bluuebunny/crossref_metadata_2025 huggingface dataset:
An Island Grouping Genetic Algorithm for Fuzzy Partitioning Problems
Authors: Salcedo-Sanz S. , Del Ser J. , Geem Z. W.
Published: May 2014

This paper presents a novel fuzzy clustering technique based on grouping genetic algorithms (GGAs), which are a class of evolutionary algorithms especially modified to tackle grouping problems. Our approach hinges on a GGA devised for fuzzy clustering by means of a novel encoding of individuals (containing elements and clusters sections), a new fitness function (a superior modification of the Davies Bouldin index), specially tailored crossover and mutation operators, and the use of a scheme based on a local search and a parallelization process, inspired from an island-based model of evolution. The overall performance of our approach has been assessed over a number of synthetic and real fuzzy clustering problems with different objective functions and distance measures, from which it is concluded that the proposed approach shows excellent performance in all cases.
Validation of Planning Target Volume Margins by Analyzing Intrafractional Localization Errors for 14 Prostate Cancer Patients Based on Three-Dimensional Cross-Correlation between the Prostate Images of Planning CT and Intrafraction Cone-Beam CT during Volumetric Modulated Arc Therapy
Authors: Shiraishi Kenshiro , Futaguchi Masahiko , Haga Akihiro , Sakumi Akira , Sasaki Katsutake , Yamamoto Kentaro , Igaki Hiroshi , Ohtomo Kuni , Yoda Kiyoshi , Nakagawa Keiichi
Published: May 2014

Time-averaged intreatment prostate localization errors were calculated, for the first time, by three-dimensional prostate image cross-correlation between planning CT and intrafraction kilovoltage cone-beam CT (CBCT) during volumetric modulated arc therapy (VMAT). The intrafraction CBCT volume was reconstructed by an inhouse software after acquiring cine-mode projection images during VMAT delivery. Subsequently, the margin between a clinical target volume and a planning target volume (PTV) was obtained by applying the van Herk and variant formulas using the calculated localization errors. The resulting PTV margins were approximately 2 mm in lateral direction and 4 mm in craniocaudal and anteroposterior directions, which are consistent with the margin prescription employed in our facility.
Recurrent Acute Nonrheumatic Streptococcal Myocarditis Mimicking STEMI in a Young Adult
Authors: Chikly Amanda , Durst Ronen , Lotan Chaim , Chen Shmuel
Published: May 2014

Myocarditis consists of an inflammation of the cardiac muscle, definitively diagnosed by endomyocardial biopsy. The causal agents are primarily infectious: in developed countries, viruses appear to be the main cause, whereas in developing countries rheumatic carditis, Chagas disease, and HIV are frequent causes. Furthermore, myocarditis can be indirectly induced by an infectious agent and occurs following a latency period during which antibodies are created. Typically, myocarditis observed in rheumatic fever related to group A streptococcal (GAS) infection occurs after 2- to 3-week period of latency. In other instances, myocarditis can occur within few days following a streptococcal infection; thus, it does not fit the criteria for rheumatic fever. Myocarditis classically presents as acute heart failure, and can also be manifested by tachyarrhythmia or chest pain. Likewise, GAS-related myocarditis reportedly mimics myocardial infarction (MI) with typical chest pain, electrocardiograph changes, and troponin elevation. Here we describe a case of recurrent myocarditis, 5 years apart, with clinical presentation imitating an acute MI in an otherwise healthy 37-year-old man. Both episodes occurred 3 days after GAS pharyngitis and resolved quickly following medical treatment.
Coupling Metallic Nanostructures to Thermally Responsive Polymers Allows the Development of Intelligent Responsive Membranes
Authors: Morones-Ramírez J. Rubén
Published: May 2014

Development of porous membranes capable of controlling flow or changing their permeability to specific chemical entities, in response to small changes in environmental stimuli, is an area of appealing research, since these membranes present a wide variety of applications. The synthesis of these membranes has been mainly approached through grafting of environmentally responsive polymers to the surface walls of polymeric porous membranes. This synergizes the chemical stability and mechanical strength of the polymer membrane with the fast response times of the bonded polymer chains. Therefore, different composite membranes capable of changing their effective pore size with environmental triggers have been developed. A recent interest has been the development of porous membranes responsive to light, since these can achieve rapid, remote, noninvasive, and localized flow control. This work describes the synthesis pathway to construct intelligent optothermally responsive membranes. The method followed involved the grafting of optothermally responsive polymer-metal nanoparticle nanocomposites to polycarbonate track-etched porous membranes (PCTEPMs). The nanoparticles coupled to the polymer grafts serve as the optothermal energy converters to achieve optical switching of the pores. The results of the paper show that grafting of the polymer andin situsynthesis of the metallic particles can be easily achieved. In addition, the composite membranes allow fast and reversible switching of the pores using both light and heat permitting control of fluid flow.
Iterative Learning Control Design and Application for Linear Continuous Systems with Variable Initial States Based on 2‐D System Theory
Authors: Guan Wei , Zhu Qiao , Wang Xu-Dong , Liu Xu-Hui
Published: May 2014

This paper is concerned with the variable initial states problem in iterative learning control (ILC) for linear continuous systems. Firstly, the properties of the trajectory of 2‐D continuous‐discrete Roesser model are analyzed by using Lyapunov′s method. Then, for any variable initial states which absolutely converge to the desired initial state, some ILC design criteria in the form of linear matrix inequalities (LMI) are given to ensure the convergence of the PD‐type ILC rules. The convergence for variable initial states implies that the ILC rules can be used to achieve the perfect tacking for variable initial states, even if the system dynamic is unknown. Finally, the micropropulsion system is considered to illustrate efficiency of the proposed ILC design criteria.
Effect of Linear Chain Carboxylic Acid Anhydrides on Physical and Mechanical Properties of Rubber (Hevea brasiliensis), Acacia, (Acacia spp.), and Oil Palm (Tinnera spp.) Woods
Authors: Mohtar Mohd Afiq , Hamid Norul Hisham , Sahri Mohd Hamami
Published: May 2014

