bluuebunny/crossref_metadata_2025 huggingface dataset:
Spectroscopic and Morphological Studies of Metal-Organic and Metal-Free Dyes onto Titania Films for Dye-Sensitized Solar Cells
Authors: Di Carlo Gabriella , Caschera Daniela , Toro Roberta G. , Riccucci Cristina , Ingo Gabriel M. , Padeletti Giuseppina , De Marco Luisa , Gigli Giuseppe , Pennesi Giovanna , Zanotti Gloria , Paoletti Anna M. , Angelini Nicola
Published: October 2013

We have investigated the spectroscopic behavior of three different sensitizers adsorbed onto titania thin films in order to gain information both on the electron transfer process from dye to titania and on the anchorage of the chromophore onto the semiconductor. We have examined by UV-Vis and fluorescence spectroscopy the widely used ruthenium complexcis-di(thiocyanato)bis(2,2′-bipyridyl-4,4′-dicarboxylato)ruthenium(II) (N719), the more recently developed organic molecular 3-(5-(4-(diphenylamino)styryl)thiophen-2-yl)-2-cyanoacrylic acid (D5), and apush-pullzinc phthalocyanine sensitizer (ZnPc). Three type of titania films with different morphology, characterized by SEM and FT-IR measurement, were considered: a mesoporous transparent film deposited by spin-coating (TiMS), a semiopaque film deposited by doctor-blade from mesoporous titania (TiMS_DB) and a semiopaque film deposited by doctor-blade form commercial P25 titania (P25_DB). The use of TiMS is responsible for the adsorption of a higher amount of dye since the mesoporous structure allows increasing the interfacial area between dye and titania. Moreover, the fluorescence emission peak is weaker when the sensitizers are adsorbed onto TiMS. These findings suggest that mesostructured films could be considered the most promising substrates to realize photoanodes with a fast electron transfer process.
T Helper 17 Cells in Autoimmune Liver Diseases
Authors: Abe Masanori , Hiasa Yoichi , Onji Morikazu
Published: October 2013

Many autoimmune diseases are driven by self-reactive T helper (Th) cells. A new population of effector CD4+T cells characterized by the secretion of interleukin (IL)-17, referred to as Th17 cells, has been demonstrated to be phenotypically, functionally, and developmentally distinct from Th1 and Th2 cells. Because the liver is known to be an important source of transforming growth factor-βand IL-6, which are cytokines that are crucial for Th17 differentiation, it is very likely that Th17 cells contribute to liver inflammation and autoimmunity. In contrast, another distinct subset of T cells, regulatory T cells (Treg), downregulate immune responses and play an important role in maintaining self-tolerance. In addition, there is a reciprocal relationship between Th17 cells and Tregs, in development and effector functions, and the balance between Th17 and Treg cells can affect the outcome of immune responses, particularly in autoimmune diseases. In this review, we will focus on the latest investigative findings related to Th17 cells in autoimmune liver disease.
A Semiautomated Framework for Integrating Expert Knowledge into Disease Marker Identification
Authors: Wang Jing , Webb-Robertson Bobbie-Jo M. , Matzke Melissa M. , Varnum Susan M. , Brown Joseph N. , Riensche Roderick M. , Adkins Joshua N. , Jacobs Jon M. , Hoidal John R. , Scholand Mary Beth , Pounds Joel G. , Blackburn Michael R. , Rodland Karin D. , McDermott Jason E.
Published: October 2013

Background. The availability of large complex data sets generated by high throughput technologies has enabled the recent proliferation of disease biomarker studies. However, a recurring problem in deriving biological information from large data sets is how to best incorporate expert knowledge into the biomarker selection process.Objective. To develop a generalizable framework that can incorporate expert knowledge into data-driven processes in a semiautomated way while providing a metric for optimization in a biomarker selection scheme.Methods. The framework was implemented as a pipeline consisting of five components for the identification of signatures from integrated clustering (ISIC). Expert knowledge was integrated into the biomarker identification process using the combination of two distinct approaches; a distance-based clustering approach and an expert knowledge-driven functional selection.Results. The utility of the developed framework ISIC was demonstrated on proteomics data from a study of chronic obstructive pulmonary disease (COPD). Biomarker candidates were identified in a mouse model using ISIC and validated in a study of a human cohort.Conclusions. Expert knowledge can be introduced into a biomarker discovery process in different ways to enhance the robustness of selected marker candidates. Developing strategies for extracting orthogonal and robust features from large data sets increases the chances of success in biomarker identification.
Temperature-Responsive Gelation of Type I Collagen Solutions Involving Fibril Formation and Genipin Crosslinking as a Potential Injectable Hydrogel
Authors: Yunoki Shunji , Ohyabu Yoshimi , Hatayama Hirosuke
Published: October 2013

We investigated the temperature-responsive gelation of collagen/genipin solutions using pepsin-solubilized collagen (PSC) and acid-solubilized collagen (ASC) as substrates. Gelation occurred in the PSC/genipin solutions at genipin concentrations 0–2 mM under moderate change in temperature from 25 to 37°C. The PSC/genipin solutions exhibited fluidity at room temperature for at least 30 min, whereas the ASC/genipin solutions rapidly reached gel points. In specific cases PSC would be preferred over ASC as an injectable gel system. The temperature-responsive gelation of PSC/genipin solutions was due to temperature responses to genipin crosslinking and collagen fibril formation. The elastic modulus of the 0.5% PSC/genipin gel system could be adjusted in a range of 2.5 to 50 kPa by the PSC and genipin concentrations, suggesting that a PSC/genipin solution is a potential injectable gel system for drug and cell carriers, with mechanical properties matching those of living tissues.
Biodistribution of Mesenchymal Stem/Stromal Cells in a Preclinical Setting
Authors: Sensebé Luc , Fleury-Cappellesso Sandrine
Published: October 2013

