bluuebunny/crossref_metadata_2025 huggingface dataset:
A Comparison of the Transient and Heated-Coating Methods for the Measurement of Local Heat Transfer Coefficients on a Pin Fin
Authors: Baughn J. W. , Ireland P. T. , Jones T. V. , Saniei N.
Published: October 2009

Measurements of the local heat transfer coefficients on a pin fin (i.e., a short cylinder in crossflow) in a duct have been made using two methods, both of which employ liquid crystals to map an isotherm on the surface. The transient method uses the liquid crystal to determine the transient response of the surface temperature to a change in the fluid temperature. The local heat transfer coefficient is determined from the surface response time and the thermal properties of the substrate. The heated-coating method uses an electrically heated coating (vacuum-deposited gold in this case) to provide a uniform heat flux, while the liquid crystal is used to locate an isotherm on the surface. The two methods compare well, especially the value obtained near the center stagnation point of the pin fin where the difference in the thermal boundary condition of the two methods has little effect. They are close but differ somewhat in other regions.
Mixed Convection Plume—Application of Superposition
Authors: Wang C. Y.
Published: October 2009

By comparing with the exact similarity solution for the mixed convection plume of the point source, the limitation of the Oseen boundary layer solution is established. Superposition principles are given and applied to the cases of the vertical and the horizontal finite heated wire. Three-dimensional thermal and velocity fields are determined.
Wind Tunnel Experiments on Cooling Tower Plumes: Part 1—In Uniform Crossflow
Authors: Andreopoulos J.
Published: October 2009

Measurements of velocity and temperature field and flow visualization results are reported for an ideal case of a cooling-tower plume in the presence of a uniform crossflow for various velocity ratios, densimetric Froude numbers, and Reynolds numbers. Coherent structures in the form of jetlike, wakelike, or mushroom-type vortices have been observed. The type of structure depends primarily on the velocity ratio. As the Reynolds number increases, turbulent structures appear, which have vorticity of the same sign as the partner vortices in the low Reynolds number case. The measurements showed that there is a strong interaction between the bending plume or jet and the wake of the cooling tower, which is basically responsible for the downwash effect. The latter is generally quite strong at low velocity ratios and high Reynolds numbers. High turbulence intensities are produced in the wake of the tower for a distance of 6 to 8 diameters. The plume is diluted faster as the velocity ratio increases and buoyancy decreases. In the wake region of the stack dilution increases with increased buoyancy.
The Energy Equation for Freezing of Biological Tissue
Authors: Rubinsky B.
Published: October 2009

In the past, the process of freezing in biological tissue was modeled using the regular energy equation for a homogeneous compound. New experimental evidence shows that in tissue the water freezes separately in the vascular system and in the cells. The freezing process is affected by the water transport between the cells and the blood vessels. A new equation was developed to model the experimental results. In this work the general equation for freezing of biological tissue will be presented together with a linearized version of the new equation. A perturbation solution is obtained for the linearized equation to illustrate the effect of the water transport on the freezing process in tissue.
Wingless Promotes Proliferative Growth in a Gradient-Independent Manner
Authors: Baena-Lopez Luis Alberto , Franch-Marro Xavier , Vincent Jean-Paul
Published: October 2009

Proliferation of cells in the
Drosophila
wing does not require a gradient of the morphogen Wingless.
Memorable microRNA
Authors: Gough Nancy R.
Published: October 2009

In
Aplysia
, long-term plasticity involves the reduction in miR-124, which increases the abundance of the transcription factor CREB1.
Focus Issue: The Long and Short of Redox Signaling
Authors: Gough Nancy R.
Published: October 2009

Reactive oxygen species mediate local and long-distance signals.
Science Signaling
Podcast: 6 October 2009
Authors: Vincent Jean-Paul , VanHook Annalisa M.
Published: October 2009

Graded distribution of Wingless is not required for cell proliferation in the fly wing disc.
Apoptosis: Calling Time on Apoptosome Activity
Authors: Adrain Colin , Martin Seamus J.
Published: October 2009

Caspase-9 autoprocessing displaces active caspase-9 bound to the apoptosome, thereby limiting proteolytic activity.
JAK Goes Nuclear
Authors: Ray L. Bryan
Published: October 2009

