bluuebunny/crossref_metadata_2025 huggingface dataset:
ACUTE CARPAL TUNNEL SYNDROME SECONDARY TO CALCIFIC TENDINITIS: CASE REPORT
Authors: Saleh Waleed Riad , Yajima Hiroshi , Nakanishi Akito
Published: April 2009

Acute carpal tunnel syndrome (CTS) secondary to calcific deposition is rarely reported. In this article we describe a case of acute CTS in the dominant hand of a 94-year-old female patient secondary to calcific tendinitis within the carpal tunnel. Diagnosis was difficult clinically and radiologically. Urgent complete median nerve decompression led to a good clinical recovery.
Severe spontaneous bradycardia associated with respiratory disruptions in rat pups with fewer brain stem 5-HT neurons
Authors: Cummings Kevin J. , Commons Kathryn G. , Fan Kenneth C. , Li Aihua , Nattie Eugene E.
Published: April 2009

The medullary 5-HT system has potent effects on heart rate and breathing in adults. We asked whether this system mitigates the respiratory instability and bradycardias frequently occurring during the neonatal period. 5,7-Dihydroxytryptamine (5,7-DHT) or vehicle was administered to rat pups at postnatal day 2 (P2), and we then compared the magnitude of bradycardias occurring with disruptions to eupnea in treated and vehicle control littermates at P5–6 and P10–12. We then used a novel method that would allow accurate assessment of the ventilatory and heart rate responses to near square-wave challenges of hypoxia (10% O2), hypercapnia (5 and 8% CO2in normoxia and hyperoxia), and asphyxia (8% CO2-10% O2), and to the induction of the Hering-Breuer inflation reflex (HBR), a potent, apnea-inducing reflex in newborns. The number of 5-HT-positive neurons was reduced ∼80% by drug treatment. At both ages, lesioned animals had considerably larger bradycardias during brief apnea; at P5–6, average and severe events were ∼50% and 70% greater, respectively, in lesioned animals ( P = 0.002), whereas at P10–12, events were ∼ 23% and 50% greater ( P = 0.018). However, lesioning had no effect on the HR responses to sudden gas challenge or the HBR. At P5–6, lesioned animals had reduced breathing frequency and ventilation (V̇e), but normal V̇e relative to metabolic rate (V̇e/V̇o2). At P10–12, lesioned animals had a more unstable breathing pattern ( P = 0.04) and an enhanced V̇e response to moderate hypercapnia ( P = 0.007). Within the first two postnatal weeks, the medullary 5-HT system plays an important role in cardiorespiratory control, mitigating spontaneous bradycardia, stabilizing the breathing pattern, and dampening the hypercapnic V̇e response.
Expression and function of NFAT5 in medullary thick ascending limb (mTAL) cells
Authors: Hao Shoujin , Zhao Hong , Darzynkiewicz Zbigniew , Battula Sailaja , Ferreri Nicholas R.
Published: April 2009

The contribution of nuclear factor of activated T cells 5 (NFAT5) to the regulation of tumor necrosis factor-α (TNF) production in medullary thick ascending limb (mTAL) cells is unclear. RT-PCR analysis was performed on primary cultures of mouse mTAL cells and freshly isolated mTAL tubules to determine which NFAT isoforms are present in this nephron segment. Primer pairs were designed, based on published sequences for mouse NFAT1-5, to produce fragments of ∼200 bp. Analysis of PCR products by gel electrophoresis and subsequent DNA sequencing indicated that cells and tubules contained mRNA for all five NFAT isoforms. The relative expression of NFAT isoforms was then determined using quantitative real-time RT-PCR. The data indicate that NFAT isoforms 5 ≥ 1 are the predominant isoforms present in mTAL cells and tubules. Western blot analysis demonstrated constitutive expression of NFAT5 in nuclear extracts from mTAL tubules and primary culture cells; expression in mTAL cells also was detected by immunofluorescence. Expression of NFAT5 was increased in mTAL cells transiently transfected with an NFAT5 overexpression vector (pcDNA3.1-NFAT5), resulting in increased basal and calcium-sensing receptor (CaR)-mediated TNF production. Transient transfection of mTAL cells with a small hairpin RNA vector that targeted exon 8 of NFAT5 (U6-N5 ex8) significantly inhibited TNF promoter activity. Transient transfection with U6-N5 ex8 also reduced nuclear expression of NFAT5, TNF mRNA accumulation, and attenuated CaR-mediated activation of Cl−entry into polarized mTAL cells. Collectively, these data suggest that activation of NFAT5 is part of a TNF-dependent pathway that inhibits apical Cl−influx in the mTAL after activation of CaR.
Colchicine attenuates inflammatory cell infiltration and extracellular matrix accumulation in diabetic nephropathy
Authors: Li Jin Ji , Lee Sun Ha , Kim Dong Ki , Jin Ri , Jung Dong-Sub , Kwak Seung-Jae , Kim Seung Hye , Han Seung Hyeok , Lee Jung Eun , Moon Sung Jin , Ryu Dong-Ryeol , Yoo Tae-Hyun , Han Dae Suk , Kang Shin-Wook
Published: April 2009

