bluuebunny/crossref_metadata_2025 huggingface dataset:
Single‐institution experience with ipilimumab in advanced melanoma patients in the compassionate use setting
Authors: Ku Geoffrey Y. , Yuan Jianda , Page David B. , Schroeder Sebastian E. A. , Panageas Katherine S. , Carvajal Richard D. , Chapman Paul B. , Schwartz Gary K. , Allison James P. , Wolchok Jedd D.
Published: February 2010

BACKGROUND:

Ipilimumab is a monoclonal antibody that antagonizes cytotoxic T lymphocyte antigen‐4, a negative regulator of the immune system. The authors report on advanced refractory melanoma patients treated in a compassionate use trial of ipilimumab at the Memorial Sloan‐Kettering Cancer Center.

METHODS:

Patients with advanced refractory melanoma were treated in a compassionate use trial with ipilimumab 10 mg/kg every 3 weeks for 4 doses. Those with evidence of clinical benefit at Week 24 (complete response [CR], partial response [PR], or stable disease [SD]) then received ipilimumab every 12 weeks.

RESULTS:

A total of 53 patients were enrolled, with 51 evaluable. Grade 3/4 immune‐related adverse events were noted in 29% of patients, with the most common immune‐related adverse events being pruritus (43%), rash (37%), and diarrhea (33%). On the basis of immune‐related response criteria, the response rate (CR + PR) was 12% (95% confidence interval [CI], 5%‐25%), whereas 29% had SD (95% CI, 18%‐44%). The median progression‐free survival was 2.6 months (95% CI, 2.3‐5.2 months), whereas the median overall survival (OS) was 7.2 months (95% CI, 4.0‐13.3 months). Patients with an absolute lymphocyte count (ALC) ≥1000/μL after 2 ipilimumab treatments (Week 7) had a significantly improved clinical benefit rate (51% vs 0%; P = .01) and median OS (11.9 vs 1.4 months; P < .001) compared with those with an ALC <1000/μL.

CONCLUSIONS:

The results confirm that ipilimumab is clinically active in patients with advanced refractory melanoma. The ALC after 2 ipilimumab treatments appears to correlate with clinical benefit and OS, and should be prospectively validated. Cancer 2010. © 2010 American Cancer Society.
Phase 1/2 study of preoperative docetaxel and mitoxantrone for high‐risk prostate cancer
Authors: Garzotto Mark , Higano Celestia S. , O'Brien Catherine , Rademacher Brooks L. S. , Janeba Nicole , Fazli Ladan , Lange Paul H. , Lieberman Stephen , Beer Tomasz M.
Published: February 2010

BACKGROUND:

A study was conducted to determine the 5‐year recurrence‐free survival in patients with high‐risk prostate cancer after neoadjuvant combination chemotherapy followed by surgery. Secondary endpoints included safety, pathologic effects of chemotherapy, and predictors of disease recurrence.

METHODS:

Fifty‐seven patients were enrolled in a phase 1/2 study of weekly docetaxel 35 mg/m2 and escalating mitoxantrone to 4 mg/m2 before prostatectomy. Patients were treated with 16 weeks of chemotherapy administered weekly on a 3 of every 4 week schedule. A tissue microarray, constructed from the prostatectomy specimens, served to facilitate the exploratory evaluation of biomarkers. The primary endpoint was recurrence‐free survival. Disease recurrence was defined as a confirmed serum prostate‐specific antigen (PSA) >0.4 ng/mL.

RESULTS:

Of the 57 patients, 54 received 4 cycles of docetaxel and mitoxantrone before radical prostatectomy. Grade 4 toxicities were limited to leukopenia, neutropenia, and hyperglycemia. Serum testosterone levels remained stable after chemotherapy. Negative surgical margins were attained in 67% of cases. Lymph node involvement was detected in 18.5% of cases. With a median follow‐up of 63 months, 27 of 57 (47.4%) patients recurred. The Kaplan‐Meier recurrence‐free survival at 2 years was 65.5% (95% confidence interval [CI], 53.0%‐78.0%) and was 49.8% at 5 years (95% CI, 35.5%‐64.1%). Pretreatment serum PSA, lymph node involvement, and postchemotherapy tissue vascular endothelial growth factor expression were independent predictors of early recurrence.

CONCLUSIONS:

Preoperative chemotherapy with docetaxel and mitoxantrone is feasible. Approximately half of the high‐risk patients remain free of disease recurrence at 5 years, and clinical and molecular predictors of early recurrence were identified. Cancer 2010. © 2010 American Cancer Society.
Effectiveness of a patient‐ and practice‐level colorectal cancer screening intervention in health plan members
Authors: Lewis Carmen , Pignone Michael , Schild Laura A. , Scott Tracy , Winquist Andrea , Rimer Barbara K. , Glanz Karen
Published: February 2010

BACKGROUND:

Evidence‐based interventions have been found effective in increasing colorectal cancer (CRC) screening. Translating these successful interventions into real world settings, such as health plans, can be challenging.

METHODS:

CHOICE (Communicating Health Options through Information and Cancer Education) is a controlled trial to test the effectiveness of a patient‐ and practice‐level intervention to increase use of recommended CRC screening tests. The patient‐level intervention was a patient decision aid and stage‐targeted brochures, mailed to eligible health plan members, to provide information about CRC, available screening tests, and how to obtain CRC screening at their physicians' practices. The practice‐level intervention was academic detailing to prepare practices to facilitate CRC testing once the patient was activated by the decision aid. Surveys and claims data will be used to assess CRC screening test completion.