Nuclear JAK2 protein kinase controls gene expression through modification of chromatin.
Quiet Clock
Authors: Ray L. Bryan
Published: October 2009

Clock-containing neurons in the mouse brain display complex electrophysiology not seen in other brain cells.
Delivering the Wnt Signal
Authors: Gough Nancy R.
Published: October 2009

Evi delivers two synaptic mediators required for formation of the neuromuscular junction: transsynaptic Wnt and postsynaptic dGRIP.
Gee Fizz
Authors: Ray L. Bryan
Published: October 2009

The enzyme carbonic anhydrase mediates the taste sensation of carbonated drinks.
Emerging Miniaturized Proteomic Technologies to Study Cell Signaling in Clinical Samples
Authors: Gujral Taranjit S. , MacBeath Gavin
Published: October 2009

Assessing the state of signaling networks in limited quantity samples may facilitate personalized medical care.
Radioprotection in Normal Tissue and Delayed Tumor Growth by Blockade of CD47 Signaling
Authors: Maxhimer Justin B. , Soto-Pantoja David R. , Ridnour Lisa A. , Shih Hubert B. , DeGraff William G. , Tsokos Maria , Wink David A. , Isenberg Jeff S. , Roberts David D.
Published: October 2009

Inhibition of a membrane receptor protects normal tissue from radiation injury and simultaneously enhances the ability of ionizing radiation to delay tumor growth.
What the Patient Should Order
Authors: Kush Rebecca Daniels
Published: October 2009

Clinical information must be converted into research data that can be aggregated to provide a sufficiently large set for reliable analyses to inform health care decisions.
COCYCLES FOR CANTOR MINIMAL ℤd-SYSTEMS
Authors: GIORDANO THIERRY , PUTNAM IAN F. , SKAU CHRISTIAN F.
Published: October 2009

We consider a minimal, free action, φ, of the group ℤd on the Cantor set X, for d ≥ 1. We introduce the notion of small positive cocycles for such an action. We show that the existence of such cocycles allows the construction of finite Kakutani–Rohlin approximations to the action. In the case, d = 1, small positive cocycles always exist and the approximations provide the basis for the Bratteli–Vershik model for a minimal homeomorphism of X. Finally, we consider two classes of examples when d = 2 and show that such cocycles exist in both.
EQUATIONS FOR $\overline M_{0,n}$
Authors: KEEL SEAN , TEVELEV JENIA
Published: October 2009

We show that the log canonical bundle, κ, of [Formula: see text] is very ample, show the homogeneous coordinate ring is Koszul, and give a nice set of rank 4 quadratic generators for the homogeneous ideal: The embedding is equivariant for the symmetric group, and the image lies on many Segre embedded copies of ℙ1 × ⋯ × ℙn-3, permuted by the symmetric group. The homogeneous ideal of [Formula: see text] is the sum of the homogeneous ideals of these Segre embeddings.
The Role of Sterile Neutrinos in Cosmology and Astrophysics
Authors: Boyarsky Alexey , Ruchayskiy Oleg , Shaposhnikov Mikhail
Published: October 2009

We present a comprehensive overview of an extension of the Standard Model that contains three right-handed (sterile) neutrinos with masses below the electroweak scale [the Neutrino Minimal Standard Model (νMSM)]. We consider the history of the Universe from the inflationary era through today and demonstrate that most of the observed phenomena beyond the Standard Model can be explained within the framework of this model. We review the mechanism of baryon asymmetry of the Universe in the νMSM and discuss a dark matter candidate that can be warm or cold and that satisfies all existing constraints. From the viewpoint of particle physics, the model provides an explanation for neutrino flavor oscillations. Verification of the νMSM is possible with existing experimental techniques.
Functional analysis of FSP27 protein regions for lipid droplet localization, caspase-dependent apoptosis, and dimerization with CIDEA
Authors: Liu Kun , Zhou Shengli , Kim Ji-Young , Tillison Kristin , Majors David , Rearick David , Lee Jun Ho , Fernandez-Boyanapalli Ruby F. , Barricklow Katherine , Houston M. Sue , Smas Cynthia M.
Published: October 2009