Due to their multi/pluripotency and immunosuppressive properties, mesenchymal stem/stromal cells (MSCs) are important tools for treatment of immune disorders and tissue repair. The increasing uses of MSCs lead to the development of production processes that need to be in accordance with good manufacturing practices (GMP). In Europe, MSCs are somatic cell-therapy products, referred to as advanced-therapy medicinal products (ATMPs), and in the United States MSCs must comply with current good tissue practice requirements. The safety and efficacy of MSCs must be ensured, whatever the cell source, and studies of dose and biodistribution are important aspects of safety testing. Preclinical data on biodistribution and pharmacodynamics are mandatory for approval. It is important to demonstrate that MSCs do not have unwanted homing that could drive to inappropriate differentiation in some organ or to support cancer development as suggested in some experiments. All these aspects should be addressed in a risk-based approach according to recently published guidelines by EMA. In the present article, we summarize the main approaches for labeling and tracking of infused MSCs, report on current animal models, and give an overview of available results on biodistribution.
Exact Analytical Solution for Suction and Injection Flow with Thermal Enhancement of Five Nanofluids over an Isothermal Stretching Sheet with Effect of the Slip Model: A Comparative Study
Authors: Aly Emad H. , Ebaid Abdelhalim
Published: October 2013

We introduced a direct and effective approach to obtain the exact analytical solution for the nanoparticles-water flow over an isothermal stretching sheet with the effect of the slip model. In particular, we examined and compared the effect of the existence of five metallic and nonmetallic nanoparticles, namely, Silver, Copper, Alumina, Titania, and Silicon Dioxide, in a base of water. The most interesting physical parameters were then discussed in the presence of no-slip model, first order slip, and second order slip parameters. It is found that, with no-slip effect, the present exact solutions are in a very good agreement with the previous published results. On the other hand, with the effect of the slip model, increase in the nanoparticle volume friction decreases the velocity for the high density of nanoparticles, increases it for the low density of them, and increases the temperature for all investigated nanoparticles. Further, increase in the wall mass decreases the velocity and temperature; however, it increases the local skin friction. Furthermore, increase in the slips slows down the velocity, increases the temperature with an impressive effect in the injection case, and decreases the local skin friction and the reduced Nusselt number. It was also demonstrated that, as the nanoparticle becomes heavier, this results in increase and decrease in reduced skin friction coefficient and reduced Nusselt number, respectively, with significant effect in the presence of the second slip. Finally, Silver is the suitable nanoparticle if slowing down the velocity and increasing the temperature are needed; Silicon Dioxide is the appropriate nanoparticle if different behavior is to be considered.
The Node Arrangement Methodology of Wireless Sensor Networks for Long-Span Bridge Health Monitoring
Authors: Zhou Guang-Dong , Yi Ting-Hua
Published: October 2013

Wireless sensor networks (WSNs), which are a promising technology for the implementation of long-span bridge health monitoring, have gained increasing attention from both the research community and actual users. The limited energy of sensor emphasizes the importance of performance optimization of WSNs. In this paper, a methodology and strategy of node arrangement are developed to improve the performance of WSN for long-span bridge health monitoring, including balancing energy consumption, increasing data capacity, and reducing deployment cost. A composite WSN organized by sensor nodes and relay nodes is introduced for structural health monitoring. The energy consumption model of the composite WSN is firstly presented. And then, the data acquisition efficiency (DAE) defined as data capacity per unit deployment cost is suggested to evaluate the performance of WSN. Subsequently, the node arrangement is divided into two phases of sensor node arrangement and relay node arrangement. An improved general genetic algorithm is proposed to configure sensor nodes, and a nonuniform node arrangement method is developed to distribute relay nodes. Based on the DAE, the theoretical formulae of nonuniform node arrangement are deduced. The process of two-phase node arrangement is also provided for practical bridge engineers.
Influence of Root Exudates on the Bacterial Degradation of Chlorobenzoic Acids
Authors: Vrchotová Blanka , Lovecká Petra , Dražková Milena , Macková Martina , Macek Tomas
Published: October 2013

Degradation of chlorobenzoic acids (e.g., products of microbial degradation of PCB) by strains of microorganisms isolated from PCB contaminated soils was assessed. From seven bulk‐soil isolates two strains unique in ability to degrade a wider range of chlorobenzoic acids than others were selected, individually and even in a complex mixture of 11 different chlorobenzoic acids. Such a feature is lacking in most tested degraders. To investigate the influence of vegetation on chlorobenzoic acids degraders, root exudates of two plant species known for supporting PCB degradation in soil were tested. While with individual chlorobenzoic acids the presence of plant exudates leads to a decrease of degradation yield, in case of a mixture of chlorobenzoic acids either a change in bacterial degradation specificity, associated with 3‐ and 4‐chlorobenzoic acid, or an extension of the spectrum of degraded chlorobenzoic acids was observed.
Design of Telerobotic Drilling Control System with Haptic Feedback
Authors: Shah Faraz , Polushin Ilia G.
Published: October 2013

The paper deals with the design of control algorithms for virtual reality based telerobotic system with haptic feedback that allows for the remote control of the vertical drilling operation. The human operator controls the vertical penetration velocity using a haptic device while simultaneously receiving the haptic feedback from the locally implemented virtual environment. The virtual environment is rendered as a virtual spring with stiffness updated based on the estimate of the stiffness of the rock currently being cut. Based on the existing mathematical models of drill string/drive systems and rock cutting/penetration process, a robust servo controller is designed which guarantees the tracking of the reference vertical penetration velocity of the drill bit. A scheme for on-line estimation of the rock intrinsic specific energy is implemented. Simulations of the proposed control and parameter estimation algorithms have been conducted; consequently, the overall telerobotic drilling system with a human operator controlling the process using PHANTOM Omni haptic device is tested experimentally, where the drilling process is simulated in real time in virtual environment.
Review of Mass Spectrometry–Based Metabolomics in Cancer Research
Authors: Liesenfeld David B. , Habermann Nina , Owen Robert W. , Scalbert Augustin , Ulrich Cornelia M.
Published: October 2013

