bluuebunny/crossref_metadata_2025 huggingface dataset:
AN EFFICIENT SEVENTH POWER RESIDUE SYMBOL ALGORITHM
Authors: CARANAY PERLAS C. , SCHEIDLER RENATE
Published: January 2011

Power residue symbols and their reciprocity laws have applications not only in number theory, but also in other fields like cryptography. A crucial ingredient in certain public key cryptosystems is a fast algorithm for computing power residue symbols. Such algorithms have only been devised for the Jacobi symbol as well as for cubic and quintic power residue symbols, but for no higher powers. In this paper, we provide an efficient procedure for computing 7th power residue symbols. The method employs arithmetic in the field ℚ(ζ), with ζ a primitive 7th root of unity, and its ring of integers ℤ[ζ]. We give an explicit characterization for an element in ℤ[ζ] to be primary, and provide an algorithm for finding primary associates of integers in ℤ[ζ]. Moreover, we formulate explicit forms of the complementary laws to Kummer's 7th degree reciprocity law, and use Lenstra's norm-Euclidean algorithm in the cyclotomic field.
A SURVEY OF RAMANUJAN EXPANSIONS
Authors: LUCHT LUTZ G.
Published: January 2011

This paper summarizes the development of Ramanujan expansions of arithmetic functions since Ramanujan's paper in 1918, following Carmichael's mean-value-based concept from 1932 up to 1994. A new technique, based on the concept of related arithmetic functions, is introduced that leads to considerable extensions of preceding results on Ramanujan expansions. In particular, very short proofs of theorems for additive and multiplicative functions going far beyond previous borders are presented, and Ramanujan expansions that formerly have been considered mysterious are explained.
ON A KIND OF DUALITY OF MULTIPLE ZETA-STAR VALUES
Authors: KANEKO MASANOBU , OHNO YASUO
Published: January 2011

A duality-type relation for height one multiple zeta-star values is established. A conjectural generalization to the case of arbitrary height is also presented.
Fractal analysis of the ore-forming process in a skarn deposit: a case study in the Shizishan area, China
Authors: Wang Qingfei , Deng Jun , Liu Huan , Wan Li , Zhang Zhijun
Published: January 2011

This paper presents a tool for analysing the element distribution and mineralization intensity. The Hurst exponents and
a
-
f
(
a
) multifractal spectrum are utilized to analyse the irregular element distribution in Shizishan skarn orefield, China. The Hurst exponents reveal the Cu, Ag, Au and Zn distributions in the skarn-dominated drill cores are persistent and those in marble-dominated drill core are nearly random; the persistence indicates the mineralized segments are repeatedly developed, with accordance to multi-layer structure of the ore-controlling bedding faults and orebodies. The small
a
min
(minimum multifractal singularity) of the Cu, Ag and Au in M
1
reflect bare mineralization. The
a
min
also displays that the mineralization intensities are varied for distinct elements and for different locations, yet the similarity of the distinct ore-forming processes is manifested by constant
a
min
/
f
(
a
min
) ratio. The constant ratio indicates the wider mineralization range denotes a more compact concentration distribution. The compact distributions represent the wide Cu, Ag and Au mineralization in skarns, and the loose distributions reflect the bare Cu, Ag and Au mineralization in marbles. Moreover
a
min
shows a positive correlation with Hurst exponents in the Shizishan skarn orefield. Using fractal analysis the author's show that although the mineralization intensities for different elements and different locations along the Shizishan skarn orefield is not consistent, similar mineralization processes can be correlated to similar fractal exponents.
Geological setting, alteration, and fluid inclusion characteristics of Zaglic and Safikhanloo epithermal gold prospects, NW Iran
Authors: Ebrahimi Susan , Alirezaei Saeed , Pan Yuanming
Published: January 2011

The Zaglic and Safikhanloo epithermal gold prospects are located in the Arasbaran zone, to the west of the Cenozoic Alborz-Azarbaijan magmatic belt in NW Iran. Mineralization is mainly restricted to quartz and quartz -carbonate veins and veinlets. Pyrite is the main sulphide, associated with subordinate chalcopyrite and bornite. Gold occurs as microscopic and submicroscopic grains in quartz and pyrite.

The country rocks are Tertiary intermediate–mafic volcanic and volcaniclastic rocks of andesite to trachy-andesite composition intruded by a composite granitic to syenitic pluton. They are medium- to high-K, calc-alkaline and alkaline rocks and display fractionated REE (rare earth element) patterns, with light rare earth elements (LREE) significantly enriched relative to the heavy rare elements (HREE). On primitive mantle normalized plots, they display depletions in Nb, Ti and P, and enrichments in Pb, which are common characteristics of arc-related magmas worldwide. Hydrothermal alteration minerals developed in the wall rocks include quartz, calcite, pyrite, kaolinite, montmorillonite, illite, chlorite, and epidote. Minor alunite occurs in Safikhanloo. Gold is locally enriched in the altered rocks immediate to the veins.

The ore-stage quartz from both prospects is dominated by liquid-rich fluid inclusions; vapour-rich inclusions are rare. The homogenization temperature varies between 170–230 and 170–330 °C and salinity varies between 1.4 to 9.5 and <1 to 6.7 wt% NaCl equivalent, for Safikhanloo and Zaglic, respectively. The occurrence of hydrothermal breccias, bladed calcite, adularia, and rare coexisting vapour- and liquid-dominant inclusions suggest that boiling occurred in the course of the evolution of the ore fluids. The large variations in Th and the salinity values can be explained by boiling and/or mixing.