The physical and mechanical properties of Rubber wood, Acacia wood, and Oil palm wood that reacted with acetic, propionic, and butyric anhydrides using a microwave heating for 4 minutes were investigated. A sample dimension of 300 mm × 100 mm × 25 mm (L×W×T) was used for modification and they were cut into smaller specimens for different testing method. This study found that the density increment and void volume changes were not significantly different from anhydrides. The modification of wood with anhydrides was not significantly affected by the static bending properties, except for the Oil palm. The compression strength for any anhydrides shows an improvement for the Rubber wood and Acacia spp. but not Oil palm. The hardness was also not significantly different from anhydrides for all wood species. The impact strength of Rubber wood and Oil palm significantly increased compared to the untreated wood, but this was not the case for Acacia spp. Generally, the highest improvement in mechanical properties was obtained by modification of Rubber and Acacia woods with butyric anhydride.
β-Catenin Activation in a Novel Liver Progenitor Cell Type Is Sufficient to Cause Hepatocellular Carcinoma and Hepatoblastoma
Authors: Mokkapati Sharada , Niopek Katharina , Huang Le , Cunniff Kegan J. , Ruteshouser E. Cristy , deCaestecker Mark , Finegold Milton J. , Huff Vicki
Published: May 2014

Hepatocellular carcinoma (HCC) was thought historically to arise from hepatocytes, but gene expression studies have suggested that it can also arise from fetal progenitor cells or their adult progenitor progeny. Here, we report the identification of a unique population of fetal liver progenitor cells in mice that can serve as a cell of origin in HCC development. In the transgenic model used, mice carry the Cited1-CreERTM-GFP BAC transgene in which a tamoxifen-inducible Cre (CreERTM) and GFP are controlled by a 190-kb 5′ genomic region of Cited1, a transcriptional coactivator protein for CBP/p300. Wnt signaling is critical for regulating self-renewal of progenitor/stem cells and has been implicated in the etiology of cancers of rapidly self-renewing tissues, so we hypothesized that Wnt pathway activation in CreERTM-GFP+ progenitors would result in HCC. In livers from the mouse model, transgene-expressing cells represented 4% of liver cells at E11.5 when other markers were expressed, characteristic of the hepatic stem/progenitor cells that give rise to adult hepatocytes, cholangiocytes, and SOX9+ periductal cells. By 26 weeks of age, more than 90% of Cited1-CreERTM-GFP;Ctnnb1ex3(fl) mice with Wnt pathway activation developed HCC and, in some cases, hepatoblastomas and lung metastases. HCC and hepatoblastomas resembled their human counterparts histologically, showing activation of Wnt, Ras/Raf/MAPK, and PI3K/AKT/mTOR pathways and expressing relevant stem/progenitor cell markers. Our results show that Wnt pathway activation is sufficient for malignant transformation of these unique liver progenitor cells, offering functional support for a fetal/adult progenitor origin of some human HCC. We believe this model may offer a valuable new tool to improve understanding of the cellular etiology and biology of HCC and hepatoblastomas and the development of improved therapeutics for these diseases. Cancer Res; 74(16); 4515–25. ©2014 AACR.
Analysis of Chemotherapeutic Response in Ovarian Cancers Using Publicly Available High-Throughput Data
Authors: Bosquet Jesus Gonzalez , Marchion Douglas C. , Chon HyeSook , Lancaster Johnathan M. , Chanock Stephen
Published: May 2014

A third of patients with epithelial ovarian cancer (OVCA) will not respond to standard treatment. The determination of a robust signature that predicts chemoresponse could lead to the identification of molecular markers for response as well as possible clinical implementation in the future to identify patients at risk of failing therapy. This pilot study was designed to identify biologic processes affecting candidate pathways associated with chemoresponse and to create a robust gene signature for follow-up studies. After identifying common pathways associated with chemoresponse in serous OVCA in three independent gene-expression experiments, we assessed the biologic processes associated with them using The Cancer Genome Atlas (TCGA) dataset for serous OVCA. We identified differential copy-number alterations (CNA), mutations, DNA methylation, and miRNA expression between patients that responded to standard treatment and those who did not or recurred prematurely. We correlated these significant parameters with gene expression to create a signature of 422 genes associated with chemoresponse. A consensus clustering of this signature identified two differentiated clusters with unique molecular patterns: cluster 1 was significant for cellular signaling and immune response (mainly cell-mediated); and cluster 2 was significant for pathways involving DNA-damage repair and replication, cell cycle, and apoptosis. Validation through consensus clustering was performed in five independent OVCA gene-expression experiments. Genes were located in the same cluster with consistent agreement in all five studies (κ coefficient ≥ 0.6 in 4). Integrating high-throughput biologic data have created a robust molecular signature that predicts chemoresponse in OVCA. Cancer Res; 74(14); 3902–12. ©2014 AACR.
Therapeutic Efficacy of an Fc-Enhanced TCR-like Antibody to the Intracellular WT1 Oncoprotein
Authors: Veomett Nicholas , Dao Tao , Liu Hong , Xiang Jingyi , Pankov Dmitry , Dubrovsky Leonid , Whitten Joseph A. , Park Sun-Mi , Korontsvit Tatyana , Zakhaleva Victoria , Casey Emily , Curcio Michael , Kharas Michael G. , O'Reilly Richard J. , Liu Cheng , Scheinberg David A.
Published: May 2014

Purpose: RMFPNAPYL (RMF), a Wilms' tumor gene 1 (WT1)–derived CD8 T-cell epitope presented by HLA-A*02:01, is a validated target for T-cell–based immunotherapy. We previously reported ESK1, a high avidity (Kd < 0.2 nmol/L), fully-human monoclonal antibody (mAb) specific for the WT1 RMF peptide/HLA-A*02:01 complex, which selectively bound and killed WT1+ and HLA-A*02:01+ leukemia and solid tumor cell lines.

