bluuebunny/crossref_metadata_2025 huggingface dataset:
Mixed Convective Low Flow Pressure Drop in Vertical Rod Assemblies: II—Experimental Validation
Authors: Suh K. Y. , Todreas N. E. , Rohsenow W. M.
Published: October 2009

An experimental study has been conducted to validate the predictive models and correlations for laminar and transition flow frictional pressure loss in vertical rod bundles under mixed convection conditions. An experimental procedure has been developed to measure low differential pressures under mixed convection conditions in 19 heated rod bare and wire-wrapped assemblies. The proposed model has been found successfully to predict the effects of wire wrapping, power skew, transition from laminar regime, developing and Interacting flow redistributions, and rod number on the friction loss characteristics in bundle geometries over the bundle average Grq/Re number range of 6 to 18,500.
Combined Natural Convection and Forced Flow Through Small Openings in a Horizontal Partition, With Special Reference to Flows in Multicompartment Enclosures
Authors: Epstein M. , Kenton M. A.
Published: October 2009

Estimates of the magnitude of buoyancy-driven exchange flows through openings in partitions that separate compartments are needed to assess the movement of toxic gases and smoke through buildings. An experiment using water and brine as a substitute for a light gas moving in a dense gas was designed to measure combined forced and buoyancy-driven exchange flow through a single opening in a horizontal partition. No theoretical treatment exists for this configuration. The same apparatus was used to determine the magnitude of the forced flow required to purge the opening of the oppositely directed buoyant component (i.e., the “flooding” limit). Finally, combined forced and buoyancy-driven flows in a multicompartment enclosure were measured. It has been demonstrated that the combined forced and buoyancy-generated flows in the multicompartment structure can be predicted by a direct application of the results of the study of exchange flow through a single opening.
Leishmania
GP63 Alters Host Signaling Through Cleavage-Activated Protein Tyrosine Phosphatases
Authors: Gomez Maria Adelaida , Contreras Irazu , Hallé Maxime , Tremblay Michel L. , McMaster Robert W. , Olivier Martin
Published: October 2009

The parasite protein GP63 triggers cleavage and activation of host protein tyrosine phosphatases to promote infection.
Chemical Genetics Identifies c-Src as an Activator of Primitive Ectoderm Formation in Murine Embryonic Stem Cells
Authors: Meyn Malcolm A. , Smithgall Thomas E.
Published: October 2009

Kinases engineered for inhibitor resistance reveal a unique role for c-Src in embryonic stem cell differentiation.
Coordinated Responses to Oxygen and Sugar Deficiency Allow Rice Seedlings to Tolerate Flooding
Authors: Lee Kuo-Wei , Chen Peng-Wen , Lu Chung-An , Chen Shu , Ho Tuan-Hua David , Yu Su-May
Published: October 2009

The protein kinase CIPK15 integrates the response to hypoxia with sugar signaling to allow submerged rice seedlings to grow.
STIM2 Regulates Capacitive Ca
2+
Entry in Neurons and Plays a Key Role in Hypoxic Neuronal Cell Death
Authors: Berna-Erro Alejandro , Braun Attila , Kraft Robert , Kleinschnitz Christoph , Schuhmann Michael K. , Stegner David , Wultsch Thomas , Eilers Jens , Meuth Sven G. , Stoll Guido , Nieswandt Bernhard
Published: October 2009

Neurons lacking the calcium sensor STIM2 are protected from hypoxia-induced cell death.
Sweet Talking
Authors: Foley John F.
Published: October 2009

Mannose- and fucose-based carbohydrates differentially modulate cytokine production in dendritic cells through their interactions with DC-SIGN.
Butterfly Navigation
Authors: Sugden Andrew
Published: October 2009

Monarch butterfly antennae contain the timing mechanism for time-compensated Sun compass orientation.
Sending ROS on a Bullet Train
Authors: Wong Hann Ling , Shimamoto Ko
Published: October 2009

Hydrogen peroxide is an auto-propagating, rapid systemic stress signal generated by RBOHD in
Arabidopsis.
Transduction of Redox Signaling by Electrophile-Protein Reactions
Authors: Rudolph Tanja K. , Freeman Bruce A.
Published: October 2009

Attachment of electrophilic products of redox reactions to proteins links cell function to changes in metabolic and inflammatory status.
Mimicking Caloric Restriction
Authors: Ray L. Bryan
Published: October 2009

A signaling pathway in mice mediates the effects of caloric restriction that protect against age-related diseases.
Snapshots Form a Big Picture of Guanine Nucleotide Exchange
Authors: Rittinger Katrin
Published: October 2009

DOCK9 uses a unique mechanism to discriminate between GDP- and GTP-bound forms of Cdc42.
Stressful Bone Building
Authors: Foley John F.
Published: October 2009

The ER stress transducer OASIS is required for BMP2-dependent bone formation by osteoblasts.
Breaching a Barrier
Authors: Adler Elizabeth M.
Published: October 2009

AMPK plays a role in the increase in permeability of the intestinal epithelial barrier mediated by IFN-γ.
Gas and Brakes Required
Authors: VanHook Annalisa M.
Published: October 2009

The ability of land plants to sense and respond to cytokinins co-evolved with a mechanism for attenuating cytokinin signaling.
Science Signaling
Podcast: 13 October 2009
Authors: Meyn Malcolm A. , VanHook Annalisa M.
Published: October 2009

Distinct Src kinases regulate the differentiation of embryonic stem cells.
Preserving Both Life and Fertility
Authors: Adler Elizabeth M.
Published: October 2009