Lack of sulphate minerals in the veins suggests that sulphides and gold precipitated from a reduced, H
2
S-dominant fluid. Calculated δ
34
S values for the ore fluid vary between −4.6 and −9.3‰. Sulphur could have been derived directly from magmatic sources, or leached from the volcanic and plutonic country rocks. Ore formation in Zaglic and Safikhanloo occurred in response to mixing, boiling, and interactions with wall rocks. Considering the intermediate-argillic alteration, the low contents of base metal sulphides, and the overall low salinities, the Zaglic and Safikhanloo can be classified as low-sulphidation epithermal systems.
Dual-color quantum dot detection of a heterotetrameric potassium channel (hKCa3.1)
Authors: Waschk Daniel E. J. , Fabian Anke , Budde Thomas , Schwab Albrecht
Published: January 2011

Potassium channels play a key role in establishing the cell membrane potential and are expressed ubiquitously. Today, more than 70 mammalian K+ channel genes are known. The diversity of K+ channels is further increased by the fact that different K+ channel family members may assemble to form heterotetramers. We present a method based on fluorescence microscopy to determine the subunit composition of a tetrameric K+ channel. We generated artificial “heteromers” of the K+ channel hKCa3.1 by coexpressing two differently tagged hKCa3.1 constructs containing either an extracellular hemagglutinin (HA) or an intracellular V5 epitope. hKCa3.1 channel subunits were detected in the plasma membrane of MDCK-F cells or HEK293 cells by labeling the extra- and intracellular epitopes with differently colored quantum dots (QDs). As previously shown for the extracellular part of hKCa3.1 channels, its intracellular domain can also bind only one QD label at a time. When both channel subunits were coexpressed, 27.5 ± 1.8% and 24.9 ± 2.1% were homotetramers consisting of HA- and V5-tagged subunits, respectively. 47.6 ± 3.2% of the channels were heteromeric and composed of both subunits. The frequency distribution of HA- and V5-tagged homo- and heteromeric hKCa3.1 channels is reminiscent of the binomial distribution ( a + b)2 = a2 + 2 ab + b2. Along these lines, our findings are consistent with the notion that hKCa3.1 channels are assembled from two homomeric dimers and not randomly from four independent subunits. We anticipate that our technique will be applicable to other heteromeric membrane proteins, too.
Atypical antipsychotic drugs perturb AMPK-dependent regulation of hepatic lipid metabolism
Authors: Oh Kyoung-Jin , Park Jinyoung , Lee Su Yeon , Hwang Injae , Kim Jae Bum , Park Tae-Sik , Lee Heon-Jeong , Koo Seung-Hoi
Published: January 2011

Dysregulation of lipid metabolism is a key feature of metabolic disorder related to side effects of antipsychotic drugs. Here, we investigated the molecular mechanism by which second-generation atypical antipsychotic drugs (AAPDs) affect hepatic lipid metabolism in liver. AAPDs augmented hepatic lipid accumulation by activating expression of sterol regulatory element-binding protein (SREBP) transcription factors, with subsequent induction of downstream target genes involved in lipid and cholesterol synthesis in hepatocytes. We confirmed the direct involvement of SREBPs on AAPD-induced expression of lipogenic and cholesterogenic genes by utilization of adenovirus for dominant negative SREBP (Ad-SREBP-DN). Interestingly, AAPDs significantly decreased phosphorylation of AMPKα and expression of fatty acid oxidation genes. Treatment of constitutive active AMPK restored AAPD-mediated dysregulation of genes involved in both lipid synthesis and fatty acid oxidation. Moreover, AAPDs decreased transcriptional activity of PPARα, a critical transcriptional regulator for controlling hepatic fatty acid oxidation, via an AMPK-dependent manner. Close investigations revealed that mutations at the known p38 MAPK phosphorylation sites (S6/12/21A), but not mutations at the putative AMPKα phosphorylation sites (S167/373/453A), block AAPD-dependent reduction of PPARα transcriptional activity, suggesting that p38 MAPK might be also involved in the regulatory pathway as a downstream effector of AAPDs/AMPK. Taken together, these data suggest that AAPD-stimulated hepatic dysregulation of lipid metabolism could result from the inhibition of AMPK activity, and pharmaceutical means to potentiate AMPK activity would contribute to restore hepatic lipid homeostasis that occurs during AAPD treatment.
Volume loading reduces pulmonary vascular resistance in ventilated animals with acute lung injury: evaluation of RV afterload
Authors: Mitchell Jamie R. , Doig Christopher J. , Whitelaw William A. , Tyberg John V. , Belenkie Israel
Published: January 2011

During mechanical ventilation, increased pulmonary vascular resistance (PVR) may decrease right ventricular (RV) performance. We hypothesized that volume loading, by reducing PVR, and, therefore, RV afterload, can limit this effect. Deep anesthesia was induced in 16 mongrel dogs (8 oleic acid-induced acute lung injury and 8 controls). We measured ventricular pressures, dimensions, and stroke volumes during positive end-expiratory pressures of 0, 6, 12, and 18 cmH2O at three left ventricular (LV) end-diastolic pressures (5, 12, and 18 mmHg). Oleic acid infusion (0.07 ml/kg) increased PVR and reduced respiratory system compliance ( P < 0.05). With positive end-expiratory pressure, PVR was greater at a lower LV end-diastolic pressure. Increased PVR was associated with a decreased transseptal pressure gradient, suggesting that leftward septal shift contributed to decreased LV preload, in addition to that caused by external constraint. Volume loading reduced PVR; this was associated with improved RV output and an increased transseptal pressure gradient, which suggests that rightward septal shift contributed to the increased LV preload. If PVR is used to reflect RV afterload, volume loading appeared to reduce PVR, thereby improving RV and LV performance. The improvement in cardiac output was also associated with reduced external constraint to LV filling,; since calculated PVR is inversely related to cardiac output, increased LV output would reduce PVR. In conclusion, our results, which suggest that PVR is an independent determinant of cardiac performance, but is also dependent on cardiac output, improve our understanding of the hemodynamic effects of volume loading in acute lung injury.
Tamm-Horsfall protein-deficient thick ascending limbs promote injury to neighboring S3 segments in an MIP-2-dependent mechanism
Authors: El-Achkar Tarek M. , McCracken Ruth , Rauchman Michael , Heitmeier Monique R. , Al-Aly Ziyad , Dagher Pierre C. , Wu Xue-Ru
Published: January 2011

