bluuebunny/crossref_metadata_2025 huggingface dataset:
On the Optimization of Ebeam Lithography Using Hydrogen Silsesquioxane (HSQ) for Innovative Self-Aligned CMOS Process
Authors: Coquand Remi , Monfray Stephane , Pradelles Jonathan , Martin Luc , Samson Marie-Pierre , Bustos Jessy , Barraud Sylvain , Boeuf Frederic , Skotnicki Thomas , Ghibaudo Gérard , Poiroux Thierry , Faynot Olivier
Published: May 2013

Next generation CMOS architectures tend to thin-film devices and multi-gate devices, such as FinFET or TriGate [1,2], and ultimately to Gate-All-Around devices thanks to their higher electrostatics immunity at short gate length compared to conventional planar CMOS. This paper presents recent optimizations of ebeam lithography using HSQ (Hydogen Silses Quioxane, H8Si8O12) resist, used to form self-aligned cavities and finally gate-all-around or double-gated devices. HSQ has demonstrated many features making it an attractive candidate for such applications: it is a high-resolution [3] and low Line-Edge-Roughness [4] negative tone inorganic resist for electron beam lithography [5] that can be converted into amorphous silicon oxide after exposition/bake treatment. It is compatible with conventional front-end silicon technology devices manufacturing and presents excellent gap/cavity fill and planarization performances. Finally, its compatibility with EUV radiation [6] paves the way to the end of the semiconductor roadmap.
On the Resistive Switching and Current Conduction Mechanisms of Amorphous LaGdO3 Films Grown by Pulsed Laser Deposition
Authors: Misra Pankaj , Pavunny Shojan Pullockaran , Katiyar Ram S.
Published: May 2013

The unipolar resistive switching properties of the amorphous LaGdO3 thin films deposited by pulsed laser deposition have been investigated. Reliable and repeatable nonvolatile switching of the resistance of LaGdO3 films was obtained between two well defined states of low and high resistance with nearly constant resistance ratio ~ 106 and non-overlapping switching voltages in the range of 0.6-0.75 V and 2.5-4 V respectively. The current conduction mechanism of the device in low and high resistance states were found to be dominated by the Ohmic behavior and Poole-Frenkel emission respectively. The resistance of low and high resistance states of the film showed no obvious degradation for up to ~ 12 hours indicating good retention. The switching between low and high resistance states was attributed to formation and rupture of conductive filaments. The achieved characteristics of the resistive switching in LaGdO3 thin films seem to be promising for futuristic nonvolatile memory applications.
(Invited) Challenges in 3D Integration
Authors: Koyanagi Mitsumasa , Lee Kang Wook , Fukushima Takafumi , Tanaka Tetsu
Published: May 2013

Three-dimensional (3D) LSIs using TSVs are indispensable to achieve high performance and low power LSIs with smaller form factor. A wafer-to-wafer (WtW) technology is suitable for stacking chips with high production yield such as DRAM since the overall yield after stacking rapidly decreases as the number of stacking layers increases. The chip-to-wafer (CtW) is suitable for stacking known good dies (KGDs). In addition, chips with different size which are fabricated using different process technologies can be stacked in the CtW technology. The inherent problem in the CtW technology, however, is low production throughput. To solve these problems, we have proposed a new 3D heterogeneous integration technology called a super-chip technology using self-assembly and electrostatic (SAE) bonding method.
Missense mutation T485S alters NBCe1-A electrogenicity causing proximal renal tubular acidosis
Authors: Zhu Quansheng , Shao Xuesi M. , Kao Liyo , Azimov Rustam , Weinstein Alan M. , Newman Debra , Liu Weixin , Kurtz Ira
Published: May 2013

Mutations in SLC4A4, the gene encoding the electrogenic Na+-HCO3− cotransporter NBCe1, cause severe proximal renal tubular acidosis (pRTA), growth retardation, decreased IQ, and eye and teeth abnormalities. Among the known NBCe1 mutations, the disease-causing mechanism of the T485S (NBCe1-A numbering) mutation is intriguing because the substituted amino acid, serine, is structurally and chemically similar to threonine. In this study, we performed intracellular pH and whole cell patch-clamp measurements to investigate the base transport and electrogenic properties of NBCe1-A-T485S in mammalian HEK 293 cells. Our results demonstrated that Ser substitution of Thr485 decreased base transport by ∼50%, and importantly, converted NBCe1-A from an electrogenic to an electroneutral transporter. Aqueous accessibility analysis using sulfhydryl reactive reagents indicated that Thr485 likely resides in an NBCe1-A ion interaction site. This critical location is also supported by the finding that G486R (a pRTA causing mutation) alters the position of Thr485 in NBCe1-A thereby impairing its transport function. By using NO3− as a surrogate ion for CO32−, our result indicated that NBCe1-A mediates electrogenic Na+-CO32− cotransport when functioning with a 1:2 charge transport stoichiometry. In contrast, electroneutral NBCe1-T485S is unable to transport NO3−, compatible with the hypothesis that it mediates Na+-HCO3− cotransport. In patients, NBCe1-A-T485S is predicted to transport Na+-HCO3− in the reverse direction from blood into proximal tubule cells thereby impairing transepithelial HCO3− absorption, possibly representing a new pathogenic mechanism for generating human pRTA.
NLRP3 deletion protects from hyperoxia-induced acute lung injury
Authors: Fukumoto Jutaro , Fukumoto Itsuko , Parthasarathy Prasanna Tamarapu , Cox Ruan , Huynh Bao , Ramanathan Gurukumar Kollongod , Venugopal Rajan Babu , Allen-Gipson Diane S. , Lockey Richard F. , Kolliputi Narasaiah
Published: May 2013