Imatinib protects oocytes from cisplatin-induced apoptosis.
Coupling Clocks and Metabolism
Authors: Kiberstis Paula A.
Published: October 2009

The protein kinase AMPK couples circadian clocks and metabolism in mammals through effects on a cryptochrome protein.
Focus Issue: Addressing Complicated Questions in Neuroscience
Authors: Gough Nancy R.
Published: October 2009

Multiple approaches are needed to understand brain biology and pathology.
Slow Elimination of Multidrug-Resistant Tuberculosis
Authors: Dye Christopher , Williams Brian G.
Published: October 2009

The spread of drug-resistant tuberculosis may be halted and reversed through appropriate use of drugs and diagnostics.
My Heart's All Aflutter
Authors: Kelner Katrina L.
Published: October 2009

Specialized cells in the heart similar to skin melanocytes may trigger the common heart arrhythmia, atrial fibrillation.
Fishermen and Farmers Share SNPs and Severe Fibrosis
Authors: LaMarco Kelly
Published: October 2009

Single-nucleotide polymorphisms found in ethnically and geographically diverse populations correlate with schistosomiasis-associated severe liver fibrosis.
Pleasure or Pain: A Matter of Perception
Authors: Khidr Lily
Published: October 2009

Scientists use imaging technology to pinpoint a specific region of the central nervous system involved in pain relief caused by placebos in humans.
INFORMATION ACQUISITION USING EYE-GAZE TRACKING FOR PERSON-FOLLOWING WITH MOBILE ROBOTS
Authors: LATIF HEMIN OMER , SHERKAT NASSER , LOTFI AHMAD
Published: October 2009

In the effort of developing natural means for human-robot interaction (HRI) significant amount of research has been focusing on Person-Following (PF) for mobile robots. PF, which generally consists of detecting, recognizing and following people, is believed to be one of the required functionalities for most future robots that share their environments with their human companions. Research in this field is mostly directed towards fully automating this functionality, which makes the challenge even more tedious. Focusing on this challenge leads research to divert from other challenges that coexist in any PF system. A natural PF functionality consists of a number of tasks that are required to be implemented in the system. However, in more realistic life scenarios, not all the tasks required for PF need to be automated. Instead, some of these tasks can be operated by human operators and therefore require natural means of interaction and information acquisition. In order to highlight all the tasks that are believed to exist in any PF system, this paper introduces a novel taxonomy for PF. Also, in order to provide a natural means for HRI, TeleGaze is used for information acquisition in the implementation of the taxonomy. TeleGaze was previously developed by the authors as a means of natural HRI for teleoperation through eye-gaze tracking. Using TeleGaze in the aid of developing PF systems is believed to show the feasibility of achieving a realistic information acquisition in a natural way.
VISUAL FEEDBACK METHODS FOR NANOHANDLING AUTOMATION
Authors: FATIKOW SERGEJ , DAHMEN CHRISTIAN , WORTMANN TIM , TUNNELL ROBERT
Published: October 2009

This paper presents different image processing methods and algorithms, which are needed to enable the reliable automation of nanohandling processes. These applications use the scanning electron microscope (SEM) as a visual sensor. SEMs are widespread and powerful tools for manipulations on the nanoscale. Due to the timing constraints in automated setups, the trade-off between SEM scanning speed and image quality is a concern for algorithm development. Tasks to be fulfilled on image data provided by the SEM include object recognition, object tracking and depth estimation. A selection of algorithms that have been applied in automated setups for nanomanipulation is discussed and validated.
Alignment Behavior of Crystal with Magnetic Anisotropy of χc< χaunder Rotating Magnetic Field
Authors: Iwai Kazuhiko , Niimi Masahiro , Kohama Takenori
Published: October 2009

The alignment behavior of a crystal has been investigated by numerical calculation and anin situobservation experiment with a process combining magnetic field imposition and sample rotation to form unidirectionally aligned crystals with a magnetic anisotropy of χc< χa. The experimentally observed alignment behavior of a polymeric fiber and its alignment time agreed with the numerically calculated ones. Crystal alignment under the out-of-step condition alternately repeats the alignment duration and the keeping of a constant duration, and finally the crystal aligns in a specific direction. The alignment time under the synchronous condition is longer than that under the out-of-step condition if the magnetic field intensity is constant. To reduce the alignment time, a strong magnetic field under the out-of-step condition is desirable in this process.
Fatty acids induce amylin expression and secretion by pancreatic β-cells
Authors: Qi Dongfei , Cai Kun , Wang Oumei , Li Zongmeng , Chen Juan , Deng Bo , Qian Lihua , Le Yingying
Published: October 2009

