Evolution of Molecular Biology and Cancer: Crucial Turning Points and Startling Discoveries in a Continual Battle

Cancer is the leading cause of morbidity and mortality worldwide. Comprehensive understanding of the evolution of molecular cell biology and cancer, and their crucial turning points in a chronological order, is of enormous importance for researchers, physicians, medical students, & other health professionals. This would allow better recognition of what we currently do have and what we have to do next to beat cancer. It is also central to realize that, while the field of molecular cell biology of cancer strived to bare the etiology of cancer or to produce a cure, it had immensely increased the understanding of the molecular biology of mammalian cells. We thus also discuss in this article how the study of cancer cells helped us to develop many of the molecular techniques used nowadays in our laboratories and clinics. Despite the surplus capacity of our cells in accommodating defects, cancer has frighteningly become a disease of the genome, and genomics is thus now considered a “dissecting” tool and a major part of cancer care. Looking to the future, there is a need to generate “individual” comprehensive genomic-based signatures, and develop better information systems for collection and integration of multiple data to improve our understanding of malignancy processes and tackle the increasing complexity (intra-/inter-individual heterogeneity) of cancer patients. This would be another turning point in the history of cancer research, and inevitably pave the way for a successful translation into clinical application in precision cancer medicine

NDM-550: COMPREHENSIVE STUDY OF WIND-INDUCED TORSIONAL LOADS ON LOW- AND MEDIUM-RISE BUILDINGS

This paper summarizes the findings of extensive wind tunnel parametric investigations on wind-induced torsion acting on rectangular flat- and gable-roofed buildings. Experiments collected data for different configurations in terms of terrain exposure, wind direction and building height. In addition, wind load combinations (i.e. shear forces and torsion) in transverse and longitudinal building directions were examined. Comparisons with the results obtained from provisions specified in current design standards and codes of practice were also carried out. Three building models (scaled at 1:400) have the same horizontal dimensions (length = 61 m, width = 39 m) but with different gabled-roof angles (0o, 18.5o, and 45o). All building models were tested at different eave building heights (6, 12, 25, 30, 40, 50 and 60 m) in open and urban terrain exposures for different wind directions (every 15o). Figure 1 presents the three building models in addition to a schematic representative of external pressure distributions on building envelope at a certain instant, the exerted shear forces (FX, FY) and torsional moment (MT). The synchronized wind tunnel measurements are presented in terms of pressures, shear, and torsional coefficients

Comparative study between multi-detector computed tomography and echocardiography in evaluation of congenital vascular rings

Vascular rings are unusual anomalies represent less than 1% of all cardiac anomalies, it is abnormal development of aortic arch complex leading to formation of a ring formed by vessels that encircle both the trachea and esophagus, echocardiography had limited acoustic window which leads to inadequate evaluation of great vessels, Multi-detector computed tomography (MDCT) is one of the most important non invasive diagnostic tool for detection the vascular ring anomalies.The Aim: To evaluate role of MDCT Scanning for diagnosis of congenital vascular rings anomalies compared to echocardiography.Methods: This is a prospective study of 21 children suspected to have vascular ring anomalies. All patients underwent chest radiography, echocardiography examinations and MDCT Scanning using a 128-row CT scanner with 3D reconstruction.Results: Twenty-one patients (11 male and 10 female), mean age (14 months) were diagnosed as vascular ring anomalies by MDCT then confirmed by surgical results MDCT diagnosed 14 patients with (double aortic arch), 4 patients (right sided aortic arch with aberrant left subclavian), 2 patients (left sided aortic arch with aberrant right subclavian artery) and one patient with pulmonary sling. MDCT also diagnosed seven patients with tracheobronchial stenosis. Echocardiography succeeded only in nine patients with DAA and failed in five and succeeded in diagnosis of two cases of (right aortic arch with aberrant left subclavian).Conclusion: MDCT is an excellent diagnostic tool for optimum detection of vascular ring anomalies and other extra cardiac lesions compared to echocardiography.Keywords: Vascular ring, MDCT, Double aortic arch, Congenital heart diseas