Inspiration of a high concentration of oxygen, a therapy for acute lung injury (ALI), could unexpectedly lead to reactive oxygen species (ROS) production and hyperoxia-induced acute lung injury (HALI). Nucleotide-binding domain and leucine-rich repeat PYD-containing protein 3 (NLRP3) senses the ROS, triggering inflammasome activation and interleukin-1β (IL-1β) production and secretion. However, the role of NLRP3 inflammasome in HALI is unclear. The main aim of this study is to determine the effect of NLRP3 gene deletion on inflammatory response and lung epithelial cell death. Wild-type (WT) and NLRP3−/− mice were exposed to 100% O2 for 48–72 h. Bronchoalveolar lavage fluid and lung tissues were examined for proinflammatory cytokine production and lung inflammation. Hyperoxia-induced lung pathological score was suppressed in NLRP3−/− mice compared with WT mice. Hyperoxia-induced recruitment of inflammatory cells and elevation of IL-1β, TNFα, macrophage inflammatory protein-2, and monocyte chemoattractant protein-1 were attenuated in NLRP3−/− mice. NLRP3 deletion decreased lung epithelial cell death and caspase-3 levels and a suppressed NF-κB levels compared with WT controls. Taken together, this research demonstrates for the first time that NLRP3-deficient mice have suppressed inflammatory response and blunted lung epithelial cell apoptosis to HALI.
Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity
Authors: Saben Jessica , Zhong Ying , Gomez-Acevedo Horacio , Thakali Keshari M. , Borengasser Sarah J. , Andres Aline , Shankar Kartik
Published: May 2013

Obesity is associated with low-grade chronic inflammation, which contributes to cellular dysfunction promoting metabolic disease. Obesity during pregnancy leads to a proinflammatory milieu in the placenta; however, the underlying causes for obesity-induced placental inflammation remain unclear. Here, we examine the mechanisms by which saturated fatty acids and inflammatory cytokines induce inflammation in placental trophoblasts. We conducted global transcriptomic profiling in BeWo cells following palmitate and/or TNFα treatment and gene/protein expression analyses of MAPK pathways and characterized downstream transcription factors directly regulating inflammatory cytokines. Microarray analysis revealed increased expression of genes regulating inflammation, stress response, and immediate early response in cytotrophoblasts in response to palmitic acid (PA), TNFα, or a combination of both (PA + TNFα). Both gene ontology and gene set enrichment analysis revealed MAPK and EGR-1 signaling to be upregulated in BeWo cells, which was confirmed via immunoblotting. Importantly, activation of JNK signaling was necessary for increased proinflammatory cytokine ( IL-6, TNFα, and IL-8) and EGR1 mRNA. Consistent with the requirement of JNK signaling, ChIP analysis confirmed the recruitment of c-Jun and other MAPK-responsive immediate early factors on the EGR1 promoter. Moreover, recruitment of EGR-1 on cytokine promoters ( IL-6, TNFα, and IL-8) and an impaired proinflammatory response following knockdown of EGR-1 suggested it as a central component of the mechanism facilitating inflammatory gene expression. Finally, akin to in vitro findings, term placenta from obese women also had both increased JNK and p38 signaling and greater EGR-1 protein relative to lean women. Our results demonstrate that lipotoxic insults induce inflammation in placental cells via activation of JNK/EGR-1 signaling.
Resistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscle
Authors: Apró William , Wang Li , Pontén Marjan , Blomstrand Eva , Sahlin Kent
Published: May 2013

The current dogma is that the muscle adaptation to resistance exercise is blunted when combined with endurance exercise. The suggested mechanism (based on rodent experiments) is that activation of adenosine monophosphate-activated protein kinase (AMPK) during endurance exercise impairs muscle growth through inhibition of the mechanistic target of rapamycin complex 1 (mTORC1). The purpose of this study was to investigate potential interference of endurance training on the signaling pathway of resistance training [mTORC1 phosphorylation of ribosomal protein S6 kinase 1 (S6K1)] in human muscle. Ten healthy and moderately trained male subjects performed on two separate occasions either acute high-intensity and high-volume resistance exercise (leg press, R) or R followed by 30 min of cycling (RE). Muscle biopsies were collected before and 1 and 3 h post resistance exercise. Phosphorylation of mTOR (Ser2448) increased 2-fold ( P < 0.05) and that of S6K1 (Thr389) 14-fold ( P < 0.05), with no difference between R and RE. Phosphorylation of eukaryotic elongation factor 2 (eEF2, Thr56) was reduced ∼70% during recovery in both trials ( P < 0.05). An interesting finding was that phosphorylation of AMPK (Thr172) and acetyl-CoA carboxylase (ACC, Ser79) decreased ∼30% and ∼50%, respectively, 3 h postexercise ( P < 0.05). Proliferator-activated receptor-γ coactivator-1 (PGC-1α) mRNA increased more after RE (6.5-fold) than after R (4-fold) (RE vs. R: P < 0.01) and was the only gene expressed differently between trials. These data show that the signaling of muscle growth through the mTORC1-S6K1 axis after heavy resistance exercise is not inhibited by subsequent endurance exercise. It is also suggested that prior activation of mTORC1 signaling may repress subsequent phosphorylation of AMPK.
Reproductive physiology of a humanized GnRH receptor mouse model: application in evaluation of human-specific analogs
Authors: Tello Javier A. , Kohout Trudy , Pineda Rafael , Maki Richard A. , Scott Struthers R. , Millar Robert P.
Published: May 2013

