-Gly (GPLG) as a novel Cathepsin B-cleavable linker for tumor-targeting drug conjugates. Compared to GFLG, VCit, and VA, all conjugated to paclitaxel via a PABC-N,N '-dimethylethylenediamine spacer, GPLG exhibited the fastest Cathepsin B cleavage within the first 30 min of the assay, and higher stability at pH 5.4 and in both human and rat plasma samples. These results highlight GPLG as a promising lysosomal-sensitive linker for next-generation SMDCs and ADCs
Synthesis and Biological Evaluation of a Novel Dual-Targeting Small Molecule Drug Conjugate Modulating the Crosstalk between α5β1 Integrin and MDM2 in Glioblastoma
Full text linkNegative crosstalk between alpha 5 beta 1 integrin and the p53-MDM2 regulatory axis contributes to glioblastoma progression and therapeutic resistance. To explore the potential of dual inhibition of these two biological targets, the dual targeting small molecule drug conjugate (SMDC) (1) was designed by coupling the MDM2 inhibitor SAR405838 to a selective alpha 5 beta 1 integrin ligand cyclo(phg-isoDGR-k) (7) through a stable chemical linker. The resulting conjugate retained antiproliferative activity in U87-MG glioblastoma cells and induced p53 reactivation with minimal MDM2 induction. Cell cycle distribution analysis revealed a redistribution of cells from the G0/G1 phase to the G2/M phase exclusively upon treatment with conjugate 1, suggesting that a different mechanism of action is engaged. These findings support the potential of this dual-targeting approach through a dual-targeting SMDC as a promising therapeutic strategy against high-grade glioma overexpressing the alpha 5 beta 1 integrin receptor
Dispelling the Myths Behind First-author Citation Counts
Full text linkWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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