Experimental Design: We engineered a second-generation mAb, ESKM, to have enhanced antibody-dependent cell-mediated cytotoxicity (ADCC) function due to altered Fc glycosylation. ESKM was compared with native ESK1 in binding assays, in vitro ADCC assays, and mesothelioma and leukemia therapeutic models and pharmacokinetic studies in mice. ESKM toxicity was assessed in HLA-A*02:01+ transgenic mice.

Results: ESK antibodies mediated ADCC against hematopoietic and solid tumor cells at concentrations below 1 μg/mL, but ESKM was about 5- to 10-fold more potent in vitro against multiple cancer cell lines. ESKM was more potent in vivo against JMN mesothelioma, and effective against SET2 AML and fresh ALL xenografts. ESKM had a shortened half-life (4.9 days vs. 6.5 days), but an identical biodistribution pattern in C57BL/6J mice. At therapeutic doses of ESKM, there was no difference in half-life or biodistribution in HLA-A*02:01+ transgenic mice compared with the parent strain. Importantly, therapeutic doses of ESKM in these mice caused no depletion of total WBCs or hematopoetic stem cells, or pathologic tissue damage.

Conclusions: The data provide proof of concept that an Fc-enhanced mAb can improve efficacy against a low-density, tumor-specific, peptide/MHC target, and support further development of this mAb against an important intracellular oncogenic protein. Clin Cancer Res; 20(15); 4036–46. ©2014 AACR.
Semi-Mechanistic Pharmacokinetic/Pharmacodynamic Modeling of the Antitumor Activity of LY2835219, a New Cyclin-Dependent Kinase 4/6 Inhibitor, in Mice Bearing Human Tumor Xenografts
Authors: Tate Sonya C. , Cai Shufen , Ajamie Rose T. , Burke Teresa , Beckmann Richard P. , Chan Edward M. , De Dios Alfonso , Wishart Graham N. , Gelbert Lawrence M. , Cronier Damien M.
Published: May 2014

Purpose: Selective inhibition of cyclin-dependent kinases 4 and 6 (CDK4/6) represents a promising therapeutic strategy. However, despite documented evidence of clinical activity, limited information is available on the optimal dosing strategy of CDK4/6 inhibitors. Here, we present an integrated semi-mechanistic pharmacokinetic/pharmacodynamic model to characterize the quantitative pharmacology of LY2835219, a CDK4/6 inhibitor, in xenograft tumors.

Experimental Design: LY2835219 plasma concentrations were connected to CDK4/6 inhibition and cell-cycle arrest in colo-205 human colorectal xenografts by incorporating the biomarkers, phospho-(ser780)-Rb, topoisomerase II α, and phosphohistone H3, into a precursor-dependent transit compartment model. This biomarker model was then connected to tumor growth inhibition (TGI) by: (i) relating the rate of tumor growth to mitotic cell density, and (ii) incorporating a concentration-dependent mixed cytostatic/cytotoxic effect driving quiescence and cell death at high doses. Model validation was evaluated by predicting LY2835219-mediated antitumor effect in A375 human melanoma xenografts.

Results: The model successfully described LY2835219-mediated CDK4/6 inhibition, cell-cycle arrest, and TGI in colo-205, and was validated in A375. The model also demonstrated that a chronic dosing strategy achieving minimum steady-state trough plasma concentrations of 200 ng/mL is required to maintain durable cell-cycle arrest. Quiescence and cell death can be induced by further increasing LY2835219 plasma concentrations.

Conclusions: Our model provides mechanistic insight into the quantitative pharmacology of LY2835219 and supports the therapeutic dose and chronic dosing strategy currently adopted in clinical studies. Clin Cancer Res; 20(14); 3763–74. ©2014 AACR.
A High-Affinity, High-Stability Photoacoustic Agent for Imaging Gastrin-Releasing Peptide Receptor in Prostate Cancer
Authors: Levi Jelena , Sathirachinda Ataya , Gambhir Sanjiv S.
Published: May 2014

Purpose: To evaluate the utility of targeted photoacoustic imaging (PAI) in providing molecular information to complement intrinsic functional and anatomical details of the vasculature within prostate lesion.

Experimental Design: We developed a PAI agent, AA3G-740, that targets gastrin-releasing peptide receptor (GRPR), found to be highly overexpressed in prostate cancer. The binding specificity of the agent was evaluated in human prostate cancer cell lines, PC3 and LNCaP, and antagonist properties determined by cell internalization and intracellular calcium mobilization studies. The imaging sensitivity was assessed for the agent itself and for the PC3 cells labeled with agent. The in vivo stability of the agent was determined in human plasma and in the blood of living mice. The in vivo binding of the agent was evaluated in PC3 prostate tumor models in mice, and was validated ex vivo by optical imaging.

Results: AA3G-740 demonstrated strong and specific binding to GRPR. The sensitivity of detection in vitro indicated suitability of the agent to image very small lesions. In mice, the agent was able to bind to GRPR even in poorly vascularized tumors leading to nearly 2-fold difference in photoacoustic signal relative to the control agent.