The human GnRH receptor (GNRHR1) has a specific set of properties with physiological and pharmacological influences not appropriately modeled in laboratory animals or cell-based systems. To address this deficiency, we have generated human GNRHR1 knock-in mice and described their reproductive phenotype. Measurement of pituitary GNRHR1 transcripts from homozygous human GNRHR1 knock-in ( ki/ ki) mice revealed a severe reduction (7- to 8-fold) compared with the mouse Gnrhr1 in wild-type mice. 125I-GnRH binding assays on pituitary membrane fractions corroborated reduced human GNRHR1 protein expression in ki/ ki mice, as occurs with transfection of human GNRHR1 in cell lines. Female homozygous knock-in mice displayed normal pubertal onset, indicating that a large reduction in GNRHR1 expression is sufficient for this process. However, ki/ ki females exhibited periods of prolonged estrous and/or metestrous and reduced fertility. No impairment was found in reproductive maturity or adult fertility in male ki/ ki mice. Interestingly, the serum LH response to GnRH challenge was reduced in both knock-in males and females, indicating a reduced GNRHR1 signaling capacity. Small molecules targeting human GPCRs usually have poor activities at homologous rodent receptors, thus limiting their use in preclinical development. Therefore, we tested a human-specific GnRH1 antagonist, NBI-42902, in our mouse model and demonstrated abrogation of a GnRH1-induced serum LH rise in ki/ ki mice and an absence of effect in littermates expressing the wild-type murine receptor. This novel model provides the opportunity to study the human receptor in vivo and for screening the activity of human-specific GnRH analogs.
Adenosine A2Areceptors regulate the activity of sleep regulatory GABAergic neurons in the preoptic hypothalamus
Authors: Kumar Sunil , Rai Seema , Hsieh Kung-Chiao , McGinty Dennis , Alam Md. Noor , Szymusiak Ronald
Published: May 2013

The median preoptic nucleus (MnPN) and the ventrolateral preoptic area (VLPO) are two hypothalamic regions that have been implicated in sleep regulation, and both nuclei contain sleep-active GABAergic neurons. Adenosine is an endogenous sleep regulatory substance, which promotes sleep via A1and A2Areceptors (A2AR). Infusion of A2AR agonist into the lateral ventricle or into the subarachnoid space underlying the rostral basal forebrain (SS-rBF), has been previously shown to increase sleep. We examined the effects of an A2AR agonist, CGS-21680, administered into the lateral ventricle and the SS-rBF on sleep and c-Fos protein immunoreactivity (Fos-IR) in GABAergic neurons in the MnPN and VLPO. Intracerebroventricular administration of CGS-21680 during the second half of lights-on phase increased sleep and increased the number of MnPN and VLPO GABAergic neurons expressing Fos-IR. Similar effects were found with CGS-21680 microinjection into the SS-rBF. The induction of Fos-IR in preoptic GABAergic neurons was not secondary to drug-induced sleep, since CGS-21680 delivered to the SS-rBF significantly increased Fos-IR in MnPN and VLPO neurons in animals that were not permitted to sleep. Intracerebroventricular infusion of ZM-241385, an A2AR antagonist, during the last 2 h of a 3-h period of sleep deprivation caused suppression of subsequent recovery sleep and reduced Fos-IR in MnPN and VLPO GABAergic neurons. Our findings support a hypothesis that A2AR-mediated activation of MnPN and VLPO GABAergic neurons contributes to adenosinergic regulation of sleep.
Reduced heart rate variability during sleep in long-duration spaceflight
Authors: Xu D. , Shoemaker J. K. , Blaber A. P. , Arbeille P. , Fraser K. , Hughson R. L.
Published: May 2013

Limited data are available to describe the regulation of heart rate (HR) during sleep in spaceflight. Sleep provides a stable supine baseline during preflight Earth recordings for comparison of heart rate variability (HRV) over a wide range of frequencies using both linear, complexity, and fractal indicators. The current study investigated the effect of long-duration spaceflight on HR and HRV during sleep in seven astronauts aboard the International Space Station up to 6 mo. Measurements included electrocardiographic waveforms from Holter monitors and simultaneous movement records from accelerometers before, during, and after the flights. HR was unchanged inflight and elevated postflight [59.6 ± 8.9 beats per minute (bpm) compared with preflight 53.3 ± 7.3 bpm; P < 0.01]. Compared with preflight data, HRV indicators from both time domain and power spectral analysis methods were diminished inflight from ultralow to high frequencies and partially recovered to preflight levels after landing. During inflight and at postflight, complexity and fractal properties of HR were not different from preflight properties. Slow fluctuations (<0.04 Hz) in HR presented moderate correlations with movements during sleep, partially accounting for the reduction in HRV. In summary, substantial reduction in HRV was observed with linear, but not with complexity and fractal, methods of analysis. These results suggest that periodic elements that influence regulation of HR through reflex mechanisms are altered during sleep in spaceflight but that underlying system complexity and fractal dynamics were not altered.
Functional interaction of COMMD3 and COMMD9 with the epithelial sodium channel
Authors: Liu Yong Feng , Swart Marianne , Ke Ying , Ly Kevin , McDonald Fiona J.
Published: May 2013

The epithelial sodium channel (ENaC) plays an important role in controlling Na+ homeostasis, extracellular fluid volume, and blood pressure. Copper metabolism Murr1 domain-containing protein 1 (COMMD1) interacts with ENaC and downregulates ENaC. COMMD1 belongs to the COMMD family consisting of COMMD1–10, and all COMMD family members share a C-terminal COMM domain. Here, we report that COMMD2–10 also interacts with ENaC, and COMMD3 and COMMD9 were selected for further study. Amiloride-sensitive current in mammalian epithelia expressing ENaC was significantly reduced by COMMD3 or COMMD9, and ENaC expression at the cell surface was significantly decreased in the presence of COMMD3 or COMMD9. COMMD3 and COMMD9 retained their ability to reduce current when COMMD1 was knocked down. COMMD3 and COMMD9 were widely expressed in kidney and were colocalized with ENaC in renal collecting duct cells. These data suggest that COMMD3 and COMMD9 may be endogenous regulators of ENaC to regulate Na+ transport through altering ENaC cell surface expression.
Inhibitory inputs tune the light response properties of dopaminergic amacrine cells in mouse retina
Authors: Newkirk G. S. , Hoon M. , Wong R. O. , Detwiler P. B.
Published: May 2013