RESULTS:

Thirty‐two primary care practices in Florida and Georgia participated. The authors recruited 443 participating health plan members for the trial; 211 were patients in intervention practices, and 232 were in usual care practices. Study participants reflected an insured population; the majority were white and aged <60 years. The authors also mailed the intervention to 343 people from intervention practices who did not respond to the eligibility or baseline survey. Receipt of screening in that group will be compared with screening among 319 people from usual care practices who did not respond to these surveys using claims data.

CONCLUSIONS:

The CHOICE study will demonstrate the effect of 2 combined evidence‐based interventions on CRC screening test completion among health plan members. Cancer 2010. © 2010 American Cancer Society.
Textile‐Compatible Substrate Electrodes with Electrodeposited ZnO—A New Pathway to Textile‐Based Photovoltaics
Authors: Loewenstein Thomas , Rudolph Melanie , Mingebach Markus , Strauch Kerstin , Zimmermann Yvonne , Neudeck Andreas , Sensfuss Steffi , Schlettwein Derck
Published: February 2010

A strategy is presented to realize textile‐based photovoltaic cells motivated by developments of textile‐based electronics and their demand of grid‐independent energy supply. Beyond this, a development of textile‐based photovoltaics also represents an attractive pathway towards very flexible and rugged solar cells. The need for compatibility of an appropriate photovoltaic technology with the physical limitations of textiles is stressed. Electrodeposition from aqueous solutions is presented as a successful strategy to realize semiconductor structures on textiles and detailed control and influence of the deposition conditions is discussed. The role of microelectrode effects, options of forced convection, deposition under pulsed potential, alternative deposition baths and different substrate metals are emphasized. An active electrode material is presented which reaches a conversion efficiency close to the 1 % limit under AM 1.5 illumination conditions and thereby opens the door for a further optimization towards devices of technical interest.
Differential Behavior of Amino–Imino Constitutional Isomers in Nonlinear Optical Processes
Authors: Latorre Sonia , Moreira Ibério de P. R. , Villacampa Belén , Julià Lluís , Velasco Dolores , Bofill Josep Maria , López‐Calahorra Francisco
Published: February 2010

A detailed study of the “blocked” amino–imino tautomers derived from N‐acridine‐substituted 2‐aminobenzothiazole—and their effect on the nonlinear optical response—is presented. The synthesis, characterization, and nonlinear optical properties of these frozen tautomers, namely, N‐methyl‐N‐(2‐nitroacridin‐6‐yl)‐2‐aminobenzothia‐zole and 3‐methyl‐N‐(7‐nitroacridin‐3‐yl)‐2‐iminobenzothiazole, are reported. A theoretical model based on valence–bond theory is also proposed and used to analyze the effects of the nuclear configuration corresponding to each frozen tautomer structure. In the present case, the aromatic form and the allylic‐anion‐like system of the NCN group inherent to each isomer are crucial for understanding and analyzing the different responses of each “blocked” tautomer.
Almost‐anywhere theories: Reductionism and universality of emergence
Authors: Licata Ignazio
Published: February 2010

Here, we aim to show that reductionism and emergence play a complementary role in understanding natural processes and in the dynamics of science explanation. In particular, we will show that the renormalization group—one of the most refined tools of Theoretical Physics—allows to understand the importance of emergent processes' role in Nature identifying them as universal organization processes, that is, they are scale independent. We can use the syntaxes of Quantum Field Theory and the processes of Spontaneous Symmetry Breaking as a trans‐disciplinary theoretical scenario for many other forms of complexity, especially the biological and cognitive ones. © 2010 Wiley Periodicals, Inc. Complexity, 2010
Precise conditional immortalization of mouse cells using tetracycline‐regulated SV40 large T‐antigen
Authors: Anastassiadis Konstantinos , Rostovskaya Maria , Lubitz Sandra , Weidlich Stefanie , Stewart A. Francis
Published: February 2010

Cellular immortalization provides a way for expansion and subsequent molecular characterization of rare cell types. Ideally, immortalization can be achieved by the reversible expression of immortalizing proteins. Here, we describe the use of conditional immortalization based on a modified tetracycline‐regulated system for the expression of SV40 large T‐antigen in embryonic stem (ES) cells and mice. The modified system relies on a codon improved reverse tetracycline transactivator (irtTA) fused to the ligand‐binding domain (LBD) of the androgen receptor (irtTA‐ABD) or of a mutated glucocorticoid receptor (irtTA‐GBD*). Induction of T‐antigen is conferred only after addition of two ligands, one to activate the LBD (mibolerone for irtTA‐ABD or dexamethasone for irtTA‐GBD*) and one to activate the tetracycline transactivator (doxycycline). In ES cells, changes in gene expression upon large T induction were limited and reversible upon deinduction. Similarly, expression of T‐antigen was very tightly regulated in mice. We have isolated and expanded bone marrow mesenchymal stem cells that could be genetically manipulated and maintained their differentiation properties after several passages of expansion under conditions that induce the expression of large T‐antigen. genesis 48:220–232 2010. © 2010 Wiley‐Liss, Inc.
A transgenic Cre mouse line for the study of cortical and hippocampal development
Authors: Zhou Wei , Zhang Ying , Li Yiping , Wei Yu‐Sheng , Liu Guang , Liu De‐Pei , Pleasure Samuel J , Xie Wei , Zhao Chunjie
Published: February 2010