Metabolomics, the systematic investigation of all metabolites present within a biologic system, is used in biomarker development for many human diseases, including cancer. In this review, we investigate the current role of mass spectrometry–based metabolomics in cancer research. A literature review was carried out within the databases PubMed, Embase, and Web of Knowledge. We included 106 studies reporting on 21 different types of cancer in 7 different sample types. Metabolomics in cancer research is most often used for case–control comparisons. Secondary applications include translational areas, such as patient prognosis, therapy control and tumor classification, or grading. Metabolomics is at a developmental stage with respect to epidemiology, with the majority of studies including less than 100 patients. Standardization is required especially concerning sample preparation and data analysis. In the second part of this review, we reconstructed a metabolic network of patients with cancer by quantitatively extracting all reports of altered metabolites: Alterations in energy metabolism, membrane, and fatty acid synthesis emerged, with tryptophan levels changed most frequently in various cancers. Metabolomics has the potential to evolve into a standard tool for future applications in epidemiology and translational cancer research, but further, large-scale studies including prospective validation are needed. Cancer Epidemiol Biomarkers Prev; 22(12); 2182–201. ©2013 AACR.
Contrasting Expression Patterns of Histone mRNA and microRNA 760 in Patients with Gastric Cancer
Authors: Iwaya Takeshi , Fukagawa Takeo , Suzuki Yutaka , Takahashi Yusuke , Sawada Genta , Ishibashi Masahisa , Kurashige Junji , Sudo Tomoya , Tanaka Fumiaki , Shibata Kohei , Endo Fumitaka , Katagiri Hirokatsu , Ishida Kaoru , Kume Kohei , Nishizuka Satoshi , Iinuma Hisae , Wakabayashi Go , Mori Masaki , Sasako Mitsuru , Mimori Koshi
Published: October 2013

Purpose: Recent studies revealed that both disseminated tumor cells and noncancerous cells contributed to cancer progression cooperatively in the bone marrow. Here, RNA-seq analysis of bone marrow from gastric cancer patients was performed to identify prognostic markers for gastric cancer.

Experimental Design: Bone marrow samples from eight gastric cancer patients (stages I and IV: n = 4 each) were used for RNA-seq analysis. Results were validated through quantitative real-time PCR (qRT-PCR) analysis of HIST1H3D expression in 175 bone marrow, 92 peripheral blood, and 115 primary tumor samples from gastric cancer patients. miR-760 expression was assayed using qRT-PCR in 105 bone marrow and 96 primary tumor samples. Luciferase reporter assays were performed to confirm whether histone mRNAs were direct targets of miR-760. miR-760 expression was also evaluated in noncancerous cells from gastric cancer patients.

Results: RNA-seq analysis of bone marrow samples from gastric cancer patients revealed higher expression of multiple histone mRNAs in stage IV patients. HIST1H3D expression in the bone marrow, peripheral blood, and primary tumor of stage IV patients was higher than that in stage I patients (P = 0.0284, 0.0243, and 0.0006, respectively). In contrast, miR-760 was downregulated in the bone marrow and primary tumor of stage IV patients compared with stage I patients (P = 0.0094 and 0.0018, respectively). Histone mRNA and miR-760 interacted directly. Furthermore, miR-760 was downregulated in noncancerous mucosa in stage IV gastric cancer patients.

Conclusion: Histone mRNA was upregulated, whereas miR-760 was downregulated in the bone marrow and primary tumor of advanced gastric cancer patients, suggesting that the histone mRNA/miR-760 axis had a crucial role in the development of gastric cancer. Clin Cancer Res; 19(23); 6438–49. ©2013 AACR.
EZH2 Protein Expression Associates with the Early Pathogenesis, Tumor Progression, and Prognosis of Non–Small Cell Lung Carcinoma
Authors: Behrens Carmen , Solis Luisa M. , Lin Heather , Yuan Ping , Tang Ximing , Kadara Humam , Riquelme Erick , Galindo Hector , Moran Cesar A. , Kalhor Neda , Swisher Stephen G. , Simon George R. , Stewart David J. , Lee J. Jack , Wistuba Ignacio I.
Published: October 2013

Purpose: Enhancer of zeste homolog 2 (EZH2) promotes carcinogenesis by epigenetically silencing tumor suppressor genes. We studied EZH2 expression by immunohistochemistry in a large series of non–small cell lung carcinomas (NSCLC) in association with tumor characteristics and patient outcomes.

Experimental Design: EZH2 immunohistochemistry expression was analyzed in 265 normal and premalignant bronchial epithelia, 541 primary NSCLCs [221 squamous cell carcinomas (SCC) and 320 adenocarcinomas] and 36 NSCLCs with paired brain metastases. An independent set of 91 adenocarcinomas was also examined. EZH2 expression was statistically correlated with clinico-pathological information, and EGFR/KRAS mutation status.

Results: EZH2 expression was significantly (P < 0.0001) higher in SCCs compared with adenocarcinomas and in brain metastasis relative to matched primary tumors (P = 0.0013). EZH2 expression was significantly (P < 0.0001) elevated in bronchial preneoplastic lesions with increasing severity. In adenocarcinomas, higher EZH2 expression significantly correlated with younger age, cigarette smoking, and higher TNM stage (P = 0.02 to P < 0.0001). Higher EZH2 expression in adenocarcinoma was associated with worse recurrence-free survival (RFS; P = 0.025; HR = 1.54) and overall survival (OS; P = 0.0002; HR = 1.96). Furthermore, lung adenocarcinomas with low EZH2 levels and high expression of the lineage-specific transcription factor, TTF-1, exhibited significantly improved RFS (P = 0.009; HR = 0.51) and OS (P = 0.0011; HR = 0.45), which was confirmed in the independent set of 91 adenocarcinomas.