Dopamine (DA) is a neuromodulator that in the retina adjusts the circuitry for visual processing in dim and bright light conditions. It is synthesized and released from retinal interneurons called dopaminergic amacrine cells (DACs), whose basic physiology is not yet been fully characterized. To investigate their cellular and input properties as well as light responses, DACs were targeted for whole cell recording in isolated retina using two-photon fluorescence microscopy in a mouse line where the dopamine receptor 2 promoter drives green fluorescent protein (GFP) expression. Differences in membrane properties gave rise to cell-to-cell variation in the pattern of resting spontaneous spike activity ranging from silent to rhythmic to periodic burst discharge. All recorded DACs were light sensitive and generated responses that varied with intensity. The threshold response to light onset was a hyperpolarizing potential change initiated by rod photoreceptors that was blocked by strychnine, indicating a glycinergic amacrine input onto DACs at light onset. With increasing light intensity, the ON response acquired an excitatory component that grew to dominate the response to the strongest stimuli. Responses to bright light (photopic) stimuli also included an inhibitory OFF response mediated by GABAergic amacrine cells driven by the cone OFF pathway. DACs expressed GABA (GABAAα1 and GABAAα3) and glycine (α2) receptor clusters on soma, axon, and dendrites consistent with the light response being shaped by dual inhibitory inputs that may serve to tune spike discharge for optimal DA release.
Cyclophosphamide-induced cystitis reduces ASIC channel but enhances TRPV1 receptor function in rat bladder sensory neurons
Authors: Dang Khoa , Bielefeldt Klaus , Gebhart G. F.
Published: May 2013

Using patch-clamp techniques, we studied the plasticity of acid-sensing ion channels (ASIC) and transient receptor potential V1 (TRPV1) channel function in dorsal root ganglia (DRG) neurons retrogradely labeled from the bladder. Saline (control) or cyclophosphamide (CYP) was given intraperitoneally on days 1, 3, and 5. On day 6, lumbosacral (LS, L6–S2) or thoracolumbar (TL, T13–L2) DRG were removed and dissociated. Bladders and bladder DRG neurons from CYP-treated rats showed signs of inflammation (greater myeloperoxidase activity; lower intramuscular wall pH) and increased size (whole cell capacitance), respectively, compared with controls. Most bladder neurons (>90%) responded to protons and capsaicin. Protons produced multiphasic currents with distinct kinetics, whereas capsaicin always triggered a sustained response. The TRPV1 receptor antagonist A-425619 abolished capsaicin-triggered currents and raised the threshold of heat-activated currents. Prolonged exposure to an acidic environment (pH range: 7.2 to 6.6) inhibited proton-evoked currents, potentiated the capsaicin-evoked current, and reduced the threshold of heat-activated currents in LS and TL bladder neurons. CYP treatment reduced density but not kinetics of all current components triggered by pH 5. In contrast, CYP-treatment was associated with an increased current density in response to capsaicin in LS and TL bladder neurons. Correspondingly, heat triggered current at a significantly lower temperature in bladder neurons from CYP-treated rats compared with controls. These results reveal that cystitis differentially affects TRPV1- and ASIC-mediated currents in both bladder sensory pathways. Acidification of the bladder wall during inflammation may contribute to changes in nociceptive transmission mediated through the TRPV1 receptor, suggesting a role for TRPV1 in hypersensitivity associated with cystitis.
CR-Submanifolds of Generalized -Space Forms
Authors: Jaafari Matehkolaee Mahmood
Published: May 2013

We study sectional curvature, Ricci tensor, and scalar curvature of submanifolds of generalized -space forms. Then we give an upper bound for foliate -horizontal (and vertical) CR-submanifold of a generalized -space form and an upper bound for minimal -horizontal (and vertical) CR-submanifold of a generalized -space form. Finally, we give the same results for special cases of generalized -space forms such as -space forms, generalized Sasakian space forms, Sasakian space forms, Kenmotsu space forms, cosymplectic space forms, and almost -manifolds.
A Uniqueness Theorem for Bessel Operator from Interior Spectral Data
Authors: Sat Murat , Panakhov Etibar S.
Published: May 2013

Inverse problem for the Bessel operator is studied. A set of values of eigenfunctions at some internal point and parts of two spectra are taken as data. Uniqueness theorems are obtained. The approach that was used in investigation of problems with partially known potential is employed.
EYA1 Phosphatase Function Is Essential to Drive Breast Cancer Cell Proliferation through Cyclin D1
Authors: Wu Kongming , Li Zhaoming , Cai Shaoxin , Tian Lifeng , Chen Ke , Wang Jing , Hu Junbo , Sun Ye , Li Xue , Ertel Adam , Pestell Richard G.
Published: May 2013