Amylin is the major component of pancreatic amyloid, which is implicated in the development of type 2 diabetes. It is costored with insulin in the secretory granules of pancreatic β-cells and cosecreted with insulin following stimulation with glucose. Here, we investigate the effect of fatty acids (FAs) on amylin expression and secretion by β-cells and explore the underlying mechanisms. Palmitate and oleate dose-dependently induced amylin mRNA accumulation in murine pancreatic β-cell line MIN6 and primary pancreatic islets. the inductive effect of FAs on amylin expression is independent of glucose concentration. FAs upregulated amylin expression at the transcriptional level, and FAs must be metabolized to induce amylin expression. FAs also significantly induced human amylin promoter activation. Pretreatment of MIN6 cells with Ca2+chelator (EGTA, BAPTA-AM) PKC inhibitor Gö-6976 or protein synthesis inhibitor cycloheximide significantly inhibited FA-induced amylin mRNA expression. Transcription factors cAMP-responsive element-binding protein, pancreatic and duodenal homeobox factor-1, and peroxisome proliferator-activated receptor were not involved in FA-induced amylin expression. Palmitate and oleate both increased amylin and insulin release from MIN6 cells and stimulated amylin expression but had no effect on insulin expression. Mice refed with Intralipid had significantly higher levels of plasma FFA, amylin, and insulin than those refed with saline. These data demonstrate that FAs differently regulate amylin and insulin expression and induce both amylin and insulin release. Ca2+and PKC signaling pathways and de novo-synthesized protein(s) were involved in FA-induced amylin expression. Induction of amylin production and release by FA may contribute to its biological functions under physiological conditions.
Effects of extensively oxidized low-density lipoprotein on mitochondrial function and reactive oxygen species in porcine aortic endothelial cells
Authors: Roy Chowdhury Subir K. , Sangle Ganesh V. , Xie Xueping , Stelmack Gerald L. , Halayko Andrew J. , Shen Garry X.
Published: October 2009

Atherosclerotic cardiovascular disease is the leading cause of mortality in the Western world. Dysfunction of the mitochondrial respiratory chain and overproduction of reactive oxygen species (ROS) are associated with atherosclerosis and cardiovascular disease. Oxidation increases the atherogenecity of LDL. Oxidized LDL may be apoptotic or nonapoptotic for vascular endothelial cells (EC), depending on the intensity of oxidation. A previous study demonstrated that nonapoptotic oxidized LDL increased activity of mitochondrial complex I in human umbilical vein EC. The present study examined the impact of extensively oxidized LDL (eoLDL) on oxygen consumption and the activities of key enzymes in the mitochondrial respiratory chain of cultured porcine aortic EC. Oxygraphy detected that eoLDL significantly reduced oxygen consumption in various mitochondrial complexes. Treatment with eoLDL significantly decreased NADH-ubiquinone dehydrogenase (complex I), succinate cytochrome c reductase (complex II/III), ubiquinone cytochrome c reductase (complex III), and cytochrome c oxidase (complex IV) activities and the NAD+-to-NADH ratio in EC compared with mildly oxidized LDL, LDL, or vehicle. Butylated hydroxytoluene, a potent antioxidant, normalized eoLDL-induced reductions in complex I and III enzyme activity in EC. Mitochondria-associated intracellular ROS and release of ROS from EC were significantly increased after eoLDL treatment. These findings suggest that eoLDL impairs enzyme activity in mitochondrial respiratory chain complexes and increases ROS generation from mitochondria of arterial EC. Collectively, these effects could contribute to vascular injury and atherogenesis under conditions of hypercholesterolemia and oxidative stress.
Diabetic GK/Par rat β-cells are spontaneously protected against H2O2-triggered apoptosis. A cAMP-dependent adaptive response
Authors: Lacraz Grégory , Figeac Florence , Movassat Jamileh , Kassis Nadim , Portha Bernard
Published: October 2009

The alteration of the β-cell population in the Goto-Kakizaki rat (GK/Par line), a model of spontaneous type 2 diabetes, has been ascribed to significantly decreased β-cell replication and neogenesis, while β-cell apoptosis is surprisingly not enhanced and remains in the normal range. To gain insight into the mechanisms by which those β-cells are protected from death, we studied ex vivo the apoptotic activity and the expression of a large set of pro/antiapoptotic and pro/antioxidant genes in GK/Par islet cells. This was done in vitro in freshly isolated islets as well as in response to culture conditions and calibrated reactive oxygen species (ROS) exposure (i.e., H2O2). We also investigated the intracellular mechanisms of the diabetic β-cell response to ROS, the role if any of the intracellular cAMP metabolism, and finally the kinetic of ROS response, taking advantage of the GK/Par rat normoglycemia until weaning. Our results show that the peculiar GK/Par β-cell phenotype was correlated with an increased expression of a large panel of antioxidant genes as well as pro/antiapoptotic genes. We demonstrate that such combination confers resistance to cytotoxic H2O2exposure in vitro, raising the possibility that at least some of the activated stress/defense genes have protective effects against H2O2-triggered β-cell death. We also present some evidence that the GK/Par β-cell resistance to H2O2is at least partly cAMP dependent. Finally, we show that such a phenotype is not innate but is spontaneously acquired after diabetes onset as the result of an adaptive response to the diabetic environment.
Enhancement of ITD Coding Within the Initial Stages of the Auditory Pathway
Authors: Pecka Michael , Siveke Ida , Grothe Benedikt , Lesica Nicholas A.
Published: October 2009

Sensory systems use a variety of strategies to increase the signal-to-noise ratio in their inputs at the receptor level. However, important cues for sound localization are not present at the individual ears but are computed after inputs from the two ears converge within the brain, and we hypothesized that additional strategies to enhance the representation of these cues might be employed in the initial stages after binaural convergence. Specifically, we investigated the transformation that takes place between the first two stages of the gerbil auditory pathway that are sensitive to differences in the arrival time of a sound at the two ears (interaural time differences; ITDs): the medial superior olive (MSO), where ITD tuning originates, and the dorsal nucleus of the lateral lemniscus (DNLL), to which the MSO sends direct projections. We use a combined experimental and computational approach to demonstrate that the coding of ITDs is dramatically enhanced between these two stages, with the mutual information in the responses of single neurons increasing by a factor of 2. We also show that this enhancement is related to an increase in dynamic range for neurons with high preferred frequencies and a decrease in variability for neurons with low preferred frequencies. These results suggest that a major role of the initial stages of the ITD pathway may be to enhance the representation created at the site of coincidence detection and illustrate the potential of this pathway as a model system for the study of strategies for enhancing sensory representations in the mammalian brain.
Convexity of the Set of Fixed Points Generated by Some Control Systems
Authors: Azhmyakov Vadim
Published: October 2009