Recent studies have demonstrated that an inflammatory mechanism contributes to the pathogenesis of diabetic nephropathy (DN). It is also known that colchicine (Col) can prevent various renal injuries via its anti-inflammatory action. However, the effect of colchicine on DN has never been explored. This study was undertaken to elucidate the effect of colchicine on inflammation and extracellular matrix accumulation in DN. In vivo, 64 rats were injected with diluent (C; n = 32) or streptozotocin intraperitoneally (DM, n = 32). Sixteen rats from each group were treated with Col. In vitro, rat mesangial cells and NRK-52E cells were cultured in media with 5.6 mM glucose (NG) or 30 mM glucose (HG) with or without 10−8M Col. Monocyte chemotactic protein-1 (MCP-1) mRNA expression was determined by real-time PCR (RT-PCR), and the levels of MCP-1 in renal tissue and culture media were measured by ELISA. RT-PCR and Western blotting were also performed for intercellular adhesion molecule-1 (ICAM-1) and fibronectin (FN) mRNA and protein expression, respectively, and immunohistochemical staining (IHC) for ICAM-1, FN, and ED-1 with renal tissue. Twenty-four-hour urinary albumin excretion at 6 wk and 3 mo were significantly higher in DM compared with C rats ( P < 0.05), and colchicine treatment significantly reduced albuminuria in DM rats ( P < 0.05). Col significantly inhibited the increase in MCP-1 mRNA expression and protein levels under diabetic conditions both in vivo and in vitro. ICAM-1 and FN expression showed a similar pattern to the expression of MCP-1. IHC revealed that the number of ED-1(+) cells were significantly higher in DM compared with C kidney ( P < 0.005), and this increase was significantly attenuated by Col treatment ( P < 0.01). In conclusion, Col prevents not only inflammatory cell infiltration via inhibition of enhanced MCP-1 and ICAM-1 expression but also ECM accumulation in DN. These findings provide a new perspective on the renoprotective effects of Col in DN.
Low-dose carbon monoxide inhibits progressive chronic allograft nephropathy and restores renal allograft function
Authors: Nakao Atsunori , Faleo Gaetano , Nalesnik Michael A. , Seda-Neto Joao , Kohmoto Junichi , Murase Noriko
Published: April 2009

Chronic allograft nephropathy (CAN) represents progressive deterioration of renal allograft function with fibroinflammatory changes. CAN, recently reclassified as interstitial fibrosis (IF) and tubular atrophy (TA) with no known specific etiology, is a major cause of late renal allograft loss and remains a significant deleterious factor of successful renal transplantation. Carbon monoxide (CO), an effector byproduct of heme oxygenase pathway, is known to have potent anti-inflammatory and antifibrotic functions. We hypothesized that inhaled CO would inhibit fibroinflammatory process of CAN and restore renal allograft function, even when the treatment was initiated after CAN was established. Lewis rat kidney grafts were orthotopically transplanted into binephrectomized allogenic Brown Norway rats under brief tacrolimus (0.5 mg/kg im, days 0– 6). At day 60, CO (20 ppm) inhalation was initiated to recipients and continued until day 150 or animal death. Development of CAN was confirmed at day 60 with decreased creatinine clearance (CCr), significant proteinuria, and histopathological findings of TA, IF, and intimal arteritis. Air-treated control recipients continued to deteriorate with further declines of CCr and increases of urinary protein excretion and died with a median survival of 82 days. In contrast, progression of CAN was decelerated when recipients received CO on days 60– 150, showing markedly improved graft histopathology, restored renal function, and improved recipient survival to a median of >150 days. CO significantly reduced intragraft mRNA levels for IFN-γ and TNF-α at day 90. Expression of profibrotic TGF-β/Smad was significantly suppressed with CO, together with downregulation of ERK-MAPK pathways. Continuous CO (20 ppm) treatment for days 0– 30, days 30– 60, or days 0– 90, or daily 1-h CO (250 ppm) treatment for days 0– 90, also showed efficacy in inhibiting CAN. The study demonstrates that CO is able to inhibit progression of fibroinflammatory process of CAN, restore renal allograft function, and improve survival even when the treatment is started after CAN is diagnosed.
Effect of thrombin fragment (TP508) on myocardial ischemia-reperfusion injury in hypercholesterolemic pigs
Authors: Osipov Robert M. , Robich Michael P. , Feng Jun , Clements Richard T. , Liu Yuhong , Glazer Hilary P. , Wagstaff John , Bianchi Cesario , Sellke Frank W.
Published: April 2009

Myocardial ischemia-reperfusion (IR) injury occurs frequently in the setting of hypercholesterolemia. We investigated the potential efficacy of a novel thrombin fragment (TP508) on IR injury in a hypercholesterolemic porcine model. Twenty-one hypercholesterolemic male Yucatan pigs underwent 60 min of mid-left anterior descending coronary artery occlusion followed by 120 min of reperfusion. Pigs received either placebo (control, n = 7) or TP508 in two doses (TP508 low dose, n = 7, as bolus of 0.5 mg/kg 50 min into ischemia and an infusion of 1.25 mg·kg−1·h−1 during reperfusion period or TP508 high dose, n = 7, a double dose of TP508 low-dose group). Myocardial function was monitored throughout the experiment. The area at risk and myocardial necrosis were determined by Monastryl blue/triphenyl tetrazolium chloride staining. Apoptosis in the ischemic territory was assessed. Coronary microvascular reactivity to endothelium-dependent and -independent factors was measured. Myocardial necrosis was lower in both TP508-treated groups vs. control ( P < 0.05). Regional left ventricular function was improved only in the TP508 high-dose group ( P < 0.05). Endothelium-dependent coronary microvascular reactivity was greater in both TP508-treated groups ( P < 0.05) vs. control. The expression of proteins favoring cell survival, 90-kDa heat shock protein and phospho-Bad (Ser112) was higher in the TP508 high-dose group ( P < 0.05). The expression of the cell death signaling proteins, cleaved caspase-3 ( P < 0.05), apoptosis-inducing factor ( P < 0.05), and poly-ADP ribose polymerase ( P = 0.07) was lower in the TP508 low-dose group vs. TP508 high-dose and control. The terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling positive cell count was lower in both TP508 groups compared with the control ( P < 0.05). This study demonstrates that, in hypercholesterolemic pigs, TP508 decreases myocardial necrosis and apoptosis after IR. Thus TP508 may offer a novel approach in protecting the myocardium from IR injury.
The Role of The TRPV1 Endogenous AgonistN-Oleoyldopamine in Modulation of Nociceptive Signaling at the Spinal Cord Level
Authors: Spicarova Diana , Palecek Jiri
Published: April 2009