Conclusion: In lung, EZH2 expression is involved in early pathogenesis of SCC and correlates with a more aggressive tumor behavior of adenocarcinoma. When EZH2 and TTF-1 expressions are considered together, they serve as a prognostic marker in patients with surgically resected lung adenocarcinomas. Clin Cancer Res; 19(23); 6556–65. ©2013 AACR.
Effects of Adjuvant Chemoradiotherapy on the Frequency and Function of Regulatory T Cells in Patients with Head and Neck Cancer
Authors: Schuler Patrick J. , Harasymczuk Malgorzata , Schilling Bastian , Saze Zenichiro , Strauss Laura , Lang Stephan , Johnson Jonas T. , Whiteside Theresa L.
Published: October 2013

Purpose: Regulatory T cells (Treg) accumulate in tumor tissues and the peripheral blood of cancer patients and may persist after therapies. This cross-sectional study examines effects of adjuvant chemoradiotherapy (CRT) on Treg numbers and function in head and neck squamous cell carcinoma (HNSCC) patients.

Experimental Design: The frequency and absolute numbers of CD4+, ATP-hydrolyzing CD4+CD39+ and CD8+ T cells, and expression levels of CD39, CD25, TGF-β–associated LAP and GARP on Treg were measured by flow cytometry in 40 healthy donors (NC) and 71 HNSCC patients [29 untreated with active disease (AD); 22 treated with surgery; 20 treated with CRT]. All treated subjects had no evident disease (NED) at the time of phlebotomy. In an additional cohort of 40 subjects with AD (n = 15), NED (n = 10), and NC (n = 15), in vitro sensitivity of CD4+ T-cell subsets to cisplatin and activation-induced cell death (AICD) was tested in Annexin V–binding assays.

Results: CRT decreased the frequency of circulating CD4+ T cells (P < 0.002) but increased that of CD4+CD39+ Treg (P ≤ 0.001) compared with untreated or surgery-only patients. Treg frequency remained elevated for >3 years. CRT increased surface expression of LAP, GARP, and CD39 on Treg. In vitro Treg were resistant to AICD or cisplatin but conventional CD4+ T cells (Tconv) were not. CRT-induced Treg from AD or NC subjects upregulated prosurvival proteins whereas Tconv upregulated proapoptotic Bax.

Conclusions: Highly suppressive, cisplatin-resistant Treg increase in frequency and persist after CRT and could be responsible for suppression of antitumor immune responses and recurrence in HNSCC. Clin Cancer Res; 19(23); 6585–96. ©2013 AACR.
Interleukin-7 Mediates Selective Expansion of Tumor-redirected Cytotoxic T Lymphocytes (CTLs) without Enhancement of Regulatory T-cell Inhibition
Authors: Perna Serena K. , Pagliara Daria , Mahendravada Aruna , Liu Hao , Brenner Malcolm K. , Savoldo Barbara , Dotti Gianpietro
Published: October 2013

Purpose: The antitumor activity of chimeric antigen receptor (CAR)–redirected CTLs should be enhanced if it were possible to increase their proliferation and function after adoptive transfer without concomitantly increasing the proliferation and function of regulatory T cells (Treg). Here, we explored whether the lack of IL-7Rα in Treg can be exploited by the targeted manipulation of the interleukin-7 (IL-7) cytokine–cytokine receptor axis in CAR-engrafted Epstein–Barr Virus–specific CTLs (EBV-CTLs) to selectively augment their growth and antitumor activity even in the presence of Treg.

Experimental Design: We generated a bicistronic retroviral vector encoding a GD2-specific CAR and the IL-7Rα subunit, expressed the genes in EBV-CTLs, and assessed their capacity to control tumor growth in the presence of Treg in vitro and in vivo when exposed to either interleukin-2 (IL-2) or IL-7 in a neuroblastoma xenograft.

Results: We found that IL-7, in sharp contrast with IL-2, supports the proliferation and antitumor activity of IL-7Rα.CAR-GD2+ EBV-CTLs both in vitro and in vivo even in the presence of fully functional Treg.

Conclusions: IL-7 selectively favors the survival, proliferation, and effector function of IL-7Rα-transgenic/CAR-redirected EBV-CTLs in the presence of Treg both in vitro and in vivo. Thus, IL-7 can have a significant impact in sustaining expansion and persistence of adoptively CAR-redirected CTLs. Clin Cancer Res; 20(1); 131–9. ©2013 AACR.
A Phase I Trial of Imetelstat in Children with Refractory or Recurrent Solid Tumors: A Children's Oncology Group Phase I Consortium Study (ADVL1112)
Authors: Thompson Patrick A. , Drissi Rachid , Muscal Jodi A. , Panditharatna Eshini , Fouladi Maryam , Ingle Ashish M. , Ahern Charlotte H. , Reid Joel M. , Lin Tong , Weigel Brenda J. , Blaney Susan M.
Published: October 2013

Purpose: Imetelstat is a covalently-lipidated 13-mer thiophosphoramidate oligonucleotide that acts as a potent specific inhibitor of telomerase. It binds with high affinity to the template region of the RNA component of human telomerase (hTERC) and is a competitive inhibitor of telomerase enzymatic activity. The purpose of this study was to determine the recommended phase II dose of imetelstat in children with recurrent or refractory solid tumors.

Experimental Design: Imetelstat was administered intravenously more than two hours on days 1 and 8, every 21 days. Dose levels of 225, 285, and 360 mg/m2 were evaluated, using the rolling-six design. Imetelstat pharmacokinetic and correlative biology studies were also performed during the first cycle.

