bluuebunny/crossref_metadata_2025 huggingface dataset:
The Prognostic Value of Early Left Ventricular Longitudinal Systolic Dysfunction in Asymptomatic Subjects With Cardiovascular Risk Factors
Authors: Di Salvo Giovanni , Di Bello Vitantonio , Salustri Alessandro , Antonini‐Canterin Francesco , La Carrubba Salvatore , Materazzo Carlo , Badano Luigi , Caso Pio , Pezzano Antonio , Calabrò Raffaele , Carerj Scipione ,   on behalf of the Research Group of the Italian Society of Cardiovascular Echography (SIEC).
Published: July 2011

Background:

Early diagnosis of left ventricular (LV) dysfunction represents a major challenge in asymptomatic subjects with cardiovascular (CV) risk factors. Tissue Doppler imaging (TDI) has emerged as an important tool with clinical relevance in several cardiac diseases.

Hypothesis:

To evaluate the prognostic ability of TDI in detecting early longitudinal ventricular dysfunction in a large group of asymptomatic subjects with CV risk factors (RsF), normal LV systolic function, and normal diastolic function.

Methods:

A total of 554 subjects (mean age 55 ± 13 years, 39% men) formed our study population: controls, 144 healthy subjects; group 1, 163 subjects with 1 CV RsF; group 2, 147 subjects with 2 CV RsF; group 3, 100 subjects with ≥3 CV RsF. All subjects underwent a comprehensive standard echo‐Doppler evaluation, including posterior wall TDI study. Follow‐up data were available in all the studied samples (mean 28 ± 16 mo).

Results:

Upon follow‐up, 18 individuals (3.2%) developed a first overt CV event. The presence of a peak systolic velocity <7.5 cm/second showed a significant additional predictive value compared with the presence of CV RsF (P<0.001).

Conclusions:

Tissue Doppler imaging is able to identify early longitudinal LV systolic abnormalities in the presence of apparently normal systolic and diastolic function. It demonstrated a significant additional prognostic value compared with the simple presence of coexisting CV RsF. These findings could be clinically relevant in identifying asymptomatic subjects with CV RsF who need early, tailored preventive treatment. © 2011 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.
Influence of Low‐Dose Aspirin (81 mg) on the Incidence of Definite Stent Thrombosis in Patients Receiving Bare‐Metal and Drug‐Eluting Stents
Authors: Lotfi Amir , Cui Jiang , Wartak Siddharth , Columbo Jesse , Mulvey Scott , Davis Mary , Schweiger Marc , Giugliano Gregory R.
Published: July 2011

Background:

Dual antiplatelet therapy with aspirin plus clopidogrel is the mainstay of therapy in patients undergoing percutaneous coronary intervention (PCI). However, the optimal dose of aspirin following PCI has not been established.

Hypothesis:

There is no difference for definite stent thrombosis in patients taking low dose versus standard aspirin.

Methods:

Low‐dose (81 mg) aspirin was used as part of a standard dual antiplatelet therapy in patients receiving bare‐metal stents (BMS) or drug‐eluting stents (DES) at a large tertiary medical center. We retrospectively analyzed 5368 consecutive cases treated with stent placement and dual antiplatelet therapy. The incidence of definite stent thrombosis (DST) at our institution was compared to DST as reported in a large, published cohort of 24 trials and 12973 patients. We stratified DST events into early (<30 days) and late (>30 days) timing and also stratified by stent type. The effect of aspirin dosing was evaluated using χ2, Cochran‐Mantel‐Haenszel, and homogeneity testing.

Results:

A total of 5187 patients underwent 7604 stent implantations during the study period. The cumulative incidence of DST was 0.60% (95% confidence interval [CI], 0.42%–0.84%) at 30 days and 0.76% (95% CI, 0.56%–1.03%) at 1 year. The overall incidence of DST during the study period was not different based on type of stent (0.53% for DES and 0.75% for BMS, P = 0.36). Compared to the historic, standard‐dose aspirin (162–325 mg) cohort, DST in our low‐dose aspirin (81 mg) cohort was not significantly different at either 30 days (0.72% vs 0.60%, P = 0.39) or at 1 year (1.08% vs 0.76%, P = 0.07). There was no appreciable interaction of aspirin dose on the incidence of DST, controlling for stent type, or timing of the event.

Conclusions:

Low‐dose aspirin therapy in combination with clopidogrel following implantation of either BMS or DES in our cohort does not appear to increase the risk of DST compared to a higher‐dose aspirin regimen. © 2011 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.
Hospital‐level variation in the quality of urologic cancer surgery
Authors: Gore John L. , Wright Jonathan L. , Daratha Kenn B. , Roberts Kenneth P. , Lin Daniel W. , Wessells Hunter , Porter Michael
Published: July 2011

BACKGROUND:

Unexplained variation in outcomes after common surgeries raises concerns about the quality and appropriateness of surgical care. Understanding variation in surgical outcomes may identify processes that could affect the quality of surgical and postoperative care. The authors of this report examined hospital‐level variation in outcomes after inpatient urologic oncology procedures.

METHODS:

Patients who underwent radical cystectomy, radical nephrectomy, and radical prostatectomy were identified from the Washington State Comprehensive Hospital Abstract Reporting System for the years 2003 through 2007. The postoperative length of stay (LOS) was measured, and LOS that exceeded the 75th percentile was classified as prolonged. The occurrence of Agency for Healthcare Quality patient safety indicators (PSIs), readmissions, and deaths also were measured. Analyses were adjusted for patient age and comorbidity in random effects, multilevel, multivariable models that assessed hospital‐level outcomes.