Transient receptor potential vanilloid (TRPV1) receptors are abundant in a subpopulation of primary sensory neurons that convey nociceptive information from the periphery to the spinal cord dorsal horn. The TRPV1 receptors are expressed on both the peripheral and central branches of these dorsal root ganglion (DRG) neurons and can be activated by capsaicin, heat, low pH, and also by recently described endogenous lipids. Using patch-clamp recordings from superficial dorsal horn (DH) neurons in acute spinal cord slices, the effect of application of the endogenous TRPV1 agonist N-oleoyldopamine (OLDA) on the frequency of miniature excitatory postsynaptic currents (mEPSCs) was evaluated. A high concentration OLDA (10 μM) solution was needed to increase the mEPSC frequency, whereas low concentration OLDA (0.2 μM) did not evoke any change under control conditions. The increase was blocked by the TRPV1 antagonists SB366791 or BCTC. Application of a low concentration of OLDA evoked an increase in mEPSC frequency after activation of protein kinase C by phorbol ester (PMA) and bradykinin or in slices from animals with peripheral inflammation. Increasing the bath temperature from 24 to 34°C enhanced the basal mEPSC frequency, but the magnitude of changes in the mEPSC frequency induced by OLDA administration was similar at both temperatures. Our results suggest that presumed endogenous agonists of TRPV1 receptors, like OLDA, could have a considerable impact on synaptic transmission in the spinal cord, especially when TRPV1 receptors are sensitized. Spinal TRPV1 receptors could play a pivotal role in modulation of nociceptive signaling in inflammatory pain.
Group III Metabotropic Glutamate Receptors (mGluRs) Modulate Transmission of Gustatory Inputs in the Brain Stem
Authors: Hallock Robert M. , Martyniuk Christopher J. , Finger Thomas E.
Published: April 2009

Glutamate is the principal neurotransmitter at the primary sensory afferent synapse in the medulla for the taste system. At this synapse, glutamate activates N-methyl-d-aspartate (NMDA) and non-NMDA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid [AMPA] and kainate) ionotropic receptors to effect a response in the second-order neurons. The current experiment is the first to examine the role of metabotropic glutamate receptors (mGluRs) in the transmission of taste information. In an in vitro slice preparation of the primary vagal gustatory nucleus in goldfish, primary gustatory afferent fibers were stimulated electrically, whereas evoked dendritic field potentials were recorded in the sensory layers. Recordings were made before, during, and after bath application of mGluR agonists for various mGluR groups and subtypes. Whereas l-AP4, a group III agonist, reduced the field potential, group I and group II agonists had no effect. Furthermore, the selective mGluR4 agonist ACPT-III and mGluR8 agonist PPG were effective at reducing the field potential, whereas agonists selective for mGluR6 and 7 were not. MAP4, a group III mGluR antagonist, attenuated frequency-dependent depression, indicating that endogenous glutamate binds to presynaptic mGluRs under normal conditions. Furthermore, polymerase chain reaction showed that mRNA for mGluR4 and 8 is expressed in the vagal ganglia, a prerequisite if those receptors are expressed presynaptically in the vagal lobe. Collectively, these experiments indicate that mGluR4 and 8 are presynaptic at the primary gustatory afferent synapse and that their activation inhibits glutamatergic release.
Kinetic and Mechanistic Studies on the Reaction of DL-Methionine with in Aqueous Medium at Physiological pH
Authors: Das Tandra , Datta A.  K. , Ghosh A. K.
Published: April 2009

The reaction has been studied spectrophotometrically; the reaction shows two steps, both of which are dependent on ligand concentration and show a limiting nature. An associative interchange mechanism is proposed. Kinetic and activation parameters ( and ) and (, , , and ) have been calculated. From the temperature dependence of the outer sphere association equilibrium constant, thermodynamic parameters ( and ; and ) have also been calculated.
On Properties of Geodesic -Preinvex Functions
Authors: Ahmad I. , Iqbal Akhlad , Ali Shahid
Published: April 2009

The present paper deals with the properties of geodesic -preinvex functions and their relationships with -invex functions and strictly geodesic -preinvex functions. The geodesic -pre-pseudo-invex and geodesic -pre-quasi-invex functions on the geodesic invex set are introduced and some of their properties are discussed.
Effects of Ubiquinol-10 on MicroRNA-146a Expression In Vitro and In Vivo
Authors: Schmelzer Constance , Kitano Mitsuaki , Rimbach Gerald , Niklowitz Petra , Menke Thomas , Hosoe Kazunori , Döring Frank
Published: April 2009

MicroRNAs (miRs) are involved in key biological processes via suppression of gene expression at posttranscriptional levels. According to their superior functions, subtle modulation of miR expression by certain compounds or nutrients is desirable under particular conditions. Bacterial lipopolysaccharide (LPS) induces a reactive oxygen species-/NF-κB-dependent pathway which increases the expression of the anti-inflammatory miR-146a. We hypothesized that this induction could be modulated by the antioxidant ubiquinol-10. Preincubation of human monocytic THP-1 cells with ubiquinol-10 reduced the LPS-induced expression level of miR-146a to 78.9±13.22%. In liver samples of mice injected with LPS, supplementation with ubiquinol-10 leads to a reduction of LPS-induced miR-146a expression to 78.12±21.25%. From these consistent in vitro and in vivo data, we conclude that ubiquinol-10 may fine-tune the inflammatory response via moderate reduction of miR-146a expression.
Assessments of F16 Special Sensor Microwave Imager and Sounder Antenna Temperatures at Lower Atmospheric Sounding Channels
Authors: Yan Banghua , Weng Fuzhong
Published: April 2009