Tamm-Horsfall protein (THP) is a glycoprotein expressed exclusively in thick ascending limbs (TAL) of the kidney. We recently described a novel protective role of THP against acute kidney injury (AKI) via downregulation of inflammation in the outer medulla. Our current study investigates the mechanistic relationships among the status of THP, inflammation, and tubular injury. Using an ischemia-reperfusion model in wild-type and THP−/− mice, we demonstrate that it is the S3 proximal segments but not the THP-deficient TAL that are the main targets of tubular injury during AKI. The injured S3 segments that are surrounded by neutrophils in THP−/− mice have marked overexpression of neutrophil chemoattractant MIP-2 compared with wild-type counterparts. Neutralizing macrophage inflammatory protein-2 (MIP-2) antibody rescues S3 segments from injury, decreases neutrophil infiltration, and improves kidney function in THP−/− mice. Furthermore, using immunofluorescence volumetric imaging of wild-type mouse kidneys, we show that ischemia alters the intracellular translocation of THP in the TAL cells by partially shifting it from its default apical surface domain to the basolateral domain, the latter being contiguous to the basolateral surface of S3 segments. Concomitant with this is the upregulation, in the basolateral surface of S3 segments, of the scavenger receptor SRB-1, a putative receptor for THP. We conclude that TAL affects the susceptibility of S3 segments to injury at least in part by regulating MIP-2 expression in a THP-dependent manner. Our findings raise the interesting possibility of a direct role of basolaterally released THP on regulating inflammation in S3 segments.
Hepatic gene expression profiling of 5′-AMP-induced hypometabolism in mice
Authors: Zhao Zhaoyang , Miki Takao , Van Oort-Jansen Anita , Matsumoto Tomoko , Loose David S. , Lee Cheng Chi
Published: January 2011

There is currently much interest in clinical applications of therapeutic hypothermia. Hypothermia can be a consequence of hypometabolism. We have recently established a procedure for the induction of a reversible deep hypometabolic state in mice using 5′-adenosine monophosphate (5′-AMP) in conjunction with moderate ambient temperature. The current study aims at investigating the impact of this technology at the gene expression level in a major metabolic organ, the liver. Our findings reveal that expression levels of the majority of genes in liver are not significantly altered by deep hypometabolism. However, among those affected by hypometabolism, more genes are differentially upregulated than downregulated both in a deep hypometabolic state and in the early arousal state. These altered gene expression levels during 5′-AMP induced hypometabolism are largely restored to normal levels within 2 days of the treatment. Our data also suggest that temporal control of circadian genes is largely stalled during deep hypometabolism.
Adipose tissue transcriptome changes during obesity development in female dogs
Authors: Grant Ryan W. , Vester Boler Brittany M. , Ridge Tonya K. , Graves Thomas K. , Swanson Kelly S.
Published: January 2011

During the development of obesity, adipose tissue undergoes major expansion and remodeling, but the biological processes involved in this transition are not well understood. The objective of this study was to analyze global gene expression profiles of adipose tissue in dogs, fed a high-fat diet, during the transition from a lean to obese phenotype. Nine female beagles (4.09 ± 0.64 yr; 8.48 ± 0.35 kg) were randomized to ad libitum feeding or body weight maintenance. Subcutaneous adipose tissue biopsy, blood, and dual x-ray absorptiometry measurements were collected at 0, 4, 8, 12, and 24 wk of feeding. Serum was analyzed for glucose, insulin, fructosamine, triglycerides, free fatty acids, adiponectin, and leptin. Formalin-fixed adipose tissue was used for determination of adipocyte size. Adipose RNA samples were hybridized to Affymetrix Canine 2.0 microarrays. Statistical analysis, using repeated-measures ANOVA, showed ad libitum feeding increased ( P < 0.05) body weight (0 wk, 8.36 ± 0.34 kg; 24 wk, 14.64 ± 0.34 kg), body fat mass (0 wk, 1.36 ± 0.24 kg; 24 wk, 6.52 ± 0.24 kg), adipocyte size (0 wk, 114.66 ± 17.38 μm2; 24 wk, 320.97 ± 0.18.17 μm2), and leptin (0 wk, 0.8 ± 1.0 ng/ml; 24 wk, 12.9 ± 1.0 ng/ml). Microarrays displayed 1,665 differentially expressed genes in adipose tissue as weight increased. Alterations were seen in adipose tissue homeostatic processes including metabolism, oxidative stress, mitochondrial homeostasis, and extracellular matrix. Adipose transcriptome changes highlight the dynamic and adaptive response to ad libitum feeding and obesity development.
p73-Binding Partners and Their Functional Significance
Authors: Ozaki Toshinori , Kubo Natsumi , Nakagawara Akira
Published: January 2011

