bluuebunny/crossref_metadata_2025 huggingface dataset:
The Triassic chronostratigraphic scale: history and status
Authors: Lucas Spencer G.
Published: June 2010

The Triassic chronostratigraphic scale is a hierarchy of three series, seven stages and 15 substages developed during nearly two centuries of research. The first geological studies of Triassic rocks began in Germany in the late 1700s and culminated in 1834 when Friedrich August von Alberti coined the term ‘Trias’ for the Bunten Sandsteins, Muschelkalk and Keuper, a thick succession of strata between the Zechstein and the Lias. Recognition of the Trias outside of Germany soon followed, and by the 1860s Austrian geologist Edmund von Mojsisovics began constructing a detailed Triassic chronostratigraphy based on ammonoid biostratigraphy. In 1895, Mojsisovics and his principal collaborators, Wilhelm Waagen and Carl Diener, published a Triassic timescale that contains most of the stage and substage names still used today. In 1934, Leonard Spath proposed a Triassic ammonoid-based biochronological timescale that differed little from that of Mojsisovics and his collaborators. In the 1960s, E. Timothy Tozer proposed a Triassic ammonoid-based timescale based on North American standards, and his timescale included proposal of four Lower Triassic stages (Griesbachian, Dienerian, Smithian and Spathian). The work of the Subcommission on Triassic Stratigraphy began in the 1970s and resulted in current recognition of seven Triassic stages in three series: Lower Triassic–Induan, Olenekian; Middle Triassic–Anisian, Ladinian; Upper Triassic–Carnian, Norian and Rhaetian. The 1990s saw the rise of Triassic conodont biostratigraphy so that four intervals that have agreed on Triassic GSSPs use conodont occurrences as defining features: bases of Induan, Olenekian, Anisian and Rhaetian. The bases of the Ladinian and Carnian are defined by ammonoid events. The base of the Norian remains undefined, but will most likely be defined by conodonts.

Except for the Rhaetian, the Middle and Upper Triassic stages and substages have been fairly stable for decades, but there has been much less agreement on Lower Triassic chronostratigraphic subdivisions. Issues in the development of a Triassic chronostratigraphic scale include those of: stability and priority of nomenclature and concepts; disagreement over and changing taxonomy; the use of ammonoid v. conodont biostratigraphy; differences in the perceived significance of biotic events for chronostratigraphic classification; disagreements about the utility of relatively short stages; correlation problems between the Tethyan and Boreal realms (provinces); and competing standards from the Old and New worlds. Most of these issues have been resolved in the recognition of three Triassic series and seven stages. Further development of the Triassic chronostratigraphic scale needs to focus on definition and characterization of the 15 Triassic substages as these will provide a much more detailed basis for subdivision of Triassic time than do the seven stages.
T cells from burn-injured mice demonstrate a loss of sensitivity to glucocorticoids
Authors: D'Elia Michele , Patenaude Julie , Dupras Charles , Bernier Jacques
Published: June 2010

Glucocorticoids (GC) are steroid hormones that modulate T cell functions and restrain their hyperresponsiveness following stimulation. Naive T lymphocytes are sensitive to GC but become more resistant when they are activated. A balance between activation and inhibition signals is important for a targeted and effective T cell response. Thermal injury is characterized by an immune dysfunction and hyperactive T cells visible at day 10 postburn. In this study, our objective was to evaluate T cell sensitivity to GC following thermal injury and to identify mechanisms that could modulate their sensitivity. One mechanism that we hypothesized was increased p38 mitogen-activated protein kinase (MAPK) activity that could lead to GC resistance. Male C57BL/6 mice underwent a full-thickness 20% total body surface area. At 10 days postinjury, splenic T cells were isolated. Glucocorticoid receptor (GR) expression was higher in T cells from burn-injured mice. Interestingly, these cells were also less sensitive to GC-induced apoptosis prior to and poststimulation. Furthermore, anti-CD3-activated T cells from burn-injured mice showed increased proliferation and CD25 expression, which resisted corticosterone's (CORT) suppressive effect. Anti-CD3-activated CD4+CD44+memory cells from burn-injured mice expressed the highest level of CD25 and were resistant to CORT. Increased phosphorylation of p38 MAPK was also noted in activated T cells from burn-injured mice. Pharmacological inhibition of p38 MAPK decreased cell proliferation and normalized interferon-γ (IFNγ) production. In conclusion, we demonstrate that a unique event like burn injury induces a loss of sensitivity to GC in splenic T cells and have identified p38 MAPK as a key modulator for this resistance.
Action Potential–Enhanced ATP Release From Taste Cells Through Hemichannels
Authors: Murata Yoshihiro , Yasuo Toshiaki , Yoshida Ryusuke , Obata Kunihiko , Yanagawa Yuchio , Margolskee Robert F. , Ninomiya Yuzo
Published: June 2010

Only some taste cells fire action potentials in response to sapid stimuli. Type II taste cells express many taste transduction molecules but lack well-elaborated synapses, bringing into question the functional significance of action potentials in these cells. We examined the dependence of adenosine triphosphate (ATP) transmitter release from taste cells on action potentials. To identify type II taste cells we used mice expressing a green fluorescence protein (GFP) transgene from the α-gustducin promoter. Action potentials were recorded by an electrode basolaterally attached to a single GFP-positive taste cell. We monitored ATP release from gustducin-expressing taste cells by collecting the electrode solution immediately after tastant-stimulated action potentials and using a luciferase assay to quantify ATP. Stimulation of gustducin-expressing taste cells with saccharin, quinine, or glutamate on the apical membrane increased ATP levels in the electrode solution; the amount of ATP depended on the firing rate. Increased spontaneous firing rates also induced ATP release from gustducin-expressing taste cells. ATP release from gustducin-expressing taste cells was depressed by tetrodotoxin and inhibited below the detection limit by carbenoxolone. Our data support the hypothesis that action potentials in taste cells responsive to sweet, bitter, or umami tastants enhance ATP release through pannexin 1, not connexin-based hemichannels.
Changes in Theory-Based Psychological Factors Predict Weight Loss in Women with Class III Obesity Initiating Supported Exercise
Authors: Annesi James J. , Gorjala Srinivasa
Published: June 2010