The adipocyte-specific protein FSP27, also known as CIDEC, is one of three cell death-inducing DFF45-like effector (CIDE) proteins. The first known function for CIDEs was promotion of apoptosis upon ectopic expression in mammalian cells. Recent studies in endogenous settings demonstrated key roles for CIDEs in energy metabolism. FSP27 is a lipid droplet-associated protein whose heterologous expression enhances formation of enlarged lipid droplets and is required for unilocular lipid droplets typical of white adipocytes in vivo. Here, we delineate relationships between apoptotic function and lipid droplet localization of FSP27. We demonstrate that ectopic expression of FSP27 induces enlarged lipid droplets in multiple human cell lines, which is indicative that its mechanism involves ubiquitously present, rather than adipocyte-specific, cellular machinery. Furthermore, promotion of lipid droplet formation in HeLa cells via culture in exogenous oleic acid offsets FSP27-mediated apoptosis. Using transient cotransfections and analysis of lipid droplets in HeLa cells stably expressing FSP27, we show that FSP27 does not protect lipid droplets from action of ATGL lipase. Domain mapping with eGFP-FSP27 deletion constructs indicates that lipid droplet localization of FSP27 requires amino acids 174–192 of its CIDE C domain. The apoptotic mechanism of FSP27, which we show involves caspase-9 and mitochondrial cytochrome c, also requires this 19-amino acid region. Interaction assays determine the FSP27 CIDE C domain complexes with CIDEA, and Western blot reveals that FSP27 protein levels are reduced by coexpression of CIDEA. Overall, our findings demonstrate the function of the FSP27 CIDE C domain and/or regions thereof for apoptosis, lipid droplet localization, and CIDEA interaction.
Selective activation of PPARγ in skeletal muscle induces endogenous production of adiponectin and protects mice from diet-induced insulin resistance
Authors: Amin Rajesh H. , Mathews Suresh T. , Camp Heidi S. , Ding Liyun , Leff Todd
Published: October 2009

The nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ plays a key role in regulating whole body glucose homeostasis and insulin sensitivity. Although it is expressed most highly in adipose, it is also present at lower levels in many tissues, including skeletal muscle. The role muscle PPARγ plays in metabolic regulation and in mediating the antidiabetic effects of the thiazolidinediones is not understood. The goal of this work was to examine the molecular and physiological effects of PPARγ activation in muscle cells. We found that pharmacological activation of PPARγ in primary cultured myocytes, and genetic activation of muscle PPARγ in muscle tissue of transgenic mice, induced the production of adiponectin directly from muscle cells. This muscle-produced adiponectin was functional and capable of stimulating adiponectin signaling in myocytes. In addition, elevated skeletal muscle PPARγ activity in transgenic mice provided a significant protection from high-fat diet-induced insulin resistance and associated changes in muscle phenotype, including reduced myocyte lipid content and an increase in the proportion of oxidative muscle fiber types. Our findings demonstrate that PPARγ activation in skeletal muscle can have a significant protective effect on whole body glucose homeostasis and insulin resistance and that myocytes can produce and secrete functional adiponectin in a PPARγ-dependent manner. We propose that activation of PPARγ in myocytes induces a local production of adiponectin that acts on muscle tissue to improve insulin sensitivity.
Noncanonical TGF-β pathways, mTORC1 and Abl, in renal interstitial fibrogenesis
Authors: Wang Shinong , Wilkes Mark C. , Leof Edward B. , Hirschberg Raimund
Published: October 2009