Wnt signaling regulates cortical and hippocampal development. In a previous study we found that a particular Wnt receptor, Frizzled9 (Fzd9), was selectively expressed in both the developing and adult hippocampus. Taking advantage of the specificity of this promoter, we generated a transgenic cre mouse line using the putative control elements of the Fzd9 gene. In the Fzd9‐cre mice, Cre is mainly detected in the developing cortex and hippocampus and is confined to the CA fields and dentate gyrus in adults. Furthermore, by crossing the Fzd9‐cre mouse with the ROSA26 reporter line, we examined the activity of Cre and found that it has very high recombination efficiency. Thus, this mouse line will likely prove to be a useful tool for studying cortical and hippocampal development via activation or inactivation of interesting genes. genesis 48:343–350, 2010. © 2010 Wiley‐Liss, Inc.
Building a zoo of mice for genetic analyses: A comprehensive protocol for the rapid generation of BAC transgenic mice
Authors: Johansson Torbjörn , Broll Ilja , Frenz Theresa , Hemmers Saskia , Becher Burkhard , Zeilhofer Hanns Ulrich , Buch Thorsten
Published: February 2010

Transgenic mice are highly valuable tools for biological research as they allow cell type–specific expression of functionally instrumental genes. In this protocol, the generation of bacterial artificial chromosome (BAC) transgenic constructs is described. We give an overview of different transgenic inserts, such as fluorescent proteins (alone or in combination with Cre variants), diphtheria toxin receptor, lacZ, and light‐activated ion channels. The most reliable and versatile approach to express these genes is by using BACs, which allow “highjacking” of the expression pattern of a gene without characterizing its transcriptional control elements. Here, we describe the necessary cloning techniques compared with conventional transgenesis. With the provided “toolbox” of already available transgene constructs, the generation of the BAC transgenes is made easy and rapid. We provide a comprehensive outline how to insert the different transgenes into a chosen BAC by either ET cloning or recombineering. We also describe in detail the methods to identify the correct insertion and the integrity of the final BAC construct, and finally, the preparation of the BAC DNA for oocyte injection is described. genesis 48:264–280, 2010. © 2010 Wiley‐Liss, Inc.
Comparison of methods for identifying and assessing obese patients with binge eating disorder in primary care settings
Authors: Barnes Rachel D. , Masheb Robin M. , White Marney A. , Grilo Carlos M.
Published: February 2010

Objective:

Given the prevalence and health significance of binge eating disorder (BED) it is important to determine if time‐efficient self‐reports can adequately assess BED and its features in primary care settings. We compared the Eating Disorder Examination‐Questionnaire (EDE‐Q) and Questionnaire for Eating and Weight Patterns‐Revised (QEWP‐R), administered to obese patients with BED in primary care setting to the Eating Disorder Examination (EDE) interview.

Method:

Sixty‐six participants completed the questionnaires and were interviewed.

Results:

The EDE interview was significantly correlated with the EDE‐Q (binge eating, four subscales, and global score) and the QEWP‐R (binge eating, distress, and body image). The EDE‐Q yielded significantly lower estimates of binge eating and significantly higher scores on the EDE subscales. The QEWP‐R yielded significantly higher scores on the behavioral indicators and distress about binge eating and body image variables.

Discussion:

These findings suggest that these two self‐report measures have potential utility for identifying BED in obese patients in primary care. © 2010 by Wiley Periodicals, Inc.
Bulimia nervosa with history of anorexia nervosa: Could the clinical subtype of anorexia have implications for clinical status and treatment response?
Authors: Vaz‐Leal Francisco J. , Santos Laura Rodríguez , García‐Herráiz M. Angustias , Monge‐Bautista Melchora , López‐Vinuesa Beatriz
Published: February 2010

Objective:

To investigate whether the subtype of anorexia nervosa (AN) could influence the bulimic syndrome and treatment response in bulimia nervosa (BN) patients with a history of AN (BN/AN+).

Method:

Seventy female BN patients were assessed for eating disorder, psychopathology and personality, and treated for 6 months.

Results:

BN/AN+ patients retained some traits of their past condition: lower body weight, higher perfectionism, and higher reward dependence. They also had more severe symptoms, longer evolution time, and worse response to treatment. A history of restricting AN was associated to higher age, longer evolution time, higher impulsivity, and greater tendency to use diet pills and diuretics. A history of binge‐purging AN was associated to more severe vomiting, lower body dissatisfaction and less depressive symptoms, as well as better outcome.

Discussion:

The influence of the AN subtype in BN/AN+ patients is worthy of further study as it might have clinical implications. © 2010 by Wiley Periodicals, Inc (Int J Eat Disord 2011; 44:212–219)
Spectroscopic and Computational Study of Ligand Photodissociation from [Ru(dipyrido[3,2‐a:2′,3′‐c]phenazine)(4‐aminopyridine)4]2+
Authors: Ruiu Tiziana , Garino Claudio , Salassa Luca , Pizarro Ana M. , Nervi Carlo , Gobetto Roberto , Sadler Peter J.
Published: February 2010

The new complex [Ru(dppz)(4AP)4]2+ (1, in which dppz = dipyrido[3,2‐a:2′,3′‐c]phenazine and 4AP = 4‐aminopyridine) has been synthesized, characterized and its photophysical and photochemical properties have been studied by combining spectroscopic and computational [DFT and time‐dependent (TD) DFT] methods. Upon irradiation in aqueous solution, complex 1 selectively photoreleases one 4AP ligand and subsequently coordinates a water molecule to form [Ru(dppz)(4AP)3(OH2)]2+.
Chemoenzymatic Dynamic Kinetic Resolution of Alcohols and Amines (Eur. J. Org. Chem. 6/2010)
Authors: Lee Jin Hee , Han Kiwon , Kim Mahn‐Joo , Park Jaiwook
Published: February 2010

