Ab-Initio Calculation of Molecular Aggregation Effects: a Coumarin-343 Case Study

We present time-dependent density functional theory (TDDFT) calculations for single and dimerized Coumarin-343 molecules in order to investigate the quantum mechanical effects of chromophore aggregation in extended systems designed to function as a new generation of sensors and light-harvesting devices. Using the single-chromophore results, we describe the construction of effective Hamiltonians to predict the excitonic properties of aggregate systems. We compare the electronic coupling properties predicted by such effective Hamiltonians to those obtained from TDDFT calculations of dimers, and to the coupling predicted by the transition density cube (TDC) method. We determine the accuracy of the dipole-dipole approximation and TDC with respect to the separation distance and orientation of the dimers. In particular, we investigate the effects of including Coulomb coupling terms ignored in the typical tight-binding effective Hamiltonian. We also examine effects of orbital relaxation which cannot be captured by either of these models

Computational Cancer Biology: An Evolutionary Perspective

ISSN:1553-734XISSN:1553-735

wKinMut: An integrated tool for the analysis and interpretation of mutations in human protein kinases

BACKGROUND: Protein kinases are involved in relevant physiological functions and a broad number of mutations in this superfamily have been reported in the literature to affect protein function and stability. Unfortunately, the exploration of the consequences on the phenotypes of each individual mutation remains a considerable challenge. RESULTS: The wKinMut web-server offers direct prediction of the potential pathogenicity of the mutations from a number of methods, including our recently developed prediction method based on the combination of information from a range of diverse sources, including physicochemical properties and functional annotations from FireDB and Swissprot and kinase-specific characteristics such as the membership to specific kinase groups, the annotation with disease-associated GO terms or the occurrence of the mutation in PFAM domains, and the relevance of the residues in determining kinase subfamily specificity from S3Det. This predictor yields interesting results that compare favourably with other methods in the field when applied to protein kinases. Together with the predictions, wKinMut offers a number of integrated services for the analysis of mutations. These include: the classification of the kinase, information about associations of the kinase with other proteins extracted from iHop, the mapping of the mutations onto PDB structures, pathogenicity records from a number of databases and the classification of mutations in large-scale cancer studies. Importantly, wKinMut is connected with the SNP2L system that extracts mentions of mutations directly from the literature, and therefore increases the possibilities of finding interesting functional information associated to the studied mutations. CONCLUSIONS: wKinMut facilitates the exploration of the information available about individual mutations by integrating prediction approaches with the automatic extraction of information from the literature (text mining) and several state-of-the-art databases. wKinMut has been used during the last year for the analysis of the consequences of mutations in the context of a number of cancer genome projects, including the recent analysis of Chronic Lymphocytic Leukemia cases and is publicly available at http://wkinmut.bioinfo.cnio.es

Isolated sixth cranial nerve palsy as the presenting symptom of a rapidly expanding ACTH positive pituitary adenoma: a case report

<p>Abstract</p> <p>Background</p> <p>Pituitary adenoma may present with neuro-ophthalmic manifestations and, typically, rapid tumor expansion is the result of apoplexy. Herein, we present the first case of an isolated sixth cranial nerve palsy as initial feature of a rapidly expanding ACTH positive silent tumor without apoplexy.</p> <p>Case Presentation</p> <p>A 44 year old female with a history of sarcoidosis presented with an isolated sixth cranial nerve palsy as the initial clinical feature of a rapidly expanding ACTH positive silent pituitary adenoma. The patient underwent emergent transsphenoidal hypophysectomy for this rapidly progressive tumor and subsequently regained complete vision and ocular motility. Despite tumor extension into the cavernous sinus, the other cranial nerves were spared during the initial presentation.</p> <p>Conclusions</p> <p>This case illustrates the need to consider a rapidly growing pituitary tumor as a possibility when presented with a rapidly progressive ophthalmoplegia.</p