Renal interstitial fibrosis is a major determinant of renal failure in the majority of chronic renal diseases. Transforming growth factor-β (TGF-β) is the single most important cytokine promoting renal fibrogenesis. Recent in vitro studies identified novel non-smad TGF-β targets including p21-activated kinase-2 (PAK2), the abelson nonreceptor tyrosine kinase (c-Abl), and the mammalian target of rapamycin (mTOR) that are activated by TGF-β in mesenchymal cells, specifically in fibroblasts but less in epithelial cells. In the present studies, we show that non-smad effectors of TGF-β including PAK2, c-Abl, Akt, tuberin (TSC2), and mTOR are activated in experimental unilateral obstructive nephropathy in rats. Treatment with c-Abl or mTOR inhibitors, imatinib mesylate and rapamycin, respectively, each blocks noncanonical (non-smad) TGF-β pathways in the kidney in vivo and diminishes the number of interstitial fibroblasts and myofibroblasts as well as the interstitial accumulation of extracellular matrix proteins. These findings indicate that noncanonical TGF-β pathways are activated during the early and rapid renal fibrogenesis of obstructive nephropathy. Moreover, the current findings suggest that combined inhibition of key regulators of these non-smad TGF-β pathways even in dose-sparing protocols are effective treatments in renal fibrogenesis.
Slow Spike Frequency Adaptation in Neurons of the Rat Subthalamic Nucleus
Authors: Barraza David , Kita Hitoshi , Wilson Charles J.
Published: October 2009

Neurons of the subthalamic nucleus (STN) are very sensitive to applied currents, firing at 10–20/s during spontaneous activity, but increasing to peak firing rates of 200/s with applied currents <0.5 nA. They receive a powerful tonic excitatory input from neurons in the cerebral cortex, yet in vivo maintain an irregular firing rate only slightly higher than the autonomous firing rate seen in slices. Spike frequency adaptation acts to normalize background firing rate by removing slow trends in firing due to changes in average input. Subthalamic neurons have been previously described as showing little spike frequency adaptation, but this was based on tests using brief stimuli. We applied long-duration depolarizing current steps to STN neurons in slices and observed a very strong spike frequency adaptation with a time constant of 20 s and that recovered at a similar rate. This adaptation could return firing to near-baseline levels during prolonged current pulses that transiently drove the cells at high rates. The current responsible for adaptation was studied in voltage clamp during and after high-frequency driving of the cell and was determined to be a slowly accumulating K+ current. This current was independent of calcium or sodium entry and could be induced with long-duration voltage steps after blockade of action potentials. In addition to the adaptation current, driven firing produced slow inactivation of the persistent Na+ current, which also contributed to the reduced excitability of STN cells during and after driven firing.
On Approximate Euler Differential Equations
Authors: Jung Soon-Mo , Min Seungwook
Published: October 2009

We solve the inhomogeneous Euler differential equations of the form and apply this result to the approximation of analytic functions of a special type by the solutions of Euler differential equations.
Preservation of Methane Hydrates Prepared from Dilute Electrolyte Solutions
Authors: Sato Hiroshi , Tsuji Takanori , Nakamura Tetsunari , Uesugi Koichi , Kinoshita Takahiro , Takahashi Masahiro , Mimachi Hiroko , Iwasaki Toru , Ohgaki Kazunari
Published: October 2009

The anomalous or self-preservation of methane hydrate at atmospheric pressure and temperatures below the ice point was investigated to determine whether this phenomenon might have applications in the storage and transportation of natural gas. Particular attention was paid to the effects of dilute electrolytes, as the presence of impurities in water is unavoidable in commercial transportation processes. The presence of electrolytes had a marked effect on the decomposition kinetics of methane hydrate at temperatures between 243 and 269 K. It was also found that chloride and sulfate ions may exhibit greater effects than do sodium and magnesium ions.
Evaluation of the Nutrient Status of Some Hydrophytes in the Water Courses of Nile Delta, Egypt
Authors: Shaltout Kamal H. , Galal Tarek M. , El-Komi Thanaa M.
Published: October 2009