The main reflector of the Special Sensor Microwave Imager/Sounder (SSMIS) aboard the Defense Meteorological Satellite Program (DMSP) F-16 satellite emits variable radiation, and the SSMIS warm calibration load is intruded by direct and indirect solar radiation. These contamination sources produce antenna brightness temperature anomalies of around 2 K at SSMIS sounding channels which are obviously inappropriate for assimilation into numerical weather prediction models and remote sensing retrievals of atmospheric and surface parameters. In this study, antenna brightness temperature anomalies at several lower atmospheric sounding (LAS) channels are assessed, and the algorithm is developed for corrections of these antenna temperature anomalies. When compared against radiative transfer model simulations and simultaneous observations from AMSU-A aboard NOAA-16, the SSMIS antenna temperatures at 52.8, 53.6, 54.4, 55.5, 57.3, and 59.4 GHz after the anomaly correction exhibit small residual errors (<0.5 K). After such SSMIS antenna temperatures are applied to the National Center for Environmental Prediction Numerical Weather Prediction (NWP) model, more satellite data is used and the analysis field of the geopotential height is significantly improved throughout troposphere and lower stratosphere. Therefore, the SSMIS antenna temperatures after the anomaly correction have demonstrated their potentials in NWP models.
Morphological Investigation of Foamed Aluminum Parts Produced by Melt Gas Injection
Authors: Surace R. , De Filippis L. A. C. , Niini E. , Ludovico A. D. , Orkas J.
Published: April 2009

Porous metal materials are a new class of materials with low densities, large specific surface, and novel physical and mechanical properties. Their applications are extremely varied: for light weight structural components, for filters and electrodes, and for shock or sound absorbing products. Recently, interesting foaming technology developments have proposed metallic foams as a valid commercial chance; foam manufacturing techniques include solid, liquid, or vapor state methods. The foams presented in this study are produced by Melt Gas Injection (MGI) process starting from melt aluminum. The aim of this investigation is to obtain complex foamed aluminum parts in order to make the MGI more flexible. This new method, called MGI‐mould process, makes possible to produce 3D‐shaped parts with complicated shape or configuration using some moulds obtained by traditional investment casting process.
Synthesis, Characterization, and Biological Studies of Organotin(IV) Derivatives with o‐ or p‐hydroxybenzoic Acids
Authors: Abdellah Mohamed A. , Hadjikakou Sotiris K. , Hadjiliadis Nick , Kubicki Maciej , Bakas Thomas , Kourkoumelis Nikolaos , Simos Yannis V. , Karkabounas Spyros , Barsan Mirela M. , Butler Ian S.
Published: April 2009

Organotin(IV) complexes with o‐ or p‐hydroxybenzoic acids (o‐H2BZA or p‐H2BZA) of formulae [R2Sn(HL)2] (where H2L = o‐H2BZA and R = Me‐ (1), n‐Bu‐ (2)); [R3Sn(HL)] (where H2L = o‐H2BZA and R = n‐Bu‐ (3), Ph‐ (4) or H2L = p‐H2BZA and R = n‐Bu‐ (5), Ph‐ (6)) were synthesized by reacting a methanolic solution of di‐ and triorganotin(IV) compounds with an aqueous solution of the ligand (o‐H2BZA or p‐H2BZA) containing equimolar amounts of potassium hydroxide. The complexes were characterized by elemental analysis, FT‐IR, Far‐IR, TGA‐DTA, FT‐Raman, Mössbauer spectroscopy,  1H,  119Sn‐NMR, UV/Vis spectroscopy, and Mass spectroscopy. The X‐ray crystal structures of complexes 1 and 2 have also been determined. Finally, the influence of these complexes 1–6 upon the catalytic peroxidation of linoleic acid to hydroperoxylinoleic acid by the enzyme lipoxygenase (LOX) was kinetically studied and the results showed that triorganotin(IV) complex 6 has the lowest IC50 value. Also complexes 1–6 were studied for their in vitro cytotoxicity against sarcoma cancer cells (mesenchymal tissue) from the Wistar rat, and the results showed that the complexes have high activity against these cell lines with triphenyltin((IV) complex 4 to be the most active one.
BEP/SEP and Outage Performance Analysis of -Branch Maximal-Ratio Combiner for Fading
Authors: Milišić Mirza , Hamza Mirza , Hadžialić Mesud
Published: April 2009

Maximal-ratio combiner (MRC) performances in fading channels have been of interest for a long time, which can be seen by a number of papers concerning this topic. In this paper we treat bit error probability (BEP), symbol error probability (SEP) and outage probability of MRC in presence of fading. We will present fading model, probability density function (PDF), and cumulative distribution function (CDF). We will also present PDF, CDF, and outage probability of theL-branch MRC output. BEP/SEP will be evaluated for broad class of modulation types and for coherent and noncoherent types of detection. BEP/SEP and outage performances of the MRC will be evaluated for different number of branches via Monte Carlo simulations and theoretical expressions.
Temporal Matching in Endoscopic Images for Remote-Controlled Robotic Surgery
Authors: Gu Jia , Wolters Rolf , Gustafsson Ulf
Published: April 2009

Temporal matching is applied in the frame of the formation of high-level entities in remote-controlled robotic surgery. The objective is to track tumor boundaries over time to improve the segmentation stage in each image of the sequence to facilitate the tracking and localization of the tumor. It makes use of an attributed string matching technique to find the correspondence between tumor boundaries over time. Relationships are then exploited to reconstitute the tumor boundaries and remove the inconsistencies coming from the detection errors. Input data are free form shapes of different length representing the tumor boundary, extracted at a previous stage.
Technical and Scale Efficiency in Spanish Urban Transport: Estimating with Data Envelopment Analysis
Authors: García Sánchez I. M.
Published: April 2009