Background. Psychological factors' effect on weight loss is poorly understood, in general, and specifically in the severely obese.Objective. To examine whether a behavioral model based on tenets of social cognitive and self-efficacy theory will increase understanding of the relationship between exercise and weight loss.Methods. Fifty-one women with severe obesity participated in a 24-week exercise and nutrition information treatment and were measured on changes in psychological factors and exercise attendance.Results. A significant portion of the variance in BMI change (adjusted for number of predictors) was accounted for by the behavioral model . Entry of exercise session attendance only marginally improved the prediction to 0.27. Only 19% of the weight lost was directly attributable to caloric expenditure from exercise.Conclusions. Findings suggest that participation in an exercise program affects weight loss through psychological pathways and, thus, may be important in the behavioral treatment of severe obesity.
Role of Antimicrobial Selective Pressure and Secondary Factors on Antimicrobial Resistance Prevalence inEscherichia colifrom Food-Producing Animals in Japan
Authors: Harada Kazuki , Asai Tetsuo
Published: June 2010

The use of antimicrobial agents in the veterinary field affects the emergence, prevalence, and dissemination of antimicrobial resistance in bacteria isolated from food-producing animals. To control the emergence, prevalence, and dissemination of antimicrobial resistance, it is necessary to implement appropriate actions based on scientific evidence. In Japan, the Japanese Veterinary Antimicrobial Resistance Monitoring System (JVARM) was established in 1999 to monitor the antimicrobial susceptibility of foodborne and commensal bacteria from food-producing animals. The JVARM showed that the emergence and prevalence of resistantEscherichia coliwere likely linked to the therapeutic antimicrobial use in food-producing animals through not only direct selection of the corresponding resistance but also indirect selections via cross-resistance and coresistance. In addition, relevant factors such as host animals and bacterial properties might affect the occurrence and prevalence of antimicrobial-resistantE. coliunder the selective pressure from antimicrobial usage. This paper reviews the trends in antimicrobial resistance inE. coliand consumption of antimicrobials agents in Japan and introduces the relationship between antimicrobial usage and prevalence of antimicrobial-resistant bacteria, from food-producing animals under the JVARM program. In this paper, we will provide the underlying information about the significant factors that can help control antimicrobial resistance in bacteria in veterinary medicine.
A Transient UWB Antenna Array Used with Complex Impedance Surfaces
Authors: Godard A. , Desrumaux L. , Bertrand V. , Andrieu J. , Lalande M. , Jecko B. , Couderc V. , Brishoual M. , Guillerey R.
Published: June 2010

The conception of a novel Ultra-Wideband (UWB) antenna array, designed especially for transient radar applications through the frequency band (300 MHz–3 GHz), is proposed in this paper. For these applications, the elementary antenna must be compact and nondispersive, and the array must be able to steer in two dimensions. The geometry of the elementary antenna and its radiation characteristics are presented. The array beam steering is analyzed and a technique making the increase of the transient front-to-back ratio possible is described.
Detection of Mesiobuccal Canal in Maxillary Molars and Distolingual Canal in Mandibular Molars by Dental CT: A Retrospective Study of 100 Cases
Authors: Rathi Sushma , Patil Jayaprakash , Jaju Prashant P.
Published: June 2010

Objective. To detect presence of MB2 canal in maxillary molars and distolingual canal in mandibular molars by Dental CT.Material and Methods. A retrospective study of 100 Dental CTs was done. Axial and paraxial images obtained were used to assess the presence of MB2 canal in maxillary molars and distolingual canal in mandibular molars.Results. The youngest patient was of 11 years while the eldest patient was of 77 years. Males were 58 in number and females were 42 in number. MB2 canals were present in 57 patients and distolingual canal was present in 18 patients. Maximum MB2 canals were present in age group between 51 and 60 years, while distolingual canals were present in age group of 21–30 years.Conclusion. Dental CT allows adequate visualization of variation in root canal morphology and can be important diagnostic tool for successful endodontic therapy.
The Enormity of Chronic Kidney Disease in Nigeria: The Situation in a Teaching Hospital in South-East Nigeria
Authors: Ulasi Ifeoma I. , Ijoma Chinwuba K.
Published: June 2010

Background. The magnitude of the problem of chronic kidney disease (CKD) is enormous, and the prevalence keeps rising. To highlight the burden of CKD in developing countries, the authors looked at end-stage renal disease (ESRD) patients seen at the University of Nigeria Teaching Hospital (UNTH), Enugu, South-East Nigeria.Method. ESRD patients seen from 01/05/1990 to 31/12/2003 were recruited. Records from A&E Department, medical-out-patients, wards and dialysis unit were used.Results. A total of 1001 male versus 537 female patients were reviewed. About 593 male versus 315 female patients had haemodialysis. The mean age was years and 86.5% were <60 years. Primary renal disease could not be determined in 51.6% while hypertension and glomerulonephritis accounted for −17.2% and 14.6%, respectively. Death from renal causes constituted 22.03% of medical deaths.Conclusion. The prognosis for CKD patients in Nigeria is abysmal. Only few patients had renal-replacement-therapy (RRT). The prohibitive cost precludes many patients. This underscores the need for preventive measures to reduce the impact of CKD in the society.
Introducing Randomness into First‐Order and Second‐Order Deterministic Differential Equations
Authors: Moxnes John F. , Hausken Kjell
Published: June 2010