Wind-Induced Torsional Loads on Low- and Medium-Rise Buildings

Proper building design against wind loads depends primarily on the adequacy of the provisions of codes of practice and wind load standards. During the past decades, much has been learned about along- and across-wind forces on buildings. However, studies on wind-induced torsional loads on buildings are very limited. The recent trends towards construction of more complex building shapes and structural systems can result in an increase of the unbalanced wind loads yielding an increase of torsional moments. Thus, re-visiting the wind load provisions is of an utmost concern to ensure their adequacy in evaluating torsion on low- and medium-rise buildings and to achieve safe, yet economic building design. It is noteworthy that most of the wind loading provisions on torsion have been developed from the research work largely directed towards very tall and flexible buildings for which resonant responses are significant. However, the dynamic response of most low- and medium-rise buildings is dominated by quasi-steady gust loading with little resonant effect. Moreover, the lack of knowledge regarding wind-induced torsion is reflected in having different approaches in evaluating torsion in the international wind loading codes and standards. The current research program undertakes the investigation of shear and torsional wind loads on low- and medium-rise buildings. The study demonstrates that North American and European Codes and Standards have quite different provisions for wind-induced torsion acting on low- and medium-rise buildings with typical geometries – namely, for horizontal aspect ratios (L/B) equal to 1, 2, and 3. In the experimental phase, several buildings with different configurations, i.e. different roof angles (0°, 18.4°, 45°) and heights (ranging from 6 m to 60 m) were tested in the boundary layer wind tunnel of Concordia University for different wind directions (every 15°). The measured shear and torsional loads were compared with the Canadian and American code provisions. The study found that NBCC 2010 underestimates torsion on low-rise buildings significantly, while discrepancies were found for medium-rise buildings. In addition, wind load combinations for low- and medium-rise buildings were studied. For flat-roofed buildings, it was found that maximum torsion for winds in transverse direction is associated with 80% of the overall shear force perpendicular to the longer horizontal building dimension; and 45% of the maximum shear occurs perpendicular to the smaller horizontal building dimension. Suggested approaches and load combination factors were introduced to enhance the current building codes and standards aiming at an adequate evaluation of wind load effects on low- and medium-rise buildings

Analytical Study for the Charge-Transfer Complexes of Risperidone in Pure and Dosage Forms

Two simple, accurate and sensitive spectrophotometric methods were carried out to investigate through charge-transfer reactions of risperidone (RIS) as n-electron donor with various π acceptors: 7, 7, 8, 8-tetracyanoquinodimethane (TCNQ) and p-chloranilic acid (pCA). The absorbance of reaction product was measured at 842 and 520 nm for TCNQ and pCA reagents respectively. Different experimental parameters affecting the reactions were carefully studied. The reaction pathway was postulated. The proposed spectrophotometric method was utilized for the analysis of RIS in pure form as well as in its pharmaceutical preparations. Under the optimum reaction conditions, Beer’s law is obeyed over the concentration range of 1-12 µg mL-1 and 10-180 µg mL-1 for TCNQ and pCA respectively. The limit of assays detection (LOD) is 0.114 µg mL-1 and 2.55 µg mL-1 for TCNQ and pCA respectively. The mean recovery percentage was 99.72 ± 1.06 and 100.50 ± 1.07 for TCNQ and pCA respectively. The results were compared favorably with those obtained by comparison method. The proposed method was validated statistically according to ICH guidelines

