Molecular mechanistic associations of human diseases

<p>Abstract</p> <p>Background</p> <p>The study of relationships between human diseases provides new possibilities for biomedical research. Recent achievements on human genetic diseases have stimulated interest to derive methods to identify disease associations in order to gain further insight into the network of human diseases and to predict disease genes.</p> <p>Results</p> <p>Using about 10000 manually collected causal disease/gene associations, we developed a statistical approach to infer meaningful associations between human morbidities. The derived method clustered cardiometabolic and endocrine disorders, immune system-related diseases, solid tissue neoplasms and neurodegenerative pathologies into prominent disease groups. Analysis of biological functions confirmed characteristic features of corresponding disease clusters. Inference of disease associations was further employed as a starting point for prediction of disease genes. Efforts were made to underpin the validity of results by relevant literature evidence. Interestingly, many inferred disease relationships correspond to known clinical associations and comorbidities, and several predicted disease genes were subjects of therapeutic target research.</p> <p>Conclusions</p> <p>Causal molecular mechanisms present a unifying principle to derive methods for disease classification, analysis of clinical disorder associations, and prediction of disease genes. According to the definition of causal disease genes applied in this study, these results are not restricted to genetic disease/gene relationships. This may be particularly useful for the study of long-term or chronic illnesses, where pathological derangement due to environmental or as part of sequel conditions is of importance and may not be fully explained by genetic background.</p

Advanced Computational Biology Methods Identify Molecular Switches for Malignancy in an EGF Mouse Model of Liver Cancer

The molecular causes by which the epidermal growth factor receptor tyrosine kinase induces malignant transformation are largely unknown. To better understand EGFs' transforming capacity whole genome scans were applied to a transgenic mouse model of liver cancer and subjected to advanced methods of computational analysis to construct de novo gene regulatory networks based on a combination of sequence analysis and entrained graph-topological algorithms. Here we identified transcription factors, processes, key nodes and molecules to connect as yet unknown interacting partners at the level of protein-DNA interaction. Many of those could be confirmed by electromobility band shift assay at recognition sites of gene specific promoters and by western blotting of nuclear proteins. A novel cellular regulatory circuitry could therefore be proposed that connects cell cycle regulated genes with components of the EGF signaling pathway. Promoter analysis of differentially expressed genes suggested the majority of regulated transcription factors to display specificity to either the pre-tumor or the tumor state. Subsequent search for signal transduction key nodes upstream of the identified transcription factors and their targets suggested the insulin-like growth factor pathway to render the tumor cells independent of EGF receptor activity. Notably, expression of IGF2 in addition to many components of this pathway was highly upregulated in tumors. Together, we propose a switch in autocrine signaling to foster tumor growth that was initially triggered by EGF and demonstrate the knowledge gain form promoter analysis combined with upstream key node identification

The Mouse That Trolled: The Long and Tortuous History of a Gene Mutation Patent That Became an Expensive Impediment to Alzheimer\u27s Research

This case study presents the tale of the academic discovery of a rare mutation for early-onset Alzheimer\u27s disease that was patented by a sole inventor and licensed to a non-practicing entity (NPE), the Alzheimer\u27s Institute of America (AIA). Our aims are (1) to relate this story about patents, research tools, and impediments to medical progress, and (2) to inform ongoing debates about how patents affect research, disposition of university inventions, and the distribution of benefits from publicly funded research. We present an account of the hunt for Alzheimer\u27s genes, their patenting, assignment, and enforcement based on literature, litigation records and judicial decisions. While AIA\u27s litigation eventually failed, its suits against 18 defendants, including one university, one foundation, and three non-profit organizations were costly in court years, legal fees, and expert time. Reasons for the failure included non-disclosure of co-inventors, State laws on ownership and assignment of university inventions, and enablement. We discuss the policy implications of the litigation, questioning the value of patents in the research ecosystem and the role of NPEs (“patent trolls”) in biotechnological innovation. The case illustrates tactics that may be deployed against NPEs, including, avenues to invalidate patent claims, Authorization and Consent, legislative reforms specifically targeting NPEs, reforms in the America Invents Act, and judicial action and rules for judicial proceedings. In the highly competitive research environment of Alzheimer\u27s genetics in the 1990s, patents played a minor, subordinate role in spurring innovation. The case produces a mixed message about the patent system. It illustrates many mistakes in how patents were obtained, administered, and enforced, but, eventually, the legal system rectified these mistakes, albeit slowly, laboriously, and at great cost

A multi-perspective and multi-theoretical approach on the role of Knowledge Process Capabilities in enhancing patient safety: the case of Chiapas

Knowledge in medical practice is indispensable in accomplishing the objective of healing, conserving and protecting human health. Health institutions are organisations of knowledge; through their human resources, processes, methods, practices and instruments, they constantly promote the generation, access, transference and application of knowledge. Therefore, governments in developing countries such as Mexico can integrate knowledge management strategies, considering as a reference the best practices of developed countries and adapting them to the context of public policies and institutions. However, in the adoption and adaptation process, the local context conditions influencing any knowledge-based initiative's success or failure must be carefully analysed and evaluated. Therefore, an exploratory study will provide insight into the contribution of different critical factors to the development of knowledge capabilities of healthcare professionals and their impact on the improvement of patient safety from the view of a public Mexican health institution.This research proposed a methodology composed of three phases. First, The knowledge generation to understand the foundations of Knowledge Management through a literature review of the theories, perspectives, disciplines, critical factors, and evidence from past studies that support this field of study. Second, the knowledge and evidence generated through rigorous statistical analyses to evaluate three structural models whose relationships were established based on previously identified theoretical foundations. The critical factors considered in this study are the Organisational Enablers of Knowledge Management, Culture of Collaboration, Technology Acceptance, Knowledge-Sharing Behaviour, Knowledge Process Capabilities developed by healthcare professionals, and Organisational Performance in terms of Patient Safety. Third, the knowledge generated through a dialogue between the evidence generated by statistical analyses and the conditions of the local context that affect the behaviours proposed by the theories.Identifying the context effects of a developing country such as Mexico will let to identify and analyse the conditions of the social, cultural, and economic dimensions and governmental practices that can obstruct the development of knowledge capabilities in healthcare professionals, as well as the formal establishment of knowledge practices. The importance of this contribution relies on the fact that health institutions are pillars for the development of society, so strengthening their different capabilities and knowledge strategies is more than ever essential for the well-being and development of countries