We deal with an application of the fixed point theorem for nonexpansive mappings to a class of control systems. We study closed‐loop and open‐loop controllable dynamical systems governed by ordinary differential equations (ODEs) and establish convexity of the set of trajectories. Solutions to the above ODEs are considered as fixed points of the associated system‐operator. If convexity of the set of trajectories is established, this can be used to estimate and approximate the reachable set of dynamical systems under consideration. The estimations/approximations of the above type are important in various engineering applications as, for example, the verification of safety properties.
Genotoxicity Revaluation of Three Commercial Nitroheterocyclic Drugs: Nifurtimox, Benznidazole, and Metronidazole
Authors: Buschini Annamaria , Ferrarini Lisa , Franzoni Susanna , Galati Serena , Lazzaretti Mirca , Mussi Francesca , Northfleet de Albuquerque Cristina , Maria Araújo Domingues Zucchi Tânia , Poli Paola
Published: October 2009

Nitroheterocyclic compounds are widely used as therapeutic agents against a variety of protozoan and bacterial infections. However, the literature on these compounds, suspected of being carcinogens, is widely controversial. In this study, cytotoxic and genotoxic potential of three drugs, Nifurtimox (NFX), Benznidazole (BNZ), and Metronidazole (MTZ) was re-evaluated by different assays. Only NFX reduces survival rate in actively proliferating cells. The compounds are more active for base-pair substitution than frameshift induction in Salmonella; NFX and BNZ are more mutagenic than MTZ; they are widely dependent from nitroreduction whereas microsomal fraction S9 weakly affects the mutagenic potential. Comet assay detects BNZ- and NFX-induced DNA damage at doses in the range of therapeutically treated patient plasma concentration; BNZ seems to mainly act through ROS generation whereas a dose-dependent mechanism of DNA damaging is suggested for NFX. The lack of effects on mammalian cells for MTZ is confirmed also in MN assay whereas MN induction is observed for NFX and BNZ. The effects of MTZ, that shows comparatively low reduction potential, seem to be strictly dependent on anaerobic/hypoxic conditions. Both NFX and BNZ may not only lead to cellular damage of the infective agent but also interact with the DNA of mammalian cells.
Adherence to Artesunate-Amodiaquine Therapy for Uncomplicated Malaria in Rural Ghana: A Randomised Trial of Supervised versus Unsupervised Drug Administration
Authors: Asante Kwaku Poku , Owusu Ruth , Dosoo David , Awini Elizabeth , Adjei George , Amenga Etego Seeba , Chandramohan Daniel , Owusu-Agyei Seth
Published: October 2009

Introduction. To enhance effective treatment, african nations including Ghana changed its malaria treatment policy from monotherapy to combination treatment with artesunate-amodiaquine (AS+AQ). The major challenge to its use in loose form is adherence.Objective. The objectives of this study were to investigate adherence and treatment outcome among patients treated with AS+AQ combination therapy for acute uncomplicated malaria.Methodology. The study was conducted in two rural districts located in the middle belt of Ghana using quantitative methods. Patients diagnosed with acute uncomplicated malaria as per the Ghana Ministry of Health malaria case definitions were randomly allocated to one of two groups. All patients in both groups were educated about the dose regimen of AS+AQ therapy and the need for adherence. Treatment with AS+AQ was supervised in one group while the other group was not supervised. Adherence was assessed by direct observation of the blister package of AS+AQ left on day 2.Results. 401 participants were randomized into the supervised (211) and unsupervised (190) groups. Compliance in both supervised (95.7%) and unsupervised (92.6%) groups were similar (P=.18). The commonest side-effects reported on day 2 among both groups were headaches, and body weakness. Parasite clearance by day 28 was >95% in both groups.Discussion/Conclusions. Administration of AS-AQ in both groups resulted in high levels of adherence to treatment regimen among adolescent and adult population in central Ghana. It appears that high level of adherence to AS-AQ is achievable through a rigorous education programme during routine clinic visits.
Capability of a Portable Chromatic Unit for Monitoring Airborne Particles over Wide Urban Areas
Authors: Aceves-Fernandez M. A. , Jones G. R. , Kolupula Y. R. , Reichelt T. , Spencer J. W. , Pedraza-Ortega C. , Gorrostieta E.
Published: October 2009

Investigations are described into the use of a compact, portable unit, using polychromatic scattered light, for the preliminary monitoring airborne PM 2–10 particulates over widespread urban areas subjected to vehicular traffic. The monitoring unit has been used at a city centre bus terminus, at sites along an urban bus corridor and outside a local school adjacent to an air quality monitoring station. Holistic results are presented which demonstrate the use of the unit for the preliminary identification of locations and conditions with elevated levels of PM 2–10 particles which can be investigated in greater detail with particle‐specific, high‐precision instruments.
Common Fixed Points of Multistep Noor Iterations with Errors for a Finite Family of Generalized Asymptotically Quasi‐Nonexpansive Mappings
Authors: Imnang S. , Suantai S.
Published: October 2009

