Is part of the Bibliography
Predictive value of interferon-lambda gene polymorphisms for treatment response in chronic hepatitis C
- Background: IL28B gene polymorphism is the best baseline predictor of response to interferon alfa-based antiviral therapies in chronic hepatitis C. Recently, a new IFN-L4 polymorphism was identified as first potential functional variant for induction of IL28B expression. Individualization of interferon alfa-based therapies based on a combination of IL28B/IFN-L4 polymorphisms may help to optimize virologic outcome and economic resources.
Methods: Optimization of treatment outcome prediction was assessed by combination of different IL28B and IFN-L4 polymorphisms in patients with chronic HCV genotype 1 (n = 385), 2/3 (n = 267), and 4 (n = 220) infection treated with pegylated interferon alfa (PEG-IFN) and ribavirin with (n = 79) or without telaprevir. Healthy people from Germany (n = 283) and Egypt (n = 96) served as controls.
Results: Frequencies of beneficial IL28B rs12979860 C/C genotypes were lower in HCV genotype 1/4 infected patients in comparison to controls (20–35% vs. 46–47%) this was also true for ss469415590 TT/TT (20–35% vs. 45–47%). Single interferon-lambda SNPs (rs12979860, rs8099917, ss469415590) correlated with sustained virologic response (SVR) in genotype 1, 3, and 4 infected patients while no association was observed for genotype 2. Interestingly, in genotype 3 infected patients, best SVR prediction was based on IFN-L4 genotype. Prediction of SVR with high accuracy (71–96%) was possible in genotype 1, 2, 3 and 4 infected patients who received PEG-IFN/ribavirin combination therapy by selection of beneficial IL28B rs12979860 C/C and/or ss469415590 TT/TT genotypes (p<0.001). For triple therapy with first generation protease inhibitors (PIs) (boceprevir, telaprevir) prediction of high SVR (90%) rates was based on the presence of at least one beneficial genotype of the 3 IFN-lambda SNPs.
Conclusion: IFN-L4 seems to be the best single predictor of SVR in genotype 3 infected patients. For optimized prediction of SVR by treatment with dual combination or first generation PI triple therapies, grouping of interferon-lambda haplotypes may be helpful with positive predictive values of 71–96%.
High Variability in Oral Glucose Tolerance among 1,128 Patients with Cystic Fibrosis: A Multicenter Screening Study
Reinhard W. Holl
Julia M. Hermann
Silke van Koningsbruggen-Rietschel
In cystic fibrosis, highly variable glucose tolerance is suspected. However, no study provided within-patient coefficients of variation. The main objective of this short report was to evaluate within-patient variability of oral glucose tolerance.
In total, 4,643 standardized oral glucose tolerance tests of 1,128 cystic fibrosis patients (median age at first test: 15.5 [11.5; 21.5] years, 48.8% females) were studied. Patients included were clinically stable, non-pregnant, and had at least two oral glucose tolerance tests, with no prior lung transplantation or systemic steroid therapy. Transition frequency from any one test to the subsequent test was analyzed and within-patient coefficients of variation were calculated for fasting and two hour blood glucose values. All statistical analysis was implemented with SAS 9.4.
A diabetic glucose tolerance was confirmed in 41.2% by the subsequent test. A regression to normal glucose tolerance at the subsequent test was observed in 21.7% and to impaired fasting glucose, impaired glucose tolerance or both in 15.2%, 12.0% or 9.9%. The average within-patient coefficient of variation for fasting blood glucose was 11.1% and for two hour blood glucose 25.3%.
In the cystic fibrosis patients studied, a highly variable glucose tolerance was observed. Compared to the general population, variability of two hour blood glucose was 1.5 to 1.8-fold higher.
In How Many Ways is the Approximate Number System Associated with Exact Calculation?
Vitor Geraldi Haase
- The approximate number system (ANS) has been consistently found to be associated with math achievement. However, little is known about the interactions between the different instantiations of the ANS and in how many ways they are related to exact calculation. In a cross-sectional design, we investigated the relationship between three measures of ANS acuity (non-symbolic comparison, non-symbolic estimation and non-symbolic addition), their cross-sectional trajectories and specific contributions to exact calculation. Children with mathematical difficulties (MD) and typically achieving (TA) controls attending the first six years of formal schooling participated in the study. The MD group exhibited impairments in multiple instantiations of the ANS compared to their TA peers. The ANS acuity measured by all three tasks positively correlated with age in TA children, while no correlation was found between non-symbolic comparison and age in the MD group. The measures of ANS acuity significantly correlated with each other, reflecting at least in part a common numerosity code. Crucially, we found that non-symbolic estimation partially and non-symbolic addition fully mediated the effects of non-symbolic comparison in exact calculation.
