bluuebunny/crossref_metadata_2025 huggingface dataset:
Cathodic Stripping Voltammetry of Uracil. Experimental and Theoretical Study Under Conditions of Square‐Wave Voltammetry
Authors: Mirčeski Valentin , Skrzypek Sławomira , Lovrić Milivoj
Published: December 2008

The electrode mechanism of uracil at a hanging mercury drop electrode (HMDE) is studied under cathodic stripping square‐wave voltammetric mode owing to the cathodic dissolution of a sparingly soluble compound formed between the electrode material and uracil. The experimental results can be partly explained in the light of the recent theory for cathodic stripping processes of insoluble salts under conditions of square‐wave voltammetry. It is established that the electrode reaction is complicated by attractive interactions between the deposited species of the insoluble compound. To elucidate the electrode mechanism completely a novel theoretical model is developed considering adsorption of the reacting analyte and lateral interactions between species of the insoluble compound. With the help of numerical simulations the effect of interactions is studied in detail, emphasizing the properties of the response that can be used as diagnostic criteria for recognition of the type of interaction forces. Theoretically predicted voltammetric properties agree well with the experimental results enabling clarification of the complex electrode mechanism of uracil at HMDE.
Interactions of Dissolved dsDNA with Intercalating Drug by Anodic Voltammetry and Spectroscopy. Influence of pH
Authors: Nowicka Anna M. , Zabost Ewelina , Klim Barbara , Mazerska Zofia , Stojek Zbigniew
Published: December 2008

The interactions of C‐1305 (5‐dimethylaminopropylamino‐8‐hydroxy‐6H‐v‐triazolo[4,5,1‐de]acridin‐6‐one) with DNA were studied using differential pulse voltammetry and UV‐vis spectroscopy. C‐1305 interacts with dsDNA in two ways: by intercalation and by binding to the minor‐groove. For the intercalation at physiological pH (7.4) the values of the binding constant, K1, and the binding‐site size, n1, equal 3.36×105 M−1 and 2.5, respectively. For the weak interactions the K2 and n2 parameters equal 0.18×105 M−1 and 4. In the presence of excess NaCl the weak interactions do not vanish, therefore they are assigned to the minor groove binding. Substantial and complex is the influence of pH.
Recent progress in the use of ionic polymers as pseudostationary phases for electrokinetic chromatography
Authors: Palmer Christopher P.
Published: December 2008

This review is an account of the development, utilization, and characterization of polymeric pseudostationary phases (PSPs) for EKC since the previous review in this series in 2007. Improvements in performance by means of new polymeric phases and modifications to previously reported materials are described. The use of EKC and spectroscopic studies to characterize the interactions between polymeric PSPs and analytes is discussed. The application of polymeric PSPs for techniques or approaches to which they provide particular advantages is reviewed. Chief among these is the application of polymeric PSPs for the combination of EKC with MS detection.
Recent advances in the methodology, optimisation and application of MEEKC
Authors: Ryan Richie , Donegan Sheila , Power Joe , McEvoy Eamon , Altria Kevin
Published: December 2008

MEEKC is an electrodriven separation technique. Oil‐in‐water microemulsions (MEs) and to a lesser extent water‐in‐oil MEs have been used in MEEKC as BGEs to achieve separation of a diverse range of solutes. The more common (oil‐in‐water) MEs are composed of nanometre‐sized droplets of oil suspended in an aqueous buffer. Interfacial tension between the oil and aqueous phase is reduced close to zero by the presence of a surfactant and a co‐surfactant. MEEKC is capable of providing fast and efficient separations for a wide range of acidic, basic and neutral, water‐soluble and ‐insoluble compounds. This review details the advances in MEEKC‐based separations from the period 2006 to 2008. Areas covered include online sample concentration, chiral separation, suppressed electroosmosis MEEKC, MEEKC‐MS, and the use of MEEKC in predicting migration behaviour and solute characteristics. A fundamental introduction to MEEKC, along with the presentation and discussion of recent applications is also included.
Non‐aqueous capillary electrophoresis 2005–2008
Authors: Geiser Laurent , Veuthey Jean‐Luc
Published: December 2008

This review article presents recent developments and applications of non‐aqueous capillary electrophoresis (NACE): The text covers the period from the previous review (L. Geiser, J. L. Veuthey, Electrophoresis 2007, 28, 45–57) to summer 2008. We focus primarily on the analysis of pharmaceutical drugs by non‐aqueous solvents in CZE within different matrices including phytochemical plant extracts and biological fluids. We also extend our discussion to other application fields (e.g. food material and environmental samples) and to chiral separations by NACE. This review focuses on practical aspects of NACE, illustrating which organic solvents and electrolytes are best suited for NACE analyses and their compatibilities with different detection techniques, including UV, LIF and MS. The review emphasizes the interests of using non‐aqueous solvents in place of water for the analysis by CZE, and as an alternative to MEKC.
CE‐MS in metabolomics
Authors: Ramautar Rawi , Somsen Govert W. , de Jong Gerhardus J.
Published: December 2008