We incorporate randomness into deterministic theories and compare analytically and numerically some well‐known stochastic theories: the Liouville process, the Ornstein‐Uhlenbeck process, and a process that is Gaussian and exponentially time correlated (Ornstein‐Uhlenbeck noise). Different methods of achieving the marginal densities for correlated and uncorrelated noise are discussed. Analytical results are presented for a deterministic linear friction force and a stochastic force that is uncorrelated or exponentially correlated.
Thermomechanical Assessment of Plastic Deformation in Model Amorphous Polyamide/Clay Nanocomposites
Authors: Tulsyan Kunal , Toshniwal Saurabh , Dorairaju Gowri , Schmidt Daniel F. , Reynaud Emmanuelle
Published: June 2010

In an effort to isolate the role of nanofiller independent of changes in polymer microstructure, we report the processing and characterization of model amorphous polyamide/clay nanocomposites. Analyses confirm fully amorphous character, no change in Tg or thermal stability, and a partially exfoliated structure. The tensile modulus, yield stress, and failure stress increase with the clay content, both in dried and conditioned samples. In contrast, failure strain decreases with increasing clay content in conditioned samples but is independent of clay content in dried samples. Concurrently, the conversion of mechanical work to heat during plastic deformation was studied using infrared thermography, with the heat of deformation estimated based on these results and compared to the work of deformation. These results allow us to quantify changes in deformation mechanism and to conclude that the presence of clay enhances the conversion of mechanical energy to heat in these materials.
Gamma‐Ray Bursts in the Era of Rapid Followup
Authors: Mundell C. G. , Guidorzi C. , Steele I. A.
Published: June 2010

We present a status report on the study of gamma‐ray bursts (GRBs) in the era
of rapid followup using the world′s largest robotic optical telescopes—the 2 m Liverpool
and Faulkes telescopes. Within the context of key unsolved issues in GRB
physics, we describe (1) our innovative software that allows real‐time automatic
analysis and interpretation of GRB light curves, (2) the novel instrumentation that
allows unique types of observations (in particular, early time polarisation measurements),
and (3) the key science questions and discoveries to which robotic observations
are ideally suited, concluding with a summary of current understanding of GRB
physics provided by combining rapid optical observations with simultaneous observations
at other wavelengths.
Application of He′s Homotopy Perturbation Method for Cauchy Problem of Ill‐Posed Nonlinear Diffusion Equation
Authors: Zakeri Ali , Aminataei Azim , Jannati Qodsiyeh
Published: June 2010

We consider a Cauchy problem of unidimensional
nonlinear diffusion equation on finite interval. This problem is ill‐posed
and its approximate solution is unstable. We apply the He′s homotopy
perturbation method (HPM) and obtain the third‐order asymptotic expansion. We show that if the conductivity term in diffusion equation has
a specified condition, the above solution can be estimated. Finally, a
numerical experiment is provided to illustrate the method.
Characterizations of Chitosan-Based Polymer Electrolyte Photovoltaic Cells
Authors: Buraidah M. H. , Teo L. P. , Majid S. R. , Yahya R. , Taha R. M. , Arof A. K.
Published: June 2010

The membranes 55 wt.% chitosan-45 wt.% NH4I, 33 wt.% chitosan-27 wt.% NH4I-40 wt.% EC, and 27.5 wt.% chitosan-22.5 wt.% NH4I-50 wt.% buthyl-methyl-imidazolium-iodide (BMII) exhibit conductivity of3.73×10−7,7.34×10−6, and3.43×10−5 S cm−1, respectively, at room temperature. These membranes have been used in the fabrication of solid-state solar cells with configuration ITO/TiO2/polymer electrolyte membrane/ITO. It is observed that the short-circuit current density increases with conductivity of the electrolyte. The use of anthocyanin pigment obtained by solvent extraction from black rice and betalain from the callus ofCelosia plumosaalso helps to increase the short-circuit current.
Comprehensive Analysis of Missense Variations in the BRCT Domain of BRCA1 by Structural and Functional Assays
Authors: Lee Megan S. , Green Ruth , Marsillac Sylvia M. , Coquelle Nicolas , Williams R. Scott , Yeung Telford , Foo Desmond , Hau D. Duong , Hui Ben , Monteiro Alvaro N.A. , Glover J.N. Mark
Published: June 2010

Genetic screening of the breast and ovarian cancer susceptibility gene BRCA1 has uncovered a large number of variants of uncertain clinical significance. Here, we use biochemical and cell-based transcriptional assays to assess the structural and functional defects associated with a large set of 117 distinct BRCA1 missense variants within the essential BRCT domain of the BRCA1 protein that have been documented in individuals with a family history of breast or ovarian cancer. In the first method, we used limited proteolysis to assess the protein folding stability of each of the mutants compared with the wild-type. In the second method, we used a phosphopeptide pull-down assay to assess the ability of each of the variants to specifically interact with a peptide containing a pSer-X-X-Phe motif, a known functional target of the BRCA1 BRCT domain. Finally, we used transcriptional assays to assess the ability of each BRCT variant to act as a transcriptional activation domain in human cells. Through a correlation of the assay results with available family history and clinical data, we define limits to predict the disease risk associated with each variant. Forty-two of the variants show little effect on function and are likely to represent variants with little or no clinical significance; 50 display a clear functional effect and are likely to represent pathogenic variants; and the remaining 25 variants display intermediate activities. The excellent agreement between the structure/function effects of these mutations and available clinical data supports the notion that functional and structure information can be useful in the development of models to assess cancer risk. Cancer Res; 70(12); 4880–90. ©2010 AACR.
Regulation of Vascular Endothelial Growth Factor Receptors by Rb and E2F1: Role of Acetylation
Authors: Pillai Smitha , Kovacs Michelle , Chellappan Srikumar
Published: June 2010