Curare - a curative poison: a scientometric analysis
Jan David Alexander Groneberg
- Introduction: Curare is one of the best-examined neurotoxins of the world, which has empirically been used for centuries by American Indigenes. Research on curare has been performed much later, a global scientometric analysis on curare research or its derivates does not yet exist. This bibliometric analysis is part of the global NewQis-project and should illuminate both toxic and historic issues of research on curare.
Methods: The ISI Web of Science was searched for data covering 1900 to 2013 using a term which included as many original articles on curare as possible. 3,867 articles were found and analyzed for common bibliometric items such as the number of citations, language of the articles or the (modified) Hirsch-Index (h-index). Results are illustrated utilizing modern density equalizing map projections (DEMP) or beam diagrams.
Results: Most publications were located in North America and Europe. The USA has the highest number of publications as well as the highest h-index. The number of publications overall rose until the late 1990s and later decreased. Furthermore, sudden increases of research activity are ascribable to historic events, like the first use of curare as muscle relaxant during surgery.
Discussion: This scientometric analysis of curare research reflects several tendencies as previously seen in other bibliometric investigations, i.e. the scientific quality standard of North America and Europe. Research on curare decreased however, due to the declining attention towards this muscle relaxant. This work exemplifies also how scientometric methods can be used to illuminate historic circumstances immediately stimulating scientific research.
Esthetic outcome of implant-based reconstructions in augmented bone: comparison of autologous and allogeneic bone block grafting with the pink esthetic score (PES)
- From 2003 to 2009, 67 patients underwent alveolar ridge augmentation and were enrolled in the study, 41 meet the inclusion criteria and 31 agreed to take part in the study. Patients were 18-69 years old (mean: 49.3 ± 13.8 years), and predominantly female. Patients received bone block grafts either autologous (n = 48) (AUBB) or allografts (ABB) (n = 19). Implants were inserted 4-7 months (autografts) or 5-6 months (allografts) after bone grafting. The Pink Esthetic Score (PES) as well as radiographic and subjective assessments were employed for the outcome analysis. The PES was assessed twice within one month based on digital photographic images that were randomly rearranged between evaluations by three independent, experienced investigators.
Synthesis of new 1,2,3-triazol-4-yl-quinazoline nucleoside and acyclonucleoside analogues
Joachim W. Engels
Hassan B. Lazrek
- In this study, we describe the synthesis of 1,4-disustituted-1,2,3-triazolo-quinazoline ribonucleosides or acyclonucleosides by means of 1,3-dipolar cycloaddition between various O or N-alkylated propargyl-quinazoline and 1'-azido-2',3',5'-tri-O-benzoylribose or activated alkylating agents under microwave conditions. None of the compounds selected showed significant anti-HCV activity in vitro.
First-line treatment of EGFR-mutated nonsmall cell lung cancer: critical review on study methodology
- Recent advances in understanding the mechanisms of nonsmall cell lung cancer (NSCLC) has led to the development of targeted treatments, including the reversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib, and the irreversible ErbB family blocker afatinib. Several important activating EGFR mutations have now been identified, which correlate strongly with response to treatment with these agents. Multiple randomised controlled trials have confirmed the association between the presence of activating EGFR mutations and objective response to gefitinib, erlotinib and afatinib, thus demonstrating their superiority over platinum-based chemotherapy as first-line treatment for NSCLC patients with EGFR mutation-positive tumours, and resulting in approval of these agents for use in this setting. It can be tempting to compare outcome data across multiple clinical trials and agents; however, substantial differences in methodology between studies, including investigator versus independent assessment and differences in patient eligibility, makes such comparisons fraught with difficulty. This critical review provides an overview of the evolution of the methodology used in eight phase III trials investigating first-line targeted treatment of NSCLC, identifies key differences in methodology and reporting, and critically assesses how these differences should be taken into account when interpreting the findings from such trials.