The paper undertakes a comparative efficiency analysis of public bus transport in Spain using Data Envelopment Analysis. A procedure for efficiency evaluation was established with a view to estimating its technical and scale efficiency. Principal components analysis allowed us to reduce a large number of potential measures of supply- and demand-side and quality outputs in three statistical factors assumed in the analysis of the service. A statistical analysis (Tobit regression) shows that efficiency levels are negative in relation to the population density and peak-to-base ratio. Nevertheless, efficiency levels are not related to the form of ownership (public versus private). The results obtained for Spanish public transport show that the average pure technical and scale efficiencies are situated at 94.91 and 52.02%, respectively. The excess of resources is around 6%, and the increase in accessibility of the service, one of the principal components summarizing the large number of output measures, is extremely important as a quality parameter in its performance.
Fixed Points for w‐Contractive Multimaps
Authors: Latif Abdul , Kutbi Marwan A.
Published: April 2009

Using the generalized Caristi′s fixed point theorems we
prove the existence of fixed points for self and nonself multivalued weakly w‐contractive maps. Consequently, Our results either improve or generalize
the corresponding fixed point results due to Latif (2007), Bae (2003), Suzuki, and Takahashi (1996) and others.
PPARγ2Pro12Ala Polymorphism and Human Health
Authors: He Weimin
Published: April 2009

The nuclear hormone receptor peroxisome proliferator activated receptor gamma (PPARγ) is an important transcription factor regulating adipocyte differentiation, lipid and glucose homeostasis, and insulin sensitivity. Numerous genetic mutations of PPARγ have been identified and these mutations positively or negatively regulate insulin sensitivity. Among these, a relatively common polymorphism of PPARγ, Pro12Ala of PPARγ2, the isoform expressed only in adipose tissue has been shown to be associated with lower body mass index, enhanced insulin sensitivity, and resistance to the risk of type 2 diabetes in human subjects carrying this mutation. Subsequent studies in different ethnic populations, however, have revealed conflicting results, suggesting a complex interaction between the PPARγ2 Pro12Ala polymorphism and environmental factors such as the ratio of dietary unsaturated fatty acids to saturated fatty acids and/or between the PPARγ2 Pro12Ala polymorphism and genetic factors such as polymorphic mutations in other genes. In addition, this polymorphic mutation in PPARγ2 is associated with other aspects of human diseases, including cancers, polycystic ovary syndrome, Alzheimer disease and aging. This review will highlight findings from recent studies.
Comparison of the Molecular Dynamics of C70 in the Solid and Liquid Phases
Authors: Hughes R. M. , Mutzenhardt P. , Rodriguez A. A.
Published: April 2009

A previous study of C70 in deuterated benzenes generated evidence suggesting C70 exhibited unique reorientational behavior depending on its environment. We present a comparison of the dynamic behavior of this fullerene, in the solid and solution phases, to explore any unique features between these two phases. The effective correlation times, , of C70 in the solid state are 2 to 3 times longer than in solution. In the solid state, a noticeable decrease in all the carbons′ correlation times is seen between 293 K to 303 K; suggesting a transition from isotropic to anisotropic reorientational behavior at this temperature change. Although C70 in solution experiences van der Waals type interactions, these interactions are not strong enough to slow the solution‐state motion below what is observed in the solid state. All observed differences in the diffusion constants, DX and DZ, in solution are smaller than in the solid state suggesting a lower energy of activation between these two modes of reorientation in the liquid phase. A small‐step diffusion “like” condition appears to be thermally generated in the solid phase at 323 K.
AMP-activated protein kinase promotes human prostate cancer cell growth and survival
Authors: Park Hyeon Ung , Suy Simeng , Danner Malika , Dailey Vernon , Zhang Ying , Li Henghong , Hyduke Daniel R. , Collins Brian T. , Gagnon Gregory , Kallakury Bhaskar , Kumar Deepak , Brown Milton L. , Fornace Albert , Dritschilo Anatoly , Collins Sean P.
Published: April 2009

The molecular mechanisms underlying the development and progression of prostate cancer are poorly understood. AMP-activated protein kinase (AMPK) is a serine-threonine kinase that is activated in response to the hypoxic conditions found in human prostate cancers. In response to energy depletion, AMPK activation promotes metabolic changes to maintain cell proliferation and survival. Here, we report prevalent activation of AMPK in human prostate cancers and provide evidence that inhibition or depletion of AMPK leads to decreased cell proliferation and increased cell death. AMPK was highly activated in 40% of human prostate cancer specimens examined. Endogenous AMPK was active in both the androgen-sensitive LNCaP cells and the androgen-independent CWR22Rv1 human prostate cancer cells. Depletion of AMPK catalytic subunits by small interfering RNA or inhibition of AMPK activity with a small-molecule AMPK inhibitor (compound C) suppresses human prostate cancer cell proliferation. Apoptotic cell death was induced in LNCaP and CWR22Rv1 cells at compound C concentrations that inhibited AMPK activity. The evidence provided here is the first report that the activated AMPK pathway is involved in the growth and survival of human prostate cancer and offers novel potential targets for chemoprevention of human prostate cancer. [Mol Cancer Ther 2009;8(4):733–41]
Increased AKT S473 phosphorylation after mTORC1 inhibition is rictor dependent and does not predict tumor cell response to PI3K/mTOR inhibition
Authors: Breuleux Madlaina , Klopfenstein Matthieu , Stephan Christine , Doughty Cheryl A. , Barys Louise , Maira Saveur-Michel , Kwiatkowski David , Lane Heidi A.
Published: April 2009