Conclusions: The ability to image both vasculature and molecular profile outside the blood vessels gives molecular PAI a unique advantage over currently used imaging techniques. The imaging method presented here can find application both in diagnosis and in image-guided biopsy. Clin Cancer Res; 20(14); 3721–9. ©2014 AACR.
Real-Time Immune Monitoring to Guide Plasmid DNA Vaccination Schedule Targeting Prostatic Acid Phosphatase in Patients with Castration-Resistant Prostate Cancer
Authors: McNeel Douglas G. , Becker Jordan T. , Eickhoff Jens C. , Johnson Laura E. , Bradley Eric , Pohlkamp Isabel , Staab Mary Jane , Liu Glenn , Wilding George , Olson Brian M.
Published: May 2014

Purpose: We have previously reported that a DNA vaccine encoding prostatic acid phosphatase (PAP) could elicit PAP-specific T cells in patients with early recurrent prostate cancer. In the current pilot trial, we sought to evaluate whether prolonged immunization with regular booster immunizations, or “personalized” schedules of immunization determined using real-time immune monitoring, could elicit persistent, antigen-specific T cells, and whether treatment was associated with changes in PSA doubling time (PSA DT).

Experimental Design: Sixteen patients with castration-resistant, nonmetastatic prostate cancer received six immunizations at 2-week intervals and then either quarterly (arm 1) or as determined by multiparameter immune monitoring (arm 2).

Results: Patients were on study a median of 16 months; four received 24 vaccinations. Only one event associated with treatment >grade 2 was observed. Six of 16 (38%) remained metastasis-free at 2 years. PAP-specific T cells were elicited in 12 of 16 (75%), predominantly of a Th1 phenotype, which persisted in frequency and phenotype for at least 1 year. IFNγ-secreting T-cell responses measured by ELISPOT were detectable in 5 of 13 individuals at 1 year, and this was not statistically different between study arms. The overall median fold change in PSA DT from pretreatment to posttreatment was 1.6 (range, 0.6–7.0; P = 0.036).

Conclusions: Repetitive immunization with a plasmid DNA vaccine was safe and elicited Th1-biased antigen-specific T cells that persisted over time. Modifications in the immunization schedule based on real-time immune monitoring did not increase the frequency of patients developing effector and memory T-cell responses with this DNA vaccine. Clin Cancer Res; 20(14); 3692–704. ©2014 AACR.
Ectopic Expression of Cancer–Testis Antigens in Cutaneous T-cell Lymphoma Patients
Authors: Litvinov Ivan V. , Cordeiro Brendan , Huang Yuanshen , Zargham Hanieh , Pehr Kevin , Doré Marc-André , Gilbert Martin , Zhou Youwen , Kupper Thomas S. , Sasseville Denis
Published: May 2014

Purpose: The pathogenesis of cutaneous T-cell lymphoma (CTCL) remains only partially understood. A number of recent studies attempted to identify novel diagnostic markers and future therapeutic targets. One group of antigens, cancer–testis (CT) antigens, normally present solely in testicular germ cells, can be ectopically expressed in a variety of cancers. Currently, only a few studies attempted to investigate the expression of CT antigens in CTCL.

Experimental Design: In the present work, we test the expression of CT genes in a cohort of patients with CTCL, normal skin samples, skin from benign inflammatory dermatoses, and in patient-derived CTCL cells. We correlate such expression with the p53 status and explore molecular mechanisms behind their ectopic expression in these cells.

Results: Our findings demonstrate that SYCP1, SYCP3, REC8, SPO11, and GTSF1 genes are heterogeneously expressed in patients with CTCL and patient-derived cell lines, whereas cTAGE1 (cutaneous T-cell lymphoma-associated antigen 1) was found to be robustly expressed in both. Mutated p53 status did not appear to be a requirement for the ectopic expression of CT antigens. While T-cell stimulation resulted in a significant upregulation of STAT3 and JUNB expression, it did not significantly alter the expression of CT antigens. Treatment of CTCL cells in vitro with vorinostat or romidepsin histone deacetylase inhibitors resulted in a significant dose-dependent upregulation of mRNA but not protein. Further expression analysis demonstrated that SYCP1, cTAGE1, and GTSF1 were expressed in CTCL, but not in normal skin or benign inflammatory dermatoses.

Conclusions: A number of CT genes are ectopically expressed in patients with CTCL and can be used as biomarkers or novel targets for immunotherapy. Clin Cancer Res; 20(14); 3799–808. ©2014 AACR.
Hypoxia Regulates Alternative Splicing of HIF and non-HIF Target Genes
Authors: Sena Johnny A. , Wang Liyi , Heasley Lynn E. , Hu Cheng-Jun
Published: May 2014

Hypoxia is a common characteristic of many solid tumors. The hypoxic microenvironment stabilizes hypoxia-inducible transcription factor 1α (HIF1α) and 2α (HIF2α/EPAS1) to activate gene transcription, which promotes tumor cell survival. The majority of human genes are alternatively spliced, producing RNA isoforms that code for functionally distinct proteins. Thus, an effective hypoxia response requires increased HIF target gene expression as well as proper RNA splicing of these HIF-dependent transcripts. However, it is unclear if and how hypoxia regulates RNA splicing of HIF targets. This study determined the effects of hypoxia on alternative splicing (AS) of HIF and non-HIF target genes in hepatocellular carcinoma cells and characterized the role of HIF in regulating AS of HIF-induced genes. The results indicate that hypoxia generally promotes exon inclusion for hypoxia-induced, but reduces exon inclusion for hypoxia-reduced genes. Mechanistically, HIF activity, but not hypoxia per se is found to be necessary and sufficient to increase exon inclusion of several HIF targets, including pyruvate dehydrogenase kinase 1 (PDK1). PDK1 splicing reporters confirm that transcriptional activation by HIF is sufficient to increase exon inclusion of PDK1 splicing reporter. In contrast, transcriptional activation of a PDK1 minigene by other transcription factors in the absence of endogenous HIF target gene activation fails to alter PDK1 RNA splicing.