The cover picture shows the synthesis of optically active esters and amides by chemoenzymatic dynamic kinetic resolution (DKR) from racemic alcohols and amines, respectively. Racemic substrates are transformed into single enantiomeric products by the combination of metal‐catalyzed racemization and enzymatic acylation. The background is “The Hands of Win‐Win” of Homigot, 22 km east of Pohang along the East Sea of Korea. Many people visit Homigot to see the hands and the sun rise. The hands are chiral and racemic. The Microreview by M.‐J. Kim, J. Park et al. on p. 999 ff describes the DKR of racemic alcohols and amines by emphasizing the characteristics of the racemization catalysts developed so far.
DNA damages induced by trans, trans‐2,4‐decadienal (tt‐DDE), a component of cooking oil fume, in human bronchial epithelial cells
Authors: Young Shun‐Chieh , Chang Louis W. , Lee Hui‐Ling , Tsai Lung‐Hung , Liu Yin‐Chang , Lin Pinpin
Published: February 2010

Epidemiological studies have demonstrated that cooking oil fumes (COF) are an environmental risk factor for the development of lung adenocarcinoma among nonsmoking females in Taiwan. Aside from polycyclic aromatic hydrocarbons, aldehydes, especially trans, trans‐2,4‐decadienal (tt‐DDE) are found to be abundant in COF. Although there is indication that tt‐DDE induces DNA damage, the precise role of tt‐DDE in the induction of DNA damage in lung cells is still not clear. When we assessed DNA breaks with the Comet assay, we found that the DNA breaks induced by 1 μM tt‐DDE in human bronchial epithelial cells (BEAS‐2B) could be significantly reduced by antioxidants, suggesting that oxidative stress was involved. Indeed, when tt‐DDE‐treated cells were coincubated with endonuclease III/formamidopyrimidine‐DNA glycosylase or with nuclear extract (NE), an enhancement of DNA breaks was observed at 1 hr after tt‐DDE exposure. Furthermore, when NE was incubated with an antibody against 8‐oxoguanine DNA glycosylase (anti‐OGG1), a reduction in tt‐DDE/NE‐induced DNA breaks could be demonstrated. Since OGG1 is a specific repair enzyme for 8‐oxo‐deoxyguanosine (8‐oxo‐dG), these findings indicated that 8‐oxo‐dG was involved. On the other hand, when NE was incubated with antibodies against nucleotide excision repair enzymes, there was a significant reduction in tt‐DDE/NE‐induced DNA breaks at 4 hr after tt‐DDE treatment. These observations indicate that, in addition to early oxidative DNA damage, nonoxidative DNA damage such as bulky adduct formation, was also induced by tt‐DDE. Our study further affirms that tt‐DDE is genotoxic to human lung cells and can increase carcinogenic risk. Environ. Mol. Mutagen., 2010. © 2010 Wiley‐Liss, Inc.
Strategies for DNA interstrand crosslink repair: Insights from worms, flies, frogs, and slime molds
Authors: McVey Mitch
Published: February 2010

DNA interstrand crosslinks (ICLs) are complex lesions that covalently link both strands of the DNA double helix and impede essential cellular processes such as DNA replication and transcription. Recent studies suggest that multiple repair pathways are involved in their removal. Elegant genetic analysis has demonstrated that at least three distinct sets of pathways cooperate in the repair and/or bypass of ICLs in budding yeast. Although the mechanisms of ICL repair in mammals appear similar to those in yeast, important differences have been documented. In addition, mammalian crosslink repair requires other repair factors, such as the Fanconi anemia proteins, whose functions are poorly understood. Because many of these proteins are conserved in simpler metazoans, nonmammalian models have become attractive systems for studying the function(s) of key crosslink repair factors. This review discusses the contributions that various model organisms have made to the field of ICL repair. Specifically, it highlights how studies performed withC. elegans, Drosophila, Xenopus, and the social amoeba Dictyostelium serve to complement those from bacteria, yeast, and mammals. Together, these investigations have revealed that although the underlying themes of ICL repair are largely conserved, the complement of DNA repair proteins utilized and the ways in which each of the proteins is used can vary substantially between different organisms. Environ. Mol. Mutagen., 2010. © 2010 Wiley‐Liss, Inc.
Degradation of triclosan in the combined reaction of Fe2+ and UV‐C: Comparison with the Fenton and photolytic reactions
Authors: Son Hyun‐Seok , Khim Jeehyeong , Zoh Kyung‐Duk
Published: February 2010

The degradation mechanism of triclosan, which is a potent broad‐spectrum antimicrobial agent considered to be an emerging pollutant, was investigated using the Fenton reaction, UV‐C only, and the combined reaction of Fe2+ and UV‐C. In the Fenton, UV‐C only, and combined reactions, triclosan was almost completely removed within 60 min, whereas total organic carbon (TOC) was degraded by only 48.2, 58.7, and 79%, respectively, within 150 min. The production of chloride as the ionic byproduct in the Fenton, UV‐C only, and combined reactions reached 54, 62, and 78%, respectively, after 150 min. In the presence of methanol as an OH radical scavenger, the efficiencies of triclosan removal and chloride production decreased significantly in all reactions, indicating that the OH radical is the main oxidizing compound in these reactions. The concentration of Fe2+ decreased continuously during the Fenton reaction, whereas it increased after 90 min in the combined reaction, indicating that a reversible reaction between Fe2+ and Fe3+ occurred. The more efficient removal of TOC and the generation of more OH radicals by the combined reaction indicate that it is superior to other reactions for the degradation of triclosan. © 2010 American Institute of Chemical Engineers Environ Prog, 2010
Application of MPA to estimate probability of collapse of structures
Authors: Han Sang Whan , Moon Ki‐Hoon , Chopra Anil K.
Published: February 2010