Results: Twenty subjects were enrolled (median age, 14 years; range, 3–21). Seventeen were evaluable for toxicity. The most common toxicities were neutropenia, thrombocytopenia, and lymphopenia, with dose-limiting myelosuppression in 2 of 6 patients at 360 mg/m2. Pharmacokinetics is dose dependent with a lower clearance at the highest dose level. Telomerase inhibition was observed in peripheral blood mononuclear cells at 285 and 360 mg/m2. Two confirmed partial responses, osteosarcoma (n = 1) and Ewing sarcoma (n = 1), were observed.

Conclusions: The recommended phase II dose of imetelstat given on days 1 and 8 of a 21-day cycle is 285 mg/m2. Clin Cancer Res; 19(23); 6578–84. ©2013 AACR.
Loss of NAPRT1 Expression by Tumor-Specific Promoter Methylation Provides a Novel Predictive Biomarker for NAMPT Inhibitors
Authors: Shames David S. , Elkins Kristi , Walter Kimberly , Holcomb Thomas , Du Pan , Mohl Dane , Xiao Yang , Pham Thinh , Haverty Peter M. , Liederer Bianca , Liang Xiaorong , Yauch Robert L. , O'Brien Thomas , Bourgon Richard , Koeppen Hartmut , Belmont Lisa D.
Published: October 2013

Purpose: We sought to identify predictive biomarkers for a novel nicotinamide phosphoribosyltransferase (NAMPT) inhibitor.

Experimental Design: We use a NAMPT inhibitor, GNE-617, to evaluate nicotinic acid rescue status in a panel of more than 400 cancer cell lines. Using correlative analysis and RNA interference (RNAi), we identify a specific biomarker for nicotinic acid rescue status. We next determine the mechanism of regulation of expression of the biomarker. Finally, we develop immunohistochemical (IHC) and DNA methylation assays and evaluate cancer tissue for prevalence of the biomarker across indications.

Results: Nicotinate phosphoribosyltransferase (NAPRT1) is necessary for nicotinic acid rescue and its expression is the major determinant of rescue status. We demonstrate that NAPRT1 promoter methylation accounts for NAPRT1 deficiency in cancer cells, and NAPRT1 methylation is predictive of rescue status in cancer cell lines. Bisulfite next-generation sequencing mapping of the NAPRT1 promoter identified tumor-specific sites of NAPRT1 DNA methylation and enabled the development of a quantitative methylation-specific PCR (QMSP) assay suitable for use on archival formalin-fixed paraffin-embedded tumor tissue.

Conclusions: Tumor-specific promoter hypermethylation of NAPRT1 inactivates one of two NAD salvage pathways, resulting in synthetic lethality with the coadministration of a NAMPT inhibitor. NAPRT1 expression is lost due to promoter hypermethylation in most cancer types evaluated at frequencies ranging from 5% to 65%. NAPRT1-specific immunohistochemical or DNA methylation assays can be used on archival formalin paraffin-embedded cancer tissue to identify patients likely to benefit from coadministration of a Nampt inhibitor and nicotinic acid. Clin Cancer Res; 19(24); 6912–23. ©2013 AACR.
A Phase 1, Dose-Escalation, Pharmacokinetic and Pharmacodynamic Study of BIIB021 Administered Orally in Patients with Advanced Solid Tumors
Authors: Saif Muhammad Wasif , Takimoto Chris , Mita Monica , Banerji Udai , Lamanna Nicole , Castro Januario , O'Brien Susan , Stogard Christopher , Von Hoff Daniel
Published: October 2013

Purpose: BIIB021 is the first oral, synthetic, non-geldanamycin–based HSP90 inhibitor that showed activity in preclinical models at low nanomolar concentrations. We performed a phase 1 trial of BIIB021 administered to subjects with advanced solid tumors.

Experimental Design: Sixty patients received BIIB021 capsules orally on days 1, 4, 8, 11, 15, and 18 of each course in schedule 1, and on days 1, 4, 8, 11, 15, 18, 22, and 25 of each course in schedule 2. The treatment schedules were repeated every 28 days. In addition to determining the MTD, we evaluated pharmacokinetics of BIIB021 and pharmacodynamic effects of BIIB021 [Hsp70, HER2 extracellular domain (HER2-ECD)].

Results: The MTD was 700 mg twice weekly when BIIB021 was dosed for 3 weeks out of each 4-week course. The MTD for continuous dosing regimen was established at 600 mg twice weekly. Gastrointestinal (nausea, vomiting), hot flashes, and neurologic (dizziness) events characterize the safety profile of BIIB021 dosed twice weekly, with events mostly mild or moderate. Plasma exposure to BIIB021 was dose-dependent. Cmax occurred at approximately 90 minutes and t1/2 was approximately 1 hour across dosing cohorts of 25 to 800 mg BIIB021 twice weekly. The biologic activity of BIIB021 was demonstrated in serum, PBMCs, and tumor tissue. Hsp70 levels were increased (>150% from baseline) and serum HER2-ECD was significantly decreased (>15% inhibition from baseline).

Conclusions: BIIB021 twice weekly, given with or without the 1 of 4-week rest period was tolerated in subjects with advanced solid tumors at doses that are pharmacodynamically active. Clin Cancer Res; 20(2); 445–55. ©2013 AACR.
Pulmonary Vein Isolation Using a Pace-Capture–Guided Versus an Adenosine-Guided Approach
Authors: Andrade Jason G. , Pollak Scott J. , Monir George , Khairy Paul , Dubuc Marc , Roy Denis , Talajic Mario , Deyell Marc , Rivard Léna , Thibault Bernard , Guerra Peter G. , Nattel Stanley , Macle Laurent
Published: October 2013

Background—

Atrial fibrillation recurrence after pulmonary vein (PV) isolation is associated with PV to left atrium reconduction. We prospectively studied the use of 2 procedural techniques designed to facilitate identification of residual gaps within the index ablation line.