E2F transcription factors regulate a variety of cellular processes, but their role in angiogenesis is not clear. We find that many genes involved in angiogenesis such as FLT-1, KDR, and angiopoietin 2 have potential E2F1 binding sites in their promoter. Chromatin immunoprecipitation (ChIP) assays showed that E2F1 can associate with these promoters and the recruitment of E2F1 was enhanced upon vascular endothelial growth factor (VEGF) stimulation with concomitant dissociation of Rb, leading to the transcriptional activation of these promoters. Transient transfection experiments showed that these promoters were induced by E2F1 and repressed by Rb, whereas depletion of E2F1 decreased their expression. The increased binding of E2F1 to these promoters upon VEGF stimulation correlated with the acetylation of histones and E2F1; this required VEGF receptor function, as seen in ChIP-re-ChIP experiments. This suggests the existence of a positive feedback loop regulating E2F1 acetylation and VEGF receptor expression. Acetylation associated with VEGF signaling seems to be predominantly mediated by P300/CBP-associated factor, and the depletion of histone acetyl transferases disrupted the formation of angiogenic tubules. These results suggest a novel role for E2F1 and acetylation in the angiogenic process. Cancer Res; 70(12); 4931–40. ©2010 AACR.
Myc-Induced MicroRNAs Integrate Myc-Mediated Cell Proliferation and Cell Fate
Authors: Kim Jong Wook , Mori Seiichi , Nevins Joseph R.
Published: June 2010

The Myc pathway, often deregulated in cancer, is critical in determining cell fate by coordinating a gene expression program that links the control of cell proliferation with cell fate decisions. As such, precise control of the Myc pathway activity must be achieved to ensure faithful execution of appropriate cellular response and to prevent progressing toward a malignant state. With recent highlighted roles of microRNAs (miRNA) as critical components of gene control, we sought to evaluate the extent to which miRNAs may contribute in the execution of Myc function. Combined analysis of mRNA and miRNA expression profiles reveals an integration whereby the Myc-mediated induction of miRNAs leads to the repression of various mRNAs encoding tumor suppressors that block cell proliferation including p21, p27, and Rb. In addition, the proapoptotic PTEN tumor suppressor gene is also repressed by Myc-induced miRNAs, suggesting that Myc-induced miRNAs contribute to the precise control of a transcriptional program that coordinates the balance of cell proliferation and cell death. Cancer Res; 70(12); 4820–8. ©2010 AACR.
Potent Antitumor Activity in Experimental Hepatocellular Carcinoma by Adenovirus-Mediated Coexpression of TRAIL and shRNA against COX-2
Authors: Chen Qing , Lou Wenjia , Shen Junjie , Ma Leina , Yang Zhi , Liu Li , Luo Jingjing , Qian Cheng
Published: June 2010

Purpose: Recent studies have indicated that short hairpin RNA (shRNA) driven by RNA polymerase (Pol) II promoters can be transcribed into precursor mRNAs together with transgenes. It remains unclear, however, whether coexpression of shRNA and transgene from a single promoter is feasible for cancer therapy.

Experimental Design: In this study, we generated novel adenoviral vectors that permitted coexpression of shRNA against cyclooxygenase-2 (COX-2) and the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapeutic gene from a cytomegalovirus promoter to evaluate whether silencing of COX-2 could increase the sensitivity of hepatocellular carcinoma to TRAIL.

Results: Our data showed that adenovirus vector Ad-TM, in which the shRNA was inserted into the 3′ untranslated region of the TRAIL gene, not only significantly suppressed COX-2 expression, but also expressed a high level of TRAIL. Moreover, infection with Ad-TM resulted in significant cytotoxicity in hepatocellular carcinoma cell lines. In contrast, it had no effect on normal liver cell line. Impressively, treatment of the established hepatocellular carcinoma tumors with Ad-TM resulted in complete tumor regression. This potent antitumor activity induced by Ad-TM was due to strong inhibition of COX-2 and high expression of TRAIL. Furthermore, using the shRNA and transgene coexpression adenovirus system, we showed that silencing of COX-2 increased the sensitivity of hepatocellular carcinoma to TRAIL through inhibition of Bcl-2 and Bcl-w.

Conclusion: This study indicated that adenovirus carrying shRNA and transgene expressed from a single promoter represented a potent approach for cancer therapy. Clin Cancer Res; 16(14); 3696–705. ©2010 AACR.
Effect of Pazopanib on Tumor Microenvironment and Liposome Delivery
Authors: Tailor Tina D. , Hanna Gabi , Yarmolenko Pavel S. , Dreher Matthew R. , Betof Allison S. , Nixon Andrew B. , Spasojevic Ivan , Dewhirst Mark W.
Published: June 2010

Pathologic angiogenesis creates an abnormal microenvironment in solid tumors, characterized by elevated interstitial fluid pressure (IFP) and hypoxia. Emerging theories suggest that judicious downregulation of proangiogenic signaling pathways may transiently “normalize” the vascular bed, making it more suitable for drug delivery and radiotherapy. In this work, we investigate the role of pazopanib, a small-molecule inhibitor of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF) receptors, on tumor IFP, angiogenesis, hypoxia, and liposomal drug delivery. Nude mice bearing A549 human non–small cell lung cancer xenografts were treated with 100 mg/kg pazopanib (n = 20) or vehicle (n = 20) through oral gavage for 8 days, followed by a one-time intravenous dose of 10 mg/kg Doxil (liposomal doxorubicin). Pazopanib treatment resulted in significant reduction of tumor IFP and decreased vessel density, assessed by CD31 staining. Despite these trends toward normalization, high-performance liquid chromatography revealed no differences in doxorubicin concentration between pazopanib-treated and control tumors, with Doxil penetration from microvessels being significantly reduced in the pazopanib group. Additionally, tumor hypoxia, evaluated by CA-IX immunostaining and confirmed in a second study by EF5 expression (n = 4, 100 mg/kg pazopanib; n = 4, vehicle), was increased in pazopanib-treated tumors. Our results suggest that the classic definition of tumor “normalization” may undermine the crucial role of vessel permeability and oncotic pressure gradients in liposomal drug delivery, and that functional measures of normalization, such as reduced IFP and hypoxia, may not occur in parallel temporal windows. Mol Cancer Ther; 9(6); 1798–808. ©2010 AACR.
ARC Synergizes with ABT-737 to Induce Apoptosis in Human Cancer Cells
Authors: Bhat Uppoor G. , Pandit Bulbul , Gartel Andrei L.
Published: June 2010