The Drosophila Eyes Absent Homologue 1 (EYA1) is a component of the retinal determination gene network and serves as an H2AX phosphatase. The cyclin D1 gene encodes the regulatory subunits of a holoenzyme that phosphorylates and inactivates the pRb protein. Herein, comparison with normal breast showed that EYA1 is overexpressed with cyclin D1 in luminal B breast cancer subtype. EYA1 enhanced breast tumor growth in mice in vivo, requiring the phosphatase domain. EYA1 enhanced cellular proliferation, inhibited apoptosis, and induced contact-independent growth and cyclin D1 abundance. The induction of cellular proliferation and cyclin D1 abundance, but not apoptosis, was dependent upon the EYA1 phosphatase domain. The EYA1-mediated transcriptional induction of cyclin D1 occurred via the AP-1–binding site at −953 and required the EYA1 phosphatase function. The AP-1 mutation did not affect SIX1-dependent activation of cyclin D1. EYA1 was recruited in the context of local chromatin to the cyclin D1 AP-1 site. The EYA1 phosphatase function determined the recruitment of CBP, RNA polymerase II, and acetylation of H3K9 at the cyclin D1 gene AP-1 site regulatory region in the context of local chromatin. The EYA1 phosphatase regulates cell-cycle control via transcriptional complex formation at the cyclin D1 promoter. Cancer Res; 73(14); 4488–99. ©2013 AACR.
Identification of Novel Variants in Colorectal Cancer Families by High-Throughput Exome Sequencing
Authors: DeRycke Melissa S. , Gunawardena Shanaka R. , Middha Sumit , Asmann Yan W. , Schaid Daniel J. , McDonnell Shannon K. , Riska Shaun M. , Eckloff Bruce W. , Cunningham Julie M. , Fridley Brooke L. , Serie Daniel J. , Bamlet William R. , Cicek Mine S. , Jenkins Mark A. , Duggan David J. , Buchanan Daniel , Clendenning Mark , Haile Robert W. , Woods Michael O. , Gallinger Steven N. , Casey Graham , Potter John D. , Newcomb Polly A. , Le Marchand Loïc , Lindor Noralane M. , Thibodeau Stephen N. , Goode Ellen L.
Published: May 2013

Background: Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants.

Methods: We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign.

Results: We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively.

Conclusions: Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility.

Impact: Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk. Cancer Epidemiol Biomarkers Prev; 22(7); 1239–51. ©2013 AACR.
EDNRB and DCC Salivary Rinse Hypermethylation Has a Similar Performance as Expert Clinical Examination in Discrimination of Oral Cancer/Dysplasia versus Benign Lesions
Authors: Schussel Juliana , Zhou Xian Chong , Zhang Zhe , Pattani Kavita , Bermudez Francisco , Jean-Charles Germain , McCaffrey Thomas , Padhya Tapan , Phelan Joan , Spivakovsky Silvia , Brait Mariana , Li Ryan , Yoo Bowne Helen , Goldberg Judith D. , Rolnitzky Linda , Robbins Miriam , Kerr A. Ross , Sirois David , Califano Joseph A.
Published: May 2013

Purpose: Promoter hypermethylation has been recently proposed as a means for head and neck squamous cell carcinoma (HNSCC) detection in salivary rinses. In a prospective study of a high-risk population, we showed that endothelin receptor type B (EDNRB) promoter methylation in salivary rinses is a useful biomarker for oral cancer and premalignancy.

Experimental Design: Using that cohort, we evaluated EDNRB methylation status and 8 additional genes. Clinical risk assessment by expert clinicians was conducted and compared with biomarker performance in the prediction of premalignant and malignant disease. Methylation status of 9 genes was analyzed in salivary rinses of 191 patients by quantitative methylation-specific PCR.

Results: HOXA9, EDNRB, and deleted in colorectal cancer (DCC) methylation were associated (P = 0.012; P < 0.0001; P = 0.0005) with premalignant or malignant disease. On multivariable modeling, histological diagnosis was only independently associated with EDNRB (P = 0.0003) or DCC (P = 0.004) methylation. A subset of patients received clinical risk classification (CRC) by expert clinicians based on lesion examination. CRC, DCC, and EDNRB were associated with diagnosis of dysplasia/cancer on univariate (P = 0.008; P = 0.026; P = 0.046) and multivariate analysis (P = 0.012; P = 0.037; P = 0.047). CRC identified dysplasia/cancer with 56% of sensitivity and 66% of specificity with a similar area under curve [AUC; 0.61, 95% confidence interval (CI) = 0.60–0.81] when compared to EDNRB and DCC combined AUC (0.60, 95% CI = 0.51–0.69), sensitivity of 46% and specificity of 72%. A combination of EDNRB, DCC, and CRC was optimal AUC (0.67, 95% CI = 0.58–0.76).

Conclusions: EDNRB and/or DCC methylation in salivary rinses compares well to examination by an expert clinician in CRC of oral lesions. These salivary biomarkers may be particularly useful in oral premalignancy and malignancy screening in clinical care settings in which expert clinicians are not available. Clin Cancer Res; 19(12); 3268–75. ©2013 AACR.
The Efficacy of CHK1 Inhibitors Is Not Altered by Hypoxia, but Is Enhanced after Reoxygenation
Authors: Hasvold Grete , Nähse-Kumpf Viola , Tkacz-Stachowska Kinga , Rofstad Einar K. , Syljuåsen Randi G.
Published: May 2013