Methods and Results—

After wide circumferential PV isolation, 40 patients received additional ablation targeted at locations of left atrial capture during high-output pacing (pace-capture group), while 40 patients underwent adenosine testing with targeted ablation at sites of dormant conduction (adenosine group). Patients were followed up at 3, 6, and 12 months. After PV isolation, high-output pace-capture was documented in 39 PVs (25%; 50% of patients) in the pace-capture group. Dormant conduction was unmasked in 34 PVs (22%; 53% of patients) in the adenosine group. A subset of 25 patients in the pace-capture group underwent adenosine testing without targeted ablation of dormant conduction. In these patients, only 10 out of 86 PVs (11.6%; 24% of patients) demonstrated dormant conduction after the elimination of local pace-capture. At a follow-up of 329±124 days, the single procedure off antiarrhythmic drug freedom from recurrent atrial fibrillation was 67.5% in the adenosine group and 65.0% in the pace-capture group (
P
=0.814). Procedure duration and fluoroscopy time were significantly longer in the pace-capture group (
P
=0.002 and
P
<0.001), whereas radiofrequency ablation time was comparable (
P
=0.192).

Conclusions—

The use of high-output pacing post-PV isolation results in a significant reduction in the incidence of dormant conduction with a comparable long-term freedom from recurrent atrial fibrillation (versus adenosine-guided ablation). The use of these approaches requires evaluation in a long-term prospective randomized study.
Impact of Net Atrioventricular Compliance on Clinical Outcome in Mitral Stenosis
Authors: Nunes Maria Carmo P. , Hung Judy , Barbosa Marcia M. , Esteves William A. , Carvalho Vinicius T. , Lodi-Junqueira Lucas , Fonseca Neto Cirilo P. , Tan Timothy C. , Levine Robert A.
Published: October 2013

Background—

Net atrioventricular compliance (C
n
) has been reported to be an important determinant of pulmonary hypertension in mitral stenosis (MS). We hypothesized that it may be useful in assessing prognosis because C
n
reflects hemodynamic consequences of MS. To date, limited data with an assumed C
n
cutoff have indicated the need for larger prospective studies. This prospective study was designed to determine the impact of C
n
on clinical outcome and its contribution to pulmonary pressure in MS. In addition, we aimed to identify a cutoff value of C
n
for outcome prediction in this setting.

Methods and Results—

A total of 128 patients with rheumatic MS without other significant valve disease were prospectively enrolled. Comprehensive echocardiography was performed and Doppler-derived C
n
estimated using a previously validated equation. The end point was either mitral valve intervention or death. C
n
was an important predictor of pulmonary pressure, regardless of classic measures of MS severity. During a median follow-up of 22 months, the end point was reached in 45 patients (35%). Baseline C
n
predicted outcome, adding prognostic information beyond that provided by mitral valve area and functional status. C
n
≤4 mL/mm Hg best predicted unfavorable outcome in derivation and validation sets. A subgroup analysis including only initially asymptomatic patients with moderate to severe MS without initial indication for intervention (40.6% of total) demonstrated that baseline C
n
predicted subsequent adverse outcome even after adjustment for classic measures of hemodynamic MS severity (hazard ratio, 0.33; 95% confidence interval, 0.14–0.79;
P
=0.013).

Conclusions—

C
n
contributes to pulmonary hypertension beyond stenosis severity itself. In a wide spectrum of MS severity, C
n
is a powerful predictor of adverse outcome, adding prognostic value to clinical data and mitral valve area. Importantly, baseline C
n
predicts a progressive course with subsequent need for intervention in initially asymptomatic patients. C
n
assessment therefore has potential value for clinical risk stratification and monitoring in MS patients.
Multicenter Study Comparing Shunt Type in the Norwood Procedure for Single-Ventricle Lesions
Authors: Marx Gerald R. , Shirali Girish , Levine Jami C. , Guey Lin T. , Cnota James F. , Baffa Jeanne M. , Border William L. , Colan Steve , Ensing Gregory , Friedberg Mark K. , Goldberg David J. , Idriss Salim F. , John J. Blaine , Lai Wyman W. , Lu Minmin , Menon Shaji C. , Ohye Richard G. , Saudek David , Wong Pierre C. , Pearson Gail D.
Published: October 2013

Background—

The Pediatric Heart Network’s Single Ventricle Reconstruction (SVR) trial randomized infants with single right ventricles (RVs) undergoing a Norwood procedure to a modified Blalock-Taussig or RV-to-pulmonary artery shunt. This report compares RV parameters in the 2 groups using 3-dimensional echocardiography.

Methods and Results—

Three-dimensional echocardiography studies were obtained at 10 of 15 SVR centers. Of the 549 subjects, 314 underwent 3-dimensional echocardiography studies at 1 to 4 time points (pre-Norwood, post-Norwood, pre–stage II, and 14 months) for a total of 757 3-dimensional echocardiography studies. Of these, 565 (75%) were acceptable for analysis. RV volume, mass, mass:volume ratio, ejection fraction, and severity of tricuspid regurgitation did not differ by shunt type. RV volumes and mass did not change after the Norwood, but increased from pre-Norwood to pre–stage II (end-diastolic volume [milliliters]/body surface area [BSA]
1.3
, end-systolic volume [milliliters]/BSA
1.3
, and mass [grams]/BSA
1.3
mean difference [95% confidence interval]=25.0 [8.7–41.3], 19.3 [8.3–30.4], and 17.9 [7.3–28.5], then decreased by 14 months (end-diastolic volume/BSA
1.3
, end-systolic volume/BSA
1.3
, and mass/BSA
1.3
mean difference [95% confidence interval]=−24.4 [−35.0 to −13.7], −9.8 [−17.9 to −1.7], and −15.3 [−22.0 to −8.6]. Ejection fraction decreased from pre-Norwood to pre–stage II (mean difference [95% confidence interval]=−3.7 [−6.9 to −0.5]), but did not decrease further by 14 months.