This paper develops a modal pushover analysis‐ (MPA) based approximate procedure to quantify the collapse potential of structural systems. The computationally demanding incremental dynamic analysis (IDA) of the structural system is avoided by MPA of the structure in conjunction with empirical equations for the collapse strength ratio for the first‐mode single‐degree‐of‐freedom (SDF) system; higher modes of vibration play essentially no role in estimating the ground motion intensity required to cause collapse of the structure. Presented are collapse fragility curves for 6‐, 9‐, and 20‐story regular special moment‐resisting teel frames computed by the exact and approximate procedures, demonstrating that the MPA‐based approximate procedure requires only a small fraction (1% in one example) of the computational effort inherent in exact IDA and still achieves highly accurate results. Copyright © 2010 John Wiley & Sons, Ltd.
Effects of vegetation on channel morphodynamics: results and insights from laboratory experiments
Authors: Tal Michal , Paola Chris
Published: February 2010

A series of laboratory experiments demonstrates that riparian vegetation can cause a braided channel to self‐organize to, and maintain, a dynamic, single‐thread channel. The initial condition for the experiments was steady‐state braiding in non‐cohesive sand under uniform discharge. From here, an experiment consisted of repeated cycles alternating a short duration high flow with a long duration low flow, and uniform dispersal of alfalfa seeds over the bed at the end of each high flow. Plants established on freshly deposited bars and areas of braidplain that were unoccupied during low flow. The presence of the plants had the effect of progressively focusing the high flow so that a single dominant channel developed. The single‐thread channel self‐adjusted to carry the high flow. Vegetation also slowed the rate of bank erosion. Matching of deposition along the point bar with erosion along the outer bend enabled the channel to develop sinuosity and migrate laterally while suppressing channel splitting and the creation of new channel width. The experimental channels spontaneously reproduced many of the mechanisms by which natural meandering channels migrate and maintain a single dominant channel, in particular bend growth and channel cutoff. In contrast with the braided system, where channel switching is a nearly continuous process, vegetation maintained a coherent channel until wholesale diversion of flow via cutoff and/or avulsion occurred, by which point the previous channel tended to be highly unfavorable for flow. Thus vegetation discouraged the coexistence of multiple channels. Varying discharge was key to allowing expression of feedbacks between the plants and the flow and promoting the transition from braiding to a single‐thread channel that was then dynamically maintained. Copyright © 2010 John Wiley & Sons, Ltd.
Effect assessment of the herbicide paraquat on a green alga using differential gene expression and biochemical biomarkers
Authors: Jamers An , De Coen Wim
Published: February 2010

Effects of the herbicide paraquat were assessed on the green freshwater alga Chlamydomonas reinhardtii using different endpoints of toxicity. Cell concentration and growth rate were monitored, whereas flow cytometry was applied to determine changes in chlorophyll content, viability and presence of reactive oxygen species. Furthermore, a transcriptomics approach using microarray hybridizations was applied to elucidate the mechanisms of toxicity. The results reveal that paraquat concentrations above 0.25 µM induce toxic effects in C. reinhardtii, reflected in a significantly reduced growth rate and cell concentration with a corresponding median effective concentration (EC50) value of 0.26 µM. With increasing paraquat concentrations, an increase in cell volume was registered with a particle counter as well as in the forward scattering signal of flow cytometric measurements, which is a measure of cell size. Flow cytometry, moreover, showed an increase in reactive oxygen species with increasing exposure concentration, corroborating the general knowledge that this herbicide exerts its toxicity through the generation of oxidative stress. At the same time, several genes involved in oxidative stress defense mechanisms, such as L-ascorbate peroxidase, glutaredoxin, and a possible glutathione-S-transferase were differentially expressed, demonstrating the value of microarrays for elucidating possible mechanisms of toxicity. The fact that several genes were differentially expressed at paraquat concentrations that caused no adverse effects on higher levels of biological organization indicates that a transcriptomics approach allows for the detection of early effects, even before they become manifest at higher levels. Environ. Toxicol. Chem. 2010;29:893–901. © 2009 SETAC
Exposure to lead induces hypoxia—like responses in bullfrog larvae (Rana catesbeiana)
Authors: Rice Timothy M , Blackstone Brian J , Nixdorf Wendy L , Taylor Douglas H
Published: February 2010

Amphibians collected around mining sites, areas with extensive automobile traffic, and shooting ranges have been documented to contain high levels of lead. Lead—exposed amphibians might respond as if in hypoxic conditions because exposure is known to decrease hemoglobin levels, damage erythrocytes, and alter respiratory surfaces. Therefore, we exposed bullfrog larvae to either 0 or 780 μg/L Pb and either 3.50 or 7.85 mg/L oxygen for 7 d and monitored activity, trips to the surface, and buccal ventilation rates. Activity was significantly decreased in larvae exposed to low oxygen, Pb, or both compared to activity of larvae in high oxygen with no Pb. Larvae exposed to both Pb and low oxygen displayed higher buccal ventilation rates than larvae exposed to either treatment separately. Lead—exposed larvae surfaced significantly more often than unexposed larvae even under high—oxygen conditions. Lead—exposed larvae decreased in mass during the exposure period, whereas unexposed larvae increased in mass. Lead exposure could decrease survival of larvae in the field not only because of physiological problems due to decreased oxygen uptake but also because of greater predation pressure due to increased presence at the surface and reduced growth rates.
Distortion correction for diffusion‐weighted MRI tractography and fMRI in the temporal lobes
Authors: Embleton Karl V. , Haroon Hamied A. , Morris David M. , Ralph Matthew A. Lambon , Parker Geoff J.M.
Published: February 2010