Previously, we reported that the nucleoside analogue/transcriptional inhibitor ARC (4-amino-6-hydrazino-7-β-d-ribofuranosyl-7H-pyrrolo(2,3-d)-pyrimidine-5-carboxamide) was able to induce p53-independent apoptosis in multiple cancer cell lines of different origins. This occurred, at least in part, by the suppression of short-lived, prosurvival member of the Bcl-2 family, Mcl-1. In contrast, we show here that treatment of human cancer cells with the pan-Bcl-2 inhibitor ABT-737 alone led to upregulation of Mcl-1 protein expression. Combination of subapoptotic concentrations of ABT-737 and ARC induced mitochondrial injury and potent caspase-3/caspase-9–dependent apoptosis in a wide variety of human cancer cell lines. These data suggest that the ABT-737/ARC combination, which simultaneously targets Bcl-2 and Mcl-1, may be efficient against human cancer. Mol Cancer Ther; 9(6); 1688–96. ©2010 AACR.
Role of the 18:1 Lysophosphatidic Acid–Ovarian Cancer Immunoreactive Antigen Domain Containing 1 (OCIAD1)–Integrin Axis in Generating Late-Stage Ovarian Cancer
Authors: Wang Chunyan , Michener Chad M. , Belinson Jerome L. , Vaziri Susan , Ganapathi Ram , Sengupta Saubhik
Published: June 2010

Chemotherapy resistance in ovarian cancer remains an unsolved problem in caring for women with this disease. We now show that ovarian cancer immunoreactive antigen domain containing 1 (OCIAD1) has higher expression in chemoresistant compared with chemosensitive ovarian cancer cell lines. We have designed a novel secondary cell homing assay (SCHA) to test the ability of cells to withstand chemotherapy and form secondary colonies that could form recurrent disease. OCIAD1 upregulated cells had significantly higher secondary colony-forming ability than had OCIAD1 downregulated cells following treatment with paclitaxel. Additionally, 18:1 lysophosphatidic acid (LPA) increases OCIAD1 expression in a time- and dose-dependent manner. LPA stimulates OCIAD1 serine phosphorylation within two hours of stimulation. Transfection of MKK6 increases OCIAD1 expression but nuclear translocation is inhibited. Inhibition of p38 mitogen-activated protein kinase blocks LPA-induced OCIAD1 expression. Cycloheximide treatment of MKK6-transfected cells does not inhibit OCIAD1 expression, suggesting that MKK6 upregulation is not translationally controlled. OCIAD1 downregulation knocks down LPA-induced cell adhesion to collagen I and laminin 10/11 and specifically inhibits cell attachment to α2, α5, αV, and β1 integrins. Proteomic studies indicate that OCIAD1 is physically attached to α actin 4 and β actin. Thus, OCIAD1 may play a role in cytoskeletal function which can alter sensitivity to paclitaxel. This is the first study to indicate that OCIAD1 is a key player in generating ovarian cancer recurrence; it is functionally controlled by LPA and MKK6 signaling, and inhibition of OCIAD1 could be an important strategy in the management of recurrent ovarian cancer. Mol Cancer Ther; 9(6); 1709–18. ©2010 AACR.
Antitumor Activity and Immune Response Induction of a Dual Agonist of Toll-Like Receptors 7 and 8
Authors: Wang Daqing , Precopio Melissa , Lan Tao , Yu Dong , Tang Jimmy X. , Kandimalla Ekambar R. , Agrawal Sudhir
Published: June 2010

Viral and synthetic single-stranded RNAs are the ligands for Toll-like receptors 7 and 8 (TLR7 and TLR8). We have reported a novel class of synthetic oligoribonucleotides, referred to as stabilized immune-modulatory RNA compounds, which act as agonists of TLR7, TLR8, or both TLR7 and TLR8 depending on the sequence composition and the presence of specific chemical modifications. In the present study, we evaluated the antitumor activity of a dual TLR7/8 agonist in tumor-bearing mice with peritoneal disseminated CT26.CL25 colon and 3LL-C75 lung carcinomas. Peritoneal administration of dual TLR7/8 agonist in mice bearing CT26.CL25 colon carcinomas had potent dose-dependent antitumor activity, which was associated with a marked decrease in CD4+CD25+Foxp3+ T regulatory cells and a significant increase in tumor antigen–specific IFN-γ–secreting effector cell responses in splenocytes and local tumor-infiltrating cells. In 3LL-C75 lung carcinoma, dual TLR7/8 agonist induced strong immune responses and antitumor effects in C57BL/6 and TLR9−/− mice, but not in TLR7−/− and MyD88−/− mice, indicating that the agonist induces immune responses via TLR7 and through the MyD88-dependent signaling pathway. TLR8 is not functional in mice. Additionally, s.c. administration of TLR7/8 agonist effectively prevented lung metastasis of tumors in the CT26.CL25 pulmonary metastasis model. These studies show that the dual TLR7/8 agonist induced Th1-type immune responses and potent antitumor activity in mice via TLR7 and through the MyD88-dependent pathway. Mol Cancer Ther; 9(6); 1788–97. ©2010 AACR.
BMS-777607, a Small-Molecule Met Kinase Inhibitor, Suppresses Hepatocyte Growth Factor–Stimulated Prostate Cancer Metastatic Phenotype In vitro
Authors: Dai Yao , Siemann Dietmar W.
Published: June 2010