p73 is one of the tumor-suppressor p53 family of nuclear transcription factor. As expected from the structural similarity between p53 and p73, p73 has a tumor-suppressive function. However, p73 was rarely mutated in human primary tumors. Under normal physiological conditions, p73 is kept at an extremely low level to allow cells normal growth. In response to a certain subset of DNA damages, p73 is induced dramatically and transactivates an overlapping set of p53-target genes implicated in the promotion of cell cycle arrest and/or apoptotic cell death. Cells undergo cell cycle arrest and/or apoptotic cell death depending on the type and strength of DNA damages. p73 is regulated largely through the posttranslational modifications such as phosphorylation and acetylation. These chemical modifications are tightly linked to direct protein-protein interactions. In the present paper, the authors describe the functional significance of the protein-protein interactions in the regulation of proapoptotic p73.
Strong Convergence Theorem for Equilibrium Problems and Fixed Points of a Nonspreading Mapping in Hilbert Spaces
Authors: Plubtieng Somyot , Chornphrom Sukanya
Published: January 2011

We introduce an iterative method for finding a common element of the set of solutions of equilibrium problems and the set of fixed points of a nonspreading mapping in a Hilbert space. Then, we prove a strong convergence theorem which is connected with the work of S. Takahashi and W. Takahashi (2007) and Iemoto and Takahashi (2009).
The Role of Fas-FasL Signaling Pathway in Induction of Apoptosis in Patients with Sulfur Mustard-Induced Chronic Bronchiolitis
Authors: Pirzad Gila , Jafari Mahvash , Tavana Sasan , Sadrayee Homayoon , Ghavami Saeid , Shajiei Arezoo , Ghanei Mostafa
Published: January 2011

Sulfur mustard (SM) is an alkylating agent that induces apoptosis and necrosis in cells. Fas-Fas ligand (FasL) interaction could induce apoptosis as well. In this study, it was hypothesized that apoptosis might play an important role in the pathogenesis of SM-induced lung injury via Fas-FasL signaling pathway. In a case-control study, Fas and FasL levels, caspase-3 activity and percent of apoptotic cells were measured in bronchoalveolar lavage (BAL) fluid of patients 20 years after exposure to sulfur mustard and compared with the control group. Results show that Fas and FasL levels were significantly higher in BAL fluid cells in patients group compared with the control (P=.001). No significant differences were observed between mild and moderate-severe groups. BAL fluid cells caspase-3 activity was not significantly different among the mild, moderate-severe, and control groups. The data suggest that Fas-FasL-induced apoptosis was impaired in BAL fluid cells of SM-exposed patients which might be one of the initiators of pathogenesis in SM-induced lung injury in these patients.
Long-Term Relationships between the Marine Environment, Krill and Salps in the Southern Ocean
Authors: Lee Chung Il , Pakhomov Evgeny , Atkinson Angus , Siegel Volker
Published: January 2011

Long-term variations (1975–2002) in climatology of marine environmental parameters, Antarctic krill,Euphausia superba, and the pelagic tunicate,Salpa thompsoni, were compared within the Atlantic Sector of the Southern Ocean. Sea water temperature in the top 400 m increased at a rate of 0.020–0.030°C ⋅ yr−1, which was accompanied by the dissolved oxygen decline. Top 100 m water layer became fresher with lower concentrations of phosphates and nitrates, while at subsurface layers (200–400 m) both salinity and nutrients showed small increasing trend. Unlike phosphates and nitrates, silicate concentrations decreased in the entire water column. Shorter-term water temperature dynamics closely correlated with the El Nino events expressed as the Southern Oscillation Index which in turn was linked to the propagation of the Antarctic Circumpolar Wave (ACW). The variations of sea-ice extent matched well the changes in both air and water temperatures. In general, abundance of krill and salps showed opposite to each other trends. Due to large area considered in this study, no significant relationships between abiotic factors and both krill and salps were found. However, our analysis demonstrated that krill abundance was greater in years with lower sea water temperature, greater sea-ice extent and higher nutrient concentration, while salps showed the opposite pattern.
Energy of the Conduction Band in Near Critical Point Fluids
Authors: Evans C. M. , Findley G. L.
Published: January 2011

The study of the evolution of the conduction band in dense gases and supercritical fluids near
the critical point has been complicated by a lack of precise experimental measurements. Both
photoemission from an electrode immersed in the fluid and field ionization of a molecule doped
into the fluid have been used to probe solvent density effects on the energy of an excess electron as
a function of fluid number density and temperature. In this perspective, we present recent experimental results that show a strong critical point effect on the minimum conduction band energy near
the critical density and temperature of a fluid. We also discuss the recent development of a new
theoretical model that advances our understanding of the density and temperature dependence of
the conduction band minimum in near critical point fluids.
Malignant Cerebral Edema following CT Myelogram Using Isovue-M 300 Intrathecal Nonionic Water-Soluble Contrast: A Case Report
Authors: Kelley Brian C. , Roh Simon , Johnson Philip L. , Arnold Paul M.
Published: January 2011

Lumbar myelogram utilizing nonionic contrast is a commonly performed procedure to identify spinal pathology. Complication rates are low. Cerebral edema has been shown to occur following intrathecal injection of ionic contrast; however, no current literature has documented this complication relating to the ubiquitously used nonionic contrast medium. We report a case of a patient who developed malignant cerebral edema following a lumbar myelogram with Isovue-M 300 nonionic water-soluble intrathecal contrast. We believe this is the first reported case of cerebral edema resulting from the use of a nonionic contrast.
Tissue-Specific Effects of Bariatric Surgery Including Mitochondrial Function
Authors: Dankel Simon N. , Staalesen Vidar , Bjørndal Bodil , Berge Rolf K. , Mellgren Gunnar , Burri Lena
Published: January 2011