Inhibitors of CHK1 are in clinical trials for cancer treatment in combination with DNA-damaging agents. Importantly, it was previously suggested that hypoxic cancer cells may be particularly sensitive to CHK1 inhibition. However, this suggestion was based on studies in severe, toxic levels of hypoxia (anoxia). The influence of less severe hypoxia on the efficacy of CHK1 inhibitors, administered either as single agents or in combination with other treatments, remains to be investigated. Here, we have assayed the effects of the CHK1 inhibitors, AZD7762 and UCN-01, during various hypoxic conditions and after reoxygenation in the absence and presence of ionizing radiation. Treatment with CHK1 inhibitors during acute or prolonged hypoxia (< 0.03%, 0.2%, and 1% O2; 3 h or 20–24 h) gave similar effects on cell survival as treatment with these inhibitors during normoxia. CHK1 inhibitors combined with ionizing radiation showed similar radiosensitization in hypoxic and normoxic cells. However, when the inhibitors were administered after reoxygenation following prolonged hypoxia (< 0.03% and 0.2%; 20–24 h), we observed decreased cell survival and stronger induction of the DNA damage marker, γH2AX, in S-phase cells. This was accompanied by enhanced phosphorylation of the single-stranded DNA-binding replication protein A. These results suggest that the cytotoxic effects of CHK1 inhibitors are enhanced after reoxygenation following prolonged hypoxia, most likely due to the increased replication-associated DNA damage. Combining CHK1 inhibitors with other treatments that cause increased reoxygenation, such as fractionated radiotherapy, might therefore be beneficial. Mol Cancer Ther; 12(5); 705–16. ©2013 AACR.
Overlapping Functions of ABC Transporters in Topotecan Disposition as Determined in Gene Knockout Mouse Models
Authors: Tiwari Amit K. , Zhang Rong , Gallo James M.
Published: May 2013

It is established that efflux transporters of the ATP-binding cassette (ABC) superfamily can affect the pharmacokinetics of drugs through mechanisms pertaining to drug absorption, elimination, and distribution. To characterize the role of multiple transporters in topotecan's pharmacokinetics, total (lactone+carboxylate) and lactone forms were measured by liquid chromatography/tandem mass spectrometry (LC/MS-MS) in plasma, bile, urine, and feces following intravenous administration at doses of 1 and 4 mg/kg to eight mouse strains: C57BL/6 [wild-type (WT)], Abcb1−/−, Abcc2−/−, Abcc4−/−, Abcg2−/−, Abcc2;Abcb1−/−, Abcc2;Abcg2−/−, and Abcc4;Abcg2−/−. Compared with WT mice and at both dose levels, the plasma areas under the curve for topotecan lactone were not significantly different in the Abcc2−/−, Abcc4−/−, and Abcb1−/− strains, whereas significant differences were found in Abcg2−/−, Abcc2;Abcb1−/− (only at the high dose), Abcc4;Abcg2−/−, and Abcc2;Abcg2−/− mice and ranged from 2.1- to 3.3-fold higher. Consistent with these changes, the fecal and biliary excretion of topotecan was reduced, whereas renal elimination was elevated in Abcg2−/−-based strains. Similarly, the Abcc2;Abcb1−/− strain also had elevated renal elimination and reduced fecal excretion of topotecan lactone. This was more pronounced at the 4 mg/kg dose level, suggesting possible saturation of Abcg2. The Abcc4 transporter was found not to be a major determinant of topotecan pharmacokinetics. It is concluded that Abcg2 has the most significant effect on topotecan elimination, whereas both Abcb1 and Abcc2 have overlapping functions with Abcg2. As such it is relevant to examine how polymorphisms in these transporters influence topotecan activity in patients and whether coadministration of transport modulators could positively affect efficacy without increasing toxicity. Mol Cancer Ther; 12(7); 1343–55. ©2013 AACR.
Urinary PGE-M: A Promising Cancer Biomarker
Authors: Wang Dingzhi , DuBois Raymond N.
Published: May 2013

Cancer prevention, early diagnosis, and targeted therapies are the keys to success in better cancer control and treatment. A big challenge remains to identify biomarkers for predicting who may have higher cancer risk and are able to respond to certain chemopreventive agents as well as for assessing a patient's response during treatment. Although a large body of evidence indicates that chronic inflammation is a risk factor for cancer, it is unclear whether inflammatory biomarkers can be used to predict cancer risk, progression, and death. Considering the importance of the proinflammatory COX-2–derived prostaglandin E2 (PGE2) in inflammation and cancer, Morris and colleagues found that urinary PGE-M is positively associated with obesity, smoking, and lung metastases in patients with breast cancer (4). Along the same lines, Kim and colleagues showed a potential association between urinary PGE-M and breast cancer risk in postmenopausal women (beginning on page 511). In agreement with previous reports, their findings indicate that urinary PGE-M may serve as a promising biomarker for prognosticating cancer risk and disease progression. Cancer Prev Res; 6(6); 507–10. ©2013 AACR.
Does chronic kidney disease improve the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification risk scores for atrial fibrillation?
Authors: Roldán Vanessa , Marín Francisco , Manzano-Fernández Sergio , Fernández Hermógenes , Gallego Pilar , Valdés Mariano , Vicente Vicente , Lip Gregory Y. H.
Published: May 2013

Chronic Kidney Disease (CKD) constitutes an adverse risk factor in chronic anticoagulated atrial fibrillation (AF) patients, being related to adverse cardiovascular events, mortality and major bleeds. It is unclear if CKD adds independent prognostic information to stroke risk stratification schemes, as the risk factor components of the CHADS2 and CHA2DS2-VASc scores are themselves related to renal dysfunction. The aim of our study was to determine if CKD independently improves the predictive value of the CHADS2 and CHA2DS2-VASc stroke stratification scores in AF. We recruited consecutive patients (n=978) patients (49% male; median age 76) with permanent or paroxysmal AF on oral anticoagulants with acenocoumarol, from our out-patient anticoagulation clinic. After a median follow-up of 875 (IQR 706–1059) days, we recorded stroke/transient ischaemic attack (TIA), peripheral embolism, vascular events (acute coronary syndrome, acute heart failure and cardiac death) and all-cause mortality. During follow-up, 113 patients (4.82%/year) experienced an adverse cardiovascular event, of which 39 (1.66%/year) were strokes, 43 (1.83%/year) had an acute coronary syndrome and 32 (1.37%/year) had acute heart failure. Also, 102 patients (4.35%/year) died during the following up, 31 of them (1.32%/year) as a result of a thrombotic event. Based on c-statistics and the integrated discrimination improvement (IDI), CKD did not improve the prediction for stroke/systemic embolism, thrombotic events and all-cause mortality using the CHADS2 and CHA2DS2-VASc scores. In conclusion, evaluating renal function in AF patients is important as CKD would confer a poor overall prognosis in terms of thromboembolic events and all-cause mortality. Adding CKD to the CHADS2 and CHA2DS2-VASc stroke risk scores did not independently add predictive information.

