1,720,961 research outputs found
New pharmacological targets for human diseases
Full text linkINTRODUCTION In the past decade, significant steps have been made in cancer research, particularly in the field of targeted therapy driven by the identification of specific molecular alterations in various tumours. This continuous evolution of knowledge has led to the discovery of new druggable biomarkers, optimizing therapeutic efficiency while minimizing side effects associated with conventional cancer treatments. Notably, breast cancer is the most prevalent cancer, accounted for 12.5% of new cases in 2020. Lifestyle factors, including alcohol consumption, smoking, and obesity, strongly influence its occurrence. The heterogeneous nature of breast cancer poses challenges, with some cases displaying slow growth and good prognosis, while others prove aggressive and unresponsive to conventional therapies. Advances in targeted therapies, such as endocrine therapies and HER2 inhibitors, showcase promising results and exemplify personalized approaches to breast cancer. However, it is necessary to discover novel molecular targets, aiding clinicians in refining therapeutic decisions. Additionally, human behaviours, particularly obesity resulting from excessive calorie intake, plays a pivotal role in tumours onset, with approximately 20% of tumours attributed to obesity. Increasing evidence suggests specific alterations in lipid metabolism in cancer cells, emphasizing the need to explore these pathways for a deeper understanding of cancer development and outcomes. Lipid metabolism is in a constant state of dynamic equilibrium through food intake, de-novo lipogenesis, and consumption of lipids, to satisfy the needs of the body. Therefore, alterations of one or more of these processes or its dysfunctions, such as in the case of the metabolic syndrome and type 2 diabetes mellitus, can damage the liver as it represents the main organ for lipid metabolism.
This thesis is the result of a study carried out for the characterisation of two pharmacological targets and their role in the metabolic pathways respectively in mammarian cancer and non-alcoholic fatty liver disease (NAFLD) leading to liver cancer. I have divided the work in two sections as the activities for the study of each of the molecular target:
1. In the first section I report an already peer-reviewed published work based on the pharmacological inhibition of the DEAD‐box RNA helicase 3 X (DDX3X). Specifically, it focuses on the pharmacological inhibition DDX3X as a potential treatment for breast cancer. Inhibition of DDX3X has demonstrated reduced cell proliferation in various tumour tissues, particularly in breast cancer, where its expression correlates with aggressiveness. The study employed an in-silico drug discovery approach, identifying FHP01 as a promising molecule through molecular docking at DDX3X's RNA binding site. Specifically, FHP01 displayed potent antiproliferative effects against different breast cancer cell types in vitro, notably against triple-negative breast cancer (TNBC) cells. In vivo experiments with MDA MB 231-derived TNBC xenograft models showed a significant reduction in tumour growth. Importantly, FHP01 demonstrated good bioavailability and exhibited no toxicity on normal peripheral blood mononuclear cells in vitro and on several mouse tissues in vivo. The findings suggest that FHP01 and related compounds hold promise as a novel therapeutic approach with potential efficacy against breast cancer, including the challenging triple-negative subtype, where targeted therapies are limited.
2. In the second section I report recent findings on the involvement of mitogen activated protein kinase 15 (MAPK15) in non-alcoholic fatty liver disease (NAFLD). NAFLD stands out as the predominant cause of chronic liver disease globally, encompassing stages from simple steatosis to non-alcoholic steatohepatitis (NASH), which can advance to cirrhosis and hepatocellular carcinoma (HCC), the primary form of liver cancer. Notably, NASH-induced HCC is considered less sensible to cure compared to HCC resulting from viral factors. The excessive accumulation of fatty acids within hepatocytes is identified as a pivotal event in NAFLD progression. Fatty acid transporters play a crucial role in regulating fatty acid uptake across the plasma membrane. The presented data indicate a correlation between the atypical MAP kinase, MAPK15, and hepatic steatosis. Preliminary findings suggest that MAPK15 influences fatty acid transporters in vitro and in vivo. Reduced or absent expression of MAPK15 in mammalian cells is linked to increased lipid accumulation, leading to hepatic steatosis, adipose tissue accumulation, and insulin resistance factors that elevate the risk of cancer development. The data presented underscore the need for further investigation into the involvement of MAPK15 in NAFLD development. Further investigation is now needed in order to understand how MAPK15 is involved in the development of NAFLD and, finally, if its expression may represent a marker of the worsening of liver steatosis, opening new possibilities to prevent NASH and liver cancer development
Overcoming challenges in glioblastoma treatment: targeting infiltrating cancer cells and harnessing the tumor microenvironment
Full text linkGlioblastoma is a highly malignant primary brain tumor with limited treatment options and poor prognosis. Despite current treatment approaches, including surgical resection, radiation therapy, and chemotherapy with temozolomide, glioblastoma remains mostly incurable due to its invasive growth pattern, limited drug penetration beyond the blood-brain barrier, and resistance to conventional therapies. One of the main challenges in glioblastoma treatment is effectively eliminating infiltrating cancer cells that remain in the brain parenchyma after primary tumor resection
Preclinical Application of Computer-Aided High-Frequency Ultrasound (HFUS) Imaging: A Preliminary Report on the In Vivo Characterization of Hepatic Steatosis Progression in Mouse Models
No full text: Metabolic dysfunction-associated steatotic liver disease (MASLD) is one of the most common chronic liver disorders worldwide and can lead to inflammation, fibrosis, and liver cancer. To better understand the impact of an unbalanced hypercaloric diet on liver phenotype in impaired autophagy, the study compared C57BL/6J wild type (WT) and MAPK15-ERK8 knockout (KO) male mice with C57BL/6J background fed for 17 weeks with "Western-type" (WD) or standard diet (SD). Liver features were monitored in vivo by high-frequency ultrasound (HFUS) using a semi-quantitative and parametric assessment of pathological changes in the parenchyma complemented by computer-aided diagnosis (CAD) methods. Liver histology was considered the reference standard. WD induced liver steatosis in both genotypes, although KO mice showed more pronounced dietary effects than WT mice. Overall, HFUS reliably detected steatosis-related parenchymal changes over time in the two mouse genotypes examined, consistent with histology. Furthermore, this study demonstrated the feasibility of extracting quantitative features from conventional B-mode ultrasound images of the liver in murine models at early clinical stages of MASLD using a computationally efficient and vendor-independent CAD method. This approach may contribute to the non-invasive characterization of genetically engineered mouse models of MASLD according to the principles of replacement, reduction, and refinement (3Rs), with interesting translational implications
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
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
koamabayili/VECTRON-author-checklist: VECTRON author checklist
No full textWe have done our best to complete the author checklist relating to the use of animals in the hut study. Note that the objective for the hut study was to evaluate the IRS treatment applications for residual efficacy against Anopheles mosquitoes, including the local An. coluzzii mosquito population. Cows were only used to attract mosquitoes into the huts and no tests were carried out directly on the cows. The author checklist is intended for use with studies where experiments are carried out on animals, which is why we have had such difficulty in completing this for the hut study, as many of the questions do not relate to how the cows were used
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