A better understanding of the molecular links between obesity and disease is potentially of great benefit for society. In this paper we discuss proposed mechanisms whereby bariatric surgery improves metabolic health, including acute effects on glucose metabolism and long-term effects on metabolic tissues (adipose tissue, skeletal muscle, and liver) and mitochondrial function. More short-term randomized controlled trials should be performed that include simultaneous measurement of metabolic parameters in different tissues, such as tissue gene expression, protein profile, and lipid content. By directly comparing different surgical procedures using a wider array of metabolic parameters, one may further unravel the mechanisms of aberrant metabolic regulation in obesity and related disorders.
An Analytical Solution of the Advection Dispersion Equation in a Bounded Domain and Its Application to Laboratory Experiments
Authors: Massabó M. , Cianci R. , Paladino O.
Published: January 2011

We study a uniform flow in a parallel plate geometry to model contaminant
transport through a saturated porous medium in a semi‐infinite domain in
order to simulate an experimental apparatus mainly constituted by a chamber filled
with a glass beads bed. The general solution of the advection dispersion equation
in a porous medium was obtained by utilizing the Jacobi θ3 Function. The analytical
solution here presented has been provided when the inlet (Dirac) and the boundary
conditions (Dirichelet, Neumann, and mixed types) are fixed. The proposed solution
was used to study experimental data acquired by using a noninvasive technique.
3D Winding Number: Theory and Application to Medical Imaging
Authors: Becciu Alessandro , Fuster Andrea , Pottek Mark , van den Heuvel Bart , ter Haar Romeny Bart , van Assen Hans
Published: January 2011

We develop a new formulation, mathematically elegant, to detect critical points of 3D scalar images. It is based on a topological number, which is the generalization to three dimensions of the 2D winding number. We illustrate our method by considering three different biomedical applications, namely, detection and counting of ovarian follicles and neuronal cells and estimation of cardiac motion from tagged MR images. Qualitative and quantitative evaluation emphasizes the reliability of the results.
The Impact of Dosing Interval in a Novel Tandem Oral Dosing Strategy: Enhancing the Exposure of Low Solubility Drug Candidates in a Preclinical Setting
Authors: Chiang Po-Chang , South Sarah A. , Wene Steve P.
Published: January 2011

In drug discovery, time and resource constraints necessitate increasingly early decision making to accelerate or stop preclinical programs. Early discovery drug candidates may be potent inhibitors of new targets, but all too often exhibit poor pharmaceutical or pharmacokinetic properties that limit thein vivoexposure. Low solubility of a drug candidate often leads to poor oral bioavailability and poor dose linearity. This issue is more significant for efficacy and target safety studies where high drug exposures are desired. When solubility issues are confronted, enabling formulations are often required to improve the exposure. However, this approach often requires a substantial and lengthy investment to develop the formulation. Previously, we introduced a gastrointestinal (GI) transit time-based novel oral tandem dosing strategy that enhancedin vivoexposures in rats. In this study, a refined time interval versus dose theory was tested. The resultingin vivoexposures based on altering frequency and doses were compared, and significant impacts were found.
Apoptotic Sphingolipid Ceramide in Cancer Therapy
Authors: Huang Wei-Ching , Chen Chia-Ling , Lin Yee-Shin , Lin Chiou-Feng
Published: January 2011

Apoptosis, also called programmed cell death, is physiologically and pathologically involved in cellular homeostasis. Escape of apoptotic signaling is a critical strategy commonly used for cancer tumorigenesis. Ceramide, a derivative of sphingolipid breakdown products, acts as second messenger for multiple extracellular stimuli including growth factors, chemical agents, and environmental stresses, such as hypoxia, and heat stress as well as irradiation. Also, ceramide acts as tumor-suppressor lipid because a variety of stress stimuli cause apoptosis by increasing intracellular ceramide to initiate apoptotic signaling. Defects on ceramide generation and sphingolipid metabolism are developed for cancer cell survival and cancer therapy resistance. Alternatively, targeting ceramide metabolism to correct these defects might provide opportunities to overcome cancer therapy resistance.
Finding Common Solutions of a Variational Inequality, a General System of Variational Inequalities, and a Fixed-Point Problem via a Hybrid Extragradient Method
Authors: Ceng Lu-Chuan , Guu Sy-Ming , Yao Jen-Chih
Published: January 2011

We propose a hybrid extragradient method for finding a common element of the solution set of a variational inequality problem, the solution set of a general system of variational inequalities, and the fixed-point set of a strictly pseudocontractive mapping in a real Hilbert space. Our hybrid method is based on the well-known extragradient method, viscosity approximation method, and Mann-type iteration method. By constrasting with other methods, our hybrid approach drops the requirement of boundedness for the domain in which various mappings are defined. Furthermore, under mild conditions imposed on the parameters we show that our algorithm generates iterates which converge strongly to a common element of these three problems.
Amiloride Modulates Alternative Splicing in Leukemic Cells and Resensitizes Bcr-AblT315I Mutant Cells to Imatinib
Authors: Chang Wen-Hsin , Liu Ta-Chih , Yang Wen-Kuang , Lee Chien-Chih , Lin Yi-Hsiung , Chen Tsai-Yun , Chang Jan-Gowth
Published: January 2011