Most prostate cancer–related deaths are due to advanced disease with patients with metastatic prostate cancer having a 5-year survival rate of only 34%. Overexpression of c-Met receptor tyrosine kinase has been highly associated with prostate cancer progression and metastasis. In the present studies, the effect of BMS-777607, a selective and potent small-molecule Met kinase inhibitor that has been advanced to clinical evaluation, on hepatocyte growth factor (HGF)–mediated cell functions and signaling pathways was evaluated in c-Met–expressing PC-3 and DU145 prostate cancer cells. BMS-777607 treatment had little effect on tumor cell growth but inhibited cell scattering activated by exogenous HGF, with almost complete inhibition at 0.5 μmol/L in PC-3 and DU145 cells. This agent also suppressed HGF-stimulated cell migration and invasion in a dose-dependent fashion (IC50 < 0.1 μmol/L) in both cell lines. Mechanistically, nanomolar doses of BMS-777607 potently blocked HGF-stimulated c-Met autophosphorylation and downstream activation of Akt and extracellular signal-regulated kinase. In addition, both wortmannin and U0126, but not dasatinib, attenuated cell scattering and migration induced by HGF, suggesting the involvement of the phosphoinositide 3-kinase and mitogen-activated protein kinase pathways, but not of Src or focal adhesion kinase, in HGF-mediated motogenic effects. Taken together, these data indicate that the downregulation of c-Met signaling by BMS-777607 treatment can significantly disrupt key steps in the metastatic cascade, suggesting that such a targeting strategy may hold promise for the treatment of advanced prostate cancer. Mol Cancer Ther; 9(6); 1554–61. ©2010 AACR.
Differential Hemodynamic Response to Repetitive Transcranial Magnetic Stimulation in Acute Stroke Patients with Cortical versus Subcortical Infarcts
Authors: Khaleel Salma H. , Bayoumy Iman M. , El-Nabil Lobna M. , Moustafa Ramez Reda
Published: June 2010

Objective: To assess the cerebral vasomotor response to ipsilesional repetitive transcranial magnetic stimulation (rTMS) on transcranial Doppler (TCD) in patients with recent ischemic stroke without carotid occlusive disease, and to compare this response in patients with cortical and subcortical infarcts. Methods: Consecutive patients with first-ever anterior circulation acute ischemic stroke (<3 days) and no extra- or intracranial arterial stenosis were prospectively recruited. Patients were divided into 2 groups: cortical infarct (CI, n = 15) and subcortical infarct (SI, n = 16). TCD cerebral blood flow velocity (CBFV) and pulsatility index were measured before and after 10-Hz suprathreshold rTMS over the dorsolateral prefrontal cortex. Results: ANOVA showed a greater percentage increase in middle cerebral artery (MCA) CBFV in the SI group than in the CI group following rTMS (p = 0.01). The percentage change in CBFV was significantly correlated between both MCAs in SI patients but not in CI patients (r = 0.8, p < 0.001 vs. r = 0.05, p = 0.9, respectively). Conclusions: 10-Hz rTMS induces significant bilateral hemodynamic changes in patients with acute ischemic stroke, which appear to be less prominent and less synchronous in patients with cortical infarcts. These findings may allow optimization of the use of TMS in acute stroke.
Cysteinyl Leukotrienes and Their Receptors: Molecular and Functional Characteristics
Authors: Singh R.K. , Gupta S. , Dastidar S. , Ray A.
Published: June 2010

The cysteinyl leukotrienes (CysLTs) are a family of potent inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells including mast cells, eosinophils, basophils and macrophages. The family includes leukotriene C4 (LTC4), leukotriene D4 (LTD4) and leukotriene E4 (LTE4), which are potent biological mediators in the pathophysiology of inflammatory diseases and trigger contractile and inflammatory processes through the specific interaction with cell surface receptors, belonging to the superfamily of G-protein-coupled receptor. Pharmacological characterizations have suggested the existence of at least 2 types of CysLT receptors based on potency of agonist and antagonist, designated as CysLT1 and CysLT2. The CysLT1 receptors are mostly expressed in lung smooth muscle cells, interstitial lung macrophages and the spleen, and it has been studied a lot elucidating its role in the etiology of airway inflammation and asthma. On the other hand, CysLT2 receptors are present in the heart, brain and adrenal glands. This review discusses the role of CysLTs and their receptor in the pathophysiology of various inflammatory disorders. The understanding of CysLTs and their receptors in allergic airway disease is currently limited to CysLT1-receptor-mediated effects, and the role of the CysLT2 receptors is pharmacologically less well defined, as there is no specific antagonist available yet. Specific CysLT2-receptor-selective antagonists would be very helpful to identify the precise role of CysLT and their receptors. Some recent evidence indicates the existence of additional receptor subtypes and requires further investigation for a better understanding of the role of the CysLT receptors. This review is an effort to summarize the localization, regulation and expression pattern along with the molecular and functional pharmacology of the CysLT receptors and to discuss their role in the pathophysiology of different diseases along with the recent update.
Correlation of Proteinase Production with Amphotericin B Resistance in Fungi from Mycotic Keratitis
Authors: Nayak N. , Satpathy G. , Prasad Sujata , Vajpayee R.B. , Pandey R.M.
Published: June 2010