Mammalian target of rapamycin (mTOR) regulates cellular processes important for progression of human cancer. RAD001 (everolimus), an mTORC1 (mTOR/raptor) inhibitor, has broad antitumor activity in preclinical models and cancer patients. Although most tumor lines are RAD001 sensitive, some are not. Selective mTORC1 inhibition can elicit increased AKT S473 phosphorylation, involving insulin receptor substrate 1, which is suggested to potentially attenuate effects on tumor cell proliferation and viability. Rictor may also play a role because rictor kinase complexes (including mTOR/rictor) regulate AKT S473 phosphorylation. The role of raptor and rictor in the in vitro response of human cancer cells to RAD001 was investigated. Using a large panel of cell lines representing different tumor histotypes, the basal phosphorylation of AKT S473 and some AKT substrates was found to correlate with the antiproliferative response to RAD001. In contrast, increased AKT S473 phosphorylation induced by RAD001 did not correlate. Similar increases in AKT phosphorylation occurred following raptor depletion using siRNA. Strikingly, rictor down-regulation attenuated AKT S473 phosphorylation induced by mTORC1 inhibition. Further analyses showed no relationship between modulation of AKT phosphorylation on S473 and T308 and AKT substrate phosphorylation patterns. Using a dual pan-class I phosphatidylinositol 3-kinase/mTOR catalytic inhibitor (NVP-BEZ235), currently in phase I trials, concomitant targeting of these kinases inhibited AKT S473 phosphorylation, eliciting more profound cellular responses than mTORC1 inhibition alone. However, reduced cell viability could not be predicted from biochemical or cellular responses to mTORC1 inhibitors. These data could have implications for the clinical application of phosphatidylinositol 3-kinase/mTOR inhibitors. [Mol Cancer Ther 2009;8(4):742–53]
Opposing control of rhabdomyosarcoma growth and differentiation by myogenin and interleukin 4
Authors: Nanni Patrizia , Nicoletti Giordano , Palladini Arianna , Astolfi Annalisa , Rinella Paola , Croci Stefania , Landuzzi Lorena , Monduzzi Giada , Stivani Valeria , Antognoli Agnese , Murgo Annalisa , Ianzano Marianna , De Giovanni Carla , Lollini Pier-Luigi
Published: April 2009

Rhabdomyosarcoma is a tumor of striated muscle origin that displays defective myogenic differentiation. Terminal myogenesis switches off cell proliferation and migration, hence, the promotion of rhabdomyosarcoma differentiation should antagonize tumor growth and metastasis. Terminal myogenesis is controlled by cell-intrinsic myogenic transcription factors like myogenin and environmental mediators like interleukin 4 (IL-4). We studied whether the expression of myogenin or exposure to IL-4 could promote the myogenesis of poorly differentiating human rhabdomyosarcoma cells RD/12. Forced expression of myogenin amplified myosin expression and the formation of myotube-like elements, inhibited cell migration, and reduced the growth of local tumors and liver metastases in immunodepressed mice. In contrast, exposure to IL-4 promoted cell proliferation and survival, especially at high cell density, inhibited myogenin expression, and myogenesis. Moreover, IL-4 stimulated the directed migration of cells with low myogenin levels, but not of cells with higher (spontaneous or forced) levels. Thus, IL-4, which was known to promote late stages of normal myogenesis, favors growth and migration, and inhibits further differentiation of the myogenic stages attained by rhabdomyosarcoma cells. Strategies to increase myogenin expression and block IL-4 could simultaneously reduce growth and migration, and enhance terminal differentiation of rhabdomyosarcoma, thus contributing to the control of tumor growth and metastatic spread. [Mol Cancer Ther 2009;8(4):754–61]
Aminopeptidase inhibition as a targeted treatment strategy in myeloma
Authors: Moore Hannah E. , Davenport Emma L. , Smith Emma M. , Muralikrishnan Srikanth , Dunlop Alan S. , Walker Brian A. , Krige David , Drummond Alan H. , Hooftman Leon , Morgan Gareth J. , Davies Faith E.
Published: April 2009

Myeloma cells are highly dependent on the unfolded protein response to assemble folded immunoglobulins correctly. Therefore, targeting protein handling within a myeloma cell by inhibiting the aminopeptidase enzyme system, which catalyses the hydrolysis of amino acids from the proteins NH2 terminus, represents a therapeutic approach. CHR-2797, a novel aminopeptidase inhibitor, is able to inhibit proliferation and induce growth arrest and apoptosis in myeloma cells, including cells resistant to conventional chemotherapeutics. It causes minimal inhibition of bone marrow stromal cell (BMSC) proliferation but is able to overcome the microenvironmental protective effects, inhibiting the proliferation of myeloma cells bound to BMSCs and the increase in vascular endothelial growth factor levels seen when myeloma cells and BMSCs are bound together. Additive and synergistic effects are seen with bortezomib, melphalan, and dexamethasone. Apoptosis occurs via both caspase-dependent and non-caspase-dependent pathways with an increase in Noxa, cleavage of Mcl-1, and activation of the unfolded protein response. Autophagy is also seen. CHR-2797 causes an up-regulation of genes involved in the proteasome/ubiquitin pathway, as well as aminopeptidases, and amino acid deprivation response genes. In conclusion, inhibiting protein turnover using the aminopeptidase inhibitor CHR-2797 results in myeloma cell apoptosis and represents a novel therapeutic approach that warrants further investigation in the clinical setting. [Mol Cancer Ther 2009;8(4):762–70]
BIIB021, an orally available, fully synthetic small-molecule inhibitor of the heat shock protein Hsp90
Authors: Lundgren Karen , Zhang Hong , Brekken John , Huser Nanni , Powell Rachel E. , Timple Noel , Busch David J. , Neely Laura , Sensintaffar John L. , Yang Yong-ching , McKenzie Andres , Friedman Jessica , Scannevin Robert , Kamal Adeela , Hong Kevin , Kasibhatla Srinivas R. , Boehm Marcus F. , Burrows Francis J.
Published: April 2009