Note: The review process for this manuscript was fully handled by Christian Weber, Editor in Chief.
Efficacy of the CCR5 Antagonist Maraviroc in Reducing Early, Ritonavir-Induced Atherogenesis and Advanced Plaque Progression in Mice
Authors: Cipriani Sabrina , Francisci Daniela , Mencarelli Andrea , Renga Barbara , Schiaroli Elisabetta , D’Amore Claudio , Baldelli Franco , Fiorucci Stefano
Published: May 2013

Background—

CCR5 plays an important role in atherosclerosis and ischemic cardiovascular diseases, as well as in HIV replication and diffusion. HIV infection is characterized by a high burden of cardiovascular diseases, particularly in subjects exposed to ritonavir-boosted protease inhibitors. Maraviroc, a CCR5 antagonist antiretroviral drug, might provide benefit for patients with M-tropic HIV infections at high risk for cardiovascular diseases.

Methods and Results—

Exposure to maraviroc limits the evolution and associated systemic inflammation of ritonavir-induced atherosclerotic in ApoE
−/−
mice and inhibits plaques development in a late model of atherosclerosis in which dyslipidemia plays the main pathogenic role. In ritonavir-treated mice, maraviroc reduced plaque areas and macrophage infiltration; downregulated the local expression of vascular cell adhesion molecule-1, intercellular adhesion molecule-1, monocyte chemoattractant protein-1, and interleukin-17A; and reduced tumor necrosis factor-α and RANTES (regulated on activation, normal T cell expressed, and secreted). Moreover, maraviroc counterregulated ritonavir-induced lipoatrophy and interlelukin-6 gene expression in epididymal fat, along with the splenic proinflammatory profile and expression of CD36 on blood monocytes. In the late model, maraviroc inhibited atherosclerotic progression by reducing macrophage infiltration and lowering the expression of adhesion molecules and RANTES inside the plaques. However, limited systemic inflammation was observed.

Conclusions—

In a mouse model of genetic dyslipidemia, maraviroc reduced the atherosclerotic progression by interfering with inflammatory cell recruitment into plaques. Moreover, in mice characterized by a general ritonavir-induced inflammation, maraviroc reversed the proinflammatory profile. Therefore, maraviroc could benefit HIV-positive patients with residual chronic inflammation who are at a high risk of acute coronary disease despite a suppressive antiretroviral therapy. To determine these benefits, large clinical studies are needed.
New sea anemone (Anthozoa: Actiniaria) from Patagonia: Andvakia manoloi sp. nov.
Authors: LAURETTA DANIEL
Published: May 2013

A new species of sea anemone from the intertidal zone of San Matías Gulf is described. Andvakia manoloi sp. nov. is a small and inconspicuous species that differs from other species of the genus in number of tentacles, number of mesenteries at proximal and distal part of the column, column division, muscles, cnidae, size, habit and distribution. Andvakia manoloi sp. nov. is the first species of the genus from South America and the southernmost record of the genus.
Revision of Cerozodus Bigot, 1857 (Diptera, Asilidae, Asilinae) with description of a new species from Brazil
Authors: VIEIRA RODRIGO , RAFAEL JOSÉ ALBERTINO , LIMEIRA-DE-OLIVEIRA FRANCISCO
Published: May 2013

The second species of the Neotropical genus Cerozodus Bigot, 1857, Cerozodus brachylobus sp. nov. is described from Mirador, Maranhão state, Brazil and Cerozodus nodicornis (Wiedemann, 1828) is redescribed. The habitus, wing and male terminalia structures are described and illustrated.
Notes on the correct taxonomic status of Haliotis rugosa Lamarck, 1822, and Haliotis pustulata Reeve, 1846, with description of a new subspecies from Rodrigues Island, Mascarene Islands, Indian Ocean (Mollusca: Vetigastropoda: Haliotidae)
Authors: OWEN BUZZ
Published: May 2013

Haliotis rugosa Lamarck, 1822, and H. pustulata Reeve, 1846, have long been a source of confusion. Herbert (1990) suggested the synonymy of the two and designated the lectotype and type locality of H. rugosa. Examination of several hundred shells of each of the two taxa has demonstrated that the H. rugosa morphology is found only on Mauritius and Reunion, while the H. pustulata morph occurs at Madagascar and the east coast of Africa, from approximately Park Rynie, South Africa, to the Red Sea and east to Yemen. No specimens from the latter localities resemble H. rugosa; however, a very small number of specimens from Mauritius have an intermediate morphology between the two taxa. The two species-level taxa are here considered as subspecies of each other. They show some overlapping shell morphology, but are geographically isolated.
Bariatric Surgery Complications Leading to Small Bowel Transplant
Authors: Raheem Sulieman Abdal , Deen Omer J. , Corrigan Mandy L. , Parekh Neha , Quintini Cristiano , Steiger Ezra , Kirby Donald F.
Published: May 2013