Personalized Pathway Enrichment Map of Putative Cancer Genes from Next Generation Sequencing Data

BACKGROUND: Pathway analysis of a set of genes represents an important area in large-scale omic data analysis. However, the application of traditional pathway enrichment methods to next-generation sequencing (NGS) data is prone to several potential biases, including genomic/genetic factors (e.g., the particular disease and gene length) and environmental factors (e.g., personal life-style and frequency and dosage of exposure to mutagens). Therefore, novel methods are urgently needed for these new data types, especially for individual-specific genome data. METHODOLOGY: In this study, we proposed a novel method for the pathway analysis of NGS mutation data by explicitly taking into account the gene-wise mutation rate. We estimated the gene-wise mutation rate based on the individual-specific background mutation rate along with the gene length. Taking the mutation rate as a weight for each gene, our weighted resampling strategy builds the null distribution for each pathway while matching the gene length patterns. The empirical P value obtained then provides an adjusted statistical evaluation. PRINCIPAL FINDINGS/CONCLUSIONS: We demonstrated our weighted resampling method to a lung adenocarcinomas dataset and a glioblastoma dataset, and compared it to other widely applied methods. By explicitly adjusting gene-length, the weighted resampling method performs as well as the standard methods for significant pathways with strong evidence. Importantly, our method could effectively reject many marginally significant pathways detected by standard methods, including several long-gene-based, cancer-unrelated pathways. We further demonstrated that by reducing such biases, pathway crosstalk for each individual and pathway co-mutation map across multiple individuals can be objectively explored and evaluated. This method performs pathway analysis in a sample-centered fashion, and provides an alternative way for accurate analysis of cancer-personalized genomes. It can be extended to other types of genomic data (genotyping and methylation) that have similar bias problems

Reconstructing cancer genomes from paired-end sequencing data

<p>Abstract</p> <p>Background</p> <p>A cancer genome is derived from the germline genome through a series of somatic mutations. Somatic structural variants - including duplications, deletions, inversions, translocations, and other rearrangements - result in a cancer genome that is a scrambling of intervals, or "blocks" of the germline genome sequence. We present an efficient algorithm for reconstructing the block organization of a cancer genome from paired-end DNA sequencing data.</p> <p>Results</p> <p>By aligning paired reads from a cancer genome - and a matched germline genome, if available - to the human reference genome, we derive: (i) a partition of the reference genome into intervals; (ii) adjacencies between these intervals in the cancer genome; (iii) an estimated copy number for each interval. We formulate the Copy Number and Adjacency Genome Reconstruction Problem of determining the cancer genome as a sequence of the derived intervals that is consistent with the measured adjacencies and copy numbers. We design an efficient algorithm, called Paired-end Reconstruction of Genome Organization (PREGO), to solve this problem by reducing it to an optimization problem on an interval-adjacency graph constructed from the data. The solution to the optimization problem results in an Eulerian graph, containing an alternating Eulerian tour that corresponds to a cancer genome that is consistent with the sequencing data. We apply our algorithm to five ovarian cancer genomes that were sequenced as part of The Cancer Genome Atlas. We identify numerous rearrangements, or structural variants, in these genomes, analyze reciprocal vs. non-reciprocal rearrangements, and identify rearrangements consistent with known mechanisms of duplication such as tandem duplications and breakage/fusion/bridge (B/F/B) cycles.</p> <p>Conclusions</p> <p>We demonstrate that PREGO efficiently identifies complex and biologically relevant rearrangements in cancer genome sequencing data. An implementation of the PREGO algorithm is available at <url>http://compbio.cs.brown.edu/software/</url>.</p

Statistical method on nonrandom clustering with application to somatic mutations in cancer