Implications: This study demonstrates a novel function of HIF in regulating RNA splicing of HIF target genes. Mol Cancer Res; 12(9); 1233–43. ©2014 AACR.
MIF Antagonist (CPSI-1306) Protects against UVB-Induced Squamous Cell Carcinoma
Authors: Nagarajan Priyadharsini , Tober Kathleen L. , Riggenbach Judith A. , Kusewitt Donna F. , Lehman Amy M. , Sielecki Thais , Pruitt James , Satoskar Abhay R. , Oberyszyn Tatiana M.
Published: May 2014

Macrophage migration inhibitory factor (MIF) is a homotrimeric proinflammatory cytokine implicated in chronic inflammatory diseases and malignancies, including cutaneous squamous cell carcinomas (SCC). To determine whether MIF inhibition could reduce UVB light–induced inflammation and squamous carcinogenesis, a small-molecule MIF inhibitor (CPSI-1306) was utilized that disrupts homotrimerization. To examine the effect of CPSI-1306 on acute UVB-induced skin changes, Skh-1 hairless mice were systemically treated with CPSI-1306 for 5 days before UVB exposure. In addition to decreasing skin thickness and myeloperoxidase (MPO) activity, CPSI-1306 pretreatment increased keratinocyte apoptosis and p53 expression, decreased proliferation and phosphohistone variant H2AX (γ-H2AX), and enhanced repair of cyclobutane pyrimidine dimers. To examine the effect of CPSI-1306 on squamous carcinogenesis, mice were exposed to UVB for 10 weeks, followed by CPSI-1306 treatment for 8 weeks. CPSI-1306 dramatically decreased the density of UVB-associated p53 foci in non–tumor-bearing skin while simultaneously decreasing the epidermal Ki67 proliferation index. In addition to slowing the rate of tumor development, CPSI-1306 decreased the average tumor burden per mouse. Although CPSI-1306–treated mice developed only papillomas, nearly a third of papillomas in vehicle-treated mice progressed to microinvasive SCC. Thus, MIF inhibition is a promising strategy for prevention of the deleterious cutaneous effects of acute and chronic UVB exposure.

Implications: Macrophage migration inhibitory factor is a viable target for the prevention of UVB-induced cutaneous SSCs. Mol Cancer Res; 12(9); 1292–302. ©2014 AACR.
Discrimination between Intact and Decayed Pulp Regions in Carious Teeth by ADC Mapping
Authors: Cankar Ksenija , Nemeth Lidija , Bajd Franci , Vidmar Jernej , Serša Igor
Published: May 2014

The aim of this study was to evaluate an advanced magnetic resonance imaging (MRI) method, apparent diffusion coefficient (ADC) mapping, in the functional assessment of carious teeth. 38 extracted human teeth with scores of 0, 3 and 6 according to International Caries Detection and Assessment System (ICDAS) criteria were screened and subsequently analyzed by MRI at 2.35 T. Histology sectioning of teeth was used for the gold standard by analyzing two extreme cases (intact and severely decayed). ADC maps of the same teeth were calculated from corresponding diffusion-weighted images and used to obtain ADC distributions along dental pulp as functions of the relative pulp length measured from the occlusal pulp side. The measured distributions were analyzed for the best fit by a four-parameter three-segment linear regression model for ADC distribution along the pulp. MRI results were in good agreement with findings in histological sections of identical teeth. The best fit model parameters, relative decayed region depth, relative transition region width and ADC values of intact and decayed pulp tissue, showed statistically significant differences between the ADC values of intact and decayed pulp tissue (1.0 × 10-9 m2/s vs. 0.74-0.89 × 10-9 m2/s) and the relative decayed region depth progressing with ICDAS score (3 vs. 46% with ICDAS 3 vs. ICDAS 6). The results of this feasibility study confirmed relevance of ADC mapping for the discrimination and localization of intact and decayed regions in dental pulps of carious teeth.
Child Externalizing Behavior Problems Linked to Genetic and Non-Genetic Variation in Dental Caries
Authors: Lorber Michael F. , Smith Slep Amy M. , Heyman Richard E. , Bretz Walter A.
Published: May 2014

The association of environmental and genetic variation in caries with child externalizing behavior problems (inattention, hyperactivity, impulsivity, and defiance) was studied in a sample of 239 pairs of 3- to 8-year-old impoverished Brazilian twins. It was hypothesized that externalizing problems would show a stronger positive association with environmental than genetic variation in caries. Univariate twin models were estimated to parse variation in caries into three components: additive genetic (A), shared environment (C) and non-shared environment/error (E). Age-adjusted associations between externalizing problems and each variance component were tested. Contrary to the hypothesis, modest but very consistent negative associations were found between externalizing problems and both genetic and environmental variation in caries. Mutans streptococci and sweetness preference did not explain the negative associations of caries and externalizing problems. Externalizing problems in non-medicated children were associated with less dental decay that could be explained by both genetic and environmental factors.
Thrombolytic Effects in vivo of Nattokinase in a Carrageenan-Induced Rat Model of Thrombosis
Authors: Xu Jianping , Du Ming , Yang Xiulin , Chen Qingquan , Chen Hong , Lin Dong-Hong
Published: May 2014