We introduce a general iteration scheme for a finite family
of generalized asymptotically quasi‐nonexpansive mappings in Banach spaces.
The new iterative scheme includes the multistep Noor iterations with errors,
modified Mann and Ishikawa iterations, three‐step iterative scheme of Xu and
Noor, and Khan and Takahashi scheme as special cases. Our results generalize
and improve the recent ones announced by Khan et al. (2008),
H. Fukhar‐ud‐din and S. H. Khan (2007), J. U. Jeong and S. H. Kim (2006),
and many others.
Pivotal Roles of Snail Inhibition and RKIP Induction by the Proteasome Inhibitor NPI-0052 in Tumor Cell Chemoimmunosensitization
Authors: Baritaki Stavroula , Yeung Kam , Palladino Michael , Berenson James , Bonavida Benjamin
Published: October 2009

The novel proteasome inhibitor NPI-0052 has been shown to sensitize tumor cells to apoptosis by various chemotherapeutic drugs and tumor necrosis factor–related apoptosis-inducing ligand (TRAIL), although the mechanisms involved are not clear. We hypothesized that NPI-0052–mediated sensitization may result from NF-κB inhibition and downstream modulation of the metastasis inducer Snail and the metastasis suppressor/immunosurveillance cancer gene product Raf-1 kinase inhibitory protein (RKIP). Human prostate cancer cell lines were used as models, as they express different levels of these proteins. We show that NPI-0052 inhibits both NF-κB and Snail and induces RKIP expression, thus resulting in cell sensitization to CDDP and TRAIL. The direct role of NF-κB inhibition in sensitization was corroborated with the NF-κB inhibitor DHMEQ, which mimicked NPI-0052 in sensitization and inhibition of Snail and induction of RKIP. The direct role of Snail inhibition by NPI-0052 in sensitization was shown with Snail small interfering RNA, which reversed resistance and induced RKIP. Likewise, the direct role of RKIP induction in sensitization was revealed by both overexpression of RKIP (mimicking NPI-0052) and RKIP small interfering RNA that inhibited NPI-0052–mediated sensitization. These findings show that NPI-0052 modifies the NF-κB-Snail-RKIP circuitry in tumor cells and results in downstream inhibition of antiapoptotic gene products and chemoimmunosensitization. The findings also identified Snail and RKIP as targets for reversal of resistance. [Cancer Res 2009;69(21):8376–85]
Interleukin 12 Stimulates IFN-γ–Mediated Inhibition of Tumor-Induced Regulatory T-Cell Proliferation and Enhances Tumor Clearance
Authors: Cao Xuefang , Leonard Karen , Collins Lynne I. , Cai Sheng F. , Mayer Joshua C. , Payton Jacqueline E. , Walter Michael J. , Piwnica-Worms David , Schreiber Robert D. , Ley Timothy J.
Published: October 2009

To define the factors that modulate regulatory T (Treg) cells in the tumor setting, we cocultured various tumor cells with either purified Treg cells, or with unfractionated splenocytes. We found that Treg expansion occurred only with unfractionated splenocytes, suggesting that accessory cells and/or factors produced by them play an essential role in tumor-induced Treg expansion. We performed gene expression profiling on tumor-associated Treg cells to identify candidate signaling molecules and studied their effects on tumor-induced Treg expansion. We inadvertently discovered that interleukin (IL)-12 treatment blocked Treg expansion in an IL-12 receptor–dependent fashion. Additional studies showed that IL-12 acts by stimulating IFN-γ mediated inhibition of Treg cell proliferation, which may partially account for the antitumor effects of IL-12. Furthermore, IL-12 treatment was found to decrease IL-2 production, which may lead to IFN-γ–independent inhibition of Treg cells, as IL-2 is required for their survival and expansion. Mechanistic studies revealed that IFN-γ signaling directly causes cell cycle arrest in Treg cells. This study shows that an IL-12–IFN-γ axis can suppress tumor-induced Treg proliferation. This mechanism may counteract the ability of Treg cells to promote tumor growth in vivo. [Cancer Res 2009;69(22):8700–9]
ATAD2 Is a Novel Cofactor for MYC, Overexpressed and Amplified in Aggressive Tumors
Authors: Ciró Marco , Prosperini Elena , Quarto Micaela , Grazini Ursula , Walfridsson Julian , McBlane Fraser , Nucifero Paolo , Pacchiana Giovanni , Capra Maria , Christensen Jesper , Helin Kristian
Published: October 2009

The E2F and MYC transcription factors are critical regulators of cell proliferation and contribute to the development of human cancers. Here, we report on the identification of a novel E2F target gene, ATAD2, the predicted protein product of which contains both a bromodomain and an ATPase domain. The pRB-E2F pathway regulates ATAD2 expression, which is limiting for the entry into the S phase of the cell cycle. We show that ATAD2 binds the MYC oncogene and stimulates its transcriptional activity. ATAD2 maps to chromosome 8q24, 4.3 Mb distal to MYC, in a region that is frequently found amplified in cancer. Consistent with this, we show that ATAD2 expression is high in several human tumors and that the expression levels correlate with clinical outcome of breast cancer patients. We suggest that ATAD2 links the E2F and MYC pathways and contributes to the development of aggressive cancer through the enhancement of MYC-dependent transcription. [Cancer Res 2009;69(21):8491–8]
Hijacking the Chromatin Remodeling Machinery: Impact ofSWI/SNFPerturbations in Cancer
Authors: Weissman Bernard , Knudsen Karen E.
Published: October 2009