Conclusions—

We found no statistically significant differences between study groups in 3-dimensional echocardiography measures of RV size and function, or magnitude of tricuspid regurgitation. Volume unloading was seen after stage II, as expected, but ejection fraction did not improve. This study provides insights into the remodeling of the operated univentricular RV in infancy.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00115934.
Magnetic Resonance Imaging Investigation of Macrophages in Acute Cardiac Allograft Rejection After Heart Transplantation
Authors: Wu Yijen L. , Ye Qing , Eytan Danielle F. , Liu Li , Rosario Bedda L. , Hitchens T. Kevin , Yeh Fang-Cheng , Rooijen van Nico , Ho Chien
Published: October 2013

Background—

Current immunosuppressive therapy after heart transplantation either generally suppresses the recipient’s entire immune system or is mainly targeting T-lymphocytes. Monocytes/macrophages are recognized as a hallmark of acute allograft rejection, but the roles that they play are not well characterized in vivo, because the tools for accessing in situ macrophage infiltration are lacking. In this study, we used MRI to investigate the role of macrophages in acute heart allograft rejection by cellular and functional MRI with selectively depleted systemic macrophages without affecting other leukocyte population, as well as to explore the possibility that macrophages could be an alternative therapeutic target.

Methods and Results—

A rodent heterotopic working heart–lung transplantation model was used for studying acute allograft rejection. Systemic macrophages were selectively depleted by treating recipient animals with clodronate-liposomes. Macrophage infiltration in the graft hearts was monitored by cellular MRI with in vivo ultrasmall superparamagnetic iron oxide particles labeling. Graft heart function was evaluated by tagging MRI followed by strain analysis. Clodronate-liposome treatment depletes circulating monocytes/macrophages in transplant recipients, and both cellular MRI and pathological examinations indicate a significant reduction in macrophage accumulation in the rejecting allograft hearts. In clodronate-liposome–treated group, allograft hearts exhibited preserved tissue integrity, partially reversed functional deterioration, and prolonged graft survival, compared with untreated controls.

Conclusions—

Cardiac cellular and functional MRI is a powerful tool to explore the roles of targeted immune cells in vivo. Our results indicate that macrophages are essential in acute cardiac allograft rejection, and selective depletion of macrophages with clodronate-liposomes protects hearts against allograft rejection, suggesting a potential therapeutic avenue. Our findings show that there is a finite risk of forming an intraventricular mass, presumably from the cellular debris or lipid material. Further optimization of the dosing protocol is necessary before clinical applications.
Optimal Duration of Dual Antiplatelet Therapy After Drug-Eluting Stent Implantation
Authors: Lee Cheol Whan , Ahn Jung-Min , Park Duk-Woo , Kang Soo-Jin , Lee Seung-Whan , Kim Young-Hak , Park Seong-Wook , Han Seungbong , Lee Sang-Gon , Seong In-Whan , Rha Seung-Woon , Jeong Myung-Ho , Lim Do-Sun , Yoon Jung-Han , Hur Seung-Ho , Choi Yun-Seok , Yang Joo-Young , Lee Nae-Hee , Kim Hyun-Sook , Lee Bong-Ki , Kim Kee-Sik , Lee Seung-Uk , Chae Jei-Keon , Cheong Sang-Sig , Suh Il-woo , Park Hun-Sik , Nah Deuk-Young , Jeon Doo-Soo , Seung Ki-Bae , Lee Keun , Jang Jae-Sik , Park Seung-Jung
Published: October 2013

Background—

The risks and benefits of long-term dual antiplatelet therapy remain unclear.

Methods and Results—

This prospective, multicenter, open-label, randomized comparison trial was conducted in 24 clinical centers in Korea. In total, 5045 patients who received drug-eluting stents and were free of major adverse cardiovascular events and major bleeding for at least 12 months after stent placement were enrolled between July 2007 and July 2011. Patients were randomized to receive aspirin alone (n=2514) or clopidogrel plus aspirin (n=2531). The primary end point was a composite of death resulting from cardiac causes, myocardial infarction, or stroke 24 months after randomization. At 24 months, the primary end point occurred in 57 aspirin-alone group patients (2.4%) and 61 dual-therapy group patients (2.6%; hazard ratio, 0.94; 95% confidence interval, 0.66–1.35;
P
=0.75). The 2 groups did not differ significantly in terms of the individual risks of death resulting from any cause, myocardial infarction, stent thrombosis, or stroke. Major bleeding occurred in 24 (1.1%) and 34 (1.4%) of the aspirin-alone group and dual-therapy group patients, respectively (hazard ratio, 0.71; 95% confidence interval, 0.42–1.20;
P
=0.20).

Conclusions—

Among patients who were on 12-month dual antiplatelet therapy without complications, an additional 24 months of dual antiplatelet therapy versus aspirin alone did not reduce the risk of the composite end point of death from cardiac causes, myocardial infarction, or stroke.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01186146.
Combined
18
F-FDG PET-CT and DCE-MRI to Assess Inflammation and Microvascularization in Atherosclerotic Plaques
Authors: Truijman Martine T.B. , Kwee Robert M. , van Hoof Raf H.M. , Hermeling Evelien , van Oostenbrugge Robert J. , Mess Werner H. , Backes Walter H. , Daemen Mat J. , Bucerius Jan , Wildberger Joachim E. , Kooi Marianne Eline
Published: October 2013

Background and Purpose—

Hallmarks of vulnerable atherosclerotic plaques are inflammation that can be assessed with
18
fluorine-fluorodeoxyglucose positron emission tomography/computed tomography, and increased neovascularization that can be evaluated by dynamic contrast–enhanced-MRI. It remains unclear whether these parameters are correlated or represent independent imaging parameters. This study determines whether there is a correlation between inflammation and neovascularization in atherosclerotic carotid plaques.