The antihypertensive drug amiloride is being considered as a tactic to improve cancer therapy including that for chronic myelogenous leukemia. In this study, we show that amiloride modulates the alternative splicing of various cancer genes, including Bcl-x, HIPK3, and BCR/ABL, and that this effect is not mainly related to pH alteration, which is a known effect of the drug. Splice modulation involved various splicing factors, with the phosphorylation state of serine-arginine–rich (SR) proteins also altered during the splicing process. Pretreatment with okadaic acid to inhibit protein phosphatase PP1 reversed partially the phosphorylation levels of SR proteins and also the amiloride-modulated yields of Bcl-xs and HIPK3 U(-) isoforms. Genome-wide detection of alternative splicing further revealed that many other apoptotic genes were regulated by amiloride, including APAF-1, CRK, and SURVIVIN. Various proteins of the Bcl-2 family and MAPK kinases were found to be involved in amiloride-induced apoptosis. Moreover, the effect of amiloride on mRNA levels of Bcl-x was demonstrated to translate to the protein levels. Cotreatment of K562 and BaF3/Bcr-AblT315I cells with amiloride and imatinib induced more loss of cell viability than either agent alone. Our findings suggest that amiloride may offer a potential treatment option for chronic myelogenous leukemia either alone or in combination with imatinib. Cancer Res; 71(2); 383–92. ©2011 AACR.
Chromosome Breakage Is Regulated by the Interaction of the BLM Helicase and Topoisomerase IIα
Authors: Russell Beatriz , Bhattacharyya Saumitri , Keirsey Jeremy , Sandy April , Grierson Patrick , Perchiniak Erin , Kavecansky Juraj , Acharya Samir , Groden Joanna
Published: January 2011

Cells deficient in the recQ-like helicase BLM are characterized by chromosome changes that suggest the disruption of normal mechanisms needed to resolve recombination intermediates and to maintain chromosome stability. Human BLM and topoisomerase IIα interact directly via amino acids 489–587 of BLM and colocalize predominantly in late G2 and M phases of the cell cycle. Deletion of this region does not affect the inherent in vitro helicase activity of BLM but inhibits the topoisomerase IIα–dependent enhancement of its activity, based on the analysis of specific DNA substrates that represent some recombination intermediates. Deletion of the interaction domain from BLM fails to correct the elevated chromosome breakage of transfected BLM-deficient cells. Our results demonstrate that the BLM–topoisomerase IIα interaction is important for preventing chromosome breakage and elucidate a DNA repair mechanism that is critical to maintain chromosome stability in cells and to prevent tumor formation. Cancer Res; 71(2); 561–71. ©2011 AACR.
Phosphorylation of H2AX at Ser139 and a New Phosphorylation Site Ser16 by RSK2 Decreases H2AX Ubiquitination and Inhibits Cell Transformation
Authors: Zhu Feng , Zykova Tatyana A. , Peng Cong , Zhang Jishuai , Cho Yong-Yeon , Zheng Duo , Yao Ke , Ma Wei-Ya , Lau Andy T. Y. , Bode Ann M. , Dong Zigang
Published: January 2011

Histone H2AX is a histone H2A variant that is ubiquitously expressed throughout the genome. It plays a key role in the cellular response to DNA damage and has been designated as the histone guardian of the genome. Histone H2AX deficiency decreases genomic stability and increases tumor susceptibility of normal cells and tissues. However, the role of histone H2AX phosphorylation in malignant transformation and cancer development is not totally clear. Herein, we found that ribosomal S6 kinase 2 (RSK2) directly phosphorylates histone H2AX at Ser139 and also at a newly discovered site, Ser16. Epidermal growth factor (EGF)–induced phosphorylation of histone H2AX at both sites was decreased in RSK2 knockout cells. Phosphorylated RSK2 and histone H2AX colocalized in the nucleus following EGF treatment, and the phosphorylation of histone H2AX by RSK2 enhanced the stability of histone H2AX and prevented cell transformation induced by EGF. RSK2 and DNA-PK, but not ATM or ATR, are required for EGF-induced phosphorylation of H2AX at Ser139; however, only RSK2 is required for phosphorylation of H2AX at Ser16. Phosphorylation of histone H3 was suppressed in cells expressing wild-type H2AX compared with H2AX knockout (H2AX−/−) cells. EGF-associated AP-1 transactivation activity was dramatically lower in H2AX−/− cells overexpressing wild-type H2AX than H2AX−/− cells expressing mutant H2AX-AA. Thus, the RSK2/H2AX signaling pathway negatively regulates the RSK2/histone H3 pathway and therefore maintains normal cell proliferation. Cancer Res; 71(2); 393–403. ©2011 AACR.
Highly Specific Auto-Antibodies against Claudin-18 Isoform 2 Induced by a Chimeric HBcAg Virus-Like Particle Vaccine Kill Tumor Cells and Inhibit the Growth of Lung Metastases
Authors: Klamp Thorsten , Schumacher Jens , Huber Georg , Kühne Christoph , Meissner Ulrich , Selmi Abderraouf , Hiller Thomas , Kreiter Sebastian , Markl Jürgen , Türeci Özlem , Sahin Ugur
Published: January 2011