RESULTS:

The authors identified 853 patients from 37 hospitals who underwent cystectomy, 3018 patients who underwent nephrectomy from 51 hospitals, and 8228 patients who underwent prostatectomy from 51 hospitals. Complications captured by PSIs were rare. Hospital‐level variation was most profound for LOS outcomes after nephrectomy and prostatectomy (variance in prolonged LOS, 8.1% and 26.7%, respectively), thromboembolic events after nephrectomy (8% of variance), and mortality after cystectomy (7.1% of variance).

CONCLUSIONS:

Hospital‐level variation confounds the care of urologic cancer patients in the state of Washington. The authors concluded that transparent reporting of surgical outcomes and local quality‐improvement initiatives should be considered to ameliorate the observed variation and improve the quality of cystectomy, nephrectomy, and prostatectomy care. Cancer 2011;. Published 2012 by the American Cancer Society.
Bevacizumab and daily temozolomide for recurrent glioblastoma
Authors: Desjardins Annick , Reardon David A. , Coan April , Marcello Jennifer , Herndon James E. , Bailey Leighann , Peters Katherine B. , Friedman Henry S. , Vredenburgh James J.
Published: July 2011

BACKGROUND:

The authors performed a phase 2 trial of combined protracted daily temozolomide and biweekly bevacizumab for patients with recurrent glioblastoma who had previously received radiation therapy and temozolomide.

METHODS:

There was no limit on the number of previous disease progressions or previous regimens allowed. Thirty‐two adult patients were enrolled. Patients received temozolomide 50 mg/m2 daily and bevacizumab 10 mg/kg intravenously every 14 days. Patients underwent physical examination and brain magnetic resonance imaging every 8 weeks.

RESULTS:

The authors observed a 6‐month progression‐free survival (PFS) rate of 18.8% (95% confidence interval [CI], 7.6%‐33.7%) and a median PFS of 15.8 weeks. The median overall survival (OS) was 37 weeks, the 6‐month OS rate was 62.5% (95% CI, 43.5%‐76.7%), and the 12‐month OS rate was 31.3% (95% CI, 16.4%‐47.3%). Nine patients (28%) had a radiographic response, and 7 patients (22%) had disease progression within the first 8 weeks of treatment. Patterns of progression were available for 21 patients. The authors observed that 52% of patients (n = 11) progressed locally, 38% (n = 8) progressed with a diffuse pattern, and 10% (n = 2) progressed at a distant site. Two patients discontinued therapy secondary to toxicity (prolonged thrombocytopenia and grade 4 pancreatitis). One patient experienced grade 5 pneumonia.

CONCLUSIONS:

The current study demonstrated that a regimen of combined daily temozolomide and biweekly bevacizumab had some activity and was well tolerated. However, the results obtained in this study were inferior to those observed in studies of bevacizumab monotherapy and of combined irinotecan and bevacizumab therapy. The current patient population was more heterogeneous and was pretreated more heavily than patients in previous studies. Cancer 2012;. © 2011 American Cancer Society.
Which Tasks Best Discriminate between Dyslexic University Students and Controls in a Transparent Language?
Authors: Re Anna Maria , Tressoldi Patrizio E. , Cornoldi Cesare , Lucangeli Daniela
Published: July 2011

The need for a battery for testing adult dyslexia, and especially university students, is being increasingly recognized in view of the increased number of adult requests for a dyslexia examination in relation to both assistance and protection from discrimination. The present study examines the discriminative validity of a battery we have developed—the Battery for the Assessment of Reading and Writing in Adulthood—through comparison of the performance of 24 university students with a history of severe developmental dyslexia and 99 controls. All the reading, writing, lexical decision and spelling tasks of the battery, except omissions in a lexical decision task and reading comprehension, showed a good discriminatory power. In addition, use of just two of these tasks (fluency in reading a text and spelling under articulatory suppression) gave 87% sensitivity and 97% specificity. Our results confirm that in transparent languages, measures of phonological automaticity are the best indexes of reading decoding competence, particularly in adults. Copyright © 2011 John Wiley & Sons, Ltd.
PD‐L1 blockade overrides Salmonella typhimurium‐mediated diabetes prevention in NOD mice: No role for Tregs
Authors: Newland Stephen A. , Phillips Jenny M. , Mastroeni Pietro , Azuma Miyuki , Zaccone Paola , Cooke Anne
Published: July 2011

Increasingly, evidence suggests that there is a strong environmental component to the development of the autoimmune disease type 1 diabetes. Our previous data showed that NOD mice are protected from developing diabetes after infection with Salmonella typhimurium and there is some evidence that changes within the DC compartment play a crucial role in this protective effect. This paper further characterises this Salmonella‐modulated protective phenotype. We find that, contrary to other infection‐mediated models of type 1 diabetes protection, there was no expansion of Foxp3+ Tregs. Furthermore, transcriptome analysis of DCs identified a distinct Salmonella‐induced signature in which the inhibitory receptor PD‐L1 was up‐regulated. This was confirmed by flow cytometry. In vivo blockade of the PD1/PD‐L1 interaction was found to ablate the protective function of Salmonella infection. These data provide evidence for a novel regulatory DC phenotype proficient at controlling autoreactive T cells for an extended duration in the NOD mouse model of diabetes.
TLR9 regulation by proteolysis: A friend or a foe
Authors: Manoury Bénédicte
Published: July 2011

Intracellular TLRs sense viral and bacterial nucleic acids from a wide variety of pathogens. Previous studies have shown that TLR9 requires processing for signalling. Following proteolysis, a fragment corresponding to the C‐terminal part of TLR9 was shown to bind MyD88 and to induce signalling when cells were stimulated with TLR9 ligands. In this issue of the European Journal of Immunology, a study provides evidence that another proteolytic fragment of TLR9 is generated, different to that described previously, consisting of amino acids 1–723 which mediates inhibition of TLR9 signalling. These results suggest that proteolysis undoubtedly is a key step in TLR9 regulation.
Mechanism of the Acid‐Mediated Thermal Fragmentation of 5‐Spirocyclobutane‐isoxazolidines
Authors: Cordero Franca M. , Vurchio Carolina , Brandi Alberto , Gandolfi Remo
Published: July 2011

Protonation at the nitrogen of 5‐spirocyclopropane‐isoxazolidines induces clean thermal rearrangement/fragmentation to β‐lactams and ethylene. Under the same conditions, homologous 5‐spirocyclobutane‐isoxazolidines undergo unselective fragmentation to give cyclobutyl derivatives through a completely different mechanism. Experimental data and DFT calculations show that the process is initiated with less‐favored protonation at the isoxazolidine oxygen rather than nitrogen. Highly energetic O‐protonated isoxazolidines undergo N–O cleavage with concomitant endo‐ or exocyclic deprotonation to give iminium ions that, in the presence of trifluoroacetate, evolve into 2‐(1‐hydroxycyclobutyl)ethanones and N‐[2‐(1‐hydroxycyclobutyl)ethyl]trifluoroacetamides, respectively. DFT data validate protonation at oxygen of 5‐spirocyclobutane‐isoxazolidines, which requires higher energy than protonation at nitrogen, but can trigger the proposed process without any energy barrier. The N‐protonated derivatives could rearrange to give oxazaspirooctane, with enlargement of the spirocyclobutane ring, but this process, owing to its high energy barrier, cannot compete with the reaction channel promoted by oxygen protonation and, in fact, is not experimentally observed. Being independent of the presence of a strained spirofused ring, acid‐catalyzed fragmentation was also demonstrated to occur in normal isoxazolidines, such as those derived from cycloaddition of C–Ph–N–Me‐nitrone to norbornene, suggesting that isoxazolidines, widely used in organic synthesis, should not be heated in the presence of protic acids.
Synthesis of Tetrahedral Shape‐Persistent Tetranuclear Metal–salphens
Authors: Mastalerz Michael , Oppel Iris M.
Published: July 2011

The synthesis of two novel tetrakis(salicylaldehydes) based on a rigid tetraphenylmethane core is presented. These salicylaldehydes were used as precursors for the construction of three‐dimensional multimetallic salphens, as exemplified by the synthesis of rigid and shape‐persistent tetranuclearzinc–, nickel– and palladium–salphens with defined geometries and distances between the metal sites. The UV/Vis measurements of the tetranuclear metal complexes are presented.
Disgust Sensitivity and Anorexia Nervosa
Authors: Aharoni Ruth , Hertz Marianne M.
Published: July 2011

Background

Previous studies found inconsistent differences in disgust sensitivity between patients with a variety of eating disorders and normal controls.

Aim

The objective of this study was to compare disgust sensitivity between a larger and more specific sample of anorexia nervosa (AN) patients and control subjects.

Method

We compared the scores on the ‘disgust sensitivity scale’ of AN patients (N = 62) and control subjects (N = 62) using a multivariate analysis of variance. All subjects were women.

Results

AN patients scored consistently higher on all domains of disgust sensitivity. This difference was significant for six of eight disgust domains. The largest significant difference between the groups was on the domains food and magical thinking.

Conclusion

Our findings elaborate on previous findings and are in line with recent neurological findings suggesting that disgust and insular impairments are associated with AN. Clinical implications of our findings are discussed. Copyright © 2011 John Wiley & Sons, Ltd and Eating Disorders Association.
Improving uncertainty analysis in kinetic evaluations using iteratively reweighted least squares
Authors: Gao Zhenglei , Green John W , Vanderborght Jan , Schmitt Walter
Published: July 2011

Kinetic parameters of environmental fate processes are usually inferred by fitting appropriate kinetic models to the data using standard nonlinear least squares (NLS) approaches. Although NLS is appropriate to estimate the optimum parameter values, it implies restrictive assumptions on data variances when the confidence limits of the parameters must also be determined. Particularly in the case of degradation and metabolite formation, the assumption of equal error variance is often not realistic because the parent data usually show higher variances than those of the metabolites. Conventionally, such problems would be tackled by weighted NLS regression, which requires prior knowledge about the data errors. Instead of implicitly assuming equal error variances or giving arbitrary weights decided by the researcher, we use an iteratively reweighted least squares (IRLS) algorithm to obtain the maximum likelihood estimates of the model parameters and the error variances specific for the different species in a model. A study with simulated data shows that IRLS gives reliable results in the case of both unequal and equal error variances. We also compared results obtained by NLS and IRLS, with probability distributions of the parameters inferred with a Markov-Chain Monte-Carlo (MCMC) approach for data from aerobic transformation of different chemicals in soil. Confidence intervals obtained by IRLS and MCMC are consistent, whereas NLS leads to very different results when the error variances are distinctly different between different species. Because the MCMC results can be assumed to reflect the real parameter distribution imposed by the observed data, we conclude that IRLS generally yields more realistic estimates of confidence intervals for model parameters than NLS. Environ. Toxicol. Chem. 2011;30:2363–2371. © 2011 SETAC
Effects of slip conditions on stretching flow with ohmic dissipation and thermal radiation
Authors: Qasim M. , Hayat T. , Hendi Awatif. A.
Published: July 2011

The present work addresses the magnetohydrodynamic (MHD) flow and heat transfer over a permeable stretching sheet. Analysis has been carried out in the presence of thermal radiation and ohmic dissipation. The velocity and thermal slip effects are given main attention. The Rosseland approximation is used to describe the radiative heat flux in the energy equation. The non‐linear partial differential equations are reduced to a set of non‐linear ordinary differential equations which are solved analytically by the homotopy analysis method (HAM). The effects of emerging physical parameters on the velocity and temperature profiles are interpreted. Numerical data for skin friction coefficient and Nusselt number have been tabulated for various values of the parameters. The results have been compared with the known exact solution from the literature in a limiting sense. © 2011 Wiley Periodicals, Inc. Heat Trans Asian Res; Published online in Wiley Online Library (wileyonlinelibrary.com/journal/htj). DOI 10.1002/htj.20367
Secondary poisoning risk assessment of terrestrial birds and mammals exposed to Nickel
Authors: DeForest David K , Schlekat Christian E , Brix Kevin V , Fairbrother Anne
Published: July 2011

The European Union's Existing Substances regulation (EEC 793/93) was developed to assess the ecological risks posed by chemical substances such as Ni and includes the assessment of secondary poisoning risks. The basic structure of this secondary poisoning risk assessment followed the Technical Guidance Document on Risk Assessment and thus included development of predicted exposure concentrations (PECs) and predicted no-effect concentrations (PNECs). A PEC to PNEC ratio greater than 1.0 is indicative of potential risk. The Technical Guidance Document on Risk Assessment provides a generic framework for assessing secondary poisoning risks and prescribes the following terrestrial food chain: soil → earthworm → worm-eating bird or mammal. This secondary poisoning evaluation was conducted at the regional level, and it was found that the generic approach resulted in widespread estimates of potential risk, even at ambient Ni soil concentrations. Accordingly, a tiered approach was used with increasing levels of refinement, including consideration of bioavailability, consideration of a variable diet, and development of dose-based PNEC values. Based on the refined approach, all PEC to PNEC ratios were less than 1.0, except for a ratio of 1.4 in a scenario focused on a regional clay soil, which was of natural origin. This regional-level secondary poisoning evaluation highlighted key risk assessment components that should be considered in future localized secondary poisoning assessments of Ni and other metals, including ingestion rate to body weight ratios for the test organisms used to derive PNECs versus the representative wildlife species evaluated, the appropriateness of high assessment factors for deriving PNECs for naturally occurring essential elements, representative dietary compositions, relative metal bioavailability between the dietary toxicity study and natural diets, and ground-truthing of the risk predictions versus background concentrations. Integr Environ Assess Manag 2012;8:107–119. © 2011 SETAC
Assessment of risks to ground-feeding songbirds from lead in the Coeur d'Alene Basin, Idaho, USA
Authors: Sample Bradley E , Hansen James A , Dailey Anne , Duncan Bruce
Published: July 2011

Previous assessment of ecological risks within the Coeur d'Alene River Basin identified Pb as a key risk driver for ground-feeding songbirds. Because this conclusion was based almost exclusively on literature data, its strength was determined to range from low to moderate. With the support of the US Environmental Protection Agency (USEPA), the US Fish and Wildlife Service collected site-specific data to address the uncertainty associated with Pb risks to songbirds. These data, plus those from the previous Coeur d'Alene Basin ecological risk assessment, were integrated, and risks to ground-feeding songbirds were reevaluated. These site-specific data were also used to develop updated preliminary remedial goals (PRGs) for Pb in soils that would be protective of songbirds. Available data included site-specific Pb concentrations in blood, liver, and ingesta from 3 songbird species (American robin, song sparrow, and Swainson's thrush), colocated soil data, and soil data from other locations in the basin. Semi-log regression models based on the association between soil Pb and tissue Pb concentrations were applied to measured soil concentrations from the previous risk assessment to estimate Pb exposures in riparian and adjacent upland habitats throughout the Coeur d'Alene Basin. Measured and estimated tissue or dietary exposure was tabulated for 3 areas plus the reference, and then compared to multiple effects measures. As many as 6 exposure-effect metrics were available for assessing risk in any one area. Analyses of site-specific tissue- and diet-based exposure data indicate that exposure of ground-feeding songbirds to Pb in the Coeur d'Alene Basin is sufficient to result in adverse effects. Because this conclusion is based on multiple exposure-effect metrics that include site-specific data, the strength of this conclusion is high. Ecological PRGs were developed by integrating the site-specific regression models with tissue and dietary effect levels to create exposure models, which were solved for the soil concentration that produced an exposure estimate equal to the effect level (i.e., the ecological PRG). The lowest PRG obtained for any species' exposure-effect measure combination was 490 mg/kg for subclinical effects due to Pb in the blood of American robins; the highest was 7200 mg/kg for severe clinical effects due to Pb in the blood of song sparrows. Because the lowest ground-feeding songbird PRG was comparable to multiple cleanup goals developed for the basin (i.e., soil invertebrates, wildlife populations, and human health), in addition to the site-specific cleanup level of 530 mg Pb/kg sediment for the protection of waterfowl (USEPA 2002) the USEPA has made a risk-management determination that a site-specific Pb cleanup level of 530 mg/kg in soil would be protective of songbirds in the Coeur d'Alene Basin. Integr Environ Assess Manag 2011;7:596–611. © 2011 SETAC
Simultaneous targeting of Src kinase and receptor tyrosine kinase results in synergistic inhibition of renal cell carcinoma proliferation and migration
Authors: Bai Lanfang , Yang Joy C. , Ok Joon‐ha , Mack Philip C. , Kung Hsing‐Jien , Evans Christopher P.
Published: July 2011

There have been recent improvements in the treatment for metastatic renal cell carcinoma (RCC) with receptor tyrosine kinase (RTK) inhibitors being one of newer treatment options. We hypothesized that simultaneous targeting of Src kinase and the RTK may have synergistic effects to further improve therapies on metastatic RCC. The effects of Src kinase inhibitor saracatinib and multiple RTK inhibitor sunitinib on RCC cell line (ACHN) and Caki‐1 were studied. Saracatinib alone or in combination with sunitinib inhibited the migration of ACHN and Caki‐1 cells in vitro. Activation of migration related components FAK, P130Cas and Paxillin were blocked by saracatinib at 0.05‐ to 3‐μM concentrations. Combined treatment resulted in improved growth inhibition, greater loss of the S phase cell population and decreased clonogenic colony formation compared to sunitinib alone in the metastatic Caki‐1 line. Molecular studies in Caki‐1 showed that saracatinib alone and in combination with sunitinib inhibited phosphorylation of the cell progression regulator c‐Myc in a dose‐dependent manner. Sunitinib alone or in combination suppressed cyclin‐D1 expression with the combination showing greater dose‐dependent effect. Sunitinib inhibited vascular endothelial growth factor (VEGF) secretion through the inhibition of STAT3 signaling and VEGF biosynthesis. HIF1‐α expression in normoxic and hypoxic conditions in Caki‐1 cells was inhibited by either saracatinib or sunitinib when administered alone, however, a greater reduction occurred when these compounds were given in combination. Targeting Src kinase and RTK simultaneously with saracatinib and sunitinib resulted in 70–80% blockade of RCC cell migration, synergistic inhibition of cell growth and reduction of acquired drug resistance in Caki‐1 cells. The results show promise for combination targeted therapy of RCC.
Expression of C4.4A in precursor lesions of pulmonary adenocarcinoma and squamous cell carcinoma
Authors: Jacobsen Benedikte , Santoni‐Rugiu Eric , Illemann Martin , Kriegbaum Mette Camilla , Lærum Ole Didrik , Ploug Michael
Published: July 2011

The protein C4.4A, a structural homologue of the urokinase‐type plasminogen activator receptor, is a potential new biomarker in non‐small cell lung cancer, with high levels of expression recently shown to correlate to poor survival of adenocarcinoma patients. In this study, C4.4A immunoreactivity in precursor lesions of lung squamous cell carcinoma and adenocarcinoma was investigated by stainings with a specific anti‐C4.4A antibody. In the transformation from normal bronchial epithelium to squamous cell carcinoma, C4.4A was weakly expressed in basal cell hyperplasia but dramatically increased in squamous metaplasia. This was confined to the cell membrane and sustained in dysplasia, carcinoma in situ, and the invasive carcinoma. The induction of C4.4A already at the stage of hyperplasia could indicate that it is a marker of very early squamous differentiation, which aligns well with our earlier finding that C4.4A expression levels do not provide prognostic information on the survival of squamous cell carcinoma patients. In the progression from normal alveolar epithelium to peripheral adenocarcinoma, we observed an unexpected, distinct cytoplasmic staining for C4.4A in a fraction of atypical adenomatous hyperplasias, while most bronchioloalveolar carcinomas were negative. Likewise, only a fraction of the invasive adenocarcinomas was positive for C4.4A. With a view to the prognostic impact of C4.4A in adenocarcinoma patients, this finding might suggest that C4.4A could be an early biomarker for a possibly more malignant subtype of this disease.
Genetic determinants of oxidative stress‐mediated sensitization of drug‐resistant cancer cells
Authors: Maiti Amit K.
Published: July 2011

Drug resistance in cancer is an overwhelming problem, because drug‐resistant cancer cells are harder to kill with the same drug. The mechanism of drug resistance differs for various cancers based on the type of drug being used for its treatment. Most current drugs are shown to increase reactive oxygen species (ROS) in respective cancer cells that induces apoptosis, but continuous treatment with the same drug may reduce cellular ROS levels and may convert drug sensitive cancer cells into drug resistant cells. In addition, exogenous elevation of ROS in conjunction with drug resensitizes drug‐resistant cancer cells. Thus, constant maintenance of higher ROS level in cancer cells may be a prerequisite for drug efficacy in certain type of cancer cells. Thus, modulation of ROS‐mediated genetic pathway genes could be an efficient alternative to maintain higher ROS level in cancer cells for “combinational chemotherapy” with the drug. In this review, I discuss whether ROS reduction in drug‐resistant cancer cells could be a general mechanism of drug resistance for most cancers with its specific drug, and whether elevation of ROS levels with the drug could be a valuable strategy for increasing drug efficacy in most cancers.
Toll‐like receptor genes and their association with colon and rectal cancer development and prognosis
Authors: Slattery Martha L. , Herrick Jennifer S. , Bondurant Kristina L. , Wolff Roger K.
Published: July 2011

Toll‐like receptors (TLRs) are mediators of inflammation in the gut and potentially important modulators of colon and rectal cancer risk. We use data from a population‐based study of incident colon cancer cases (n = 1,555) and controls (n = 1,956) and rectal cancer cases (n = 754) and controls (n = 959). We evaluate genetic variation in TLR2 (six SNPs), TLR3 (four SNPs) and TLR4 (eight SNPs) with risk of developing colon or rectal cancer and survival after diagnosis. TLR3 rs11721827 was associated with rectal cancer (odds ratio [OR] 1.27, 95% confidence interval [CI] 1.02, 1.58 for AC/CC vs. AA genotype, Wald p = 0.035; adjusted p = 0.126); TLR3 rs3775292 and TLR4 rs11536898 were associated with colon cancer (OR 0.68, 95% CI 0.49, 0.95 for GG vs. CC/CG and OR 0.50. 95% CI 0.29, 0.87 for AA vs. CA/CC, respectively; Wald p = 0.023 and 0.015; adjusted p = 0.085 and 0.101, respectively). TLR2 rs7656411 and rs3804099, respectively, interacted with nonsteroidal anti‐inflammatory drug (NSAID) use and cigarette smoking to alter risk of colon cancer (adjusted p = 0.034 and 0.077); TLR3 rs11721827 interacted with NSAID use to alter risk of colon cancer (adjusted p = 0.071). TLR3 rs3775292 interacted with dietary carbohydrates to alter colon cancer risk and with dietary carbohydrates and saturated fat to alter rectal cancer risk (adjusted p = 0.064, 0.0035 and 0.025, respectively). Multiple SNPs in TLR2 and TLR4 were associated with colon cancer survival. Although few independent associations with TLR genes were observed, we observed significant interaction of TLR2 and TLR3 with hypothesized lifestyle factors. Interaction with dietary factors remained significant for rectal cancer after adjustment for multiple comparisons.
Implementing changes in institutions to improve young children's development
Authors: Groark Christina J. , Mccall Robert B.
Published: July 2011

An estimated 8‐million children, mostly birth to approximately 6 to 8 years of age, live in institutions worldwide. While institutional environments vary, certain characteristics are common, including relatively large groups; high children:caregiver ratios; many and frequently changing caregivers; homogeneous grouping by age and disability status; periodic graduations to new groups of peers and caregivers; and an “institutional style of caregiving'' that minimizes talking, provides rather dispassionate perfunctory care, and offers little warm, sensitive, contingently responsive caregiver–child interactions. The development of children in residence is usually delayed, sometimes extremely so, in every physical and behavioral domain. Although efforts are being made in many countries to care for children without permanent parents in family environments (e.g., domestic adoption, foster and kinship care, reunification with biological parents), it is not likely that transitions to family alternatives will be completed in all countries in the near future; thus, institutions are likely to exist for many years, if not decades. But institutions need not operate in the current manner; they can be modified to be substantially more family‐like in structure and in the behavior of caregivers. Research has indicated that when such changes are made, the development of children, both typically developing and those with special needs, is improved substantially. Based on the available literature and the authors' experience, this article describes steps that can be taken to implement such changes in residential institutions for infants and young children.
Acceleration of self‐consistent‐field convergence by combining conventional diagonalization and a diagonalization‐free procedure
Authors: Baldes Alexander , Klopper Wim , Šimunek Ján , Noga Jozef , Weigend Florian
Published: July 2011

A new scheme that combines conventional matrix diagonalization with the recently proposed diagonalization‐free algorithm has been developed to obtain the density matrix for the next self‐consistent‐field iteration from the Fock matrix of the current iteration. In this manner, the advantages of the two methods are combined. The more rapid convergence of the diagonalization‐free algorithm for density matrices rather close to self consistence and the more robust convergence of the conventional matrix diagonalization further away from self‐consistence. The scheme has been implemented in the one‐ and two‐component self‐consistent‐field procedures in the program system TURBOMOLE. The number of iterations is typically reduced by about 10%, but savings are usually much larger for slowly converging cases. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011
Intramolecular hydrogen bond energy and cooperative interactions in α‐, β‐, and γ‐cyclodextrin conformers
Authors: Deshmukh Milind M. , Bartolotti Libero J. , Gadre Shridhar R.
Published: July 2011

Accurate estimation of individual intramolecular hydrogen bond (H‐bond) energies is an intricate task for multiply H‐bonded systems. In such cases, the hydrogen bond strengths could be highly influenced by the cooperative interactions, for example, those between hydroxyl groups in sugars. In this work, we use the recently proposed molecular tailoring approach‐based quantification (Deshmukh, Gadre, and Bartolotti, J Phys Chem A 2006, 110, 12519) to the extended systems of cyclodextrins (CDs). Further, the structure and stability of different conformers of α‐, β‐, and γ‐CDs are explained based on the energetics and cooperative contribution to the strength of these H‐bonds. The estimated OH···O H‐bond energies in the various CD conformers are found to vary widely from 1.1 to 8.3 kcal mol−1. The calculated energy contributions to cooperativity toward the H‐bond strengths fall in the range of 0.25–2.75 kcal mol−1. © 2011 Wiley Periodicals, Inc. J Comput Chem, 2011
Impact of different potentials on the structures and energies of clusters
Authors: Ma Zhinan , Cai Wensheng , Shao Xueguang
Published: July 2011

Cluster studies have attracted much interest in the past decades because of their extraordinary properties. To describe the interaction between atoms or molecules and predict the energies and structures, potential functions are developed. However, different potentials generally produce different structures and energies for a cluster. To study the effect of potentials on the structure of a cluster, He clusters in the size range of 13–140 are investigated by Lennard–Jones (LJ), Pirani, and Hartree–Fock‐dispersion individual damping (HFD‐ID) potential with dynamic lattice searching (DLS) method. Potential function curves, cluster structures, bonds, and energies of the global minima are compared. The results show that cluster energies decrease with the values of the potential functions, the differences between structures depend upon the disagreements of the potentials, and the preferable motif of a cluster changes from icosahedron to decahedron with the increase of the derivative of the short‐range part of the potentials. © 2011 Wiley Periodicals, Inc. J Comput Chem 2011
Honokiol inhibits signal transducer and activator of transcription‐3 signaling, proliferation, and survival of hepatocellular carcinoma cells via the protein tyrosine phosphatase SHP‐1
Authors: Rajendran Peramaiyan , Li Feng , Shanmugam Muthu K. , Vali Shireen , Abbasi Taher , Kapoor Shweta , Ahn Kwang Seok , Kumar Alan Prem , Sethi Gautam
Published: July 2011

The activation of signal transducers and activators of transcription 3 (STAT3) has been closely linked with the proliferation, survival, invasion, and angiogenesis of hepatocellular carcinoma (HCC) and represents an attractive target for therapy. In the present report, we investigated whether honokiol mediates its effect through interference with the STAT3 activation pathway. The effect of honokiol on STAT3 activation, associated protein kinases, and phosphatase, STAT3‐regulated gene products and apoptosis was investigated using both functional proteomics tumor pathway technology platform and different HCC cell lines. We found that honokiol inhibited both constitutive and inducible STAT3 activation in a dose‐ and time‐dependent manner in HCC cells. The suppression was mediated through the inhibition of activation of upstream kinases c‐Src, Janus‐activated kinase 1, and Janus‐activated kinase 2. Vanadate treatment reversed honokiol‐induced down‐regulation of STAT3, suggesting the involvement of a tyrosine phosphatase. Indeed, we found that honokiol induced the expression of tyrosine phosphatase SHP‐1 that correlated with the down‐regulation of constitutive STAT3 activation. Moreover, deletion of SHP‐1 gene by siRNA abolished the ability of honokiol to inhibit STAT3 activation. The inhibition of STAT3 activation by honokiol led to the suppression of various gene products involved in proliferation, survival, and angiogenesis. Finally, honokiol inhibited proliferation and significantly potentiated the apoptotic effects of paclitaxel and doxorubicin in HCC cells. Overall, the results suggest that honokiol is a novel blocker of STAT3 activation and may have a great potential for the treatment of HCC and other cancers. J. Cell. Physiol. 227: 2184–2195, 2012. © 2011 Wiley Periodicals, Inc.
Immunity against a therapeutic xenoprotein/Fc construct delivered by gene transfer is reduced through binding to the inhibitory receptor FcγRIIb
Authors: Liang Yaming , Qiu Hongmin , Glinka Yelena , Lazarus Alan H. , Ni Heyu , Prud'homme Gerald J. , Wang Qinghua
Published: July 2011

Background

Therapeutic xenoproteins are immunogenic and can induce neutralizing antibodies. When delivered by intramuscular injection of a plasmid vector, this mimics classical DNA vaccination. To demonstrate this, we chose Exendin‐4 (Ex4), which is a glucagon‐like peptide‐1 mimetic xenoprotein in clinical use for treating type 2 diabetes. We constructed an Ex4 and mouse immunoglobulin (Ig)G1‐Fc fusion fragment (Ex4/Fc), and hypothesized that it would have minimal immunogenicity as a result of its capacity to bind the inhibitory Fc receptor FcγRIIb expressed by B lymphocytes.

Methods

Plasmid vectors encoding Ex4/Fc constructs, with wild‐type or mutant Fc, were injected intramuscularly into mice, and local electroporation was applied to enhance gene transfer. Gene transfer was performed in both wild‐type and FcγRIIb knockout mice. Antibody production was detected in serum by an enzyme‐linked immunosorbent assay.

Results

Recombinant Ex4/Fc bound only to B cells expressing FcγRIIb. This binding was dependent on a motif in the Fc region, which we mutated to abolish binding (Ex4/Fcmut). Ex4 antibody was detected in mice treated with Ex4, as well as Ex4/Fcmut, but not in those treated with Ex4/Fc. Thus, wild‐type Fc was associated with reduced immunogenicity. To confirm this was related to the presence of inhibitory Fc receptors, we also performed experiments in FcγRIIb‐null mice. Mice lacking this receptor produced antibodies against all Ex4 constructs, including the wild‐type Fc (Ex4/Fc).

Conclusions

The present study shows that inhibitory FcγRIIb receptors interacting with the wild‐type IgG1‐Fc reduce immunity against Ex4/Fc, suggesting an approach for reducing the immunogenicity of therapeutic proteins in the context of gene therapy. Copyright © 2011 John Wiley & Sons, Ltd.
Antimagic labelling of vertex weighted graphs
Authors: Wong Tsai‐Lien , Zhu Xuding
Published: July 2011

Suppose G is a graph, k is a non‐negative integer. We say G is k‐antimagic if there is an injection f: E→{1, 2, …, |E| + k} such that for any two distinct vertices u and v, . We say G is weighted‐k‐antimagic if for any vertex weight function w: V→ℕ, there is an injection f: E→{1, 2, …, |E| + k} such that for any two distinct vertices u and v, . A well‐known conjecture asserts that every connected graph G≠K2 is 0‐antimagic. On the other hand, there are connected graphs G≠K2 which are not weighted‐1‐antimagic. It is unknown whether every connected graph G≠K2 is weighted‐2‐antimagic. In this paper, we prove that if G has a universal vertex, then G is weighted‐2‐antimagic. If G has a prime number of vertices and has a Hamiltonian path, then G is weighted‐1‐antimagic. We also prove that every connected graph G≠K2 on n vertices is weighted‐ ⌊3n/2⌋‐antimagic. Copyright © 2011 Wiley Periodicals, Inc. J Graph Theory
On Cayley digraphs on nonisomorphic 2‐groups
Authors: Kovács István , Servatius Mary
Published: July 2011

A necessary and sufficient condition is given for two Cayley digraphs X1 = Cay(G1, S1) and X2 = Cay(G2, S2) to be isomorphic, where the groups Gi are nonisomorphic abelian 2‐groups, and the digraphs Xi have a regular cyclic group of automorphisms. Our result extends that of Morris [J Graph Theory 3 (1999), 345–362] concerning p‐groups Gi, where p is an odd prime. Copyright © 2011 Wiley Periodicals, Inc. J Graph Theory
Beneficial effects of a neurotrophic peptidergic mixture persist for a prolonged period following treatment interruption in a transgenic model of Alzheimer's disease
Authors: Rockenstein Edward , Ubhi Kiren , Pham Emiley , Michael Sarah , Doppler Edith , Novak Philipp , Inglis Chandra , Mante Michael , Adame Anthony , Alvarez X. Anton , Moessler Herbert , Masliah Eliezer
Published: July 2011

Neurodegenerative disorders such as Alzheimer's disease (AD) are characterized by the loss of neurotrophic factors, and experimental therapeutical approaches to AD have investigated the efficacy of replacing or augmenting neurotrophic factor activity. Cerebrolysin, a peptide mixture with neurotrophic‐like effects, has been shown to improve cognition in patients with AD and to reduce synaptic and behavioral deficits in transgenic (tg) mice overexpressing the amyloid precursor protein (APP). However, it is unclear how long‐lasting the beneficial effects of Cerebrolysin are and whether or not behavioral and neuropathological alterations will reappear following treatment interruption. The objective of the present study was to investigate the consequences of interrupting Cerebrolysin treatment (washout effect) 3 and 6 months after the completion of a 3‐month treatment period in APP tg mice. We demonstrate that, in APP tg mice, Cerebrolysin‐induced amelioration of memory deficits in the water maze and reduction of neurodegenerative pathology persist for 3 months after treatment interruption; however, these effects dissipate 6 months following treatment termination. Immunohistochemical analysis demonstrated that the decrease in neocortical and hippocampal amyloid plaque load observed in Cerebrolysin‐treated APP tg mice immediately after treatment was no longer apparent at 3 months after treatment interruption, indicating that the beneficial effects of Cerebrolysin at this time point were independent of its effect on amyloid‐β deposition. In conclusion, the results demonstrate that the effects of Cerebrolysin persist for a significant period of time following treatment termination and suggest that this prolonged effect may involve the neurotrophic factor‐like activity of Cerebrolysin. © 2011 Wiley‐Liss, Inc.
The tropospheric biennial oscillation in the East Asian monsoon region and its influence on the precipitation in China and large‐scale atmospheric circulation in East Asia
Authors: Si Dong , Ding Yihui
Published: July 2011

The precipitation in China manifests a remarkable quasi‐biennial signal. For interannual variability, about 70% stations over China indicate the dominance of a quasi‐2‐year period. The maximum precipitation variability associated with the quasi‐biennial oscillation is located over the Yangtze River valley (YRV) and Huaihe River valley (HRV) as well as South China. This paper attempts to reveal the spatial–temporal evolution of the precipitation in China and related large‐scale atmospheric circulation associated with the tropospheric biennial oscillation (TBO) in East Asia by using a season‐dependent empirical orthogonal function (S‐EOF) analysis approach.

The leading two modes of the TBO of summer precipitation in China and associated large‐scale circulations are examined by the S‐EOF analysis and regression analyses based on the S‐EOF time coefficients. The first TBO mode is characterized by an elongated band of positive precipitation anomalies along the YRV and negative precipitation anomalies over both North and South China. The second TBO mode is characterized by an elongated band of positive precipitation anomalies along the HRV and negative precipitation anomalies to the north of the Yellow River and to the south of the Yangtze River, respectively. Meanwhile, the leading modes of the TBO in East Asia may be determined by the meridional teleconnection Rossby wave pattern extending from the WNP to the midlatitudes of East Asia that is forced by the heating source fluctuation over the WNP during boreal summer. And the cold air activity, which is associated with the East Asian winter monsoon, may further influence the leading modes of the TBO through a modulation of the large‐scale atmosphere circulation over East Asia during the following boreal summer.

Also found is that the TBO in East Aisa depends on both the large‐scale air–sea coupling over the tropical Indo‐Pacific Ocean regions and the tropical–midlatitude interaction in the western North Pacific (WNP)‐East Asia region. A fundamental element for the TBO in East Asia is the WNP monsoon. It is not only an important component of the TBO cycle in the tropics but also serves as a major source of the TBO signal for the subtropical East Asia. The meridional teleconnection Rossby wave train over the WNP‐East Asia region acts as a conveyer belt that transports the tropical TBO signal to the midlatitudes of East Asia, and produces the TBO footprints in the large‐scale circulation and precipitation in East Asia. Furthermore, the cold air activity over the East Asia during boreal summer also services as an important link in the chain events of the tropical–midlatitude interaction, with enhancing the role of the TBO modes in East Asia. Copyright © 2011 Royal Meteorological Society