Methods—

A total of 58 patients with transient ischemic attack or minor stroke in the carotid territory and ipsilateral carotid artery stenosis of 30% to 69% were included. All patients underwent positron emission tomography/computed tomography and dynamic contrast–enhanced-MRI of the carotid plaque.
18
Fluorine-fluorodeoxyglucose standard uptake values with target/background ratio were determined. Neovascularization was quantified by the mean (leakage) volume transfer constant
K
trans
. Spearman rank correlation coefficients between target/background ratio and
K
trans
were calculated.

Results—

Images suitable for further analysis were obtained in 49 patients. A weak but significant positive correlation between target/background ratio and mean
K
trans
(Spearman ρ=0.30 [
P
=0.035]) and 75th percentile
K
trans
(Spearman ρ=0.29 [
P
=0.041]) was found.

Conclusions—

There is a weak but significant positive correlation between inflammation on positron emission tomography/computed tomography and neovascularization as assessed with dynamic contrast–enhanced-MRI. Future studies should investigate which imaging modality has the highest predictive value for recurrent stroke, as these are not interchangeable.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00451529.
A new cyst nematode, Cactodera torreyanae sp. n. (Tylenchida: Heteroderidae), parasitising romerito, Suaeda torreyana, in Texcoco, Mexico
Authors: Cid Del Prado Vera Ignacio , Subbotin Sergei A.
Published: October 2013

A new species of cyst nematode, Cactodera torreyanae sp. n., parasitising romerito plants, Suaeda torreyana (Chenopodiaceae), found in highly saline soils in Texcoco, Mexico, is described. The new species is morphologically and molecularly related to C. weissi, from which it differs in smaller fenestral diam., longer body and shorter tail lengths of second-stage juveniles (J2) and to C. rosae, from which it differs in smaller cyst size, longer body length of J2 and the presence of a smooth eggshell surface. Phylogenetic relationships within populations and species of the Punctoderinae and Cactodera are given based on the analysis of the D2-D3 expansion segments of 28S rRNA and the ITS rRNA gene sequences.
Primulina qingyuanensis (Gesneriaceae), a new species from limestone areas in Guangdong, China
Authors: NING Zu-Lin , WANG JING , SMITH JAMES F. , KANG MING
Published: October 2013

A new species, Primulina qingyuanensis from Guangdong, China, is described and illustrated. It is similar to P. bicolor (W.T. Wang) Mich. Möller & A. Weber, but differs from P. bicolor by several morphological characters, both vegetative and reproductive.
A new species of the genus Basidissus (Coleoptera: Anthribidae) from east Madagascar, with a key to species
Authors: TRÝZNA MILOŠ , BAŇAŘ PETR
Published: October 2013

A new species, Basidissus bendai Trýzna & Baňař sp. nov. (Anthribidae: Anthribinae: Platyrhinini), from east Madagascar is described, female genitalia are studied and illustrated, and the mobility of the stylus of the toothed plate is discussed. Colour photographs as well as a key to Madagascan species of the genus Basidissus are provided.
Maintaining Hierarchies in Predominantly White Organizations
Authors: Wingfield Adia Harvey , Alston Renée Skeete
Published: October 2013

Predominantly White workplaces are environments in which Whiteness is privileged in numerous ways. Studies show workers of color doing self-presentation, emotion work, and other forms of social interaction intended to help ease the difficulties associated with being in the minority. In addition to the expectation that they smooth interactions with White peers, workers of color are assigned positions and tasks which reinforce that racial status quo. In this theoretical article, we attempt to place these various processes under an umbrella term we define as “racial tasks.” We examine the ideological, interactional, and physical labor racial minorities perform in mostly White work settings, and the ways these racial tasks vary at different levels of the organizational structure. We consider the ways that the tactics and requirements associated with racial tasks maintain the racial hierarchy of predominantly White organizations and conclude by examining the implications of this work for racial minorities.
A review of pancreatic cyst fluid analysis in the differential diagnosis of pancreatic cyst lesions
Authors: Boot Christopher
Published: October 2013

Diagnosis and management of pancreatic cyst lesions is challenging as there is currently no investigation that offers both high diagnostic sensitivity and high specificity for the identification of potentially malignant lesions. Accurate classification of these lesions is vital in order to avoid unnecessary treatment of benign lesions and missed opportunities for early treatment of lesions that are malignant/pre-malignant. Pancreatic cyst fluid analysis has an important role in diagnosis, although all currently available investigations based on fluid analysis have significant limitations. Cytological analysis can reveal features that are specific for a certain class of cyst, but offers limited sensitivity in detecting malignant/pre-malignant cysts. Measurement of tumour markers, particularly carcinoembryonic antigen can also be informative. Concentrations of cyst fluid carcinoembryonic antigen tend to be higher in malignant/pre-malignant cysts, although there is a wide overlap between the various classes of cyst. A number of studies have suggested that diagnostic carcinoembryonic antigen cut-offs can be chosen that provide a high degree of specificity but limited sensitivity. Studies of the analytical validity of tumour marker assays in pancreatic cyst fluid analysis have highlighted discrepancies in some fluid specimens, which require further investigation. DNA analysis also has a role. In particular, K-Ras-2 mutational analysis appears to provide high specificity for detection of malignant/pre-malignant lesions. A number of diagnostic algorithms have been published, integrating use of available investigations in order to achieve the optimum discrimination of benign and potentially malignant cysts. Research into new biochemical markers and optimal use of available pancreatic cyst fluid analyses is ongoing.