An overview of the use of CE‐MS in the field of metabolomics is provided. Metabolomics is concerned with the comprehensive analysis of endogenous low‐molecular‐weight compounds in biological samples. CE‐MS has demonstrated to be a powerful technique for the profiling of polar metabolites in biological samples. This review covers the use of various CE separation modes, capillary coatings, MS analyzers, sample preparation techniques, and data analysis methods used in CE‐MS for metabolomics. The applicability of CE‐MS in metabolomics research is illustrated by giving examples of the analysis of bacterial extracts, plant extracts, urine, plasma, and cerebrospinal fluid samples. The relevant CE‐MS metabolomics studies published between 2000 and 2008 are presented in tabular form, including information on sample type and pretreatment and MS detection mode. Future developments with regard to the use of alternative ionization techniques, the use of coupled separation systems and the potential of microchip CE systems for metabolomics are discussed.
Recent advances in IEF in capillary tubes and microchips
Authors: Shimura Kiyohito
Published: December 2008

The methodological advancements in CIEF in tubes and microchips during the period between 2002 and early 2008 are reviewed as a continuation of previous review by the same author (Electrophoresis 2002, 23, 3847–3857). After a brief introduction, the following topics related to CIEF technologies are addressed: the materials used to form capillary tubes and chips; modes of CIEF related to the detection schemes; coatings of the capillary walls; additives to the separation media; sample‐loading methods; development of pI markers and their use; focusing time in relation to the length of the pH gradient; resolution in terms of a peak capacity; and, the reproducibility and precision of CIEF. Three principal detection methods are examined, i.e. ultraviolet absorption, fluorescence and MS. The coupling of CIEF with other electrokinetic separation methods and chromatography is discussed, including many multidimensional systems constructed for proteome analysis using mass spectrometric identification. The developments in the separation of non‐covalent complexes and microorganisms are examined. After a short conclusion, this review ends with 176 references.
Evaluation of frequencies of HPRT mutant lymphocytes in butadiene polymer workers in a Southeast Texas facility
Authors: Wickliffe Jeffrey K. , Ammenheuser Marinel M. , Adler P. Jene , Abdel‐Rahman Sherif Z. , Ward Jonathan B.
Published: December 2008

We examined the frequency of mutant lymphocytes (VFs) in workers (n = 30) occupationally exposed to the petrochemical, 1,3‐butadiene (BD), using the autoradiographic HPRT mutant lymphocyte assay. Current exposures were determined with organic vapor monitors that had a 12‐hr method detection limit (MDL) of 2.5 parts per billion (ppb). HPRT VFs were analyzed with respect to current exposure estimates, age in years, and occupational longevity (OL; defined as years working in the BD industry at this facility). Current exposures were low (mean 93.5 ppb, median 2.5 ppb) with only one individual's estimate (1683.5 ppb) exceeding the Occupational Safety and Health Administration's permissible exposure limit of 1,000 ppb. The majority (>50%) of current exposures were below the MDL. HPRT VFs were not significantly associated with current exposures (n = 29), and they were not significantly associated with age (n = 29). HPRT VFs were, however, significantly associated with OL (n = 29, R2 = 0.107, P < 0.046). This result suggests that chronic and/or past, high‐level exposures might leave a mutagenic signature that is revealed by the HPRT assay, possibly through the retention of mutant, long‐term memory T‐cells. While it is encouraging that current occupational exposures to BD in this facility do not appear to be increasing the frequency of mutant T‐lymphocytes, evidence from workers with a lengthy history in the industry (≥30 years in this case) indicates that these individuals likely require additional biomonitoring for possible mutagenic effects resulting from chronic, past exposures. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.
Investigation of the genotoxic effect of pesticides on greenhouse workers' lymphocytes
Authors: Piperakis Stylianos M. , Kontogianni Konstantia , Karanastasi Georgia , Iakovidou‐Kritsi Zafiroula , Cebulska‐Wasilewska Antonina , Piperakis Michael M.
Published: December 2008

In the present study, the genotoxic effects of commonly applied pesticides were evaluated using the alkaline comet assay (pH > 13). The amount of DNA damage (% DNA in tail) in peripheral lymphocytes of 49 male agricultural workers from Southern Poland were measured and compared to 50 men from the same area who had no previous occupational exposure to pesticides. No statistically significant differences in basal DNA damage were found between the study groups. In addition, exposure of peripheral blood lymphocytes to hydrogen peroxide (100 and 150 μM) or γ‐irradiation (2.5 or 4.2 Gy) led to a similar degree of additional DNA damage and subsequent repair (for 2 hr) for all studied populations. In conclusion, our results indicate that the greenhouse workers who participated in this study had no detectable increased DNA damage or alteration in their cellular response to DNA damage in comparison to our control population. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.
NAT2 fast acetylator genotype and MGMT promoter methylation may contribute to gender difference in K‐RAS mutation occurrence in Taiwanese colorectal cancer
Authors: Huang Chi‐Chou , Chien Wen‐Pin , Wong Ruey‐Hong , Cheng Ya‐Wen , Chen Meng‐Cheng , Lee Huei
Published: December 2008

A recent study conducted by our group showed that the NAT2 fast acetylator genotype is associated with an increasing risk for the development of colorectal cancer (CRC), especially for females. We therefore examined whether a higher risk of CRC in females with the NAT2 fast acetylator genotype was associated with the occurrence of K‐RAS mutation, and to further verify whether MGMT promoter methylation was linked to the occurrence of K‐RAS mutation in patients with the NAT2 fast acetylator genotype. Herein, 151 CRC cases were examined for NAT2 genetic polymorphisms and MGMT promoter methylation by PCR‐RFLP and methylation‐specific PCR (MSP). The results of this study show that the NAT2 fast acetylator genotype is associated with the occurrence of K‐RAS mutation in female cases (OR = 4.820, 95% CI = 1.113–20.873), but not associated with MGMT promoter methylation. Surprisingly, MGMT promoter methylation significantly deepens the impact of NAT2 fast acetylation on K‐RAS mutation in the female cases (OR = 5.129, 95% CI = 1.092–24.105). In conclusion, Taiwanese women with the NAT2 fast acetylator genotype may exhibit a higher risk of CRC with increased occurrence of K‐RAS mutation. Detection of NAT2 genotypes and MGMT promoter methylation may be useful in the risk assessment for CRC in Taiwanese women. Environ. Mol. Mutagen., 2009. © 2008 Wiley‐Liss, Inc.
Out of Africa and the evolution of human behavior
Authors: Klein Richard G.
Published: December 2008

Twenty‐one years ago, a landmark exploration of mitochondrial DNA diversity popularized the idea of a recent African origin for all living humans.1 The ancestral African population was estimated to have existed 200 ka (thousands of years ago) plus or minus a few tens of thousands of years. A corollary was that at some later date the fully modern African descendants of that population expanded to swamp or replace the Neanderthals and other nonmodern Eurasians. The basic concept soon became known as “Out of Africa,” after the Academy Award winning film (1985) that took its title, in turn, from Isak Dinesen's classic autobiography (1937). Many subsequent genetic analyses, including those of Ingman and coworkers2 and Underhill and coworkers,3 have reaffirmed the fundamental Out of Africa model. The fossil and archeological records also support it strongly. The fossil record implies that anatomically modern or near‐modern humans were present in Africa by 150 ka; the fossil and archeological records together indicate that modern Africans expanded to Eurasia beginning about 50 ka.
Multi‐objective turbomachinery optimization using a gradient‐enhanced multi‐layer perceptron
Authors: Duta M. C. , Duta M. D.
Published: December 2008

Response surface models (RSMs) have found widespread use to reduce the overall computational cost of turbomachinery blading design optimization. Recent developments have seen the successful use of gradient information alongside sampled response values in building accurate response surfaces. This paper describes the use of gradients to enhance the performance of the RSM provided by a multi‐layer perceptron. Gradient information is included in the perceptron by modifying the error function such that the perceptron is trained to fit the gradients as well as the response values. As a consequence, the back‐propagation scheme that assists the training is also changed. The paper formulates the gradient‐enhanced multi‐layer perceptron using algebraic notation, with an emphasis on the ease of use and efficiency of computer code implementation. To illustrate the benefit of using gradient information, the enhanced neural network model is used in a multi‐objective transonic fan blade optimization exercise of engineering relevance. Copyright © 2008 John Wiley & Sons, Ltd.
Improving oil fields recovery through real‐time water flooding optimization
Authors: Marescalco Pamela Alessia Chiara
Published: December 2008

Increasing oil recovery from reservoirs is a strong urge. One of the most effective ways to get the result is water flooding and that's why its application is nowadays widely used in the petroleum industry. Obviously, water flooding efficiency strongly depends on reservoir properties; this makes simulating a water injection process a priori an extremely important step of the reservoir production strategy. Simulation is commonly done adopting a finite difference (FD) simulation approach.

This paper explores a different and complementary approach, represented by streamline‐based simulation, coupled with a tool to optimize water flooding campaigns and to help quick decision making. In the present study, water flooding simulation is performed via two commercial software: an FD and a streamline‐based simulator, to highlight advantages and disadvantages of both simulation techniques in describing a water injection campaign and to exploit the two approaches' uniqueness in parallel.

The final goal of iteratively converging to the optimal water flooding scheme, which is the core of the present work, is achieved through a customized Matlab script. The generated automatic procedure shows its effectiveness in improving oil recovery, expediting decision making and saving time and FD simulation runs. A three steps workflow is outlined to get the best water flooding scheme for the examples shown below. Copyright © 2008 John Wiley & Sons, Ltd.
Mechanisms of gene amplification and evidence of coamplification in drug‐resistant human osteosarcoma cell lines
Authors: Hattinger Claudia M. , Stoico Giuseppina , Michelacci Francesca , Pasello Michela , Scionti Isabella , Remondini Daniel , Castellani Gastone C. , Fanelli Marilù , Scotlandi Katia , Picci Piero , Serra Massimo
Published: December 2008

Gene amplification and copy number changes play a pivotal role in malignant transformation and progression of human tumor cells by mediating the activation of genes and oncogenes, which are involved in many different cellular processes including development of drug resistance. Since doxorubicin (DX) and methotrexate (MTX) are the two most important drugs for high‐grade osteosarcoma (OS) treatment, the aim of this study was to identify genes gained or amplified in six DX‐ and eight MTX‐resistant variants of the human OS cell lines U‐2OS and Saos‐2, and to get insights into the mechanisms underlying the amplification processes. Comparative genomic hybridization techniques identified amplification of MDR1 in all six DX‐resistant and of DHFR in three MTX‐resistant U‐2OS variants. In addition, progressive gain of MLL was detected in the four U‐2OS variants with higher resistance levels either to DX or MTX, whereas gain of MYC was found in all Saos‐2 MTX‐resistant variants and the U‐2OS variant with the highest resistance level to DX. Fluorescent in situ hybridization revealed that MDR1 was amplified in U‐2OS and Saos‐2/DX‐resistant variants manifested as homogeneously staining regions and double minutes, respectively. In U‐2OS/MTX‐resistant variants, DHFR was amplified in homogeneously staining regions, and was coamplified with MLL in relation to the increase of resistance to MTX. Gene amplification was associated with gene overexpression, whereas gene gain resulted in up‐regulated gene expression. These results indicate that resistance to DX and MTX in human OS cell lines is a multigenic process involving gene copy number and expression changes. © 2008 Wiley‐Liss, Inc.
Papillary and muscle invasive bladder tumors with distinct genomic stability profiles have different DNA repair fidelity and KU DNA‐binding activities
Authors: Bentley Johanne , L'Hôte Corine , Platt Fiona , Hurst Carolyn D. , Lowery Johanna , Taylor Claire , Sak Sei C. , Harnden Patricia , Knowles Margaret A. , Kiltie Anne E.
Published: December 2008

Low‐grade noninvasive papillary bladder tumors are genetically stable whereas muscle invasive bladder tumors display high levels of chromosomal aberrations. As cells deficient for nonhomologous end‐joining (NHEJ) pathway components display increased genomic instability, we sought to determine the NHEJ repair characteristics of bladder tumors and correlate this with tumor stage and grade. A panel of 13 human bladder tumors of defined stage and grade were investigated for chromosomal aberrations by comparative genomic hybridization and for NHEJ repair fidelity and function. Repair assays were conducted with extracts made directly from bladder tumor specimens to avoid culture‐induced phenotypic alterations and selection bias as only a minority of bladder tumors grow in culture. Four noninvasive bladder tumors (pTaG2), which were genetically stable, repaired a partially incompatible double‐strand break (DSB) by NHEJ‐dependent annealing of termini and fill‐in of overhangs with minimal loss of nucleotides. In contrast, four muscle invasive bladder cancers (pT2‐3G3), which displayed gross chromosomal rearrangements, repaired DSBs in an error‐prone manner involving extensive resection and microhomology association. Four minimally invasive bladder cancers (pT1G3) had characteristics of both repair types. Error‐prone repair in bladder tumors correlated with reduced KU DNA‐binding and loss of TP53 function. In conclusion, there were distinct differences in DSB repair between noninvasive papillary tumors and higher stage/grade invasive cancers. End‐joining fidelity correlated with stage and was increasingly error‐prone as tumors became more invasive and KU binding activity reduced; these changes may underlie the different genomic profiles of these tumors. © 2008 Wiley‐Liss, Inc.
Regional brain activation changes and abnormal functional connectivity of the ventrolateral prefrontal cortex during working memory processing in adults with attention‐deficit/hyperactivity disorder
Authors: Wolf Robert C. , Plichta Michael M. , Sambataro Fabio , Fallgatter Andreas J. , Jacob Christian , Lesch Klaus‐Peter , Herrmann Martin J. , Schönfeldt‐Lecuona Carlos , Connemann Bernhard J. , Grön Georg , Vasic Nenad
Published: December 2008

Previous studies on working memory (WM) function in adults with attention‐deficit/hyperactivity disorder (ADHD) suggested aberrant activation of the prefrontal cortex and the cerebellum. Although it has been hypothesized that activation differences in these regions most likely reflect aberrant frontocerebellar circuits, the functional coupling of these brain networks during cognitive performance has not been investigated so far. In this study, functional magnetic resonance imaging (fMRI) and both univariate and multivariate analytic techniques were used to investigate regional activation changes and functional connectivity differences during cognitive processing in healthy controls (n = 12) and ADHD adults (n = 12). Behavioral performance during a parametric verbal WM paradigm did not significantly differ between adults with ADHD and healthy controls. During the delay period of the activation task, however, ADHD patients showed significantly less activation in the left ventrolateral prefrontal cortex (VLPFC), as well as in cerebellar and occipital regions compared with healthy control subjects. In both groups, independent component analyses revealed a functional network comprising bilateral lateral prefrontal, striatal, and cingulate regions. ADHD adults had significantly lower connectivity in the bilateral VLPFC, the anterior cingulate cortex, the superior parietal lobule, and the cerebellum compared with healthy controls. Increased connectivity in ADHD adults was found in right prefrontal regions, the left dorsal cingulate cortex and the left cuneus. These findings suggest both regional brain activation deficits and functional connectivity changes of the VLPFC and the cerebellum as well as functional connectivity abnormalities of the anterior cingulate and the parietal cortex in ADHD adults during WM processing. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.
Functional brain imaging of swallowing: An activation likelihood estimation meta‐analysis
Authors: Sörös Peter , Inamoto Yoko , Martin Ruth E.
Published: December 2008

A quantitative, voxel‐wise meta‐analysis was performed to investigate the cortical control of water and saliva swallowing. Studies that were included in the meta‐analysis (1) examined water swallowing, saliva swallowing, or both, and (2) reported brain activation as coordinates in standard space. Using these criteria, a systematic literature search identified seven studies that examined water swallowing and five studies of saliva swallowing. An activation likelihood estimation (ALE) meta‐analysis of these studies was performed with GingerALE. For water swallowing, clusters with high activation likelihood were found in the bilateral sensorimotor cortex, right inferior parietal lobule, and right anterior insula. For saliva swallowing, clusters with high activation likelihood were found in the left sensorimotor cortex, right motor cortex, and bilateral cingulate gyrus. A between‐condition meta‐analysis revealed clusters with higher activation likelihood for water than for saliva swallowing in the right inferior parietal lobule, right postcentral gyrus, and right anterior insula. Clusters with higher activation likelihood for saliva than for water swallowing were found in the bilateral supplementary motor area, bilateral anterior cingulate gyrus, and bilateral precentral gyrus. This meta‐analysis emphasizes the distributed and partly overlapping cortical networks involved in the control of water and saliva swallowing. Water swallowing is associated with right inferior parietal activation, likely reflecting the sensory processing of intraoral water stimulation. Saliva swallowing more strongly involves premotor areas, which are crucial for the initiation and control of movements. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.
Extraction of situational meaning by integrating multiple meanings in a complex environment: A functional MRI study
Authors: Sugiura Motoaki , Wakusawa Keisuke , Sekiguchi Atsushi , Sassa Yuko , Jeong Hyeonjeong , Horie Kaoru , Sato Shigeru , Kawashima Ryuta
Published: December 2008

Humans extract behaviorally significant meaning from a situation by integrating meanings from multiple components of a complex daily environment. To determine the neural underpinnings of this ability, the authors performed functional magnetic resonance imaging of healthy subjects while the latter viewed naturalistic scenes of two people and an object, including a threatening situation of a person being attacked by an offender with an object. The authors used a two‐factorial design: the object was either aversive or nonaversive, and the offender's action was either directed to the person or elsewhere. This allowed the authors to examine the neural response to object aversiveness and person‐directed intention separately. A task unrelated to threat was also used to address incidental (i.e., subconscious or unintentional) detection. Assuming individual differences in incidental threat detection, the authors used a functional connectivity analysis using principal components analysis of intersubject variability. The left lateral orbitofrontal cortex and medial prefrontal cortex (MPFC) were specifically activated in response to a threatening situation. The threat‐related component of intersubject variability was extracted from these data and showed a significant correlation with personality scores. There was also a correlation between threat‐related intersubject variability and activation for object aversiveness in the left temporal pole and lateral orbitofrontal cortex; person‐directed intention in the left superior frontal gyrus; threatening situations in the left MPFC; and independently for both factors in the right MPFC. Results demonstrate independent processing of object aversiveness and person‐directed intention in the left temporal‐orbitofrontal and superior frontal networks, respectively, and their integration into situational meaning in the MPFC. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.
Neural basis of individualistic and collectivistic views of self
Authors: Chiao Joan Y. , Harada Tokiko , Komeda Hidetsugu , Li Zhang , Mano Yoko , Saito Daisuke , Parrish Todd B. , Sadato Norihiro , Iidaka Tetsuya
Published: December 2008

Individualism and collectivism refer to cultural values that influence how people construe themselves and their relation to the world. Individualists perceive themselves as stable entities, autonomous from other people and their environment, while collectivists view themselves as dynamic entities, continually defined by their social context and relationships. Despite rich understanding of how individualism and collectivism influence social cognition at a behavioral level, little is known about how these cultural values modulate neural representations underlying social cognition. Using cross‐cultural functional magnetic resonance imaging (fMRI), we examined whether the cultural values of individualism and collectivism modulate neural activity within medial prefrontal cortex (MPFC) during processing of general and contextual self judgments. Here, we show that neural activity within the anterior rostral portion of the MPFC during processing of general and contextual self judgments positively predicts how individualistic or collectivistic a person is across cultures. These results reveal two kinds of neural representations of self (eg, a general self and a contextual self) within MPFC and demonstrate how cultural values of individualism and collectivism shape these neural representations. Hum Brain Mapp, 2009. © 2008 Wiley‐Liss, Inc.
Pretreatment FDG‐PET standardized uptake value as a prognostic factor for outcome in head and neck cancer
Authors: Machtay Mitchell , Natwa Mona , Andrel Jocelyn , Hyslop Terry , Anne P. Rani , Lavarino Jororsali , Intenzo Charles M. , Keane William
Published: December 2008

Background.

We studied the potential prognostic significance of pretreatment 18‐fluorodeoxyglucose‐positron emission tomography (FDG‐PET) standardized uptake value (SUV) in squamous cell carcinoma of the head and neck (SCCHN).

Methods.

A retrospective review of the pretreatment FDG‐PET scans of 60 patients with SCCHN was performed. All patients received radiotherapy and 37 also received concurrent chemotherapy. SUV was calculated by 2 nuclear‐medicine physicians who were blinded to the clinical data. Disease‐free survival (DFS) was analyzed with respect to SUV (and other potential prognostic factors).

Results.

The median SUV was 7.2 (range, 1–24.7); 34 patients (57%) had SUV < 9.0 compared with 26 patients (43%) with an SUV ≥ 9.0. The group with low SUV had significantly better 2‐year DFS compared with the high SUV group (72% vs 37%), p = .007. On multivariate analysis, stage and age were also associated with DFS, but SUV remained an independent predictor of DFS (hazard ratio: 1.08; p = .016).

Conclusion.

SUV was significantly associated with outcome after modern definitive therapy of SCCHN. © 2008 Wiley Periodicals, Inc. Head Neck, 2009
Quality‐adjusted survival analysis of Radiation Therapy Oncology Group (RTOG) 90‐03: Phase III randomized study comparing altered fractionation to standard fractionation radiotherapy for locally advanced head and neck squamous cell carcinoma
Authors: Konski Andre A. , Winter Kathryn , Cole Bernard F. , Ang Kie‐Kian , Fu Karen K.
Published: December 2008

Background.

To evaluate quality‐adjusted survival (QAS) of patients with locally advanced squamous cell carcinoma of the head and neck treated with 4 different radiation fractionation schedules.

Methods.

QAS was calculated using the quality‐adjusted time without toxicity or relapse (Q‐TWiST) methodology. Utilities (patient preferences for certain health states) were obtained by threshold analysis. Q‐TWiST therefore equaled TWiST + ([weight for toxicity] × [time spent in toxicity]) + ([weight for relapse] × [time spent in relapse]).

Results.

A statistically significant increase in QAS existed for patients treated with hyperfractionated radiotherapy compared with standard fractionated radiotherapy (SFX) with a toxicity utility ≥0.57 and relapse utility ≤0.72. No statistically significant difference was observed for patients treated with the other 2 fractionation schedules compared with SFX.

Conclusion.

Q‐TWiST analysis identified patient groups that would benefit from more aggressive therapy. Further investigation with patient‐generated utilities is needed. © 2008 Wiley Periodicals, Inc. Head Neck, 2009
Comparison of outcome measures in head and neck cancer—Literature review 2000–2006
Authors: Tschiesner Uta M. , Rogers Simon N. , Harreus Ulrich , Berghaus Alexander , Cieza Alarcos
Published: December 2008

Background.

The aim of this study was to systematically analyze outcome measures in head and neck cancer trials using the International Classification of Functioning. Disability, and Health (ICF) as reference.

Methods.

Clinical trials 2000 to 2006 in MEDLINE were selected according to predefined criteria. Outcome measures were extracted, and concepts contained in the outcome measures were translated into ICF.

Results.

A total of 254 publications showed 4203 concepts that translate into 117 different, second‐level ICF‐categories. Just 2 of 117 outcome measures apply regularly: e580 (health_services) in 58% publications and b510 (ingestion_function) in 46% publications. Any other outcome measure applies to <33% publications. In the differentiation of outcome measures among tumor locations, staging, or treatment options, no systematic use of specific outcome measures was identified in any subgroup.

Conclusion.

The ICF provides a useful reference to identify and quantify outcome measures in head and neck cancertrials. Applying the ICF classification reveals little standardization in the use of outcome‐measures by different authors. However, this is not related to the heterogeneity of head and neck cancer in terms of tumor locations, staging, or treatment options. Systematic use of the ICF might increases comparability of study results and decrease data silos. © 2008 Wiley Periodicals, Inc. Head Neck, 2009
Place and value of the recurrent laryngeal nerve (RLN) palpatory method in preventing RLN palsy during thyroid surgery
Authors: Altorjay Áron , Tihanyi Zoltán , Luka Ferenc , Juhász Árpád , Bencsik Zsuzsanna , Rüll Miklós , Kecskés Gábor , Paál Balázs
Published: December 2008

Background.

In recent years, certain publications have appeared confirming that intraoperative palpation of the recurrent laryngeal nerve (RLN) is a very reliable method.

Method.

The characteristics of the surgical anatomy of 1023 RLN have been summarized on the basis of intraoperative palpability, running down, branching variations, thickness, and laryngeal entry site.

Results.

Palpation was helpful in 81.4% (833/1023), proved false positive in 8.2% (84/1023), and in 10.4% (106/1023) it was of no help in the exact localization. Definitive RLN palsy was experienced in 0.78% of all cases (8/1023), while transient paresis was encountered in 1.2% (12/1023). Only a moderately strong stochastic correlation could be found between RLN palsies and those nerves which were nonpalpable and atypical, which showed the joint occurrence of being both thinner than normal and branching already before the plane of the inferior thyroid artery (Cramer's associate coefficient, C = 0.383).

Conclusion.

Palpation alone cannot substitute visualization and proper surgical dissection of the nerve. © 2008 Wiley Periodicals, Inc. Head Neck, 2009
Aurora kinase A inhibition and paclitaxel as targeted combination therapy for head and neck squamous cell carcinoma
Authors: Mazumdar Abhijit , Henderson Ying C. , El‐Naggar Adel K. , Sen Subrata , Clayman Gary L.
Published: December 2008

Background.

Aurora kinase A (AURKA) is amplified with varying incidence in multiple human cancers including head and neck squamous cell carcinoma (HNSCC). We investigated whether AURKA is a potential therapeutic target in HNSCC.

Methods.

We conducted an immunohistochemical analysis of AURKA expression in paired normal and tumor samples (n = 63). HNSCC cells treated with siRNA specific for AURKA were assessed for AURKA mRNA and protein expression levels by reverse transcriptase‐polymerase chain reaction and Western blot analysis. Tumor cells treated with siRNA and paclitaxel were assessed for cell proliferation by MTT assay and for cell cycle distribution by flow cytometry.

Results.

AURKA expression was higher in tumor than in adjacent normal in most (85%) of the samples analyzed. HNSCC cells and primary tumors revealed high expression levels of AURKA. Most primary tumors also showed high kinase activity of the enzyme. Targeted AURKA inhibition increased the sub‐G1 cell fraction, with a concomitant reduction in the G1 cell population, indicating induction of apoptosis and thus markedly suppressed proliferation of HNSCC cells. Combining siRNA‐induced AURKA inhibition with 5 to 10 nM paclitaxel synergistically enhanced apoptosis induction.

Conclusion.

AURKA is a potential therapeutic target for HNSCC. Further investigation of small‐molecule AURKA inhibitors as therapeutic agents is warranted. © 2008 Wiley Periodicals, Inc. Head Neck, 2009
Bile acids: Trying to understand their chemistry and biology with the hope of helping patients #
Authors: Hofmann Alan F.
Published: December 2008

An informal review of the author's five decades of research on the chemistry and biology of bile acids in health and disease is presented. The review begins with a discussion of bile acid structure and its remarkable diversity in vertebrates. Methods for tagging bile acids with tritium for metabolic or transport studies are summarized. Bile acids solubilize polar lipids in mixed micelles; progress in elucidating the structure of the mixed micelle is discussed. Extensive studies on bile acid metabolism in humans have permitted the development of physiological pharmacokinetic models that can be used to simulate bile acid metabolism. Consequences of defective bile acid biosynthesis and transport have been clarified, and therapy has been developed. Methods for measuring bile acids have been improved. The rise and fall of medical and contact dissolution of cholesterol gallstones is chronicled. Finally, principles of therapy with bile acid agonists and antagonists are given. Advances in understanding bile acid biology and chemistry have helped to improve the lives of patients with hepatobiliary or digestive disease. (Hepatology 2009.)
Locating the stem cell niche and tracing hepatocyte lineages in human liver #
Authors: Fellous Tariq G. , Islam Shahriar , Tadrous Paul J. , Elia George , Kocher Hemant M. , Bhattacharya Satyajit , Mears Lisa , Turnbull Douglas M. , Taylor Robert W. , Greaves Laura C. , Chinnery Patrick F. , Taylor Geoffery , McDonald Stuart A.C. , Wright Nicholas A. , Alison Malcolm R.
Published: December 2008

We have used immunohistochemical and histochemical techniques to identify patches of hepatocytes deficient in the enzyme cytochrome c oxidase, a component of the electron transport chain and encoded by mitochondrial DNA (mtDNA). These patches invariably abutted the portal tracts and expanded laterally as they spread toward the hepatic veins. Here we investigate, using mtDNA mutations as a marker of clonal expansion, the clonality of these patches. Negative hepatocytes were laser-capture microdissected and mutations identified by polymerase chain reaction sequencing of the entire mtDNA genome. Patches of cytochrome c oxidase–deficient hepatocytes were clonal, suggesting an origin from a long-lived cell, presumably a stem cell. Immunohistochemical analysis of function and proliferation suggested that these mutations in cytochrome c oxidase-deficient hepatocytes were nonpathogenic. Conclusion: these data show, for the first time, that clonal proliferative units exist in the human liver, an origin from a periportal niche is most likely, and that the trajectory of the units is compatible with a migration of cells from the periportal regions to the hepatic veins. (Hepatology 2009.)
Systemic antigen cross-presented by liver sinusoidal endothelial cells induces liver-specific CD8 T-cell retention and tolerization #
Authors: von Oppen Nanette , Schurich Anna , Hegenbarth Silke , Stabenow Dirk , Tolba Rene , Weiskirchen Ralf , Geerts Albert , Kolanus Waldemar , Knolle Percy , Diehl Linda
Published: December 2008

Peripheral CD8 T-cell tolerance can be generated outside lymphatic tissue in the liver, but the course of events leading to tolerogenic interaction of hepatic cell populations with circulating T-cells remain largely undefined. Here we demonstrate that preferential uptake of systemically circulating antigen by murine liver sinusoidal endothelial cells (LSECs), and not by other antigen-presenting cells in the liver or spleen, leads to cross-presentation on major histocompatibility complex (MHC) I molecules, which causes rapid antigen-specific naïve CD8 T-cell retention in the liver but not in other organs. Using bone-marrow chimeras and a novel transgenic mouse model (Tie2-H-2Kb mice) with endothelial cell-specific MHC I expression, we provide evidence that cross-presentation by organ-resident and radiation-resistant LSECs in vivo was both essential and sufficient to cause antigen-specific retention of naïve CD8 T-cells under noninflammatory conditions. This was followed by sustained CD8 T-cell proliferation and expansion in vivo, but ultimately led to the development of T-cell tolerance. Conclusion: Our results show that cross-presentation of circulating antigens by LSECs caused antigen-specific retention of naïve CD8 T-cells and identify antigen-specific T-cell adhesion as the first step in the induction of T-cell tolerance. (Hepatology 2009.)
Hepatitis C virus persisting after clinically apparent sustained virological response to antiviral therapy retains infectivity in vitro #
Authors: MacParland Sonya A. , Pham Tram N. Q. , Guy Clifford S. , Michalak Tomasz I.
Published: December 2008