Background/Aims: Nattokinase is a serine protease produced by Bacillus subtilis during the fermentation of the soybean product natto. The fibrinolytic activity and thrombolytic effects of nattokinase have been observed in vitro, but the effect in vivo has still to be researched. The objective of this study was to demonstrate the activity of nattokinase in vivo. Methods: To establish a rat model of thrombosis, κ-carrageenan was injected subcutaneously into the toes of Sprague-Dawley (SD) rats. Histological examination confirmed thrombosis. The rats were then treated with varying doses of nattokinase and the resulting thrombolysis was histologically assessed. ELISA was used to determine the levels of the fibrin/fibrinogen degradation products (FDPs) and D-dimer, which are sensitive indices of fibrinolytic activity. Vermis kinase, a known thrombolytic agent, was used as a positive control. Results: Biopsy results revealed partial thrombolysis in the tail vessels of the rats treated with nattokinase or vermis kinase. FDP and D-dimer levels were higher in rats treated with high-dose nattokinase than in those treated with saline. No difference in FDP or D-dimer levels was observed between rats treated with high-dose nattokinase and those treated with vermis kinase. Conclusions: Both the histological and physiological evidence from this study indicate that nattokinase exerts thrombolytic effects in vivo.
The Prognostic Significance of Inspiratory Capacity in Pulmonary Arterial Hypertension
Authors: Richter Manuel Jonas , Tiede Henning , Morty Rory E. , Voswinckel Robert , Seeger Werner , Schulz Richard , Ghofrani Hossein Ardeschir , Reichenberger Frank
Published: May 2014

Background: Patients with pulmonary arterial hypertension (PAH) present with an altered inspiratory capacity (IC) reflecting dynamic hyperinflation (DH) that leads to mechanical constraints and excessive ventilatory demand, particularly during exercise, resulting in exertional dyspnea. Objectives: Assessment of the long-term consequences of altered IC and DH in PAH. Methods: 50 patients with newly diagnosed PAH were prospectively recruited. All patients were assessed by means of right heart catheterization, 6-min walking distance (6MWD) test, lung function and cardiopulmonary exercise testing, including the assessment of IC. Results: 37 patients with idiopathic PAH and 13 patients with conditions associated with PAH (29 female; mean age 51.6 ± 15.1 years; World Health Organization, WHO class, 2.7 ± 0.6) presented with a mean pulmonary arterial pressure of 42.8 ± 15.9 mm Hg and pulmonary vascular resistance (PVR) of 737.2 ± 592.8 dyn*s/cm5. The mean IC at rest was 87.2 ± 17.3% pred. Kaplan-Meier analysis revealed that patients with an IC at rest >89% pred. had a significantly better 5-year survival than those with lower values (94.1 vs. 75.1%; log-rank p = 0.036). Univariate analysis identified IC at rest (% pred.) as a predictor of survival with a hazard ratio (HR) of 5.05 (95% confidence interval, CI, 0.97-26.24, p = 0.054). In multivariate analysis including PVR, WHO class, 6MWD and peak oxygen uptake as covariates, IC at rest remained an independent predictor of survival (HR: 8.06, 95% CI 0.92-70.34; p = 0.059). DH expressed as ΔIC or static hyperinflation expressed as IC/total lung capacity at rest revealed no prognostic significance. Conclusion: In patients with PAH, IC at rest is of prognostic significance at the time of diagnosis.
Mitochondrial Mechanisms in Cerebral Vascular Control: Shared Signaling Pathways with Preconditioning
Authors: Busija David W. , Katakam Prasad V.
Published: May 2014

Mitochondrial-initiated events protect the neurovascular unit against lethal stress via a process called preconditioning, which independently promotes changes in cerebrovascular tone through shared signaling pathways. Activation of adenosine triphosphate (ATP)-dependent potassium channels on the inner mitochondrial membrane (mitoKATP channels) is a specific and dependable way to induce protection of neurons, astroglia, and cerebral vascular endothelium. Through the opening of mitoKATP channels, mitochondrial depolarization leads to activation of protein kinases and transient increases in cytosolic calcium (Ca2+) levels that activate terminal mechanisms that protect the neurovascular unit against lethal stress. The release of reactive oxygen species from mitochondria has similar protective effects. Signaling elements of the preconditioning pathways also are involved in the regulation of vascular tone. Activation of mitoKATP channels in cerebral arteries causes vasodilation, with cell-specific contributions from the endothelium, vascular smooth muscles, and nerves. Preexisting chronic conditions, such as insulin resistance and/or diabetes, prevent preconditioning and impair relaxation to mitochondrial-centered responses in cerebral arteries. Surprisingly, mitochondrial activation after anoxic or ischemic stress appears to protect cerebral vascular endothelium and promotes the restoration of blood flow; therefore, mitochondria may represent an important, but underutilized target in attenuating vascular dysfunction and brain injury in stroke patients.
Dissemination of Bacterial Fluoroquinolone Resistance in Two Multidrug-Resistant Enterobacteriaceae
Authors: Jung Carina M.
Published: May 2014

Bacterial resistance to antimicrobials has become one of the greatest challenges for clinical microbiologists and healthcare practitioners worldwide. Acquisition of resistance genes has proven to be difficult to characterize and is largely uncontrollable in the environment. Here we sought to characterize conjugal horizontal gene transfer of plasmid-encoded fluoroquinolone resistance genes from two strains of Enterobacteriaceae, one clinical and one from a municipal wastewater treatment plant environment. Conjugation was dissimilar between the two strains. Escherichia coli strain LR09, containing a plasmid with the aac(6′)-Ib-cr fluoroquinolone resistance gene, did not conjugate with any of the 15 strains tested, while Enterobacter aerogenes strain YS11 conjugated with two strains of E. coli. The resultant transconjugants were also dissimilar in their stability and potential persistence. The observations presented herein exemplify the difficulties in understanding and controlling the spread of antimicrobial resistance. Thus, it may be prudent to address drug disposal and destruction, incorporating a life-cycle assessment plan ‘from cradle to grave', treating antimicrobials as chemical or environmental contaminants.
Personalized Medicine, Availability, and Group Disparity: An Inquiry into How Physicians Perceive and Rate the Elements and Barriers of Personalized Medicine
Authors: Petersen Katelin E. , Prows Cynthia A. , Martin Lisa J. , Maglo Koffi N.
Published: May 2014