Strategies for antibody-mediated cancer immunotherapy, such as active immunization with virus-like particle (VLP)-based vaccines, are gaining increasing attention. We developed chimeric hepatitis B virus core antigen (HBcAg)-VLPs that display a surface epitope of the highly selective tumor-associated cell lineage marker claudin-18 isoform 2 (CLDN18.2) flanked by a mobility-increasing linker. Auto-antibodies elicited by immunization with these chimeric HBcAg-VLPs in 2 relevant species (mouse and rabbit) bind with high precision to native CLDN18.2 at physiologic densities on the surface of living cells but not to the corresponding epitope of the CLDN18.1 splice variant that differs by merely one amino acid. The induced auto-antibodies are capable of efficiently killing CLDN18.2 expressing cells in vitro by complement-dependent and antibody-dependent cell-mediated cytotoxicity. Moreover, they provide partial protective immunity against the challenge of mice with syngeneic tumor cells stably expressing CLDN18.2. Our study provides a first proof-of-concept that immunization combining VLPs as antigen carriers with specific conformational epitopes of a highly selective differentiation antigen may elicit auto-antibodies with high cytocidal and tumoricidal potential. Cancer Res; 71(2); 516–27. ©2011 AACR.
Decreased Expression and Androgen Regulation of the Tumor Suppressor Gene INPP4B in Prostate Cancer
Authors: Hodgson Myles C. , Shao Long-jiang , Frolov Anna , Li Rile , Peterson Leif E. , Ayala Gustavo , Ittmann Michael M. , Weigel Nancy L. , Agoulnik Irina U.
Published: January 2011

Patients with metastatic prostate cancer who undergo androgen-ablation therapy invariably relapse and develop incurable castration-resistant disease. Activation of the prosurvival Akt pathway accompanies androgen ablation. We discovered that the androgen receptor induces the expression of the tumor suppressor inositol polyphosphate 4-phosphatase type II (INPP4B) but not PTEN in prostate cancer cells. Optimal induction of INPP4B by an androgen receptor required the expression of the transcriptional coactivator NCoR. INPP4B dephosphorylates phosphatidylinositol-3, 4-bisphosphate, which leads to reduced phosphorylation and activity of Akt. In support of a key role for INPP4B in Akt control, INPP4B depletion activated Akt and increased cellular proliferation. The clinical significance of INPP4B in androgen-dependent prostate cancers was determined in normal or primary tumor prostate tissues derived from radical prostatectomy specimens. In primary tumors, the expression of both INPP4B and PTEN was substantially reduced compared with normal tissue. Further, the decreased expression of INPP4B reduced the time to biochemical recurrence. Thus, androgen ablation can activate the Akt pathway via INPP4B downregulation, thereby mitigating the antitumor effects of androgen ablation. Our findings reinforce the concept that patients undergoing androgen ablation may benefit from Akt-targeting therapies. Cancer Res; 71(2); 572–82. ©2011 AACR.
Minimal Engagement of CD103 on Cytotoxic T Lymphocytes with an E-Cadherin-Fc Molecule Triggers Lytic Granule Polarization via a Phospholipase Cγ–Dependent Pathway
Authors: Floc'h Audrey Le , Jalil Abdelali , Franciszkiewicz Katarzyna , Validire Pierre , Vergnon Isabelle , Mami-Chouaib Fathia
Published: January 2011

Interaction of the integrin αE(CD103)β7 expressed on tumor-infiltrating lymphocytes (TIL) with E-cadherin on epithelial tumor cells is required to trigger polarized exocytosis of cytotoxic granules in TIL that elicit tumor cell lysis. In this study, we investigated the functional and signaling properties of CD103 and its individual contribution to T-cell–mediated cancer-cell killing. Our results indicated that the binding of CD103 on tumor-specific CTL to immobilized recombinant E-cadherin-Fc is sufficient to induce the polarization of cytolytic granules, whereas the degranulation of cytolytic granules also requires the coengagement of the T-cell receptor. Moreover, minimal CD103 triggering promotes the phosphorylation of the ERK1/2 kinases and phospholipase Cγ1 (PLCγ1). Inhibiting PLCγ blocks granule relocalization, decreasing T-cell receptor–mediated cytotoxicity. Thus, our results emphasize a unique costimulatory role of CD103 in tumor-specific CTL activation by providing signals that promote T-cell effector functions needed to specifically target and lyse cancer cells. Cancer Res; 71(2); 328–38. ©2011 AACR.
MicroRNA-616 Induces Androgen-Independent Growth of Prostate Cancer Cells by Suppressing Expression of Tissue Factor Pathway Inhibitor TFPI-2
Authors: Ma Stephanie , Chan Yuen Piu , Kwan Pak Shing , Lee Terence K. , Yan Mingxia , Tang Kwan Ho , Ling Ming Tat , Vielkind Juergen R. , Guan Xin-Yuan , Chan Kwok Wah
Published: January 2011

Expression of microRNA genes is profoundly altered in cancer but their role in the development of androgen-independent prostate cancer has received limited attention as yet. In this study, we report a functional impact in prostate cancer cells for overexpression of the microRNA miR-616, which occurred consistently in cells that were androgen-independent (AI) versus androgen-dependent (AD). miR-616 overexpression was confirmed in malignant prostate tissues as opposed to benign prostate specimens. Stable miR-616 overexpression in LNCaP cells by a lentiviral-based approach stimulated AI prostate cancer cell proliferation in vitro whereas concomitantly reducing androgen-induced cell growth. More importantly, miR-616 overexpressing LNCaP cells overcame castration resistance as shown by an enhanced ability to proliferate in vivo after bilateral orchiectomy. Conversely, antagonizing miR-616 in AI prostate cancer cells yielded opposite effects. Microarray profiling and bioinformatics analysis identified the tissue factor pathway inhibitor TFPI-2 mRNA as a candidate downstream target of miR-616. In support of this candidacy, we documented interactions between miR-616 and the 3′UTR of TFPI-2 and determined TFPI-2 expression to be inversely correlated to miR-616 in a series of prostate cell lines and clinical specimens. Notably, reexpression of TFPI-2 in LNCaP cells with stable miR-616 overexpression rescued the AD phenotype, as shown by a restoration of androgen dependence and cell growth inhibition. Taken together, our findings define a functional involvement for miR-616 and TFPI-2 in the development and maintenance of androgen-independent prostate cancer. Cancer Res; 71(2); 583–92. ©2011 AACR.
p190RhoGEF (Rgnef) Promotes Colon Carcinoma Tumor Progression via Interaction with Focal Adhesion Kinase
Authors: Yu Hong-Gang , Nam Ju-Ock , Miller Nichol L. G. , Tanjoni Isabelle , Walsh Colin , Shi Lei , Kim Linda , Chen Xiao Lei , Tomar Alok , Lim Ssang-Taek , Schlaepfer David D.
Published: January 2011