Single shot echo‐planar imaging (EPI) sequences are currently the most commonly used sequences for diffusion‐weighted imaging (DWI) and functional magnetic resonance imaging (fMRI) as they allow relatively high signal to noise with rapid acquisition time. A major drawback of EPI is the substantial geometric distortion and signal loss that can occur due to magnetic field inhomogeneities close to air‐tissue boundaries. If DWI‐based tractography and fMRI are to be applied to these regions, then the distortions must be accurately corrected to achieve meaningful results. We describe robust acquisition and processing methods for correcting such distortions in spin echo (SE) EPI using a variant of the reversed direction k space traversal method with a number of novel additions. We demonstrate that dual direction k space traversal with maintained diffusion‐encoding gradient strength and direction results in correction of the great majority of eddy current‐associated distortions in DWI, in addition to those created by variations in magnetic susceptibility. We also provide examples to demonstrate that the presence of severe distortions cannot be ignored if meaningful tractography results are desired. The distortion correction routine was applied to SE‐EPI fMRI acquisitions and allowed detection of activation in the temporal lobe that had been previously found using PET but not conventional fMRI. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.
Cortical gamma‐oscillations modulated by auditory–motor tasks‐intracranial recording in patients with epilepsy
Authors: Nagasawa Tetsuro , Rothermel Robert , Juhász Csaba , Fukuda Miho , Nishida Masaaki , Akiyama Tomoyuki , Sood Sandeep , Asano Eishi
Published: February 2010

Human activities often involve hand‐motor responses following external auditory–verbal commands. It has been believed that hand movements are predominantly driven by the contralateral primary sensorimotor cortex, whereas auditory–verbal information is processed in both superior temporal gyri. It remains unknown whether cortical activation in the superior temporal gyrus during an auditory–motor task is affected by laterality of hand‐motor responses. Here, event‐related γ‐oscillations were intracranially recorded as quantitative measures of cortical activation; we determined how cortical structures were activated by auditory‐cued movement using each hand in 15 patients with focal epilepsy. Auditory–verbal stimuli elicited augmentation of γ‐oscillations in a posterior portion of the superior temporal gyrus, whereas hand‐motor responses elicited γ‐augmentation in the pre‐ and postcentral gyri. The magnitudes of such γ‐augmentation in the superior temporal, precentral, and postcentral gyri were significantly larger when the hand contralateral to the recorded hemisphere was required to be used for motor responses, compared with when the ipsilateral hand was. The superior temporal gyrus in each hemisphere might play a greater pivotal role when the contralateral hand needs to be used for motor responses, compared with when the ipsilateral hand does. Hum Brain Mapp, 2010. © 2010 Wiley‐Liss, Inc.
Hypertrophic Cardiomyopathy and Dysregulation of Cardiac Energetics in A Mouse Model of Biliary Fibrosis
Authors: Desai Moreshwar S. , Shabier Zainuer , Taylor Michael , Lam Fong , Thevananther Sundararajah , Kosters Astrid , Karpen Saul J.
Published: February 2010

Cardiac dysfunction is a major cause of morbidity and mortality in patients with end-stage liver disease; yet the mechanisms remain largely unknown. We hypothesized that the complex interrelated impairments in cardiac structure and function secondary to progression of liver diseases involve alterations in signaling pathways engaged in cardiac energy metabolism and hypertrophy, augmented by direct effects of high circulating levels of bile acids. Biliary fibrosis was induced in male C57BL/6J mice by feeding a 0.1% 3,5-diethoxycarbonyl-1,4-dihydroxychollidine (DDC) supplemented diet. After 3 weeks, mice underwent live imaging (dual energy x-ray absorptiometry [DEXA] scanning, two-dimensional echocardiography [2DE], electrocardiography, cardiac magnetic resonance imaging), exercise treadmill testing, and histological and biochemical analyses of livers and hearts. Compared with chow-fed mice, DDC-fed mice fatigued earlier on the treadmill, with reduced VO2. Marked changes were identified electrophysiologically (bradycardia and prolonged QT interval) and functionally (hyperdynamic left ventricular [LV] contractility along with increased LV thickness). Hearts of DDC-fed mice showed hypertrophic signaling (activation of v-akt murine thymoma viral oncogene/protein kinase B [AKT], inhibition of glycogen synthase kinase-3β [GSK3β], a 20-fold up-regulation of β myosin heavy chain RNA and elevated Gsα/Giα ratio. Genes regulating cardiac fatty acid oxidation pathways were suppressed, along with a threefold increase in myocardial glycogen content. Treatment of mouse cardiomyocytes (which express the membrane bile acid receptor TGR5) with potent natural TGR5 agonists, taurochenodeoxycholic acid and lithocholic acid, activated AKT and inhibited GSK3β, similar to the changes seen in DDC-fed mouse hearts. This provides support for a novel mechanism whereby circulating natural bile acids can induce signaling pathways in heart associated with hypertrophy.