Background: The success of personalized medicine depends on factors influencing the availability and implementation of its new tools to individualize clinical care. However, little is known about physicians' views of the availability of personalized medicine across racial/ethnic groups and the relationship between perceived availability and clinical implementation. This study examines physicians' perceptions of key elements/tools and potential barriers to personalized medicine in connection with their perceptions of the availability of the latter across subpopulations. Methods: Study subjects consisted of physicians recruited from Cincinnati Children's Hospital Medical Center and UC Health. An electronic survey conducted from September 2012 to November 2012 recruited 104 physicians. Wilcoxon rank sum analysis compared groups. Results: Physicians were divided about whether personalized medicine contributes to health equality, as 37.4% of them believe that personalized medicine is currently available only for some subpopulations. They also rated the importance of racial/ethnic background almost as high as the importance of genetic information in the delivery of personalized medicine. Actual elements of personalized medicine rated highest include family history, drug-drug interaction alerts in medical records, and biomarker measurements to guide therapy. Costs of gene-based therapies and genetic testing were rated the most significant barriers. The ratings of several elements and barriers were associated with perceived availability of personalized medicine across subpopulations. Conclusion: While physicians hold differing views about the availability and implementation of personalized medicine, they likewise establish complex relationships between race/ethnicity and personalized medicine that may carry serious implications for its clinical success.
Fine Needle Aspiration Cytology of Acinar Cell Cystadenoma of the Pancreas
Authors: Yergiyev Oleksandr , Krishnamurti Uma , Mohanty Alok , Thakkar Shyam , Gurram Krishna , Silverman Jan F.
Published: May 2014

Background: Acinar cell cystadenoma (ACC) is a recently recognized cystic lesion of the pancreas that demonstrates acinar differentiation and is currently believed to behave in a benign fashion. ACC enters the differential diagnosis of pancreatic cystic lesions alongside better recognized entities such as mucinous cystic and intraductal papillary mucinous neoplasms. Although uncommon, patients with ACC can undergo fine needle aspiration (FNA) of the lesion. However, the diagnosis is rarely made on cytologic examination due to sparse cellularity. Furthermore, the eosinophilic amorphous material in the cyst lumen may be mistaken for mucin, resulting in an incorrect diagnosis of a mucinous cyst. To date, there is a paucity of literature on the cytomorphology of ACC, both in peer-reviewed publications and cytopathology texts. Case: To our knowledge, we present the first detailed case report of FNA of ACC in a 22-year-old asymptomatic female. The FNA cytology specimen was hypocellular, and the presence of amorphous secretions led to the initial diagnosis of a mucinous-type neoplasm. Following surgical resection, the cytology specimen was reviewed. Conclusion: We discuss the cytomorphologic features of ACC along with the potential pitfalls and diagnostic implications.
Exophytic Glioma of the Medulla: Presentation, Management and Outcome
Authors: Ghodsi Mohammad , Mortazavi Abolghasem , Shahjouei Shima , Hanaei Sara , Esmaeili Arash , Nejat Farideh , El Khashab Mostaf
Published: May 2014

Objective: Exophytic gliomas of the medulla are rare childhood tumors that mostly are pilocytic astrocytomas. Here we report our experience in 11 ‑children with this rare tumor. Methods: A retrospective study was performed using the records of children with exophytic gliomas of the medulla at Children's Hospital Medical Center in Tehran, Iran, from 2002 through 2013. The general, clinical, and radiological data and follow-up of all patients were reviewed. Results: The patients mostly were male aged from 11 months to 7 years. Swallowing problems, failure to thrive and nausea and vomiting were the most common symptoms. The time span between the onset of symptoms and the diagnosis was 2-24 months. Gross total resection of tumor was possible in 8 patients. Most tumors were pilocytic astrocytomas. Patients were followed for 2 months to 11 years (mean = 3.6 years). There was no intraoperative mortality. Recurrence occurred in 1 child with fibrillary astrocytoma. Conclusion: Gross total resection of symptomatic dorsal exophytic medullary glioma is recommended. Most tumors are pilocytic astrocytomas. The attachment of these tumors to important brainstem structures usually inhibits total resection. Electrophysiological monitoring of sensorimotor pathways and cranial nerves can be helpful to preserve surrounding neural tissue during tumor resection and to minimize complications. Regular follow-up of patients with clinical examination and brain MRI is mandatory. Repeated surgery, radiation therapy and chemotherapy are suggested in cases with tumor recurrence or progression.
Factors Contributing to Postural Sway in Patients with Diabetes in an In-Hospital Education Program
Authors: Sugimoto Satofumi , Fukunaga Yukari , Katayama Naomi , Yoshida Tadao , Teranishi Masaaki , Sugiura Saiko , Uchida Yasue , Kamiya Hideki , Oiso Yutaka , Nakashima Tsutomu
Published: May 2014

