Variability in Immunohistochemical Detection of Programmed Death Ligand 1 (PD-L1) in Cancer Tissue Types

In normal cell physiology, programmed death 1 (PD-1) and its ligand, PD-L1, play an immunoregulatory role in T-cell activation, tolerance, and immune-mediated tissue damage. The PD-1/PD-L1 pathway also plays a critical role in immune escape of tumor cells and has been demonstrated to correlate with a poor prognosis of patients with several types of cancer. However, recent reports have revealed that the immunohistochemical (IHC) expression of the PD-L1 in tumor cells is not uniform for the use of different antibodies clones, with variable specificity, often doubtful topographical localization, and with a score not uniquely defined. The purpose of this study was to analyze the IHC expression of PD-L1 on a large series of several human tumors to correctly define its staining in different tumor tissues.     

Immobilisation and stabilisation of β-galactosidase from Kluyveromyces lactis using a glyoxyl support

β-galactosidase from Kluyveromyces lactis was covalently immobilised on a Glyoxyl Sepharose (GS) support by multi-point attachment. The enzyme immobilisation process was very efficient; the supports immobilised almost all the protein responsible for the catalytic activity in a short period of time, retaining approximately 82% of the activity in the case of the optimal immobilised preparations. Stability of the GS derivatives varied as a function of enzyme-support incubation time. The optimal immobilised preparation was produced after 2 h of incubation with the support at alkaline pH. This derivative, obtained by multi-point covalent attachment, was 100-fold more stable at pH 7 and 50 °C than the cyanogen bromide Sepharose derivative obtained by a one-point covalent immobilisation method. Stabilisation was also observed under a wide range of experimental conditions. This method allowed the immobilisation of 9000 IU enzyme g^?1 of support, resulting in highly active and stable derivatives suitable for industrial processes.     

Expanding a multilingual media monitoring and information extraction tool to a new language: Swahili

The Europe Media Monitor (EMM) family of applications is a set of multilingual tools that gather, cluster and classify news in currently fifty languages and that extract named entities and quotations (reported speech) from twenty languages. In this paper, we describe the recent effort of adding the African Bantu language Swahili to EMM. EMM is designed in an entirely modular way, allowing plugging in a new language by providing the language-specific resources for that language. We thus describe the type of language-specific resources needed, the effort involved, and ways of boot-strapping the generation of these resources in order to keep the effort of adding a new language to a minimum. The text analysis applications pursued in our efforts include clustering, classification, recognition and disambiguation of named entities (persons, organisations and locations), recognition and normalisation of date expressions, as well as the identification of reported speech quotations by and about people.     

Web 2.0, Language Resources and standards to automatically build a multilingual Named Entity Lexicon

This paper proposes to advance in the current state-of-the-art of automatic Language Resource (LR) building by taking into consideration three elements: (1) the knowledge available in existing LRs, (2) the vast amount of information available from the collaborative paradigm that has emerged from the Web 2.0 and (3) the use of standards to improve interoperability. We present a case study in which a set of LRs for different languages (WordNet for English and Spanish and Parole-Simple-Clips for Italian) are extended with Named Entities (NE) by exploiting Wikipedia and the aforementioned LRs. The practical result is a multilingual NE lexicon connected to these LRs and to two ontologies: SUMO and SIMPLE. Furthermore, the paper addresses an important problem which affects the Computational Linguistics area in the present, interoperability, by making use of the ISO LMF standard to encode this lexicon. The different steps of the procedure (mapping, disambiguation, extraction, NE identification and postprocessing) are comprehensively explained and evaluated. The resulting resource contains 974,567, 137,583 and 125,806 NEs for English, Spanish and Italian respectively. Finally, in order to check the usefulness of the constructed resource, we apply it into a state-of-the-art Question Answering system and evaluate its impact; the NE lexicon improves the system’s accuracy by 28.1%. Compared to previous approaches to build NE repositories, the current proposal represents a step forward in terms of automation, language independence, amount of NEs acquired and richness of the information represented.     

Undetected Toxicity Risk in Pharmacogenetic Testing for Dihydropyrimidine Dehydrogenase

Fluoropyrimidines, the mainstay agents for the treatment of colorectal cancer, alone or as a part of combination therapies, cause severe adverse reactions in about 10%–30% of patients. Dihydropyrimidine dehydrogenase (DPD), a key enzyme in the catabolism of 5-fluorouracil, has been intensively investigated in relation to fluoropyrimidine toxicity, and several DPD gene (DPYD) polymorphisms are associated with decreased enzyme activity and increased risk of fluoropyrimidine-related toxicity. In patients carrying non-functional DPYD variants (c.1905+1G>A, c.1679T>G, c.2846A>T), fluoropyrimidines should be avoided or reduced according to the patients’ homozygous or heterozygous status, respectively. For other common DPYD variants (c.496A>G, c.1129-5923C>G, c.1896T>C), conflicting data are reported and their use in clinical practice still needs to be validated. The high frequency of DPYD polymorphism and the lack of large prospective trials may explain differences in studies’ results. The epigenetic regulation of DPD expression has been recently investigated to explain the variable activity of the enzyme. DPYD promoter methylation and its regulation by microRNAs may affect the toxicity risk of fluoropyrimidines. The studies we reviewed indicate that pharmacogenetic testing is promising to direct personalised dosing of fluoropyrimidines, although further investigations are needed to establish the role of DPD in severe toxicity in patients treated for colorectal cancer.     

Agomelatine beyond Borders: Current Evidences of Its Efficacy in Disorders Other than Major Depression

Agomelatine, a melatonergic antidepressant with a rapid onset of action, is one of the most recent drugs in the antidepressant category. Agomelatine’s antidepressant actions are attributed to its sleep-promoting and chronobiotic actions mediated by MT1 and MT2 receptors present in the suprachiasmatic nucleus, as well as to its effects on the blockade of 5-HT2c receptors. Blockade of 5-HT2c receptors causes release of both noradrenaline and dopamine at the fronto-cortical dopaminergic and noradrenergic pathways. The combined actions of agomelatine on MT1/MT2 and 5-HT2c receptors facilitate the resynchronization of altered circadian rhythms and abnormal sleep patterns. Agomelatine appeared to be effective in treating major depression. Moreover, evidence exists that points out a possible efficacy of such drug in the treatment of bipolar depression, anxiety disorders, alcohol dependence, migraines etc. Thus, the aim of this narrative review was to elucidate current evidences on the role of agomelatine in disorders other than major depression.