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

From conjugated tertiary skipped diynes to chain-functionalized tetrasubstituted pyrroles

A novel and metal-free method for the synthesis of chain-functionalized tetrasubstituted pyrroles from easily accessible tertiary skipped diynes, was reported. The method involved modular synthesis of chain functionalized tetrasubstituted pyrroles from easily available alkyl porpiolates, acid chlorides, and primary amine. The method used a primary amine for the nitrogen source and utilized the reactivity profile of tertiary 1,4-diyne scaffolds. The synthetic manifold in the method operated in the absence of metals and accelerated by the nucleophilic addition of a primary amine on the alkynoate function. Anti-Michael ring-closing hydroamination and a [3,3]-sigmatropic rearrangement helped to complete the process of producing pyrrole. It was observed during the process that the enamine formation is more faster than the enamine cyclization.Authors thank the Spanish Ministerio de Educación y Ciencia and the European Regional Development Fund (CTQ2005-09074-C02-02), the Spanish MSC ISCIII (RETICS RD06/0020/1046), CSIC (Proyecto Intramural Especial 200719) and Fundación Instituto Canario de Investigación del Cáncer (FICI-G.I. No. 08/2007) for financial support. S.L.-T. Thanks MEC for a FPU grant.Peer Reviewe

H ypertherm ic isolated lim b perfusion with TNFa and cisplatin in the treatm ent of osteosarcom a of the extrem ities: a feasibility stu dy in healthy dogs

Abstract Pur pose. The feasibility of hyperthermic isolated limb perfusion (HILP) with tumor necrosis factor-a (TNFa ) and cisplatin for the m anagement of osteosarcoma was studied in the canine m odel. M ethods. During seven perfusions in six healthy mongrel dogs (weight 32±2 kg) technical aspects of HILP under mild hyperthermia (39± 40Ê C) were studied. In ® ve experim ents HILP was perform ed with TNFa alone (0.5 mg/l extremity volume), and in two experiments TNFa was combined with cisplatin (25 mg/l extrem ity volume). During the perfusions physiological parameters were m onitored and TNFa and total cisplatin concentrations were determined. Results. Perfusion conditions (pH, PCO 2 , PO 2 ,¯ow and pressure) rem ained within physiological ranges. Three dogs died within 24 h despite a sublethal systemic concentration of TN Fa that leaked from the perfusion circuit. Three dogs were terminated; one dog after the second experiment in accordance with Dutch ethical rules; one dog showed an invagination of the small bowel resulting in an ileus; one dog because of necrosis of the perfused limb. Conclusions. This feasibility study in healthy dogs dem onstrated that HILP with TNFa and cisplatin was associated with a high mortality rate and does not allow us to treat dogs with spontaneous osteosarcoma with TNFa and cisplatin HILP. Therefore, an alternative model should be used in the search for the ideal combination of perfusion agents for limb sparing treatment in human osteosarcoma. Key words: Osteosa rcom a of the extrem ity, hyperther m ic isolation, lim b perfusion, chem otherapy, com bination therapy, dog

An integrative computational approach to effectively guide experimental identification of regulatory elements in promoters.

Transcriptional activity of genes depends on many factors like DNA motifs, conformational characteristics of DNA, melting etc. and there are computational approaches for their identification. However, in real applications, the number of predicted, for example, DNA motifs may be considerably large. In cases when various computational programs are applied, systematic experimental knock out of each of the potential elements obviously becomes nonproductive. Hence, one needs an approach that is able to integrate many heterogeneous computational methods and upon that suggest selected regulatory elements for experimental verification