Project description:Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring BRCA1/2 mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms "PARP inhibitors" and "breast cancer", was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review.
Project description:The use of imaging systems in protein crystallisation means that the experimental setups no longer require manual inspection to determine the outcome of the trials. However, it leads to the problem of how best to find images which contain useful information about the crystallisation experiments. The adoption of a deeplearning approach in 2018 enabled a four-class machine classification system of the images to exceed human accuracy for the first time. Underpinning this was the creation of a labelled training set which came from a consortium of several different laboratories. The MARCO classification model does not have the same accuracy on local data as it does on images from the original test set; this can be somewhat mitigated by retraining the ML model and including local images. We have characterized the image data used in the original MARCO model, and performed extensive experiments to identify training settings most likely to enhance the local performance of a MARCO-dataset based ML classification model.
Project description:Molecular "fingerprints" encoding structural information are the workhorse of cheminformatics and machine learning in drug discovery applications. However, fingerprint representations necessarily emphasize particular aspects of the molecular structure while ignoring others, rather than allowing the model to make data-driven decisions. We describe molecular graph convolutions, a machine learning architecture for learning from undirected graphs, specifically small molecules. Graph convolutions use a simple encoding of the molecular graph-atoms, bonds, distances, etc.-which allows the model to take greater advantage of information in the graph structure. Although graph convolutions do not outperform all fingerprint-based methods, they (along with other graph-based methods) represent a new paradigm in ligand-based virtual screening with exciting opportunities for future improvement.
Project description:Myelofibrosis (MF) is a myeloproliferative neoplasm characterized by ineffective clonal hematopoiesis, splenomegaly, bone marrow fibrosis, and the propensity for transformation to acute myeloid leukemia. The discovery of mutations in JAK2, CALR, and MPL have uncovered activated JAK-STAT signaling as a primary driver of MF, supporting a rationale for JAK inhibition. However, JAK inhibition alone is insufficient for long-term remission and offers modest, if any, disease-modifying effects. Given this, there is great interest in identifying mechanisms that cooperate with JAK-STAT signaling to predict disease progression and rationally guide the development of novel therapies. This review outlines the latest discoveries in the biology of MF, discusses current clinical management of patients with MF, and summarizes the ongoing clinical trials that hope to change the landscape of MF treatment.
Project description:Livestock predation is a global problem and constitutes the main source of conflict between large carnivores and human interests. In Latin America, both jaguar and puma are known to prey on livestock, yet studies in Mesoamerica have been scattered and few have been carried out in Honduras. We interviewed ranchers in a biosphere reserve where jaguars and pumas are present. Local indigenous communities reported livestock predation (average annual loss of 7% from 2010-2019), with preventive and retaliatory killing as their main actions against predation by the jaguar and puma. Other sources of cattle loss included diseases and theft. The extensive management system (free grazing) lets cattle access forests where predators are more common. We found that livestock predation is not random, but rather, related to landscape variables and human influence. Sites farther from human influence and closer to forest cover were more susceptible to predation. Jaguar and puma persistence in the biosphere reserve will require measures that facilitate human-carnivore coexistence and comply with Sustainable Development Goals (SDG) 2 and 15 (zero hunger and biodiversity conservation). We propose management practices to mitigate livestock predation in the presence of large carnivores based on examples of proven human-carnivore coexistence in Venezuela, Brazil, Paraguay, and Nicaragua, such as improving the spatial arrangement of livestock (maintaining a distance from forest areas) and the incorporation of confinement pens for young calves (at least the first three months of life) and their mothers. If the pens are built close to the property's house and have constant surveillance and/or dogs, the results are likely to be more effective. Deploying these proven tools may help change the current negative perception of ranchers towards large carnivores that is essential to conservation under the aims of SDG 15. We recommend government policies and support aimed to strengthen livestock health to increase productivity and to reduce their vulnerability to predation. Finally, this study represents a baseline to understand the magnitude of the human-carnivore conflict over cattle in one of the largest biosphere reserves in Mesoamerica.
Project description:Clinicians, basic researchers, representatives from pharma and families from around the world met in Cordoba, Argentina in October, 2014 to discuss recent research progress at the 14th International Congress on Neuronal Ceroid Lipofuscinoses (NCLs; Batten disease), a group of clinically overlapping fatal, inherited lysosomal disorders with primarily neurodegenerative symptoms. This brief review article will provide perspectives on the anticipated future directions of NCL basic and clinical research as we move towards improved diagnosis, care and treatment of NCL patients. This article is part of a Special Issue entitled: Current Research on the Neuronal Ceroid Lipofuscinoses (Batten Disease).