Targeted ultra-deep sequencing reveals recurrent and mutually exclusive mutations of cancer genes in blastic plasmacytoid dendritic cell neoplasm
Jochen K. Lennerz
- Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare haematopoietic malignancy characterized by dismal prognosis and overall poor therapeutic response. Since the biology of BPDCN is barely understood, our study aims to shed light on the genetic make-up of these highly malignant tumors. Using targeted high-coverage massive parallel sequencing, we investigated 50 common cancer genes in 33 BPDCN samples. We detected point mutations in NRAS (27.3% of cases), ATM (21.2%), MET, KRAS, IDH2, KIT (9.1% each), APC and RB1 (6.1% each), as well as in VHL, BRAF, MLH1, TP53 and RET (3% each). Moreover, NRAS, KRAS and ATM mutations were found to be mutually exclusive and we observed recurrent mutations in NRAS, IDH2, APC and ATM. CDKN2A deletions were detected in 27.3% of the cases followed by deletions of RB1 (9.1%), PTEN and TP53 (3% each). The mutual exclusive distribution of some mutations may point to different subgroups of BPDCN whose biological significance remains to be explored.
1D-3D hybrid modeling-from multi-compartment models to full resolution models in space and time
Markus M. Knodel
- Investigation of cellular and network dynamics in the brain by means of modeling and simulation has evolved into a highly interdisciplinary field, that uses sophisticated modeling and simulation approaches to understand distinct areas of brain function. Depending on the underlying complexity, these models vary in their level of detail, in order to cope with the attached computational cost. Hence for large network simulations, single neurons are typically reduced to time-dependent signal processors, dismissing the spatial aspect of each cell. For single cell or networks with relatively small numbers of neurons, general purpose simulators allow for space and time-dependent simulations of electrical signal processing, based on the cable equation theory. An emerging field in Computational Neuroscience encompasses a new level of detail by incorporating the full three-dimensional morphology of cells and organelles into three-dimensional, space and time-dependent, simulations. While every approach has its advantages and limitations, such as computational cost, integrated and methods-spanning simulation approaches, depending on the network size could establish new ways to investigate the brain. In this paper we present a hybrid simulation approach, that makes use of reduced 1D-models using e.g., the NEURON simulator—which couples to fully resolved models for simulating cellular and sub-cellular dynamics, including the detailed three-dimensional morphology of neurons and organelles. In order to couple 1D- and 3D-simulations, we present a geometry-, membrane potential- and intracellular concentration mapping framework, with which graph- based morphologies, e.g., in the swc- or hoc-format, are mapped to full surface and volume representations of the neuron and computational data from 1D-simulations can be used as boundary conditions for full 3D simulations and vice versa. Thus, established models and data, based on general purpose 1D-simulators, can be directly coupled to the emerging field of fully resolved, highly detailed 3D-modeling approaches. We present the developed general framework for 1D/3D hybrid modeling and apply it to investigate electrically active neurons and their intracellular spatio-temporal calcium dynamics.
Identification of DR5 as a critical, NF-κB-regulated mediator of Smac-induced apoptosis
- Smac mimetic promotes apoptosis by neutralizing inhibitor of apoptosis (IAP) proteins and is considered as a promising cancer therapeutic. Although an autocrine/paracrine tumor necrosis factor-α (TNFα) loop has been implicated in Smac mimetic-induced cell death, little is yet known about additional factors that determine sensitivity to Smac mimetic. Using genome-wide gene expression analysis, we identify death receptor 5 (DR5) as a novel key mediator of Smac mimetic-induced apoptosis. Although several cell lines that are sensitive to the Smac mimetic BV6 die in a TNFα-dependent manner, A172 glioblastoma cells undergo BV6-induced apoptosis largely independently of TNFα/TNFR1, as the TNFα-blocking antibody Enbrel or TNFR1 knockdown provide little protection. Yet, BV6-stimulated nuclear factor-κB (NF-κB) activation is critically required for apoptosis, as inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks BV6-induced apoptosis. Unbiased genome-wide gene expression studies in IκBα-SR-overexpressing cells versus vector control cells reveal that BV6 increases DR5 expression in a NF-κB-dependent manner. Importantly, this BV6-stimulated upregulation of DR5 is critically required for apoptosis, as transient or stable knockdown of DR5 significantly inhibits BV6-triggered apoptosis. In addition, DR5 silencing attenuates formation of a RIP1/FADD/caspase-8 cytosolic cell death complex and activation of caspase-8, -3 and -9. By identifying DR5 as a critical mediator of Smac mimetic-induced apoptosis, our findings provide novel insights into the determinants that control susceptibility of cancer cells to Smac mimetic.