There is increasing evidence that alterations in chromatin remodeling play a significant role in human disease. The SWI/SNF chromatin remodeling complex family mobilizes nucleosomes and functions as a master regulator of gene expression and chromatin dynamics whose functional specificity is driven by combinatorial assembly of a central ATPase and association with 10 to 12 unique subunits. Although the biochemical consequence of SWI/SNF in model systems has been extensively reviewed, the present article focuses on the evidence linking SWI/SNF perturbations to cancer initiation and tumor progression in human disease. [Cancer Res 2009;69(21):8223–30]
Nuclear Receptor Coregulators in Cancer Biology
Authors: O'Malley Bert W. , Kumar Rakesh
Published: October 2009

Coregulators (coactivators and corepressors) occupy the driving seat for actions of all nuclear receptors, and consequently, selective receptor modulator drugs. The potency and selectivity for subreactions of transcription reside in the coactivators, and thus, they are critically important for tissue-selective gene function. Each tissue has a “quantitative finger print” of coactivators based on its relative inherited concentrations of these molecules. When the cellular concentration of a coactivator is altered, genetic dysfunction usually leads to a pathologic outcome. For example, many cancers overexpress “growth coactivators.” In this way, the cancer cell can hijack these coactivator molecules to drive proliferation and metastasis. The present review contains summaries of selective coactivators and corepressors that have been demonstrated to play important roles in the malignant process and emphasizes their importance for future therapeutic interventions. [Cancer Res 2009;69(21):8217–22]
A Role for BRCA1 in Uterine Leiomyosarcoma
Authors: Xing Deyin , Scangas George , Nitta Mai , He Lei , Xu Xuan , Ioffe Yevgeniya J.M. , Aspuria Paul-Joseph , Hedvat Cyrus Y. , Anderson Matthew L. , Oliva Esther , Karlan Beth Y. , Mohapatra Gayatry , Orsulic Sandra
Published: October 2009

Uterine leiomyosarcoma (ULMS) is a rare gynecologic malignancy with a low survival rate. Currently, there is no effective treatment for ULMS. Infrequent occurrences of human ULMS hamper the understanding of the initiation and progression of the disease, thereby limiting the ability to develop efficient therapies. To elucidate the roles of the p53 and BRCA1 tumor suppressor genes in gynecologic malignancies, we generated mice in which p53 and/or BRCA1 can be conditionally deleted using anti-Müllerian hormone type II receptor (Amhr2)–driven Cre recombinase. We showed that conditional deletion of p53 in mice results in the development of uterine tumors that resemble human ULMS and that concurrent deletion of p53 and BRCA1 significantly accelerates the progression of these tumors. This finding led to our hypothesis that BRCA1 may play a role in human ULMS development. Consistent with this hypothesis, we showed that the BRCA1 protein is absent in 29% of human ULMS and that BRCA1 promoter methylation is the likely mechanism of BRCA1 downregulation. These data indicate that the loss of BRCA1 function may be an important step in the progression of ULMS. Our findings provide a rationale for investigating therapies that target BRCA1 deficiency in ULMS. [Cancer Res 2009;69(21):8231–5]
Macrophage Inhibitory Cytokine 1: A New Prognostic Marker in Prostate Cancer
Authors: Brown David A. , Lindmark Fredrik , Stattin Pär , Bälter Katarina , Adami Hans-Olov , Zheng Sigun L. , Xu Jianfeng , Isaacs William B. , Grönberg Henrik , Breit Samuel N. , Wiklund Fredrik E.
Published: October 2009

Purpose: High serum levels of macrophage inhibitory cytokine 1 (MIC-1) are strongly associated with metastatic prostate cancer, suggesting MIC-1 is a biomarker for prostate cancer prognosis.

Experimental Design: We conducted a prospective cohort study of 1,442 Swedish men with a pathologically verified diagnosis of prostate cancer between 2001 and 2003. Blood was drawn either pretreatment (n = 431) or posttreatment (n = 1,011) and cases were followed for a mean time of 4.9 years (range, 0.1-6.8 years).

Results: MIC-1 serum levels independently predicted poor cancer-specific survival with an almost 3-fold higher cancer death rate in patients with serum levels in the highest quartile compared with men with serum levels in the lowest quartile (adjusted hazard ratio, 2.98; 95% confidence interval, 1.82-4.68). Pretreatment MIC-1 levels revealed an even stronger association with disease outcome with an 8-fold higher death rate in the highest compared with the lowest category (adjusted hazard ratio, 7.98; 95% confidence interval, 1.73-36.86). Among patients considered to have localized disease, MIC-1 significantly increased the discriminative capacity between indolent and lethal prostate cancer compared with the established prognostic markers clinical stage, pathologic grade, and prostate-specific antigen level (P = 0.016). A sequence variant in the MIC-1 gene was associated with decreased MIC-1 serum levels (P = 0.002) and decreased prostate cancer mortality (P = 0.003), suggesting a causative role of MIC-1 in prostate cancer prognosis.

Conclusions: Serum MIC-1 concentration is a novel biomarker capable of predicting prostate cancer prognosis. (Clin Cancer Res 2009;15(21):6658–64)
Regional Brain Activation during Verbal Declarative Memory in Metastatic Breast Cancer
Authors: Kesler Shelli R. , Bennett F. Chris , Mahaffey Misty L. , Spiegel David
Published: October 2009

Purpose: To determine the neurofunctional basis of verbal memory dysfunction in women with metastatic breast cancer. This objective was based on previous research suggesting memory and other cognitive deficits in this population. We attempted to determine if verbal memory impairments were related to the most commonly studied disease parameters including adjuvant chemotherapy and chronic stress-related disruption of limbic system structures.