Systematic evaluation of the effect of common SNPs onpre-mRNA splicing

Background: The evolutionary and biomedical importance of differential mRNA splicing is well established, especially with regard to pathophysiological conditions. Up to 60% of mutations that contribute to disease development have been proposed to do so by disrupting splicing events. Erroneous splice site usage is also observed in numerous diseases. Problem: Identification and functional annotation of single-nucleotides polymorphisms that interfere with splicing mechanisms (‘splice SNPs') is a major challenge and needs to be supported by an efficient method. Solution: 1) A high-throughput methodology was established to facilitate the screening of allele-dependent splicing in a high-throughput fashion (ElSharawy et al., 2006). The method integrated a package of four new software tools and was mainly based on using a panel of 92 matched pairs of individual-specific gDNA and cDNA samples. For each SNP, 16 cDNAs providing a balanced representation of the genotypes at the respective SNP were investigated by nested RT-PCR and subsequent sequencing. Putative allele-dependent splicing events were verified by cloning and sequencing. 2) A systematic, SNP-centered approach was followed and the database dbSNP was screened to filter a group of common SNPs at either canonical splice sites or ESEs that were classified as putatively splicing-relevant by bioinformatics tools. This was completed in two screening rounds using web-based tools (Alex’s splice site score calculator and ESEfinder) and neural network, respectively. A group of SNPs at NAGNAG tandem repeat sites was also tested (ElSharawy et al., 2008). Results and conclusion: As a result of genotyping, the 223 non-redundant candidate SNPs were experimentally tested, and 18 allele-dependent splicing events were identified, of which 15 were novel and 3 exhibited an already known functional relevance. However, the positive predictive value of the bioinformatics tools turned out to be low, ranging from 0% for ESEFinder to 9% (in the case of acceptor site SNPs) for the neural network. Overall, the currently available bioinformatics tools contribute little to the understanding as to how common genetic variation impacts mRNA splicing. Therefore, there is a need for an alternative system. A proof of concept and outlook: The present study made some preliminary steps to develop a novel in vitro fluorescence-based splice reporter system. The ongoing systematic and hypothesis-driven experiments, which combine the advantages of FACS-based reporter constructs with a dichromatic readout method (a defined and experimentally controlled system) and ultra-high-throughput second generation sequencing technology, will serve to establish an efficient means to address many splice-related topics, and thus, would improve our understanding of mammalian splice site anatomy.Hintergrund: Die weitreichende evolutionäre und physiologische Bedeutung des differentiellen mRNA-Spleißens ist allgemein bekannt, besonders im Hinblick auf pathophysiologische und biomedizinische Fragestellungen. Man geht davon aus, dass bis zu 60 Prozent aller krankheitsverursachenden Mutationen auf eine Zerstörung von Spleißstellen zurückzuführen sind. Eine fehlerhafte Nutzung von vorhandenen Spleißstellen ist bereits für eine Vielzahl von Krankheiten bekannt. Problemstellung: Die Identifizierung und funktionelle Annotation spleißrelevanter SNPs stellt eine große Herausforderung dar und bedarf der Unterstützung durch eine effiziente Methodik. Lösungsansatz: 1)Zur Erleichterung des Screenings nach allelabhängigen Spleißereignissen wurde eine neue Hochdurchsatzmethodik entwickelt (ElSharawy et al., 2006). Diese umfasst vier neue Software-Anwendungen und basiert hauptsächlich auf der Nutzung eines Panels von 92 übereinstimmenden Paaren individuenspezifischer gDNA- und cDNA-Proben. Für jeden der zu untersuchenden SNPs wurden 16 cDNAs mittels RT-PCR und anschließender Sequenzierung untersucht. Allelabhängige Spleißereignisse wurden durch Klonierung und Sequenzierung verifiziert. 2)In einem systematischen, SNP-zentrierten Ansatz wurden häufige SNPs an kanonischen Spleißstellen sowie an ESEs aus dbSNP gefiltert und mittels webbasierter Anwendungen als potentiell spleißrelevant klassifiziert. In einem zweiten Ansatz erfolgte die Klassifizierung der SNPs mittels eines neuronalen Netzwerkes. Die als spleißrelevant klassifizierten SNPs wurden im Anschluß mit der oben beschriebenen Methode untersucht. Zusätzlich wurde eine Gruppe von SNPs an NAGNAG Tandems Repeats getestet (ElSharawy et al., 2008). Ergebnisse und Schlussfolgerungen: Insgesamt wurden 223 nicht redundante Kandidaten-SNPs experimentell getestet. Dabei wurden 18 allelabhängige Spleißvorgänge identifiziert, von denen 15 neuartig waren und für 3 die funktionelle Relevanz bekannt ist. Dabei stellte sich die korrekte positive Vorhersagefähigkeit der bioinformatischen Tools als äußerst gering heraus - von 9% (für Spleißakzeptor-SNPs) für das neuronale Netzwerk bis zu 0% für den „ESEFinder“. Zusammenfassend konnten die verwendeten bioinformatischen Anwendungen nur wenig zum Verständnis beitragen, wie häufige genetische Variationen das mRNA-Spleißen beeinflussen. Ausblick: In der vorliegenden Arbeit wurden entscheidende vorläufige Schritte zur Entwicklung eines neuartigen fluoreszenzbasierten in vitro-Spleißreportersystems geleistet, welches zur Zeit getestet und im Hinblick auf gezielte Fragestellungen validiert wird. Die momentan durchgeführten systematischen und hypothesenorientierten Experimente kombinieren die Vorteile FACS-basierter dichromatischer Reportersyteme mit denen der Hochdurchsatz-Sequenziertechnologie (second generation sequencing technology) und könnten ein effizientes Mittel zur Aufklärung vieler spleißrelevanter Fragestellungen darstellen und unser Verständnis des allelabhängigen Spleißens entscheidend verbessern

PHYTOCHEMICAL SCREENING AND BIOLOGICAL EVALUATION OF DYPSIS LEPTOCHEILOS LEAVES EXTRACT AND MOLECULAR DOCKING STUDY OF THE ISOLATED COMPOUNDS

Objective: phytochemical investigation of the ethyl acetate fraction (EAF) of 80% aqueous methanol extract (AME) of Dypsis leptocheilos leaves, in addition to evaluation of the antioxidant, cytotoxic and antimicrobial activities of the AME and EAF. Docking was used to predict and understand cytotoxicity of the isolated compounds. Methods: The ethyl acetate fraction (EAF) of Dypsis leptocheilos leaves was subjected to different chromatographic separation techniques. Structures of the isolated compounds were established by different spectroscopic techniques (1H/13C NMR). Antioxidant activity was evaluated by DPPH assay, while cytotoxicity was evaluated by MTT cell viability assay. Antimicrobial activity was evaluated by agar diffusion method. The docking study was conducted using Auto Dock Vina; the estrogen receptor (PDB 5t92) was used as a receptor for the docking. Results: Chromatographic separation techniques were led to the isolation of five phenolic compounds; these compounds were identified to be apigenin 8-C-β-D-glucopyranoside (Vitexin) (1), apigenin 6-C-β-D-glucopyranoside (Isovitexin) (2), luteolin 7-O-β-D-glucopyranoside (3), luteolin 8-C-β-D-glucopyranoside (Orientin) (4), luteolin 6-C-β-D-glucopyranoside (Isoorientin) (5). They were isolated and identified for the first time from this plant species. The AME and EAF showed moderate activity against Gram positive and Gram negatvie bacteria, while both of them showed similar and powerful antioxidant activity with SC50 = 12.8±0.56 µg/ml and SC50 = 17±0.77 µg/ml respectively, compared to ascorbic (reference drug) SC50 = 14.2±0.35 µg/ml. The EAF showed higher cytotoxic activity on the MCF-7 cells (human breast cancer cell line), with IC50 = 12.3 ± 1.82 µg/ml, compared to Vinblastine Sulfate (reference drug). All isolated compounds showed good binding affinity to the estrogen receptors existed in the MCF-7 cell. Conclusion: Five phenolic compounds were isolated for the first time from the EAF of Dypsis leptocheilos leaves. The AME and EAF extracts showed variable antioxidant, antimicrobial and cytotoxic activities

Wind-induced Torsional Loads on Low Buildings

Wind-induced instantaneous pressures on low building envelopes continuously vary in temporal and spatial dimensions and this may lead to significant torsional moments on the building's lateral load resisting system. Studies on wind-induced torsional loads on low buildings are very limited. Wind-induced torsion provisions in the American Society of Civil Engineers Standard (ASCE/SEI 7-10, 2010), the National Building Code of Canada (NBCC, 2010), and the European Code (EN 1991-1-4, 2005) were reviewed and compared for three gabled-roof (18.4°) low buildings. Significant discrepancies were found among the provisions of these wind standards in evaluating torsional wind loads on low buildings. In addition, wind-induced torsional loads on low buildings have been measured in a boundary layer wind tunnel. Three low buildings, with the same plan dimensions but different gabled-roof angles (0°, 18.4°, 45°) and two different heights (i.e. full, and half eave building height) were tested in simulated open and urban terrain exposures for different wind directions (from 0° to 180° every 15°). The experimental results were compared with current wind-induced torsional load provisions. It was found that NBCC (2010) underestimates the torsional moments on low buildings significantly

Design Wind Loads Including Torsion for Rectangular Buildings with Horizontal Aspect Ratio of 1.6

Limited information is available regarding wind-induced torsional loads on buildings. This paper presents results of tests carried out in a boundary-layer wind tunnel using building models with the same plan dimensions (aspect ratio of 1.6) and located in a simulated open terrain exposure for different wind directions. Synchronized wind pressure measurements allowed estimating instantaneous base-shear forces and torsional moments on the tested rigid building models. Results were normalized and presented in terms of shear and torsional coefficients for two load cases, namely: maximum torsion and corresponding shear, and maximum shear and corresponding torsion. Comparison of the wind-tunnel test results with current torsion- and shear-related provisions in the American standard demonstrates good agreement for low-rise buildings but differences for medium-rise buildings

Comparison of Wind Tunnel Measurements with NBCC 2010 Wind-Induced Torsion Provisions for Low- and Medium-Rise Buildings

The aim of this study is to assess wind-induced torsional loads on low- and medium-rise buildings determined in accordance with the National Building Code of Canada (NBCC 2010). Two building models with the same horizontal dimensions but different gabled-roof angles (0° and 45°) were tested at different full-scale equivalent eave heights (6, 12, 20, 30, 40, 50, and 60 m) in open terrain exposure for several wind directions (every 15°). Wind-induced measured pressures were numerically integrated over all building surfaces and results were obtained for along-wind force, across-wind force, and torsional moment. Torsion load case (i.e., maximum torsion and corresponding shear) and shear load case (i.e., maximum shear and corresponding torsion) were evaluated to reflect the maximum actual wind load effects in the two horizontal directions (i.e., transverse and longitudinal). The evaluated torsion and shear load cases were also compared with the current torsion- and shear-related provisions in the NBCC 2010. The results demonstrated significant discrepancies between NBCC 2010 and the wind tunnel measurements regarding the evaluation of torsional wind loads on low- and medium-rise buildings. Finally, shear and torsion load cases were suggested for evaluating wind loads in the design of low- and medium-rise rectangular buildings