Conclusion:

Three weeks of DDC feeding-induced biliary fibrosis leads to multiple functional, metabolic, electrophysiological, and hypertrophic adaptations in the mouse heart, recapitulating some of the features of human cirrhotic cardiomyopathy. Hepatology 2010;51:2097–2107
A case‐control study of ocular surface squamous neoplasia (OSSN) in Uganda
Authors: Waddell Keith , Kwehangana James , Johnston William T. , Lucas Sebastian , Newton Robert
Published: February 2010

HIV increases the risk of OSSN. Here we investigate other factors in a case‐control study from Uganda with 318 cases (48 CIN I, 66 CIN II, 81 CIN III and 123 with invasive disease) and 762 controls. Initial analyses were stratified by HIV serostatus (204 cases and 202 controls were HIV seropositive), but since findings were similar in infected and uninfected people, the combined results are presented here. The risk of OSSN increased with increasing time spent in direct sunlight (ptrend = 0.003, adjusted for age, sex, residential district and HIV serostatus): compared to those who reported spending up to 1 hr a day in direct sunlight, the risk was 1.7 (95% Confidence Interval [CI] 1.2–2.4) in those reporting 2–4‐hr exposure and 1.8 (95% CI 1.1–3.1) in those reporting 5+ hr. The risk was also increased among people reporting a previous injury to the affected eye (OR 2.4, 95% CI 1.2–4.5). Pinguecula in the nasal quadrant of the unaffected eye were evident on clinical examination for 98% of cases (293/300) and for 91% of the same quadrant in the right eye (246/271) of controls (OR = 6.4, 95% CI 2.5–16.1). We confirm associations with exposure to solar ultraviolet radiation and with the presence of pinguecula and report a role for previous ocular trauma in the aetiology of OSSN. We did not identify any additional factors that point to an underlying infectious cause, although this is an area of on‐going research.
Expression of laminin γ2 chain monomer enhances invasive growth of human carcinoma cells in vivo
Authors: Tsubota Yoshiaki , Ogawa Takashi , Oyanagi Jun , Nagashima Yoji , Miyazaki Kaoru
Published: February 2010

Laminin γ2 chain is a subunit of the heterotrimeric basement membrane protein laminin‐332 (α3β3γ2). The γ2 chain is highly expressed by human cancers at the invasion fronts and this expression correlates with poor prognosis of the cancers. Our previous study showed that the γ2 chain is expressed as a monomer form in invading carcinoma cells. However, the role of the γ2 protein in tumor invasion remains unknown. Here, we demonstrate that the monomeric γ2 chain promotes invasive growth of human cancer cells in vivo. First, we analyzed regulatory factors for the γ2 chain expression using 2 gastric carcinoma cell lines. It was found that tumor necrosis factor‐α, by itself or in a combination with transforming growth factor‐β1, strongly induced the secretion of the monomeric γ2 chain. In addition, epidermal growth factor families appeared to function as the γ2 chain inducers in human cancers. Next, we established T‐24 bladder carcinoma cell lines expressing the full‐length or the short arm of the laminin γ2 chain. When these cell lines were i.p. injected into nude mice, they produced larger tumors in the abdominal cavity and showed much stronger invasive growth onto the diaphragms than the control cell line. The γ2‐expressing T‐24 cells often produced ascites fluid, but scarcely the control cells. In culture, the γ2‐expressing cells migrated through Matrigel more efficiently than the control cells. These findings imply that the γ2 monomer is induced in human cancers by inflammatory and stromal cytokines and promotes their invasive growth in vivo.
Elevated expression of tumor necrosis factor‐α signaling molecules in colonic tumors of Zucker obese (fa/fa) rats
Authors: Jain Swati S. , Bird Ranjana P.
Published: February 2010

Zucker obese rats are highly sensitive to colon cancer and possess a plethora of metabolic abnormalities including elevated levels of cytokine tumor necrosis factor‐α (TNF‐α). The main objective of this study was to determine if physiologically elevated TNF‐α affects colonic tumor phenotype with regard to an altered TNF‐α signaling pathway. Zucker obese (fa/fa, homozygous recessive for dysfunctional leptin receptors), Zucker lean (Fa/fa, Fa/Fa) and Sprague–Dawley (SD) rats were injected twice with azoxymethane (10 mg/kg) over 2 weeks. After 30 weeks, the animals were terminated and physiological and tumor parameters were assessed. Obese rats had notably higher body and organ weights as well as plasma TNF‐α, insulin and leptin levels than lean or SD animals. A 100% tumor incidence and significantly higher tumor size, multiplicity and burden were found in obese rats compared to the lean group that had 47.8% tumor incidence. The SD group had the lowest tumor incidence (20.0%). Tumors from obese animals had higher protein levels of TNF‐α, TNF‐α‐receptor‐2 (TNFR2), nuclear transcription factor‐κB (NF‐κB) and IκB‐kinaseβ (IKKβ) compared to lean animals. In both obese and lean groups, expression levels of these proteins were higher in tumors than in surrounding, normal‐appearing colonic mucosae. These findings support an important role for TNF‐α signaling in tumorigenesis and demonstrate that tumors growing in an obese state had significantly different expression levels of TNFR2 and NF‐κB, proteins known to play a critical role in growth and survival, than those growing in the lean state. It is concluded that the physiological state of the host intricately affects tumor phenotype.
The BCR/ABL‐inhibitors imatinib, nilotinib and dasatinib differentially affect NK cell reactivity
Authors: Salih Julia , Hilpert Julia , Placke Theresa , Grünebach Frank , Steinle Alexander , Salih Helmut Rainer , Krusch Matthias
Published: February 2010