<p>Abstract</p> <p>Background</p> <p>Human cancer is caused by the accumulation of tumor-specific mutations in oncogenes and tumor suppressors that confer a selective growth advantage to cells. As a consequence of genomic instability and high levels of proliferation, many passenger mutations that do not contribute to the cancer phenotype arise alongside mutations that drive oncogenesis. While several approaches have been developed to separate driver mutations from passengers, few approaches can specifically identify activating driver mutations in oncogenes, which are more amenable for pharmacological intervention.</p> <p>Results</p> <p>We propose a new statistical method for detecting activating mutations in cancer by identifying nonrandom clusters of amino acid mutations in protein sequences. A probability model is derived using order statistics assuming that the location of amino acid mutations on a protein follows a uniform distribution. Our statistical measure is the differences between pair-wise order statistics, which is equivalent to the size of an amino acid mutation cluster, and the probabilities are derived from exact and approximate distributions of the statistical measure. Using data in the Catalog of Somatic Mutations in Cancer (COSMIC) database, we have demonstrated that our method detects well-known clusters of activating mutations in KRAS, BRAF, PI3K, and <it>β</it>-catenin. The method can also identify new cancer targets as well as gain-of-function mutations in tumor suppressors.</p> <p>Conclusions</p> <p>Our proposed method is useful to discover activating driver mutations in cancer by identifying nonrandom clusters of somatic amino acid mutations in protein sequences.</p

Cut Diagrams for High Energy Scatterings

A new approach is introduced to study QCD amplitudes at high energy and comparatively small momentum transfer. Novel cut diagrams, representing resummation of Feynman diagrams, are used to simplify calculation and to avoid delicate cancellations encountered in the usual approach. Explicit calculation to the 6th order is carried out to demonstrate the advantage of cut diagrams over Feynman diagrams.Comment: uu-encoded file containing a latex manuscript with 14 postscript figure

Mechanism of Oxidative DNA Damage in Diabetes : Tuberin Inactivation and Downregulation of DNA Repair Enzyme 8-Oxo-7,8-Dihydro-2′-Deoxyguanosine-DNA Glycosylase

OBJECTIVE—To investigate potential mechanisms of oxidative DNA damage in a rat model of type 1 diabetes and in murine proximal tubular epithelial cells and primary culture of rat proximal tubular epithelial cells

Intra-operative MRI facilitates tumour resection during trans-sphenoidal surgery for pituitary adenomas

Background During trans-sphenoidal microsurgical resection of pituitary adenomas, the extent of resection may be difficult to assess, especially when extensive suprasellar and parasellar growth has occurred. In this prospective study, we investigated whether intra-operative magnetic resonance imaging (iMRI) can facilitate tumour resection. Methods Twenty patients with macroadenomas, (16 non-functioning, three growth-hormone secreting and one pharmaco-resistant prolactinoma) were selected for surgery in the iMRI. The mean tumour diameter was 27 mm (range 11–41). The mean parasellar grade, according to the Knosp classification, was 2.3. Pre-operative coronal and sagittal T1-weighted and T2-weighted images were obtained. The trans-sphenoidal tumour resection was performed at the edge of the tunnel of a Signa SP 0.5-Tesla MRI. The surgeon aimed at a radical tumour resection that was followed by a peri-operative MRI scan. When a residual tumour was visualised and deemed resectable, an extended resection was performed, followed by another MRI scan. This procedure was repeated until the imaging results were satisfactory. In all patients, we were able to obtain images to assess the extent of resection and to classify the resection as either total or subtotal. Results After primary resection, eight out of 20 cases were classified as total resections. A second resection was performed in 11 of 12 cases classified as subtotal resections, and in four of these, total resection was achieved. A third resection was performed in three of the remaining seven cases with subtotal resections, but we did not achieve total resection in any of these cases. Therefore, the use of iMRI increased the number of patients with total resection from 8/20 (40%) to 12/20 (60%). The only observed complication was a transient spinal fluid leakage. Conclusion Intra-operative MRI during trans-sphenoidal microsurgery is useful in selected patients for a safe and more complete resection. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited