bluuebunny/crossref_metadata_2025 huggingface dataset:
Preparation of porous PVC membrane via a phase inversion method from PVC/DMAc/water/additives
Authors: Mei Shuo , Xiao Changfa , Hu Xiaoyu
Published: October 2010

Poly(vinyl chloride) membranes were prepared via a phase inversion method, using N,N‐dimethylacetamide (DMAc) as solvent, polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), and sucrose as three typical additives and water as the coagulation medium. The phase diagrams of the PVC/DMAc/additives/water quaternary systems were constructed using cloud‐point experimental data. With the addition of the different additives, the effect of dope solution temperature on the dope solution viscosity and the structure of membranes were investigated. It indicates that the viscosity of the PVC/DMAc dope solution with the additive increase compared with the dope solution without any additive and the addition of the additives into the dope solution alter the morphology and structure of the resultant membranes during the phase‐inversion process. © 2010 Wiley Periodicals, Inc. J Appl Polym Sci, 2011
Seven New Monoterpenoid Indole Alkaloids from Gelsemium elegans
Authors: Yamada Yousuke , Kitajima Mariko , Kogure Noriyuki , Wongseripipatana Sumphan , Takayama Hiromitsu
Published: October 2010

Seven new indole alkaloids were isolated from the roots of Gelsemium elegans Benth. and their structures were determined by spectroscopic analysis and chemical transformation from known alkaloids. Kounaminal (1) is a new koumine‐type alkaloid that contains an unusual aminal moiety. Humantenoxenine (2) and 15‐hydroxyhumantenoxenine (3) are humantenine‐type alkaloids that contain a novel β‐amino‐α,β‐unsaturated ketone residue. The other four novel alkaloids are two gelsedilam‐related and two gelsenicine‐related alkaloids.
Lipase Congeners Designed by Genetic Code Engineering
Authors: Hoesl Michael G. , Acevedo‐Rocha Carlos G. , Nehring Sebastian , Royter Marina , Wolschner Christina , Wiltschi Birgit , Budisa Nediljko , Antranikian Garabed
Published: October 2010

Classical enzyme optimization exploits the chemistry confined to the 20 canonical amino acids encoded by the standard genetic code. ‘Genetic code engineering’ allows the global substitution of particular residues with synthetic analogues, endowing proteins with chemical diversity not found in nature. These proteins are congeners of the parent protein because they originate from the same gene sequence, but contain a fraction of noncanonical amino acids. Global substitutions of methionine, proline, phenylalanine, and tyrosine have been carried out with related analogues in Thermoanaerobacter thermohydrosulfuricus lipase. This study represents the first extensive report of an important biocatalyst substituted with a high number of noncanonical amino acids. The generated lipase congeners displayed special features such as enhanced activation, elevated enzyme activity (by up to 25 %) and substrate tolerance (by up to 40 %), and changes in optimal temperature (by up to 20 °C) and pH (by up to 3). These emergent features achieved by genetic code engineering might be important not only for academic research, but also for numerous economical applications in the food, detergent, chemical, pharmaceutical, leather, textile, cosmetic, and paper industries.
The Heck Reaction of Allylic Alcohols Catalyzed by Palladium Nanoparticles in Water: Chemoenzymatic Synthesis of (R)‐(−)‐Rhododendrol
Authors: Boffi Alberto , Cacchi Sandro , Ceci Pierpaolo , Cirilli Roberto , Fabrizi Giancarlo , Prastaro Alessandro , Niembro Sandra , Shafir Alexandr , Vallribera Adelina
Published: October 2010

The use of phosphine‐free perfluoro‐tagged palladium nanoparticles immobilized on fluorous silica gel (FSG), either through fluorous–fluorous interactions or covalent bonding, in the Heck reaction of aryl iodides with allylic alcohols under aerobic conditions in water is described. 4‐(4‐Methoxyphenyl)‐butan‐2‐one, an important fine chemical, is readily accessed by this procedure. A two‐step one‐pot process, involving a Heck reaction followed by an enantioselective enzyme‐catalyzed reduction, to form chiral alcohols is applied to the synthesis of (R)‐(−)‐rhododendrol. The palladium catalysts can be recycled several times, both in the Heck reaction and in the one‐pot chemoenzymatic process.
Structures and H2 Adsorption Properties of Porous Scandium Metal–Organic Frameworks
Authors: Ibarra Ilich A. , Lin Xiang , Yang Sihai , Blake Alexander J. , Walker Gavin S. , Barnett Sarah A. , Allan David R. , Champness Neil R. , Hubberstey Peter , Schröder Martin
Published: October 2010

Two new three‐dimensional ScIII metal–organic frameworks {[Sc3O(L1)3(H2O)3]⋅Cl0.5(OH)0.5(DMF)4(H2O)3}∞ (1) (H2L1=1,4‐benzene‐dicarboxylic acid) and {[Sc3O(L2)2(H2O)3](OH)(H2O)5(DMF)}∞ (2) (H3L2=1,3,5‐tris(4‐carboxyphenyl)benzene) have been synthesised and characterised. The structures of both 1 and 2 incorporate the trinuclear trigonal planar [Sc3(O)(O2CR)6] building block featuring three ScIII centres joined by a central μ3‐O2− donor. Each ScIII centre is further bound by four oxygen donors from four different bridging carboxylate anions, and a molecule of water located trans to the μ3‐O2− donor completes the six coordination at the metal centre. Frameworks 1 and 2 show high thermal stability with retention of crystallinity up to 350 °C. The desolvated materials 1 a and 2 a, in which the solvent has been removed from the pores but with water or hydroxide remaining coordinated to ScIII, show BET surface areas based upon N2 uptake of 634 and 1233 m2 g−1, respectively, and pore volumes calculated from the maximum N2 adsorption of 0.25 cm3 g−1 and 0.62 cm3 g−1, respectively. At 20 bar and 78 K, the H2 isotherms for desolvated 1 a and 2 a confirm 2.48 and 1.99 wt % total H2 uptake, respectively. The isosteric heats of adsorption were estimated to be 5.25 and 2.59 kJ mol−1 at zero surface coverage for 1 a and 2 a, respectively. Treatment of 2 with acetone followed by thermal desolvation in vacuo generated free metal coordination sites in a new material 2 b. Framework 2 b shows an enhanced BET surface area of 1511 m2 g−1 and a pore volume of 0.76 cm3 g−1, with improved H2 uptake capacity and a higher heat of H2 adsorption. At 20 bar, H2 capacity increases from 1.99 wt % in 2 a to 2.64 wt % for 2 b, and the H2 adsorption enthalpy rises markedly from 2.59 to 6.90 kJ mol−1.
Total Syntheses of the Thiopeptides Amythiamicin C and D
Authors: Ammer Carolin , Bach Thorsten
Published: October 2010

The thiopeptides amythiamicin C and D were synthesized by employing amide bond formation, a Stille cross‐coupling reaction, and two Negishi cross‐coupling reactions as key transformations. The central 2,3,6‐trisubstituted pyridine ring of the target compounds was introduced as a 2,6‐dibromo‐3‐iodopyridine, which was selectively metalated at the 3‐position and connected to the complete Southern fragment of the amythiamicins by a Negishi cross‐coupling. For the synthesis of amythiamicin C, this step was followed by a Negishi cross‐coupling at C‐6 of the pyridine core. Subsequent attachment of the Eastern fragment was achieved by amide bond formation and macrolactam ring closure by a Stille cross‐coupling at C‐2. The Eastern bithiazole fragment of the amythiamins was constructed also by regioselective metalation and cross‐coupling reactions. The pivotal step involved the diastereoselective addition of 4‐bromothiazole‐2‐magnesium bromide to a chiral sulfinyl imine. For the synthesis of amythiamicin D, the order of cross‐coupling at C‐6, amide bond formation, and cross‐coupling at C‐2 was changed. The amide bond formation to the Eastern fragment was performed first and it was subsequently attempted to close the macrolactam by an intramolecular regioselective Stille cross‐coupling at C‐2. Despite the low regioselectivity of this reaction it paved the way to the immediate completion of the amythiamicin D synthesis when followed by a Negishi cross‐coupling at C‐6 with 2‐zincated methyl thiazole‐5‐carboxylate.
Mean squared error estimators of small area means using survey weights
Authors: Torabi Mahmoud , Rao Jon N. K.
Published: October 2010

Using survey weights, You & Rao [You and Rao, The Canadian Journal of Statistics 2002; 30, 431–439] proposed a pseudo‐empirical best linear unbiased prediction (pseudo‐EBLUP) estimator of a small area mean under a nested error linear regression model. This estimator borrows strength across areas through a linking model, and makes use of survey weights to ensure design consistency and preserve benchmarking property in the sense that the estimators add up to a reliable direct estimator of the mean of a large area covering the small areas. In this article, a second‐order approximation to the mean squared error (MSE) of the pseudo‐EBLUP estimator of a small area mean is derived. Using this approximation, an estimator of MSE that is nearly unbiased is derived; the MSE estimator of You & Rao [You and Rao, The Canadian Journal of Statistics 2002; 30, 431–439] ignored cross‐product terms in the MSE and hence it is biased. Empirical results on the performance of the proposed MSE estimator are also presented. The Canadian Journal of Statistics 38: 598–608; 2010 © 2010 Statistical Society of Canada
Positive quadrant dependence tests for copulas
Authors: Gijbels Irène , Omelka Marek , Sznajder Dominik
Published: October 2010

In this paper the interest is in testing the null hypothesis of positive quadrant dependence (PQD) between two random variables. Such a testing problem is important since prior knowledge of PQD is a qualitative restriction that should be taken into account in further statistical analysis, for example, when choosing an appropriate copula function to model the dependence structure. The key methodology of the proposed testing procedures consists of evaluating a “distance” between a nonparametric estimator of a copula and the independence copula, which serves as a reference case in the whole set of copulas having the PQD property. Choices of appropriate distances and nonparametric estimators of copula are discussed, and the proposed methods are compared with testing procedures based on bootstrap and multiplier techniques. The consistency of the testing procedures is established. In a simulation study the authors investigate the finite sample size and power performances of three types of test statistics, Kolmogorov–Smirnov, Cramér–von‐Mises, and Anderson–Darling statistics, together with several nonparametric estimators of a copula, including recently developed kernel type estimators. Finally, they apply the testing procedures on some real data. The Canadian Journal of Statistics 38: 555–581; 2010 © 2010 Statistical Society of Canada
Atrioventricular Reverse Remodeling After Valve Repair for Chronic Severe Mitral Regurgitation: 1‐Year Follow‐Up
Authors: Song Bong Gun , On Young Keun , Jeon Eun‐Seok , Kim Duk‐Kyung , Lee Sang‐Chol , Park Seung Woo , Oh Jae K. , Sung Ki Ick , Park PyoWon
Published: October 2010

Background:

Chronic severe mitral regurgitation is associated with poor clinical outcome because chronic volume overload leads to hemodynamic changes and left ventricular and left atrial remodeling. Few data are available regarding left atrial volume index regression (LAVIR) and left ventricular mass index regression (LVMIR) after valve surgery for mitral regurgitation. We aimed to identify predictive correlates of LAVIR and LVMIR and to assess the relationship between these regressions.

Hypothesis:

Volume overload in chronic severe mitral regurgitation may influence left atrial and ventricular remodeling and reverse remodeling.

Methods:

Eighty‐five patients who underwent valve repair for severe chronic mitral regurgitation were consecutively enrolled. Plasma N‐terminal fragment of the prohormone brain natriuretic peptide (NT‐proBNP) and echocardiographic measurements were performed before surgery, before discharge, and at 12 months after surgery. LAVIR and LVMIR were assessed using serial echocardiography.

Results:

There were significant decreases in left ventricular mass index (LVMI; from 125.9 ± 31.3 g/m2 to 94.8 ± 28.6 g/m2, P = 0.001) and left atrial volume index (LAVI; from 75.3 ± 33.5 mL/m2 to 41.7 ± 16.0 mL/m2, P = 0.001) after surgery. Preoperative LAVI positively correlated with preoperative LVMI (r = 0.437, P = 0.001) and LAVIR positively correlated with LVMIR (r = 0.347, P = 0.001). In multivariate stepwise linear regression analysis, preoperative LAVI, age, hypertension, and atrial fibrillation were independently predictive of LAVIR, and preoperative LVMI, hypertension, and NT‐proBNP were independently predictive of LVMIR.

Conclusions:

Volume overload in chronic severe mitral regurgitation may influence left ventricular remodeling and reverse remodeling, as well as left atrial remodeling and reverse remodeling. Preoperative lower LAVI, younger age, absence of hypertension, and absence of atrial fibrillation may predict LAVIR, and preoperative lower LVMI, lower NT‐proBNP levels, and absence of hypertension may predict LVMIR after surgery for chronic severe mitral regurgitation. Copyright © 2010 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.
Positive Vasodilator Stress ECG With Normal Myocardial Perfusion Imaging and Its Correlation With Coronary Angiographic Findings in African Americans and Hispanics
Authors: Paladugu Neelima , Shaqra Hussein , Blum Steve , Bhalodkar Narendra C.
Published: October 2010

Background:

Ischemic electrocardiographic (ECG) changes during vasodilator stress testing (VST) in the presence of abnormal myocardial perfusion imaging (MPI) are uncommon and are associated with presence of multivessel coronary artery disease (CAD). However, there is a paucity of data regarding the significance of ischemic ECG changes during VST with normal MPI in general, and especially among African Americans and Hispanics.

Hypothesis:

Ischemic changes during VST with normal MPI are associated with significant CAD.

Methods:

A retrospective review was done of 2945 patients undergoing VST.

Results:

Only 20 patients (0.7%) had positive ECG changes with normal MPI. Their demographics were: 60% Hispanic, 40% African American; 85% female; mean age 63 ± 11 years; history of hypertension 80%, diabetes 50%, and dyslipidemia 75%; smokers 30%; atypical chest pain 60%, and typical chest pain 40%. Of these 20 patients, 12 patients underwent coronary angiography. All 12 had significant CAD; nine (75%) had multivessel disease and 3 (25%) had single‐vessel disease. Prevalence of clinical variables and risk factors for CAD were similar among both the groups who did and did not undergo coronary angiography.

Conclusions:

Among African Americans and Hispanics, ischemic ECG changes during VST with normal MPI are likely to be associated with significant CAD and may warrant coronary angiography to assess presence and extent of CAD. Copyright © 2010 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.
Association of Left Atrial Myocardial Function With Left Ventricular Diastolic Dysfunction in Subjects With Preserved Systolic Function: A Strain Rate Imaging Study
Authors: Guan Zhiqiang , Zhang Di , Huang Rongjie , Zhang Fang , Wang Qingrong , Guo Shenglan
Published: October 2010

Background:

The purpose of this study was to investigate the relationship between left atrial (LA) myocardial function and left ventricular (LV) diastolic dysfunction in subjects with preserved LV ejection fraction (LVEF).

Methods:

The study included a group of 118 hypertensive patients and normal subjects. LV diastolic dysfunction was classified into 4 groups: none, mild, moderate, and severe. Peak strain rates in systole (S‐Sr), early diastole (E‐Sr), and late diastole (A‐Sr) were obtained from Doppler‐derived strain rate imaging to evaluate LA myocardial deformation.

Results:

No significant difference in LA dimension was observed in subjects with different degrees of LV diastolic dysfunction, although LA myocardial strain rate parameters were all significantly different across the 4 groups (all with P < 0.001). Compared with patients of normal diastolic function, the mild diastolic dysfunction group had significantly lower E‐Sr (0.62 ± 0.18 s−1 vs 1.20 ± 0.38 s−1, P < 0.001) and S‐Sr (0.78 ± 0.16 s−1 vs 0.94 ± 0.22 s−1, P < 0.001) but increased A‐Sr (1.14 ± 0.29 s−1 vs 1.00 ± 0.23 s−1, P = 0.05).

Conclusions:

By using strain rate imaging, significant changes of LA deformation in response to different stages of LV diastolic dysfunction were detected in subjects with preserved LVEF. Quantification of LA myocardial function rather than LA size may have the potential to predict early LV diastolic dysfunction in subjects with preserved LVEF. Copyright © 2010 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.
Combination Rosuvastatin Plus Fenofibric Acid in a Cohort of Patients 65 Years or Older With Mixed Dyslipidemia: Subanalysis of Two Randomized, Controlled Studies
Authors: Pepine Carl J. , Jacobson Terry A. , Carlson Dawn M. , Kelly Maureen T. , Setze Carolyn M. , Gold Alex , Stolzenbach James C. , Williams Laura A.
Published: October 2010

Background

Coronary heart disease risk increases with advancing age and is further increased in patients with mixed dyslipidemia, characterized by elevated low‐density lipoprotein cholesterol (LDL‐C), low high‐density lipoprotein cholesterol (HDL‐C), and high triglycerides (TG). Combination lipid therapy is an option; however, efficacy and safety data among elderly patients are lacking.

Hypothesis

The combination of rosuvastatin and fenofibric acid (R + FA) results in more comprehensive lipid improvements than corresponding‐dose monotherapies, without additional safety concerns, in elderly patients with mixed dyslipidemia.

Methods

This post‐hoc analysis evaluated data from patients age ≥ 65 years (n = 401) with mixed dyslipidemia (LDL‐C ≥ 130 mg/dL, HDL‐C < 40 mg/dL [men] or < 50 mg/dL [women], and TG ≥ 150 mg/dL) in 2 randomized studies. Patients included in this analysis received either monotherapy (as R 5, 10, or 20 mg or FA 135 mg), or combination therapy with R (5, 10, or 20 mg) + FA 135 mg, for 12 weeks. Data were pooled and analyzed, and mean/median percent changes in multiple lipid parameters and biomarkers were compared.

Results

Combination therapy decreased LDL‐C by 31.8%–47.2% vs 10.6% with FA monotherapy (P < 0.001). Combination therapy also increased HDL‐C by 21.9%–27.0% vs 5.9%–9.9% with R monotherapy (P < 0.001), and decreased TG by 48.3%–53.5% vs 20.7%–32.8% with R monotherapy (P < 0.001). In general, safety profiles were consistent between combination therapy and individual monotherapies.

Conclusions

In these elderly patients with mixed dyslipidemia, R 5, 10, or 20 mg in combination with FA 135 mg improved the overall lipid profile, without new or unexpected safety issues. Copyright © 2010 Wiley Periodicals, Inc.

Financial support for the studies was provided by Abbott and AstraZeneca. Dr. Pepine has served as a consultant for Abbott, Angioblast, Eli Lilly, Forest, Medtelligence, NicOx, Novartis, Sanofi‐Aventis, and SLACK, Inc.; has received research grants from Baxter, Bioheart, Inc., GlaxoSmithKline, and Pfizer; and has received unrestricted educational grants from AstraZeneca, AtCor Medical, Daiichi Sankyo, Eli Lilly, Pfizer, sanofi aventis, and Schering Plough. Dr. Jacobson is a consultant for Abbott, AstraZeneca, GlaxoSmithKline, Merck, and Schering Plough. Dr. Carlson, Dr. Kelly, Ms. Setze, Dr. Stolzenbach, and Dr. Williams are Abbott employees and stockholders. Dr. Gold is an AstraZeneca employee and stockholder.
Why Did You Order That Echocardiogram?
Authors: Kowey Peter R.
Published: October 2010

The author has no funding, financial relationships, or conflicts of interest to disclose.
Spironolactone Use in Heart Failure Patients With End‐Stage Renal Disease on Hemodialysis: Is It Safe?
Authors: Chua Doson , Lo Anita , Lo Chris
Published: October 2010

Background:

Spironolactone is used in the treatment of cardiovascular disease, but is contraindicated in renal dysfunction due to the risk of hyperkalemia. It is not known if patients with end‐stage renal disease (ESRD) on hemodialysis are at the same risk for hyperkalemia. The objective of this study was to systematically review the evidence evaluating the incidence of hyperkalemia with spironolactone use in ESRD patients on hemodialysis.

Hypothesis:

Spironolactone use in ESRD patients on hemodialysis may not lead to greater incidence of hyperkalemia.

Methods:

We searched the MEDLINE, Embase, CINAHL, Cochrane, and PubMed databases up to January 2010 for English‐language, human‐subject clinical trials that evaluated the rate of hyperkalemia with spironolactone use in ESRD patients on hemodialysis. Search terms included were “spironolactone,” “eplerenone,” “aldosterone antagonist,” “heart failure,” “kidney failure,” “hemodialysis,” “dialysis,” and “renal replacement therapy.”

Results:

Six prospective trials demonstrated that spironolactone use was safe in ESRD patients on hemodialysis. The incidence of hyperkalemia with spironolactone treatment in these studies was similar to control groups. The studies involved a small population of compliant subjects who were at low risk for hyperkalemia.

Conclusions:

Small pilot studies demonstrated that spironolactone treatment in ESRD patients on hemodialysis did not result in higher hyperkalemia rates. Larger studies are needed to confirm these preliminary results before spironolactone is routinely considered in hemodialysis patients. Copyright © 2010 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.
Screening, risk assessment, and the approach to therapy in patients with prostate cancer
Authors: Freedland Stephen J.
Published: October 2010

The major challenge in prostate cancer is to identify patients at higher risk of death and to distinguish them from those more likely to die from other causes. Stratification of patients into risk groups can be used to guide management decisions at each disease stage. This review discusses the measures, tools, and nomograms available for risk assessment in prostate cancer. For patients with localized hormone‐sensitive disease, the choice is between active surveillance and radical treatment, with focal therapy an emerging option. Current guidelines recommend treatment of patients with a life expectancy ≥10 years, although active surveillance is being used with increasing frequency for low‐risk patients, even with a long life expectancy. A number of risk stratification methods have been devised to assess the risk of biochemical recurrence (BCR) after treatment, with prostate‐specific antigen (PSA) level, Gleason score, clinical stage, and tumor mass/volume all shown to be predictive of BCR. Among men with BCR after treatment, PSA doubling time (PSADT) was the best predictor of further progression. Although studies in patients with castration‐resistant prostate cancer have shown that PSA level and PSADT are associated with a risk of developing metastatic disease, there is currently no clear surrogate for disease progression or overall survival for this patient group and no standard second‐ or third‐line therapy after progression on first‐line chemotherapy. The use of newly developed risk‐stratification models and markers of disease progression should assist in the earlier identification of disease progression, allowing the optimal treatment of such patients. Cancer 2011. © 2010 American Cancer Society.
Tumor response and progression‐free survival as potential surrogate endpoints for overall survival in extensive stage small‐cell lung cancer
Authors: Foster Nathan R. , Qi Yingwei , Shi Qian , Krook James E. , Kugler John W. , Jett James R. , Molina Julian R. , Schild Steven E. , Adjei Alex A. , Mandrekar Sumithra J.
Published: October 2010

BACKGROUND:

The authors investigated the putative surrogate endpoints of best response, complete response (CR), confirmed response, and progression‐free survival (PFS) for associations with overall survival (OS), and as possible surrogate endpoints for OS.

METHODS:

Individual patient data from 870 untreated extensive stage small‐cell lung cancer patients participating in 6 single‐arm (274 patients) and 3 randomized trials (596 patients) were pooled. Patient‐level associations between putative surrogate endpoints and OS were assessed by Cox models using landmark analyses. Trial‐level surrogacy of putative surrogate endpoints were assessed by the association of treatment effects on OS and individual putative surrogate endpoints. Trial‐level surrogacy measures included:R2from weighted least squares regression model, Spearman correlation coefficient, andR2from bivariate survival model (CopulaR2).

RESULTS:

Median OS and PFS were 9.6 (95% confidence interval [CI], 9.1‐10.0) and 5.5 (95% CI, 5.2‐5.9) months, respectively; best response, CR, and confirmed response rates were 44%, 22%, and 34%, respectively. Patient‐level associations showed that PFS status at 4 months was a strong predictor of subsequent survival (hazard ratio [HR], 0.42; 95% CI, 0.35‐0.51; concordance index 0.63;P< .01), with 6‐month PFS being the strongest (HR, 0.41; 95% CI, 0.35‐0.49; concordance index, 0.66,P< .01). At the trial level, PFS showed the highest level of surrogacy for OS (weighted least squaresR2= 0.79; CopulaR2= 0.80), explaining 79% of the variance in OS. Tumor response endpoints showed lower surrogacy levels (weighted least squaresR2≤0.48).

CONCLUSIONS:

PFS was strongly associated with OS at both the patient and trial levels. PFS also shows promise as a potential surrogate for OS, but further validation is needed using data from a larger number of randomized phase 3 trials. Cancer 2011. © 2010 American Cancer Society.
A phase 1‐2 study of a farnesyltransferase inhibitor, tipifarnib, combined with idarubicin and cytarabine for patients with newly diagnosed acute myeloid leukemia and high‐risk myelodysplastic syndrome
Authors: Jabbour Elias , Kantarjian Hagop , Ravandi Farhad , Garcia‐Manero Guillermo , Estrov Zeev , Verstovsek Srdan , O'Brien Susan , Faderl Stefan , Thomas Deborah A. , Wright John J. , Cortes Jorge
Published: October 2010

BACKGROUND:

The authors conducted a phase 1/2 study of tipifarnib in combination with idarubicin and cytarabine (IA) in 95 patients with previously untreated acute myeloid leukemia (AML) or high‐risk myelodysplastic syndrome.

METHODS:

Induction consisted of idarubicin 12 mg/m2 a day on days 1‐3, cytarabine 1.5 g/m2 intravenously continuously daily on days 1‐4 (days 1‐3 if age ≥60 years), and tipifarnib, with the first cohort (n = 6) receiving 200 mg orally twice a day and all others receiving 300 mg twice a day for 21 days every 28 days. Consolidation consisted of 5 courses of idarubicin 8 mg/m2 a day on days 1‐2, cytarabine 0.75 g/m2 a day on days 1‐3, and tipifarnib 300 mg twice a day for 14 days every 4‐6 weeks. Maintenance with tipifarnib 300 mg twice a day for 21 days every 4‐6 weeks was continued for 6 months.

RESULTS:

With a median follow‐up of 33 months, 61 patients achieved complete remission (CR) (64%), and 9 achieved complete remission with incomplete platelet recovery (CRp) (9%). The median duration of CR was not reached. Median overall survival was 17 months. The most common grade 3 adverse events were gastrointestinal toxicities, liver dysfunction, and skin rash. Compared with historical IA, IA and tipifarnib showed a better CR duration (P = .04) and a trend toward a higher CR rate in patients with chromosome 5/7 abnormalities.

CONCLUSIONS:

The combination of IA and tipifarnib is safe and active. Further studies exploring different dosages and schedules are warranted, particularly in patients with poor‐risk AML. Cancer 2011. © 2010 American Cancer Society.
Prognostic factors for survival in melanoma patients with brain metastases
Authors: Davies Michael A. , Liu Ping , McIntyre Susan , Kim Kevin B. , Papadopoulos Nicholas , Hwu Wen‐Jen , Hwu Patrick , Bedikian Agop
Published: October 2010

BACKGROUND:

One of the most common and deadly complications of melanoma is brain metastases. The outcomes of advanced melanoma patients who developed brain metastases were reviewed to identify significant prognostic factors for overall survival (OS).

METHODS:

An institutional database of advanced melanoma patients enrolled on clinical trials in the Department of Melanoma Medical Oncology from 1986 to 2004 was reviewed and patients who developed brain metastases were identified. Date of diagnosis, patient age, pattern of brain involvement, timing relative to extracranial metastases, prior response to systemic therapy, and treatments given for brain metastases were assessed as potential prognostic factors for OS.

RESULTS:

Among 743 melanoma patients enrolled in clinical trials for regional or systemic metastatic disease, 330 (44%) patients developed brain metastases. The median OS after the diagnosis of brain metastases was 4.7 months. Diagnosis before 1996, increased number of parenchymal brain metastases, leptomeningeal involvement, and development of brain metastases after receiving systemic therapy for extracranial metastases were found to be significant prognostic factors for OS. Among patients who received systemic therapy as the initial treatment of brain metastases, patients who previously responded to systemic therapies had longer survival than patients who had not responded.

CONCLUSIONS:

The era, pattern, and timing of melanoma brain metastases were found to be strongly associated with survival. Previous responsiveness to systemic therapies did not predict better outcomes overall, but it did correlate with improved survival for patients with brain metastases who were treated with systemic therapies. These factors may be used in guiding patient management and for stratifying patients in clinical trials. Cancer 2011. © 2010 American Cancer Society.
Gemcitabine and radiotherapy plus cisplatin after transurethral resection as conservative treatment for infiltrating bladder cancer
Authors: Caffo Orazio , Fellin Gianni , Graffer Umberto , Mussari Salvatore , Tomio Luigi , Galligioni Enzo
Published: October 2010

BACKGROUND:

Cystectomy is the standard treatment for patients with infiltrating bladder cancer, but conservative treatment with cystoscopic resection followed by radiochemotherapy may be an alternative for highly selected patients. The addition of gemcitabine to cisplatin and radiotherapy may enhance disease control.

METHODS:

The long‐term clinical outcomes of 26 patients enrolled in a previously published dose‐finding study and a prematurely discontinued phase 2 trial were evaluated. All the patients underwent transurethral tumor resection followed by a radical dose of external radiotherapy administered at the same time as cisplatin and weekly gemcitabine therapy.

RESULTS:

After a median follow‐up of 74 months, the projected 5‐year clinical outcomes were a 70.1% overall survival rate, a 78.9% disease‐specific survival rate, and a 73.8% bladder‐intact survival rate.

CONCLUSIONS:

The long‐term follow‐up data from the current study confirmed that the addition of gemcitabine to radiotherapy and cisplatin is safe and leads to good local and distant disease control. The concomitant administration of cisplatin may explain the good long‐term organ preservation that was observed. Conducting confirmatory and comparative trials could satisfy an unmet need but requires the multidisciplinary cooperation of urologists in selecting the right patients for a bladder‐sparing strategy. Cancer 2011. © 2010 American Cancer Society.
The selective Trk inhibitor AZ623 inhibits brain‐derived neurotrophic factor–mediated neuroblastoma cell proliferation and signaling and is synergistic with topotecan
Authors: Zage Peter E. , Graham Timothy C. , Zeng Lizhi , Fang Wendy , Pien Christine , Thress Ken , Omer Charles , Brown Jeffrey L. , Zweidler ‐McKay Patrick A.
Published: October 2010

BACKGROUND:

TrkB expression is associated with poor prognosis for patients with neuroblastoma. AZ623 is a novel potent and selective inhibitor of the Trk family of tyrosine kinases. The authors hypothesized that AZ623 would inhibit TrkB‐mediated signaling in neuroblastoma tumor cells and would be synergistic when combined with chemotherapy.

METHODS:

Neuroblastoma cell lines were screened for TrkB receptor mRNA expression and for their proliferation rates in response to brain‐derived neurotrophic factor (BDNF). The effects of AZ623 on Trk receptor phosphorylation, signaling, and cell growth were evaluated in BDNF‐treated neuroblastoma cells. Mice with human neuroblastoma xenograft tumors were treated with AZ623 alone and in combination with topotecan, and tumor growth rates were determined during and after treatment.

RESULTS:

Neuroblastoma cell lines expressed various levels of the TrkB receptor and demonstrated increased proliferation in response to BDNF. BDNF treatment stimulated TrkB phosphorylation and downstream signaling that could be inhibited by AZ623. Neuroblastoma cells demonstrated in vitro sensitivity to AZ623, with concentration that inhibits 50% (IC50) values between 0.8 to 7 μM. AZ623 treatment was found to inhibit BDNF‐mediated neuroblastoma cell proliferation. Mice with human neuroblastoma xenograft tumors demonstrated tumor growth inhibition when treated with AZ623 and with AZ623 combined with topotecan. Limited tumor regrowth was noted in mice with tumors treated with AZ623 combined with topotecan after treatment discontinuation.

CONCLUSIONS:

AZ623 is a novel selective Trk inhibitor that inhibits BDNF‐mediated signaling and neuroblastoma cell proliferation. AZ623 treatment inhibits the growth of human neuroblastoma xenograft tumors, and treatment with AZ623 combined with topotecan results in the prolonged inhibition of tumor regrowth. On the basis of these results, further preclinical development is warranted. Cancer 2011. © 2010 American Cancer Society.
Innervation of the rat uterus at estrus: A study in full‐thickness, immunoperoxidase‐stained whole‐mount preparations
Authors: Gnanamanickam Greta J.E. , Llewellyn‐Smith Ida J.
Published: October 2010

The innervation of the nonpregnant rat uterus has been studied in histological sections, which contain only small samples of nerves and are unlikely to afford a complete picture of uterine innervation. Here we used whole‐mount preparations of entire full‐thickness uterine horns from nonpregnant rats in estrus to visualize autonomic or sensory nerves with peroxidase immunohistochemistry. Immunoreactivity was studied for tyrosine hydroxylase (TH)‐labeled sympathetic nerves; vesicular acetylcholine transporter (VAChT), parasympathetic nerves; and substance P (SP) and calcitonin gene‐related peptide (CGRP), sensory nerves. Neuropeptide Y (NPY) and nitric oxide synthase (NOS) identified more than one of these functionally distinct nerve types. Axons of all neurochemical classes entered the uterus at the mesometrium and innervated the uterine smooth muscle. The linea uteri, a dense band of longitudinal muscle opposite the mesometrium, contained more TH‐, NPY‐, CGRP‐, and VAChT‐immunoreactive axons than the remaining smooth muscle. Axons immunoreactive for NPY, SP, NOS, and VAChT formed a plexus near the circular muscle‐endometrium interface. Rare TH‐ and NPY‐immunoreactive axons and occasional CGRP‐immunoreactive axons occurred close to uterine glands. Blood vessels had dense perivascular plexuses of TH‐ and NPY‐containing axons and less dense NOS‐, SP‐, CGRP‐, and VAChT‐positive plexuses. The circular muscle plexus and glands were absent opposite the mesometrium. Uterine arterioles formed an interconnected network throughout the uterus. This article provides the first comprehensive description of the autonomic and sensory innervation of the nonpregnant rat uterus and will be a foundation for future studies on changes in uterine innervation caused by normal physiological or pathophysiological challenges J. Comp. Neurol. 519:621–643, 2011. © 2010 Wiley‐Liss, Inc.
Bombyx orcokinins are brain‐gut peptides involved in the neuronal regulation of ecdysteroidogenesis
Authors: Yamanaka Naoki , Roller Ladislav , Žitňan Dušan , Satake Honoo , Mizoguchi Akira , Kataoka Hiroshi , Tanaka Yoshiaki
Published: October 2010

Biosynthesis of ecdysteroids, the insect steroid hormones controlling gene expression during molting and metamorphosis, takes place primarily in the prothoracic gland (PG). The activity of the PG is regulated by various neuropeptides. In the silkworm Bombyx mori, these neuropeptides utilize both hormonal and neuronal pathways to regulate the activity of the PG, making the insect an excellent model system to investigate the complex signaling network controlling ecdysteroid biosynthesis. Here we report another group of neuropeptides, orcokinins, as neuronal prothoracicotropic factors. Using direct mass spectrometric profiling of the axons associated with the PG, we detected several peptide peaks which correspond to orcokinin gene products in addition to the previously described Bommo‐FMRFamides (BRFas). In situ hybridization and immunohistochemistry revealed that orcokinins are produced in the prominent neurosecretory cells in the ventral ganglia, as well as in numerous small neurons throughout the central nervous system and in midgut endocrine cells. One of the two pairs of BRFa‐expressing neurosecretory cells in the prothoracic ganglion coexpresses orcokinin, and these neurons project axons through the transverse nerve and terminate on the surface of the PG. Using an in vitro PG bioassay, we show that orcokinins have a clear prothoracicotropic activity and are able to cancel the static effect of BRFas on ecdysteroid biosynthesis, whereas the suppressive effect of BRFas on cAMP production remained unchanged in the presence of orcokinins. The discovery of a second regulator of PG activity in these neurons further illustrates the potential importance of the PG innervation in the regulation of insect development. J. Comp. Neurol. 519:238‐246, 2011. © 2010 Wiley‐Liss, Inc.
Spatial distribution of neural activity in the anterior olfactory nucleus evoked by odor and electrical stimulation
Authors: Kay Rachel B. , Meyer Elizabeth Amory , Illig Kurt R. , Brunjes Peter C.
Published: October 2010

Several lines of evidence indicate that complex odorant stimuli are parsed into separate data streams in the glomeruli of the olfactory bulb, yielding a combinatorial “odotopic map.” However, this pattern does not appear to be maintained in the piriform cortex, where stimuli appear to be coded in a distributed fashion. The anterior olfactory nucleus (AON) is intermediate and reciprocally interconnected between these two structures, and also provides a route for the interhemispheric transfer of olfactory information. The present study examined potential coding strategies used by the AON. Rats were exposed to either caproic acid, butyric acid, limonene, or purified air and the spatial distribution of Fos‐immunolabeled cells was quantified. The two major subregions of the AON exhibited different results. Distinct odor‐specific spatial patterns of activity were observed in pars externa, suggesting that it employs a topographic strategy for odor representation similar to the olfactory bulb. A spatially distributed pattern that did not appear to depend on odor identity was observed in pars principalis, suggesting that it employs a distributed representation of odors more similar to that seen in the piriform cortex. J. Comp. Neurol. 519:277‐289, 2011. © 2010 Wiley‐Liss, Inc.
Regular mosaic of synaptic contacts among three retinal neurons
Authors: Koizumi Amane , Jakobs Tatjana C. , Masland Richard H.
Published: October 2010

Retinal bipolar, amacrine, and ganglion cells contact each other within precisely defined synaptic laminae, but the spatial distribution of contacts between the cells is generally treated as random. Here we show that not to be the case. Excitatory inputs to inner retinal neurons were visualized by introduction of a plasmid coding for the postsynaptic protein PSD95‐GFP. Our initial finding was that synapses on the dendrites of retinal ganglion cells are regularly spaced, at 2–3‐μm intervals, along the dendrites. Thus, the presence of a PSD95 punctum creates a nearby zone from which other inputs appear to be excluded. Despite their great variation in size and different morphologies, the spacing is similar for the arbors of different retinal ganglion cell types. Regular spacing was also observed for the starburst amacrine cells. This regularity is mirrored in the spacing of axonal varicosities of the stratified bipolar cells, which have a regular, nonrandom interval consistent with that of the PSD95 puncta on ganglion cells. Thus, for each level of the inner plexiform layer all three cell types participate in a single 2D mosaic of synaptic contacts. These findings raise a new set of questions: How does the self‐avoidance of synaptic sites along an individual dendrite arise and how is it physically maintained? Why is a regular spacing of inputs important for the computational function of the cells? Finally, which of the three players, if any, is developmentally responsible for the initial establishment of the pattern? J. Comp. Neurol. 519:341‐357, 2011. © 2010 Wiley‐Liss, Inc.
Decline in adult neurogenesis during aging follows a topographic pattern in the mouse hippocampus
Authors: Jinno Shozo
Published: October 2010