In chronic myeloid leukemia (CML), BCR/ABL‐mediated oncogenic signaling can be targeted with the BCR/ABL‐inhibitors Imatinib, Nilotinib and Dasatinib. However, these agents may also affect anti‐tumor immunity. Here, we analyzed the effects of the 3 BCR/ABL‐inhibitors on natural killer (NK) cell reactivity. Exposure of CML cells (K562, Meg‐01) to pharmacological concentrations of Imatinib, Nilotinib and Dasatinib diminished expression of ligands for the activating immunoreceptor NKG2D to a similar extent. This resulted in comparably reduced NK cell cytotoxicity and IFN‐γ production. When direct effects on NK cell responses to K562 and primary CML cells as well as activating cytokines were studied, Dasatinib was found to abrogate NK cytotoxicity and cytokine production. Nilotinib did not alter cytotoxicity but, at high levels, impaired NK cytokine production, while Imatinib had no direct influence on NK cell reactivity. Of note, Nilotinib, but not the other BCR/ABL‐inhibitors increased cell death within the preferentially cytokine‐secreting CD56brightCD16− NK cell subset, which may, at least in part, serve to explain the effect of Nilotinib on NK cytokine production. Analysis of NK cell signaling revealed that Dasatinib inhibited proximal signaling events leading to decreased phosphorylation of PI3K and ERK that are crucial for NK cell reactivity. Imatinib and Nilotinib, in contrast, showed no relevant effect on NK cell PI3K or ERK activity. In light of the potential role of NK cells in the immunesurveillance of residual leukemia and for future combinatory immunotherapeutic approaches, our data indicate that choice and dosing of the most suitable BCR/ABL‐inhibitor for a given patient require careful consideration.
Deficiency or blockade of angiotensin II type 2 receptor delays tumorigenesis by inhibiting malignant cell proliferation and angiogenesis
Authors: Clere Nicolas , Corre Isabelle , Faure Sébastien , Guihot Anne‐Laure , Vessières Emilie , Chalopin Marie , Morel Alain , Coqueret Olivier , Hein Lutz , Delneste Yves , Paris François , Henrion Daniel
Published: February 2010

Despite significant expression level in cancer cells, the role of the angiotensin II Type 2 receptor (AT2R) in cancer progression remains poorly understood. We aimed to investigate the involvement of AT2R in tumorigenesis, hypothesizing a role in tumor cell proliferation and/or tumor angiogenesis. Two animal tumor models were used: fibrosarcoma induced by 3‐methylcholanthrene (3‐MCA) in FVB/N mice invalidated for AT2R (AT2R‐KO) and carcinoma LL/2 cells injected in C57BL/6N mice treated with AT2R antagonist PD123,319. Tumor growth was monitored, microvascular density (MVD) evaluated by CD31 staining. Proliferation index of LL/2 and 3‐MCA tumor cells was evaluated by expression of Ki‐67. Angiogenesis was assessed by aorta ring assay and angiogenic mediators' expression by real‐time RT‐PCR. Tumor induction by 3‐MCA was significantly delayed in AT2R‐KO compared to wild‐type mice (56 days vs. 28 days). Tumorigenesis following LL/2 cell injection in mice was also significantly reduced by early administration of the antagonist PD123,319. In vitro, inactivation or invalidation of AT2R inhibited proliferation of LL/2 and 3‐MCA tumor cells, respectively. Tumor MVD was reduced in mice treated early with PD123,319. Ex vivo experiments revealed a significant decrease in angiogenesis after PD123,319 treatment or in AT2R‐KO mice. Finally, we identified vascular endothelial growth factor (VEGF) as a soluble proangiogenic factor produced by LL/2 cells and we showed that in LL/2 and 3‐MCA tumor cells, inhibition or deficiency of AT2R was associated with impaired production of proangiogenic factors included VEGF. This study uncovered novel mechanisms by which AT2R would promote tumor development, favoring both malignant cell proliferation and tumor angiogenesis.
Substantial regional differences in human herpesvirus 8 seroprevalence in sub‐Saharan Africa: Insights on the origin of the “Kaposi's sarcoma belt”
Authors: Dollard Sheila C. , Butler Lisa M. , Jones Alison M. Graves , Mermin Jonathan H. , Chidzonga Midion , Chipato Tsungai , Shiboski Caroline H. , Brander Christian , Mosam Anisa , Kiepiela Photini , Hladik Wolfgang , Martin Jeffrey N.
Published: February 2010

Equatorial Africa has among the highest incidences of Kaposi's sarcoma (KS) in the world, thus earning the name “KS Belt.” This was the case even before the HIV epidemic. To date, there is no clear evidence that HHV‐8 seroprevalence is higher in this region but interpretation of the available literature is tempered by differences in serologic assays used across studies. We examined representatively sampled ambulatory adults in Uganda, which is in the “KS Belt,” and in Zimbabwe and South Africa which are outside the Belt, for HHV‐8 antibodies. All serologic assays were uniformly performed in the same reference laboratory by the same personnel. In the base‐case serologic algorithm, seropositivity was defined by reactivity in an immunofluorescence assay or in 2 enzyme immunoassays. A total of 2,375 participants were examined. In Uganda, HHV‐8 seroprevalence was high early in adulthood (35.5% by age 21) without significant change thereafter. In contrast, HHV‐8 seroprevalence early in adulthood was lower in Zimbabwe and South Africa (13.7 and 10.8%, respectively) but increased with age. After age adjustment, Ugandans had 3.24‐fold greater odds of being HHV‐8 infected than South Africans (p < 0.001) and 2.22‐fold greater odds than Zimbabweans (p < 0.001). Inferences were unchanged using all other serologic algorithms evaluated. In conclusion, HHV‐8 infection is substantially more common in Uganda than in Zimbabwe and South Africa. These findings help to explain the high KS incidence in the “KS Belt” and underscore the importance of a uniform approach to HHV‐8 antibody testing.