Experimental Design: We used functional magnetic resonance imaging to test our hypothesis that women with breast cancer would show significantly lower brain activation during verbal declarative memory tasks compared with age and education-matched healthy female controls. We also assessed several stress-related variables including diurnal cortisol levels to test our hypothesis that women with breast cancer would show higher stress and this would contribute to brain activation deficits during memory tasks.

Results: Women with breast cancer had significantly lower prefrontal cortex activation during the memory encoding condition compared with controls. However, the breast cancer group showed significantly greater activation than controls during the recall condition in multiple, diffuse brain regions. There were no significant differences between the groups in stress-related variables. Women who were treated with cyclophosphamide, methotrexate, and 5-fluorouracil chemotherapy showed lower prefrontal cortex activation during memory encoding.

Conclusions: These results suggest that women with metastatic breast cancer may be at risk for verbal memory impairments as a result of altered functional brain activation profiles. These findings may be associated with chemotherapy type and/or other aspects of the breast cancer disease process. (Clin Cancer Res 2009;15(21):6665–73)
T Cell–Based Immunotherapy of Metastatic Renal Cell Carcinoma: Modest Success and Future Perspective
Authors: Shablak Alaaeldin , Hawkins Robert E. , Rothwell Dominic G. , Elkord Eyad
Published: October 2009

Metastatic renal cell carcinoma (MRCC) remains a challenging malignancy to treat. Cancer immunotherapies have been extensively explored in melanoma and RCC as they poorly respond to conventional cytotoxic agents but show responses to a variety of immunologic agents. The recent considerable success of T cell–based immunotherapy in melanoma warrants further efforts to apply this treatment to other cancers including MRCC. Although RCC is an immunosensitive cancer, similar attempts in MRCC have shown a very limited success. In this review, we summarize the clinical data on T cell–based immunotherapies for MRCC showing the modest success that has been achieved to date. More importantly, we discuss potential strategies for improving its efficacy for the treatment of MRCC in light of the important achievements for treating metastatic melanoma. In particular, the growing evidence of success by combining expanded tumor-infiltrating lymphocytes with lymphodepletion merits investigation in MRCC. Identifying new RCC-associated antigens, optimized methods, and conditions for detection, isolation, and/or modification and expansion of tumor-specific T cells are all important strategies to be pursued for improving T cell–based immunotherapy of MRCC. (Clin Cancer Res 2009;15(21):6503–10)
Geranylgeranylacetone Protects against Diclofenac-Induced Gastric and Small Intestinal Mucosal Injuries in Healthy Subjects: A Prospective Randomized Placebo-Controlled Double-Blind Cross-Over Study
Authors: Niwa Yasumasa , Nakamura Masanao , Miyahara Ryoji , Ohmiya Naoki , Watanabe Osamu , Ando Takafumi , Kawashima Hiroki , Itoh Akihiro , Hirooka Yoshiki , Goto Hidemi
Published: October 2009

Background and Aims: Little information is available regarding the prevention and treatment of small intestinal mucosal injuries caused by non-steroidal anti-inflammatory drugs (NSAIDs). We planned a pilot study to investigate the protective effects of geranylgeranylacetone (GGA) against NSAID-induced small intestinal injuries using video capsule endoscopy (VCE). Subjects and Methods: Ten healthy male volunteers took oral GGA 300 mg/day (regimen A) or placebo (regimen B) in addition to diclofenac 75 mg/day + rabeprazole 20 mg/day for 7 days. We conducted a cross-over trial of regimens A and B with a 2-week washout period. All subjects underwent VCE before and after each administration period, and were evaluated for NSAID-induced gastric and small intestinal mucosal lesions. Results: The number of mucosal lesions (erosions, ulcers and a red spot with possible bleeding) detected in both stomach and small bowel changed between prior to and immediately after administration period, with significantly fewer lesions for regimen A after administration period (mean ± SD A:B = 2.6 ± 3.2:9.5 ± 8.5; p = 0.027). Conclusions: Combination therapy with GGA and rabeprazole reduced the incidence of gastroenteropathy induced by 1-week administration of diclofenac. Our findings suggest this therapy as a candidate for protecting patients on long-term NSAID therapy.
Post-Stroke Depressive Symptoms Are Associated with Post-Stroke Characteristics
Authors: Snaphaan Liselore , van der Werf Sieberen , Kanselaar Karin , de Leeuw Frank-Erik
Published: October 2009

Background: Several studies have described the frequency and risk factors of post-stroke depressive symptoms (PSDS). However, most studies did not exclude patients with depressive symptoms shortly before stroke and paid little attention to prestroke risk factors of depression, including previous depressive episodes, white matter lesions, and brain atrophy. These are potential limitations to assess the true effect of stroke on the occurrence of depressive symptoms. Our aim was to investigate the prevalence and risk factors of PSDS with adjustments for the previously mentioned prestroke factors. Methods: 420 consecutive patients with an acute clinical symptomatic transient ischemic attack or cerebral infarction were eligible for enrolment in this study. The presence of PSDS was rated by the Hospital Anxiety and Depression Scale 6–8 weeks after stroke. The relation between (pre-) stroke factors and PSDS was assessed with multivariate regression analysis. Results: The prevalence of PSDS was 13% and did not differ between stroke subtype or first-ever/ever occurrence of stroke. Higher degree of post-stroke handicap was related to PSDS (OR = 5.39; 95% CI = 2.40–12.08) and more functional independence had a protective effect on PSDS (OR = 0.88; 95% CI = 0.77–1.00). Conclusions: This is the largest study that investigated the prevalence and risk factors of PSDS by carefully excluding patients with depressive symptoms shortly before stroke. PSDS were not related to lesion side or location, but to the degree of post-stroke handicap and functional independence. Early detection of PSDS and their risk factors might help to predict long-term outcome and could promote early interventions of (behavioral) rehabilitation treatment strategies.
TIMP-2 Gene Polymorphism Is Associated with Intracerebral Hemorrhage
Authors: Reuter Bjoern , Bugert Peter , Stroick Mark , Bukow Simone , Griebe Martin , Hennerici Michael G. , Fatar Marc
Published: October 2009