Inhibition of heat shock protein 90 (Hsp90) results in the degradation of oncoproteins that drive malignant progression, inducing cell death, making Hsp90 a target of substantial interest for cancer therapy. BIIB021 is a novel, fully synthetic inhibitor of Hsp90 that binds competitively with geldanamycin in the ATP-binding pocket of Hsp90. In tumor cells, BIIB021 induced the degradation of Hsp90 client proteins including HER-2, AKT, and Raf-1 and up-regulated expression of the heat shock proteins Hsp70 and Hsp27. BIIB021 treatment resulted in growth inhibition and cell death in cell lines from a variety of tumor types at nanomolar concentrations. Oral administration of BIIB021 led to the degradation of Hsp90 client proteins measured in tumor tissue and resulted in the inhibition of tumor growth in several human tumor xenograft models. Studies to investigate the antitumor effects of BIIB021 showed activity on both daily and intermittent dosing schedules, providing dose schedule flexibility for clinical studies. Assays measuring the HER-2 protein in tumor tissue and the HER-2 extracellular domain in plasma were used to show interdiction of the Hsp90 pathway and utility as potential biomarkers in clinical trials for BIIB021. Together, these data show that BIIB021 is a promising new oral inhibitor of Hsp90 with antitumor activity in preclinical models.[Mol Cancer Ther 2009;8(4):921–9]
A proteomic approach links decreased pyruvate kinase M2 expression to oxaliplatin resistance in patients with colorectal cancer and in human cell lines
Authors: Martinez-Balibrea Eva , Plasencia Carmen , Ginés Alba , Martinez-Cardús Anna , Musulén Eva , Aguilera Rodrigo , Manzano José Luis , Neamati Nouri , Abad Albert
Published: April 2009

We aimed to gain further understanding of the molecular mechanisms involved in oxaliplatin resistance in colorectal cancer by using a proteomic approach. A 5-fold oxaliplatin-resistant cell line, HTOXAR3, was compared with its parental cell line, HT29, using two-dimensional PAGE. Mass spectrometry, Western blot, and real-time quantitative PCR confirmed the down-regulation of pyruvate kinase M2 (PK-M2) in HTOXAR3 cells. In a panel of eight colorectal cancer cell lines, we found a negative correlation between oxaliplatin resistance and PK-M2 mRNA levels (Spearman r = −0.846, P = 0.008). Oxaliplatin exposure in both HT29 and HTOXAR3 led to PK-M2 mRNA up-regulation. PK-M2 mRNA levels were measured by real-time quantitative PCR in 41 tumors treated with oxaliplatin/5-fluorouracil. Tumors with the lowest PK-M2 levels attained the lowest response rates (20% versus 64.5%, P = 0.026). High PK-M2 levels were associated with high p53 levels (P = 0.032). In conclusion, the data provided clearly link PK-M2 expression and oxaliplatin resistance mechanisms and further implicate PK-M2 as a predictive marker of response in patients with oxaliplatin-treated colorectal cancer.[Mol Cancer Ther 2009;8(4):771–8]
Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer
Authors: Liu Dong , Kojima Toru , Ouchi Masaaki , Kuroda Shinji , Watanabe Yuichi , Hashimoto Yuuri , Onimatsu Hideki , Urata Yasuo , Fujiwara Toshiyoshi
Published: April 2009

A phase I dose-escalation study of telomerase-specific oncolytic adenovirus, OBP-301 (Telomelysin), is now under way in the United States to assess feasibility and to characterize its pharmacokinetics in patients with advanced solid tumors. The present preclinical study investigates whether OBP-301 and a chemotherapeutic agent that is commonly used for lung cancer treatment, gemcitabine, are able to enhance antitumor effects in vitro and in vivo. The antitumor effects of OBP-301 infection and gemcitabine were evaluated by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt assay. In vivo antitumor effects of intratumoral injection of OBP-301 in combination with systemic administration of gemcitabine were assessed on nu/nu mice s.c. xenografted with human lung tumors. OBP-301 infection combined with gemcitabine resulted in very potent synergistic cytotoxicity in human lung cancer cells. The three human lung cancer cell lines treated with OBP-301 for 24 hours tended to accumulate in S phase compared with controls. The proportion of cells in S phase increased from 43.85% to 56.41% in H460 cells, from 46.72% to 67.09% in H322 cells, and from 38.22% to 57.67% in H358 cells. Intratumoral injection of OBP-301 combined with systemic administration of gemcitabine showed therapeutic synergism in human lung tumor xenografts. Our data suggest that the combination of OBP-301 and gemcitabine enhances the antitumor effects against human lung cancer. We also found that the synergistic mechanism may be due to OBP-301–mediated cell cycle accumulation in S phase. These results have important implications for the treatment of human lung cancer.[Mol Cancer Ther 2009;8(4):980–7]
Curcumin circumvents chemoresistance in vitro and potentiates the effect of thalidomide and bortezomib against human multiple myeloma in nude mice model
Authors: Sung Bokyung , Kunnumakkara Ajaikumar B. , Sethi Gautam , Anand Preetha , Guha Sushovan , Aggarwal Bharat B.
Published: April 2009