Obesity is a major chronic disease affecting the U.S. population. Bariatric surgery has consistently shown greater weight loss and improved outcomes compared with conservative therapy. However, complications after bariatric surgery can be catastrophic, resulting in short bowel syndrome with a potential risk of intestinal failure, ultimately resulting in the need for a small bowel transplant. A total of 6 patients became dependent on home parenteral nutrition (HPN) after undergoing bariatric surgery at an outside facility. Four of the 6 patients required evaluation for small bowel transplant; 2 of the 6 patients were successfully managed with parenteral nutrition and did not require further small bowel transplant evaluation. Catheter‐related bloodstream infection, a serious complication of HPN, occurred in 3 patients despite extensive patient education on catheter care and use of ethanol lock. Two patients underwent successful small bowel transplantation, 1 died before transplant could be performed, and 1 was listed for a multivisceral transplantation. Surgical procedures to treat morbid obesity are common and growing in popularity but are not without risk of serious complications, including intestinal failure and HPN dependency. Despite methods to prevent complications, failure of HPN may lead to the need for transplant evaluation. In selected cases, the best therapeutic treatment may be a small bowel transplant to resolve irreversible, post–bariatric surgery intestinal failure.
Effect of severe plastic deformation on hot cracking of wrought aluminium alloy in pulsed laser welding
Authors: Malekshahi Beiranvand Z , Malek Ghaini F , Sheikhi M , Abdollah-Zadeh A
Published: May 2013

The effect of friction stir processing (FSP) on the behaviour of wrought alloy 2024 in pulsed laser welding was examined. The results showed that FSP changes the microstructure and that significantly affects the susceptibility of the base metal to liquation cracking. The change in cracking behaviour is proposed to be related to the refinement of the microstructure and redistribution of precipitates along the grain boundaries, increasing the flexibility of the grain network. According to the observations, as a result of FSP, not only liquation cracks but also solidification cracks were reduced, supporting the view that liquation cracks can act as the source of some of the solidification cracks.
Microstructure and mechanical properties of arc melted Cr–Cr2Nb hypoeutectic alloy
Authors: Li K W , Li S M , Xue Y L , Fu H Z
Published: May 2013

The microstructure and mechanical properties of a binary Cr based alloy containing the Laves phase Cr2Nb and Cr phase have been studied in the arc melted condition. Microstructure consisting of fine directional divorced eutectic was observed at the bottom of the ingot, while it developed into coarse Cr primary dendrites plus interdendritic lamellar eutectic containing Cr2Nb and Cr phases in the middle and top parts of the ingot. Meanwhile, the fracture toughness values of the top and bottom parts of the ingot attained 4·5 and 7·8 MPa m1/2 at room temperature, which were about three and five times than that of monolithic Cr2Nb respectively. The enhancement was explained by the second Cr phase toughening and grain refinement toughening mechanisms. In addition, the formation mechanism of the divorced eutectic and the microstructure–property relationships were also discussed.
Effect of equal channel angular pressing on microstructural and mechanical properties of as cast Al–20 wt-Zn alloy
Authors: Aydın M , Heyal Y
Published: May 2013

The microstructural and mechanical properties, mainly the hardness, tensile properties and impact toughness of two phase Al–20 wt-Zn alloy subjected to severe plastic deformation via equal channel angular pressing (ECAP) up to two passes, were studied. High cycle fatigue behaviour of ECAP processed alloy was investigated for the first time. The ECAP almost completely eliminated the as cast dendritic microstructure including casting defects such as microporosities and formed a refined microstructure consisting of elongated microconstituents, aluminium rich α and zinc rich α+ η eutectoid phases. As a result of this microstructural change, the tensile response, impact toughness and fatigue performance of the alloy improved significantly. The rates of increase in endurance limit and impact toughness after ECAP are 89 and 122 respectively. In addition, a relationship represented by an equation between the stress amplitude σa and number of cycles to failure N values was determined to express the fatigue behaviour of the alloy in all states. It was also observed that the nature of fatigue fracture characteristics of the as cast Al–20 wt-Zn alloy changed after ECAP.
Microstructure and mechanical behaviour of asymmetric extruded Mg–3Al–1Zn alloy sheets
Authors: Yang Q S , Jiang B , Dai J H , Xiang Q , Pan F S
Published: May 2013

Microstructural evolution and mechanical responses of Mg–3Al–1Zn (AZ31) sheet processed by the asymmetric extrusion (ASE) and conventional extrusion (CE) are examined. Mechanical properties of ASE sheets were remarkably enhanced compared with CE samples. This is attributed to the subdivision of the asymmetric extrusion die along the flow passage equipped with a chamfer on one side, which would trigger the angular spread of the basal texture by introducing an asymmetry shear deformation. Moreover, subsequent annealed ASE specimens show a significant weakening of the basal texture and a combination of the superior stretch formability.
Comparison of microstructural evolution in Pt aluminised Ni based superalloys with and without Ru
Authors: Suzuki A S , Rae C M F
Published: May 2013

The microstructural evolutions in two Pt aluminised Ni based single crystal superalloys were compared to explore the effect of Ru. Ni based single crystal superalloys containing 0 and 3 wt-Ru were Pt aluminised and isothermally exposed at 1100°C for 500 h. The 0 wt-Ru alloy showed sporadic secondary reaction zone (SRZ) formation after aluminisation, whereas the 3 wt-Ru alloy developed a continuous SRZ. During exposure, the 3 wt-Ru alloy retained a continuous SRZ, while the 0 wt-Ru alloy developed voids in the coating layer in addition to sporadic SRZ formation. The 3 wt-Ru alloy showed a deeper penetration of the SRZ after exposure, almost double that of the 0 wt-Ru alloy, and demonstrated numerous nucleation sites within the SRZ layer, growing continuously under the interdiffusion zone (IDZ). In contrast, the 0 wt-Ru alloy showed a layer of retained substrate between the SRZ and IDZ, formed due to sporadic nucleation associated with defects in the coating and the growth of the coating from these sites. Ru additions to coated Ni based single crystal superalloys encourage nucleation of the SRZ in the 3 wt-Ru alloy.