Hepatitis C virus (HCV) can persist in the liver, lymphoid cells, and serum of individuals with apparently complete spontaneous or therapy-induced resolution of hepatitis C and can replicate in vivo and in vitro in human T cells. The current study was aimed at assessing the infectivity of HCV persisting at very low levels using the previously established HCV infection system in human T cells. Naive lymphoid cells were exposed to plasma and/or supernatants from cultured peripheral blood mononuclear cells from nine individuals with apparent sustained virological response after completion of antiviral therapy. Exposed cells were analyzed for HCV RNA–positive and HCV RNA–negative strands and, in selected cases, for HCV nonstructural protein 5a (NS5a), the appearance of HCV variants, and the release of virions by immunoelectron microscopy (IEM). The results showed that 11 of the 12 established cultures became HCV RNA–positive strand–reactive, whereas 4 also expressed the virus replicative strand. NS5a protein was detected in the de novo infected cells, and clonal sequencing revealed HCV variants not found in inocula. IEM demonstrated enveloped HCV particles in plasma used as inocula and in culture supernatant from T cells exposed to that plasma. Overall, HCV carried in three of the nine individuals studied elicited productive infection in vitro. Conclusion: HCV persisting at very low levels long after therapy-induced resolution of chronic hepatitis C can remain infectious. The retained biological competence of the virus might have implications with respect to the mechanisms of its persistence and the epidemiology of HCV infection. (Hepatology 2009.)
MicroRNA-122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma #
Authors: Tsai Wei-Chih , Hsu Paul Wei-Che , Lai Tsung-Ching , Chau Gar-Yang , Lin Ching-Wen , Chen Chun-Ming , Lin Chien-Der , Liao Yu-Lun , Wang Jui-Ling , Chau Yat-Pang , Hsu Ming-Ta , Hsiao Michael , Huang Hsien-Da , Tsou Ann-Ping
Published: December 2008

MicroRNAs (miRNAs), which are inhibitors of gene expression, participate in diverse biological functions and in carcinogenesis. In this study, we show that liver-specific microRNA-122 (miR-122) is significantly down-regulated in liver cancers with intrahepatic metastastasis and negatively regulates tumorigenesis. Restoration of miR-122 in metastatic Mahlavu and SK-HEP-1 cells significantly reduced in vitro migration, invasion, and anchorage-independent growth as well as in vivo tumorigenesis, angiogenesis, and intrahepatic metastasis in an orthotopic liver cancer model. Because an inverse expression pattern is often present between an miRNA and its target genes, we used a computational approach and identified multiple miR-122 candidate target genes from two independent expression microarray datasets. Thirty-two target genes were empirically verified, and this group of genes was enriched with genes regulating cell movement, cell morphology, cell-cell signaling, and transcription. We further showed that one of the miR-122 targets, ADAM17 (a disintegrin and metalloprotease 17) is involved in metastasis. Silencing of ADAM17 resulted in a dramatic reduction of in vitro migration, invasion, in vivo tumorigenesis, angiogenesis, and local invasion in the livers of nude mice, which is similar to that which occurs with the restoration of miR-122. Conclusion: Our study suggests that miR-122, a tumor suppressor microRNA affecting hepatocellular carcinoma intrahepatic metastasis by angiogenesis suppression, exerts some of its action via regulation of ADAM17. Restoration of miR-122 has a far-reaching effect on the cell. Using the concomitant down-regulation of its targets, including ADAM17, a rational therapeutic strategy based on miR-122 may prove to be beneficial for patients with hepatocellular carcinoma. (Hepatology 2009.)
Polyproline‐type helical‐structured low‐molecular weight heparin (LMWH)‐taurocholate conjugate as a new angiogenesis inhibitor
Authors: Lee Esak , Kim Yoo‐Shin , Bae Sang Mun , Kim Sang Kyoon , Jin Shunji , Chung Seung Woo , Lee Myungjin , Moon Hyun Tae , Jeon Ok‐Cheol , Park Rang Woon , Kim In San , Byun Youngro , Kim Sang Yoon
Published: December 2008

Although heparin can regulate angiogenesis, tumor growth and metastasis, its clinical application, as well as that of low‐molecular heparin (LMWH), for treating cancer are limited because of heparin's anticoagulant activity and risk of hemorrhages. LMWH‐taurocholate conjugates (LHT7), which have low anticoagulant activity, were synthesized. The structural property of LHT was evaluated by circular dichroism and the binding affinity of LHT7 to vascular endothelial growth factor 165 (VEGF165) was measured by isothermal titration calorimetry. The inhibitory effect of LHT7 on VEGF‐mediated KDR (VEGF‐receptor 2) phosphorylation in Human umbilical vein endothelial cells was evaluated. The VEGF165dependent Matrigel plug assay was performed to verify the antiangiogenic potential of LHT7 on a VEGF165inhibitor. Finally, tumor growth inhibition effects of LHT7 on SCC7 and the survival rate of animal models were investigated. Moreover, MDA‐MB231 xenograft mouse model was additionally used to confirm the therapeutic effect of LHT7 on human breast cancer cell line. As a result, LHT7 which has 12.7% of anticoagulant activity of the original LMWH showed a peculiar polyproline‐type helical structure. LHT7 binds to VEGF strongly and inhibits VEGF dependent KDR phosphorylation. The results of Matrigel plug assay proved LHT7 as a strong antiangiogenic agent inhibiting VEGF165. Remarkably, LHT7 showed a significant tumor growth inhibition potential on SCC7 with an increased survival rate. LHT7 also delayed tumor growth in MDA‐MB231 human breast cancer cell lines. © 2008 UICC