Two hundred fungal isolates (Aspergillus and Fusarium species) from mycotic keratitis were tested for in vitro susceptibilities to amphotericin B and proteinase production. Geometric mean MICs for all fungal species increased fourfold with thousandfold increase in the inoculum. The MIC50 and MIC90 values ranged between 3.12–6.25 and 3.12–12.5 µg/ml, respectively. Proteinase production was noted in 113 (56.5%) isolates. Ninety-eight (49%) showed MICs of ≧1.56 µg/ml that was above the criteria of ≧1 µg/ml for amphotericin B resistance (CLSI). Seventy-three (74.5%) of these 98 isolates were proteinase producers, whereas only 40 (39.2%) of the remaining 102 with low MICs (<1.56 µg/ml) were proteinase producers (p < 0.001). Proteinase seems to be an important virulence marker of filamentous fungi in mycotic keratitis, correlating significantly with amphotericin B resistance.
Confounding
Authors: van Stralen K.J. , Dekker F.W. , Zoccali C. , Jager K.J.
Published: June 2010

In confounding, the effect of the exposure of interest is mixed with the effect of another variable. It is important to identify relevant confounders and remove the confounding effect as much as possible. There are three criteria that need to be fulfilled to determine whether a variable could be considered a potential confounder. The first criterion is that the variable needs to be associated with the exposure. The second criterion is that the variable needs to be associated with the outcome or disease. The third criterion is that the variable should not be an intermediate variable in the causal pathway between exposure and outcome. Only if all the criteria are fulfilled is the variable under question a confounder. If one incorrectly adjusts for a variable that is not a confounder, one risks overadjustment or adjustment for spurious associations. Confounders can be prevented from entering the study, during the design of a study, or if this is not possible, one can try to remove it during the analysis phase.
Neural Network Analysis to Predict Mortality in End-Stage Renal Disease: Application to United States Renal Data System
Authors: Jacob Adam N. , Khuder Sadik , Malhotra Nathan , Sodeman Thomas , Gold Jeffrey P. , Malhotra Deepak , Shapiro Joseph I.
Published: June 2010

We examined whether we could develop models based on data provided to the United States Renal Data System (USRDS) to accurately predict survival. Records were obtained from patients beginning dialysis in 1990 through 2007. We developed linear and neural network models and optimized the fit of these models to the actual time to death. Next, we examined whether we could accurately predict survival in a dataset containing censored and uncensored patients. The results with these models were contrasted with those obtained with a Cox proportional hazards model fit to the entire dataset. The average C statistic over a 6-month to 10-year time range achieved with these models was approximately 0.7891 (linear model), 0.7804 (transformed dataset linear model), 0.7769 (neural network model), 0.7774 (transformed dataset neural network model), 0.8019 (Cox model), and 0.7970 (transformed dataset Cox model). When we used the Cox proportional hazards model, superior C statistic results were found at time points between 2 and 10 years but at earlier time points, the Cox model was slightly inferior. These results suggest that data provided to the USRDS can allow for predictive models which have a high degree of accuracy years following the initiation of dialysis.
Detection and Quantification of Myocardial Scars by Contrast-Enhanced 3D Echocardiography
Authors: Montant Patrick , Chenot Fabien , Goffinet Céline , Poncelet Alain , Vancraeynest David , Pasquet Agnès , Gerber Bernhard L. , Vanoverschelde Jean-Louis J.
Published: June 2010

Background—

Myocardial infarct scars are usually imaged by delayed-enhanced cardiac magnetic resonance (DE-cMR). In this study, we tested the hypothesis that the detection and quantification of myocardial scars can be evaluated by 3D echocardiography (3D-echo).

Methods and Results—

Fifty patients with a healed myocardial infarction (>3 months) and 10 controls underwent 3D echo and DE-cMR within 2 weeks. 3D-echo images were acquired with different settings, with or without contrast. The highest contrast-to-noise ratio was obtained with second-harmonic imaging (1.6/3.2 MHz), at a mechanical index of 0.5, in the presence of contrast. Using this modality, we calculated the sensitivity and specificity of the 3D-echo detection of cMR scars on a segmental basis to be 78% and 99%, respectively. On a per-patient basis, they were 96% and 90%, respectively. Good correlation and limits of agreement were found between the assessment of scar mass by 3D echo and DE-cMR (
r
=0.93,
P
<0.001; bias, 1.4±3.6 g), and the concordance between both techniques for the assessment of scar transmurality was good. Intraobserver, interobserver, and day-to-day reproducibility was comparable between 3D echo and DE-cMR for both the detection and quantification of scars.

Conclusions—

Contrast-enhanced 3D echo is a promising new tool for the detection and quantification of myocardial infarct scars.
Bleeding Complications With Dual Antiplatelet Therapy Among Patients With Stable Vascular Disease or Risk Factors for Vascular Disease
Authors: Berger Peter B. , Bhatt Deepak L. , Fuster Valentin , Steg P. Gabriel , Fox Keith A.A. , Shao Mingyuan , Brennan Danielle M. , Hacke Werner , Montalescot Gilles , Steinhubl Steven R. , Topol Eric J.
Published: June 2010

Background—

Uncertainty exists about the frequency, correlates, and clinical significance of bleeding with dual antiplatelet therapy (DAPT), particularly over an extended period in a stable population. We sought to determine the frequency and time course of bleeding with DAPT in patients with established vascular disease or risk factors only; identify correlates of bleeding; and determine whether bleeding is associated with mortality.