Curcumin (diferuloylmethane), a yellow pigment in turmeric, has been shown to inhibit the activation of nuclear factor-κB (NF-κB), a transcription factor closely linked to chemoresistance in multiple myeloma cells. Whether curcumin can overcome chemoresistance and enhance the activity of thalidomide and bortezomib, used to treat patients with multiple myeloma, was investigated in vitro and in xenograft model in nude mice. Our results show that curcumin inhibited the proliferation of human multiple myeloma cells regardless of their sensitivity to dexamethasone, doxorubicin, or melphalan. Curcumin also potentiated the apoptotic effects of thalidomide and bortezomib by down-regulating the constitutive activation of NF-κB and Akt, and this correlated with the suppression of NF-κB-regulated gene products, including cyclin D1, Bcl-xL, Bcl-2, TRAF1, cIAP-1, XIAP, survivin, and vascular endothelial growth factor. Furthermore, in a nude mice model, we found that curcumin potentiated the antitumor effects of bortezomib (P < 0.001, vehicle versus bortezomib + curcumin; P < 0.001, bortezomib versus bortezomib + curcumin), and this correlated with suppression of Ki-67 (P < 0.001 versus control), CD31 (P < 0.001 versus vehicle), and vascular endothelial growth factor (P < 0.001 versus vehicle) expression. Collectively, our results suggest that curcumin overcomes chemoresistance and sensitizes multiple myeloma cells to thalidomide and bortezomib by down-regulating NF-κB and NF-κB-regulated gene products. [Mol Cancer Ther 2009;8(4):959–70]
Growth inhibition of human cancer cells by 5-aza-2′-deoxycytidine does not correlate with its effects on INK4a/ARF expression or initial promoter methylation status
Authors: Xiong Jingbo , Epstein Richard J.
Published: April 2009

The cytotoxicity of 5-aza-2′-deoxycytidine (DAC) has been linked to demethylation of the INK4a/ARF tumor suppressor gene locus in various cell systems, but the causality of this association remains unproven. To test this assumption, we have examined the effects of DAC in two human cancer cell lines of differing INK4a/ARF promoter methylation status: MDA-MB-468 breast cancer cells in which INK4a/ARF is unmethylated and normally expressed, and DLD-1 colorectal cancer cells in which INK4a/ARF is methylated and repressed. In MDA-MB-468 cells, DAC induces cytotoxicity in the absence of any detectable increase of p14 or p16 expression, whereas small interfering RNA knockdown of p16/p14 expression fails to attenuate DAC cytotoxicity. In DLD-1 cells, DAC demethylates INK4a/ARF and restores both p16 and p14 expression at concentrations that fail to cause detectable growth inhibition or apoptosis; moreover, neither ARF nor INK4a transgene expression inhibits DLD-1 cell growth despite normalization of p14 and p16 expression. These data imply that neither of these cell lines depends on up-regulated expression of INK4a/ARF for DAC cytotoxicity. We propose that optimal anticancer use of this drug will await unambiguous identification of those DAC target genes primarily responsible for triggering growth inhibition, followed by clarification as to whether these upstream events are caused by hypomethylation or DNA damage.[Mol Cancer Ther 2009;8(4):779–85]
Connexin43 pseudogene in breast cancer cells offers a novel therapeutic target
Authors: Bier Andrew , Oviedo-Landaverde Irene , Zhao Jing , Mamane Yael , Kandouz Mustapha , Batist Gerald
Published: April 2009

Connexin43 (Cx43) is often deregulated in breast cancer tissue compared with normal adjacent tissue. Stable reexpression of Cx43 in cancer slows growth and renders the cells more sensitive to cytotoxic chemotherapeutics. Pseudogenes are often considered nonfunctional copies of DNA. The Cx43 pseudogene (ΨCx43) possesses all the features of an expressed gene and is exclusively transcribed in breast cancer cell lines and not in normal cells. ΨCx43 can be translated in vivo, and its protein exhibits growth-suppressive behavior similar to Cx43. We showed that ΨCx43 binds to the polyribosomes in breast cancer cells and that exogenous expression of ΨCx43 induces translational inhibition of Cx43. Furthermore, ΨCx43 is translated and binds more efficiently to the translational machinery than does Cx43 in an in vitro system. Following knockdown of ΨCx43 in breast cancer cells, we observed an increase in Cx43 RNA and protein. This results in increased cellular sensitivity to cytotoxic chemotherapy. Our results show that ΨCx43 acts as a posttranscriptional regulator of Cx43 in breast cancer cells, and that this represents an example of the regulation of genes by pseudogenes with potential therapeutic implications in cancer. [Mol Cancer Ther 2009;8(4):786–93]
Resolving conflicting data on expression of the Tn antigen and implications for clinical trials with cancer vaccines
Authors: Li Qian , Anver Miriam R. , Butcher Donna O. , Gildersleeve Jeffrey C.
Published: April 2009

The tumor-associated Tn antigen has been investigated extensively as a biomarker and therapeutic target. Cancer vaccines containing the Tn antigen as a single tumor antigen or as a component of a polyvalent vaccine have progressed into phase I and II clinical trials. One major focus of Tn-based vaccines is the treatment of prostate cancer patients. Although expression of the antigen on prostate tumors is a critical prerequisite, previous reports investigating Tn expression in prostate tumors have produced conflicting results. Using a combination of immunohistochemistry and carbohydrate microarray profiling, we show that only 4% to 26% of prostate tumors express the Tn antigen. Based on our results, the majority of prostate cancer patients do not express the appropriate antigen. Therefore, efforts to preselect the subset of prostate cancer patients with Tn-positive tumors or apply Tn vaccines to other cancers with higher rates of antigen expression could significantly improve clinical response rates. Because conflicting information on carbohydrate expression is a general problem for the field, the approach described in this article of analyzing antigen expression with multiple antibodies and using carbohydrate microarray profiles to interpret the results will be useful for the development of other carbohydrate-based cancer vaccines and diagnostics.[Mol Cancer Ther 2009;8(4):971–9)