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Summary Novel treatment options for metastatic colorectal cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of—but not all—spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitro and tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitro and in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of cancer.

Mexico ranks among the 11 major producer countries of minerals worldwide; its open pit and underground systems are 500 years old. This paper presents an overview of the Mexican mining industry from technological development, historical and economic perspectives. The efforts made by mining companies to address issues of environmental management and sustainable development expressed in national and international frameworks, as well as the Mexican environmental regulatory framework for the mining sector, are analyzed. Since, among others, life cycle assessment (LCA) has been recognized as a key topic to promote sustainable development in the Latin American and Caribbean region, this paper also examines the application of LCA in mining. Two life cycle approaches are presented: a national life cycle inventory for base metals, and an integral life cycle model for the management of mining processes.

In this paper we present several web-based tools to identify conserved patterns in sequences. In particular we present details on the functionality of PROMO version 2.0, a program for the prediction of transcription factor binding site in a single sequence or in a group of related sequences and, of MALGEN, a tool to visualize sequence correspondences among long DNA sequences. The web tools and associated documentation can be accessed at http://www.lsi.upc.es/~alggen (RESEARCH link).

Background Microarray technology is so expensive and powerful that it is essential to extract maximum value from microarray data, specially from large-sample-series microarrays. Our web tools attempt to respond to these researchers' needs by facilitating the possibility to test and formulate from a hypothesis to entire models under a holistic point of view. Results PCOPGene-Net is a web application for facilitating the study of the relationships among gene expressions under microarray conditions, to classify these conditions and to study their effect on expression relationships. Furthermore, the system guides the researcher in the navigation through the microarray data by providing the most suitable genes and information for the researcher's interests at each moment. We achieve all of these by means of the zoom-out operation, the zoom-in operation, the non-continuous analysis and crossing the PCOPGene results with external data-servers. Conclusion PCOPGene-Net helps to identify cellular states and the genes involved in these. All of that is accomplished in a flexible way, guided by the researcher's interests and taking advantage of the ability of our system to relate gene expressions, even when these relationships are non-continuous and cannot be found using linear or non-linear analytical methods. Currently, our tools are used for tumour-progression study from a holistic point of view.

Motivation: This application aims at assisting researchers with the extraction of significant medical and biological knowledge from data sets with complex relationships among their variables. Results: Non-hypothesis-driven approaches like Principal Curves of Oriented Points (PCOP) are a very suitable method for this objective. PCOP allows for obtaining of a representative pattern from a huge quantity of data of independent variables in a very flexible and direct way. A web server has been designed to automatically realize 'non-linear pattern' analysis, 'hidden-variable-dependent' clustering, and new samples 'local-dispersion-dependent' classification from the data involving new statistical techniques using the PCOP calculus. The tools facilitate the managing, comparison and visualization of results in a user-friendly graphical interface. Availability: http://ibb.uab.es/revresearch