Methods and Results—

We analyzed 15 603 patients enrolled in the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial, a double-blind, placebo-controlled, randomized trial comparing long-term clopidogrel 75 mg/d versus placebo; all patients received aspirin (75 to 162 mg) daily. Patients had either established stable vascular disease or multiple risk factors for vascular disease without established disease. Median follow-up was 28 months. Bleeding was assessed with the use of the Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries (GUSTO) criteria. Severe bleeding occurred in 1.7% of the clopidogrel group versus 1.3% on placebo (
P
=0.087); moderate bleeding occurred in 2.1% versus 1.3%, respectively (
P
<0.001). The risk of bleeding was greatest the first year. Patients without moderate or severe bleeding during the first year were no more likely than placebo-treated patients to have bleeding thereafter. The frequency of bleeding was similar in patients with established disease and risk factors only. In multivariable analysis, the relationship between moderate bleeding and all-cause mortality was strong (hazard ratio, 2.55; 95% confidence interval, 1.71 to 3.80;
P
<0.0001), along with myocardial infarction (hazard ratio, 2.92; 95% confidence interval, 2.04 to 4.18;
P
<0.0001) and stroke (hazard ratio, 4.20; 95% confidence interval, 3.05 to 5.77;
P
<0.0001).

Conclusions—

In CHARISMA, there was an increased risk of bleeding with long-term clopidogrel. The incremental risk of bleeding was greatest in the first year and similar thereafter. Moderate bleeding was strongly associated with mortality.

Clinical Trial Registration—

URL: http://www.clinicaltrials.gov. Unique identifier: NCT00050817.
Rosiglitazone Attenuates Endothelin-1–Induced Vasoconstriction by Upregulating Endothelial Expression of Endothelin B Receptor
Authors: Tian Jianwei , Wong Wing Tak , Tian Xiao Yu , Zhang Peng , Huang Yu , Wang Nanping
Published: June 2010

Thiazolidinediones improve insulin resistance and endothelial dysfunction. However, the mechanisms underlying the vasoprotective effects of thiazolidinediones remain to be fully elucidated. The present study aimed to examine the molecular mechanism for the anti-vasoconstrictive effects of rosiglitazone in response to endothelin (ET) 1. Mouse aortas were treated with rosiglitazone for 24 hours, and ET-1–induced vasoconstriction was assessed by wire myography. The results showed that rosiglitazone attenuated ET-1–induced contraction in mouse aortas; this effect was abolished by ET-B receptor (ET
B
R) antagonist, NO synthase inhibitor, and by the removal of endothelium. By using Northern blotting, real-time RT-PCR, Western blotting, and immunohistochemical techniques, we found that rosiglitazone upregulated expression of ET
B
R at both mRNA and protein levels in mouse aortas and human vascular endothelial cells. The induction of ET
B
R was prevented by peroxisome proliferator-activated receptor-γ antagonism. Luciferase reporter assay showed that rosiglitazone enhanced ET
B
R gene promoter activity. Furthermore, chromatin immunoprecipitation assays demonstrated that peroxisome proliferator-activated receptor-γ can directly bind to ET
B
R gene promoter. Furthermore, in vivo treatment with rosiglitazone also attenuated the ET-1–induced vasoconstrictions and increased the ET
B
R expression in mouse aortas and mesenteric arteries. In conclusion, these results demonstrate that rosiglitazone attenuated ET-1–induced vasoconstriction through the upregulation of endothelial ET
B
R, which is a peroxisome proliferator-activated receptor-γ direct target.
Extracellular 2′,3′-Cyclic Adenosine Monophosphate Is a Potent Inhibitor of Preglomerular Vascular Smooth Muscle Cell and Mesangial Cell Growth
Authors: Jackson Edwin K. , Ren Jin , Gillespie Delbert G. , Dubey Raghvendra K.
Published: June 2010

Recently we discovered that intact kidneys release into the extracellular compartment 2′,3′-cAMP (a positional isomer of 3′,5′-cAMP with unknown pharmacology) and metabolize 2′,3′-cAMP to 2′-AMP, 3′-AMP, and adenosine. Because adenosine inhibits growth of vascular smooth muscle cells and mesangial cells, we tested the hypothesis that extracellular 2′,3′-cAMP attenuates growth of preglomerular vascular smooth muscle and mesangial cells via production of adenosine. For comparison, all of the experiments were performed with both 2′,3′-cAMP and 3′,5′-cAMP. In study 1, 2′,3′-cAMP, 3′,5′-cAMP, 5′-AMP, 3′-AMP, or 2′-AMP was incubated with cells and purines measured in the medium by mass spectrometry. Both preglomerular vascular smooth muscle and mesangial cells metabolized 3′,5′-cAMP to 5′-AMP and adenosine; 5′-AMP to adenosine; 2′,3′-cAMP to 2′-AMP, 3′-AMP, and adenosine; and 2′-AMP and 3′-AMP to adenosine. 3-Isobutyl-1-methylxanthine (phosphodiesterase inhibitor) and 1,3-dipropyl-8-p-sulfophenylxanthine (ecto-phosphodiesterase inhibitor) blocked conversion of 3′,5′-cAMP to 5′-AMP and adenosine, and α,β-methylene-adenosine-5′-diphosphate (CD73 inhibitor) blocked conversion of 5′-AMP to adenosine. These enzyme inhibitors had little effect on metabolism of 2′,3′-cAMP, 2′-AMP, or 3′-AMP. For study 2, 2′,3′-cAMP and 3′,5′-cAMP profoundly inhibited proliferation (thymidine incorporation and cell number) of both cell types, with 2′,3′-cAMP more potent than 3′,5′-cAMP. Antagonism of A2Breceptors (MRS-1754), but not A1(1,3-dipropyl-8-cyclopentylxanthine), A2A(SCH-58261), or A3(VUF-5574) receptors, attenuated the growth inhibitory effects of 2′,3′-cAMP and 3′,5′-cAMP. Extracellular 2′,3′-cAMP inhibits growth of preglomerular vascular smooth muscle and mesangial cells more profoundly than does 3′,5′-cAMP. Although both cAMPs inhibit growth in part via conversion to adenosine followed by A2Breceptor activation, their metabolism is mediated by different enzymes.