Focal adhesion kinase (FAK) functions downstream of integrins and growth factor receptors to promote tumor cell motility and invasion. In colorectal cancer, FAK is activated by amidated gastrin, a protumorigenic hormone. However, it is unclear how FAK receives signals from the gastrin receptor or other G-protein–coupled receptors that can promote cell motility and invasion. The Rho guanine-nucleotide exchange factor p190RhoGEF (Rgnef) binds FAK and facilitates fibroblast focal adhesion formation on fibronectin. Here we report that Rgnef mRNA and protein expression are significantly increased during colorectal tumor progression. In human colon carcinoma cells, Rgnef forms a complex with FAK and upon gastrin stimulation, FAK translocates to newly-forming focal adhesions where it facilitates tyrosine phosphorylation of paxillin. short hairpin (shRNA)-mediated knockdown of Rgnef or FAK, or pharmacological inhibition of FAK activity, is sufficient to block gastrin-stimulated paxillin phosphorylation, cell motility, and invadopodia formation in a manner dependent upon upstream cholecystokinin-2 receptor expression. Overexpression of the C-terminal region of Rgnef (Rgnef-C, amino acid 1,279–1,582) but not Rgnef-CΔFAK (amino acid 1,302–1,582 lacking the FAK binding site) disrupted endogenous Rgnef-FAK interaction and prevented paxillin phosphorylation and cell motility stimulated by gastrin. Rgnef-C–expressing cells formed smaller, less invasive tumors with reduced tyrosine phosphorylation of paxillin upon orthotopic implantation, compared with Rgnef-CΔFAK–expressing cells. Our studies identify Rgnef as a novel regulator of colon carcinoma motility and invasion, and they show that a Rgnef–FAK linkage promotes colon carcinoma progression in vivo. Cancer Res; 71(2); 360–70. ©2011 AACR.
The First Tianjin, China Forum on Tumor Microenvironment
Authors: Keller Evan T. , Li Lu-Yuan
Published: January 2011

Although it is well recognized that the tumor microenvironment plays a key role in regulating tumor progression, the mechanisms through which this occurs need to be defined. Current international research activities toward defining the role of the tumor microenvironment in cancer progression were the subject of the first Tianjin Forum on Tumor Microenvironment held at Nankai University in Tianjin, China, July 2 to 4, 2010. The importance of variety of processes, such as inflammation and angiogenesis, in the role of tumor progression was described for multiple tumor types including breast, prostate, and hepatic cancers, as well as the process of bone metastasis. Identification of novel signaling pathways that impact both angiogenesis and bone remodeling were presented. Several themes emerged from this meeting, such as: (i) tumor cells modify the microenvironment to enhance their own survival and progression; (ii) targeting host factors, in addition to targeting tumor cells, will have important therapeutic effects; and (iii) host cells distribution within the tumor has both prognostic and therapeutic significance. Several priorities for future research were defined including use of a systems biology approach to define the role of host factors in tumor progression, to define the importance of targeting both arms of the bone remodeling process for therapy of bone metastasis, and to determine how different cell subsets contribute to microenvironment-mediated regulation of tumor progression. Cancer Res; 71(2); 310–3. ©2011 AACR.
Combination Therapy with Vidaza and Entinostat Suppresses Tumor Growth and Reprograms the Epigenome in an Orthotopic Lung Cancer Model
Authors: Belinsky Steven A. , Grimes Marcie J. , Picchi Maria A. , Mitchell Hugh D. , Stidley Chris A. , Tesfaigzi Yohannes , Channell Meghan M. , Liu Yanbin , Casero Robert A. , Baylin Stephen B. , Reed Mathew D. , Tellez Carmen S. , March Thomas H.
Published: January 2011

Epigenetic therapy for solid tumors could benefit from an in vivo model that defines tumor characteristics of responsiveness and resistance to facilitate patient selection. Here we report that combining the histone deacetylase inhibitor entinostat with the demethylating agent vidaza profoundly affected growth of K-ras/p53 mutant lung adenocarcinomas engrafted orthotopically in immunocompromised nude rats by targeting and ablating pleomorphic cells that occupied up to 75% of the tumor masses. A similar reduction in tumor burden was seen with epigenetic therapy in K-ras or EGFR mutant tumors growing orthotopically. Increased expression of proapoptotic genes and the cyclin-dependent kinase inhibitor p21 was seen. Hundreds of genes were demethylated highlighted by the reexpression of polycomb-regulated genes coding for transcription factor binding proteins and the p16 gene, a key regulator of the cell cycle. Highly significant gene expression changes were seen in key regulatory pathways involved in cell cycle, DNA damage, apoptosis, and tissue remodeling. These findings show the promise for epigenetic therapy in cancer management and provide an orthotopic lung cancer model that can assess therapeutic efficacy and reprogramming of the epigenome in tumors harboring different genetic and epigenetic profiles to guide use of these drugs. Cancer Res; 71(2); 454–62. ©2011 AACR.