Objective: We investigated the effect of polyneuropathy, nephropathy, and retinopathy on postural sway in patients with poorly controlled diabetes mellitus (DM) who were hospitalized for DM education. We also investigated the relationship between postural sway and hearing disturbances. Methods: We included 50 subjects who were hospitalized for the purpose of DM education. Mean age was 57.2 years, mean HbA1c was 9.4%, and mean DM duration was 11.1 years. Renal function, retina condition, and nerve conduction were evaluated in relation to DM complications (nephropathy, retinopathy, and neuropathy). Static posturography was performed to assess DM-related postural sway. Nerve conduction studies were used to obtain information on the condition of peripheral nerves. Pure-tone audiometry was measured. Stepwise multiple linear regression was used to assess DM-related factors that affected postural sway. Results: Deterioration of median nerve compound muscle action potential (CMAP) amplitude, tibial nerve CMAP conduction velocity, and peroneal nerve CMAP latency were associated with deterioration of postural sway. Deterioration of hearing in the worse ear was also associated with postural sway. Conclusion: In patients with poorly controlled DM, postural sway was particularly associated with deterioration of motor nerve conduction study parameters represented by median nerve CMAP amplitude, tibial nerve CMAP conduction velocity, and peroneal nerve CMAP latency. A link between diabetic polyneuropathy, diabetes-related postural sway, and diabetes-related hearing loss was recognized.
Choroidal Excavation in Eye with Normal Tension Glaucoma
Authors: Asao Kazunobu , Morimoto Takeshi , Nakada Atsuko , Kawasaki Yoshimi
Published: May 2014

Purpose: To report the case of an eye with normal tension glaucoma and a choroidal excavation. Methods: This is an observational case report. Results: A 59-year-old woman with normal tension glaucoma had a choroidal excavation in the left eye. Her best-corrected visual acuity and intraocular pressure were within normal limits and had been stable for 5 years. Fundus examination showed a small white lesion inferior to the macula and a nerve fiber layer defect at the inferior edge of the optic disc. Humphrey Field Analyzer (HFA) showed visual field defects corresponding to the nerve fiber layer defect with C30-2, and a central scotoma superior to the macula with C10-2. Optical coherence tomography (OCT) showed a 150-µm deep choroidal excavation. Disruptions of the IS/OS line were detected only in the area inferior to the choroidal excavation. During the 5 months of follow-up, her best-corrected visual acuity remained at 1.0 and the IOP ranged from 12 to 14 mm Hg in the left eye. The fundus and OCT images did not deteriorate and the choroidal excavation did not enlarge. Conclusions: The disruption of the inner/outer segment (IS/OS) line was detected only at the area surrounding the choroidal excavation. OCT examinations are useful in assessing the area of the residual IS/OS line, and HFA can be used to estimate the residual central visual field.
Gastric Mixed Adenoneuroendocrine Carcinoma Occurring 50 Years after a Gastroenterostomy with Braun Anastomosis
Authors: Nemoto Hiroshi , Tate Genshu , Yokomizo Kazuaki , Umemoto Takahiro , Matsubara Taketo , Mizukami Hiroki , Kigawa Gaku , Matsumiya Akihiko , Tanaka Junichi
Published: May 2014

A 75-year-old man was diagnosed with gastric cancer. Fifty years previously, he had undergone gastroenterostomy with a Braun enteroenterostomy. At present, a distal gastrectomy and small intestinal partial resection were performed. Intraoperatively, the tumor was localized to the previous stomal site. HE staining showed that the tumor comprised two elements: a tubular adenocarcinoma on the gastric side and a neuroendocrine carcinoma (NEC) on the jejunal side. The final pathologic diagnosis was mixed adenoneuroendocrine carcinoma based on an immunohistochemical analysis of endocrine markers and an elevated Ki-67 labeling index. The risk of later cancer development cancer recurrence near the gastrojejunostomy site is well known. Potentially, chronic enterogastric bile reflux may irritate the gastric mucosa and act as a promoter. Gastric NEC has a strong malignant potential. We suspect that, in the present case, the constant exposure to secondary bile may have induced a gastric mucosal adenocarcinoma, which finally differentiated into a NEC.
Primary Effusion Lymphoma in an Elderly HIV-Negative Patient with Hemodialysis: Importance of Evaluation for Pleural Effusion in Patients Receiving Hemodialysis
Authors: Sasaki Yosuke , Isegawa Takuya , Shimabukuro Akira , Yonaha Tomoki , Yonaha Hiroyasu
Published: May 2014

Pleural effusion is a ubiquitous complication in hemodialysis (HD) patients. Common etiologies of pleural effusion in this patient group are heart failure, volume overload, parapneumonic effusion, tuberculotic pleuritis, and uremic pleuritis. Although thoracentesis is a useful diagnostic method of pleural effusion, empirical reduction of the dry weight is often attempted without thoracentesis because pleural effusion is commonly caused by volume overload and responds to the dry-weight reduction. However, this empiricism has a risk of overlooking or delaying the diagnosis of potentially fatal etiologies that need specific treatments. We report an 86-year-old human immunodeficiency virus (HIV)-negative male on HD with primary effusion lymphoma (PEL), a large-cell non-Hodgkin lymphoma presenting with characteristic lymphomatous effusions in the absence of solid tumor masses, which is in association with human herpes virus 8 (HHV8) infection in immunocompromised individuals. The patient presented with left-sided pleural effusion. This is the first case report of PEL developing in a patient receiving HD. Thoracentesis and cytological analysis of the effusion was key to the diagnosis. We also review the literature regarding pleural effusion in HD patients. Further, we examine Kaposi's sarcoma herpes virus/HHV8-negative effusion-based lymphoma, a newly proposed distinct lymphoma that clinically and cytomorphologically resembles PEL, because it can be cured without chemotherapy. This report may arouse clinicians' attention regarding the importance of evaluation for pleural effusion in HD patients, especially when the effusion or symptoms associated with pleural effusion are refractory to volume control.