In the rodent brain, diverse functions are topographically distributed within the hippocampus. For instance, the dorsal (septal) hippocampus is involved in spatial memory, whereas the ventral (temporal) hippocampus is related to emotion and anxiety. Accumulating evidence shows that age‐dependent decline in hippocampal neurogenesis is associated with impairments of these functions. However, little is known about whether the decline in dentate granule cell production during aging follows a topographic pattern. Here we quantitatively estimated specific populations of adult‐born cells in young adult and middle‐aged mice by using endogenous markers and determined whether age‐dependent reductions in adult neurogenesis exhibited topographic differences. The numerical densities (NDs) of putative primary progenitors, intermediate neuronal progenitors, and neuronal lineages were higher in the dorsal dentate gyrus (DG) than in the ventral DG both in young adult and in middle‐aged mice, but the ratios of the NDs in the dorsal DG to the NDs in the ventral DG noticeably increased with age. The age‐related reductions in the numbers of these populations were larger in the ventral DG than in the dorsal DG. By contrast, the NDs of glial lineages were higher in the ventral DG than in the dorsal DG during life, and the numbers of glial lineages showed no significant age‐related changes. Our findings suggest that neurogenesis, but not gliogenesis, wanes faster in the ventral hippocampus than in the dorsal hippocampus during aging. Such age‐related topographic changes in hippocampal neurogenesis might be implicated in memory and affective impairments in older people. J. Comp. Neurol. 519:451–466, 2011. © 2010 Wiley‐Liss, Inc.
Spin‐Labeled Heparins as Polarizing Agents for Dynamic Nuclear Polarization
Authors: Dollmann Björn C. , Kleschyov Andrei L. , Sen Vasily , Golubev Valery , Schreiber Laura M. , Spiess Hans W. , Münnemann Kerstin , Hinderberger Dariush
Published: October 2010

A potentially biocompatible class of spin‐labeled macromolecules, spin‐labeled (SL) heparins, and their use as nuclear magnetic resonance (NMR) signal enhancers are introduced. The signal enhancement is achieved through Overhauser‐type dynamic nuclear polarization (DNP). All presented SL‐heparins show high 1H DNP enhancement factors up to E=−110, which validates that effectively more than one hyperfine line can be saturated even for spin‐labeled polarizing agents. The parameters for the Overhauser‐type DNP are determined and discussed. A striking result is that for spin‐labeled heparins, the off‐resonant electron paramagnetic resonance (EPR) hyperfine lines contribute a non‐negligible part to the total saturation, even in the absence of Heisenberg spin exchange (HSE) and electron spin‐nuclear spin relaxation (T1ne). As a result, we conclude that one can optimize the use of, for example, biomacromolecules for DNP, for which only small sample amounts are available, by using heterogeneously distributed radicals attached to the molecule.
Canonical Wnt/β‐catenin signaling is required for maintenance but not activation of Pitx2 expression in neural crest during eye development
Authors: Zacharias Amanda L. , Gage Philip J.
Published: October 2010

Pitx2 is a paired‐like homeodomain gene that acts as a key regulator of eye development. Despite its significance, upstream regulation of Pitx2 expression during eye development remains incompletely understood. We use neural crest‐specific ablation of Ctnnb1 to demonstrate that canonical Wnt signaling is not required for initial activation of Pitx2 in neural crest. However, canonical Wnt signaling is subsequently required to maintain Pitx2 expression in the neural crest. Eye development in Ctnnb1‐null mice appears grossly normal early but significant phenotypes emerge following loss of Pitx2 expression. LEF‐1 and β‐catenin bind Pitx2 promoter sequences in ocular neural crest, indicating a likely direct effect of canonical Wnt signaling on Pitx2 expression. Combining our data with previous reports, we propose a model wherein a sequential code of retinoic acid followed by canonical Wnt signaling are required for activation and maintenance of Pitx2 expression, respectively. Other key transcription factors in the neural crest, including Foxc1, do not require intact canonical Wnt signaling. Developmental Dynamics 239:3215–3225, 2010. © 2010 Wiley‐Liss, Inc.
cineSubstitution and the Cu Effect in Stille Cross‐Coupling Reactions: Mechanistic Perspectives and Synthetic Utility
Authors: Peng Yu , Li Wei‐Dong Z.
Published: October 2010

cineSubstitution arising from slow transmetallation occasionally occurs in classic Pd‐catalyzed Stille cross‐coupling reactions with sterically hindered vinyltin components. Mechanistic explanations of this “abnormal” cross‐coupling mode and the intriguing co‐catalytic effects of metallic Cu species in restoring theipsoselectivity are summarized. Typical synthetic applications of this unique Cu effect and the advent of Cu‐catalyzed Stille‐type cross‐coupling are also demonstrated.
Application of Fenton process for decolorization of reactive black 5 from synthetic wastewater: Kinetics and thermodynamics
Authors: Argun Mehmet Emin , Karatas Mustafa
Published: October 2010

The decolorization and degradation efficiency of the azo dye Reactive Black 5 (RB5) by Fenton system were investigated in this study. The operation parameters such as Fe2+:H2O2 ratio, pH value, initial concentration of RB5, reaction time, and temperature were examined. Maximum decolorization (99%) and degradation (88% COD removal) efficiencies were achieved at the Fe2+:H2O2 ratio of 0.05 and pH 3 for 15‐min reaction time. The decolorization kinetic of RB5 followed pseudo‐second‐order reaction kinetic. The increase of temperature caused decreasing of obtained rate constants and increasing of corresponding half‐lives. The article also discussed thermodynamic parameters including changes in Gibbs free energy, enthalpy, and entropy for the decolorization of RB5 by Fenton and exposed that the oxidation process was spontaneous and exothermic under natural conditions. © 2010 American Institute of Chemical Engineers Environ Prog, 2010