Background: Both ischemic stroke and intracerebral hemorrhage are associated with altered expression and activation of matrix metalloproteinases (MMPs). Particularly relevant are MMP-2 and MMP-9. This proteolytic effect is dampened by tissue inhibitors of metalloproteinases (TIMPs). TIMP-2 is an important endogenous inhibitor of MMP-2. Alterations in the TIMP-2 gene expression may contribute to the incidence of ischemic stroke and intracerebral hemorrhage. Methods: TIMP-2 gene SNP –261G/A was genotyped from sequentially recruited stroke patients (n = 356, f/m 151/205, mean age 68.2 years, range 19–100 years) and gender and age matched controls (n = 253, f/m 114/139, mean age 68.5 years, range 32–92 years). The SNP –261G/A was detected after gene sequencing of 95 patients and controls. Furthermore, in a subgroup of 93 patients the serum levels of TIMP-2 were measured during the first 7 days after stroke onset and compared to the genotype. Results: SNP –261G/A in the TIMP-2 gene shows an allele frequency of approximately 39.14%. Homozygosity for allele A is associated significantly with the development of ICH (p = 0.025, OR = 2.020, CI = 1.115–3.661) as compared to heterozygosity and homozygosity for allele G (recessive genotypic model). Concordantly, the serum levels of TIMP-2 showed a nonsignificant decreases, depending on the genotype (p = 0.111). Conclusion: We investigated a SNP 261 base pairs upstream of the start codon in exon 1 of TIMP-2. Our data suggest that carriers of homozygosity for allele A are at increased risk of developing intracerebral hemorrhage.
Indices of Kidney Dysfunction and Discharge Outcomes in Hospitalized Stroke Patients without Known Renal Disease
Authors: Ovbiagele Bruce , Sanossian Nerses , Liebeskind David S. , Kim Doojin , Ali Latisha K. , Pineda Sandra , Saver Jeffrey L.
Published: October 2009

Background: The utility of clinical measurements of impairments in glomerular barrier or filtration rate among hospitalized stroke patients without known chronic kidney disease (CKD) has not been well studied. We determined whether various indices of CKD would predict discharge outcomes in persons hospitalized with a recent ischemic stroke. Methods: Presence of proteinuria and estimated low glomerular filtration rate (GFR) <60 ml/min per 1.73 m2 on admission were assessed in consecutive ischemic stroke and transient ischemic attack patients admitted to a university hospital over 18 months, who had no history of CKD. The primary discharge outcomes assessed (among stroke patients only) were death or disability (modified Rankin Scale score ≥2) and being discharged home directly from hospital. Independent effects of CKD indices on the outcomes were evaluated using multivariable regression modeling. Results: Of 251 patients with recent ischemic cerebrovascular events, 198 ischemic stroke patients (79%), met the study criteria. In crude analyses, persons with proteinuria or low GFR were significantly more likely to die in the hospital (p < 0.05). After adjusting for confounders, proteinuria was independently linked with lower odds of going home directly from the hospital (OR = 0.38, 95% CI = 0.16–0.92) and poorer discharge functional status (OR = 3.19, 95% CI = 1.37–7.46), but low GFR was not independently related to either of these outcomes. Conclusions: Among hospitalized ischemic stroke patients without known CKD, presence of proteinuria on admission is independently associated with poorer discharge functional activity and lower likelihood of being discharged home directly. Low GFR was not related to either outcome in these patients without known CKD.
Safety of Eptifibatide for Subcortical Stroke Progression
Authors: Martin-Schild Sheryl , Shaltoni Hashem , Abraham Anitha T. , Barreto Andrew D. , Hallevi Hen , Gonzales Nicole R. , Grotta James C. , Savitz Sean I.
Published: October 2009

Background: There is no proven treatment for stroke progression in patients with subcortical infarcts. Eptifibatide, a glycoprotein IIb/IIIa inhibitor, might halt stroke progression by improving flow in the microcirculation. Methods: We conducted a retrospective analysis of patients with subcortical stroke who experienced deterioration and were treated with eptifibatide (loading dose 180 μg/kg; infusion 2 μg/kg/min) for 24–48 h. Oral antiplatelet agents were started 6 h before discontinuation of eptifibatide. Results: Twenty-four patients with subcortical strokes were treated. The median admission NIHSS score was 5.0, which worsened to 8.5 (motor 5.0) before starting eptifibatide. The median NIHSS score 24 h after starting eptifibatide was 5.5. At 24 h, 42% had motor NIHSS scores less than or equal to pre-deterioration scores (50% for total NIHSS), and 50% had improved at least 1 motor point compared to pre-eptifibatide scores, which was sustained until hospital discharge. At discharge, the median total NIHSS score was 4.5. Ninety-two percent of patients were discharged home or to inpatient rehabilitation. Treatment was stopped early in 1 case due to a platelet drop <100,000/μl. No systemic or intracerebral bleeding occurred. Conclusions: Eptifibatide infusion may be safe in patients with subcortical ischemic strokes. Future studies are needed to test the safety and potential efficacy of this agent in subcortical stroke progression.