The nutritive values of three dominant hydrophytes along the water courses in Nile Delta, Egypt (Echinochloa stagnina, Eichhornia crassipes, and Ceratophyllum demersum) were evaluated in terms of estimating their phytomass, organic, and inorganic chemical compositions. Shoots were collected seasonally from 25 permanent stands representing the distribution of the three species along 15 canals and 10 drains distributed in 5 localities within the Nile Delta. Living and dead parts and total phytomass were estimated. Their inorganic (Na, K, Ca, Mg, P, Cu, Mn, and Pb) and organic (carbohydrates, total nitrogen, total protein, ether extract, digestible nutrient, digestible energy, metabolized energy, and net energy) contents were estimated. The vegetative phase of E. stagnina extended during winter, spring, and summer, while it is flowering and fruiting during autumn. On the other hand, E. crassipes and C. demersum attained their maximum flowering during spring and maximum fruiting during summer, while maximum vegetative phase during autumn and winter. E. stagnina had the highest mean annual phytomass, while C. demersum had the lowest. The living parts of C. demersum had the highest concentrations of Na, Ca, and Mg, while the living parts of E. crassipes had the highest of K and N. C. demersum had the ability to accumulate more concentrations of heavy metals than the other studied species. E. crassipes had the highest values of total carbohydrate and total proteins, while E. stagnina had the highest of crude fibers, and C. demersum had the highest of ether extract and ash contents. The living parts of E. crassipes and C. demersum were considered as excellent forages, while the dead parts of all species and the living parts of E. stagnina were evaluated as poor forage.
Insulin Therapy and Body Weight, Body Composition and Muscular Strength in Patients with Type 2 Diabetes Mellitus
Authors: Gin H. , Rigalleau V. , Perlemoine C.
Published: October 2009

Aims.To determine the progression of body weight (BW) and body composition (BC) in patients with type 2 diabetes mellitus (T2D) on insulin therapy and the consequences on muscle strength (MS) as a reflect of free fat mass increases.Research design and methods.We analysed BC using air displacement plethysmography and MS by hand grip dynamometry in 40 T2D before and after three (M3) and six months (M6) of insulin therapy.Results.at baseline HbA1c was 9.76±1.6% and BW was stable with fat mass (FM) 28±10.7 kg; and fat free mass (FFM) 52.4±11 kg; at M6, HbA1c improved to 7.56±0.8%; insulin doses tended to increase. BW gain at M6 was+3.2±4.2 kg and with an increase of only 25% by M3; it was composed of FM, whereas FFM was unchanged. MS did not increase on insulin therapy.Conclusions.In T2D, BW gain was composed exclusively of FM with no improvement in MS.
Evidence for Cancer Stem Cells in Human Endometrial Carcinoma
Authors: Hubbard Sonya A. , Friel Anne M. , Kumar Beena , Zhang Ling , Rueda Bo R. , Gargett Caroline E.
Published: October 2009

Emerging evidence indicates that the highly regenerative human endometrium harbors rare populations of epithelial progenitor cells. In tumors of other regenerative epithelial tissues, rare cancer stem cells (CSC) have been identified that may have originated from normal epithelial stem/progenitor cells. We hypothesized that CSC are responsible for epithelial neoplasia associated with endometrial carcinoma, the most common gynecologic malignancy in women. Stem cell characteristics of single cells isolated from endometrial carcinoma tissues from women ages 62 ± 11.8 years (n = 34) were assessed. Twenty-five of 28 endometrial carcinoma samples contained a small population of clonogenic cells [0.24% (0-1.84%)], with no significant difference in cloning efficiency between the three grades of endometrial carcinoma or between endometrial carcinoma and normal endometrial epithelial samples. Isolated endometrial carcinoma cells transplanted under the kidney capsule of immunocompromised mice in serial dilution (2 × 106-1 × 104 cells) generated tumors in 8 of 9 samples with morphologies similar to the parent tumors. These tumors recapitulated cytokeratin, vimentin, estrogen receptor-α, and progesterone receptor expression of the parent tumor, indicating that tumor-initiating cells likely differentiated into cells comprising the endometrial carcinoma tissue. Individual clones underwent serial clonal subculture 2.5 to 4 times, with a trend of increasing number of subclonings with increasing tumor grade, indicating increasing self-renewal with greater malignancy. Clonally derived endometrial carcinoma cells also expressed the self-renewal genes BMI-1, NANOG, and SOX-2. Isolated cells from primary tumors were serially transplanted 3 to 5 times in nonobese diabetic/severe combined immunodeficient mice, showing self-renewal in vivo. This evidence of cells with clonogenic, self-renewing, differentiating, and tumorigenic properties suggests that a CSC population may be responsible for production of endometrial carcinoma tumor cells. [Cancer Res 2009;69(21):8241–8]
Simultaneous Infiltration of Polyfunctional Effector and Suppressor T Cells into Renal Cell Carcinomas
Authors: Attig Sebastian , Hennenlotter Jörg , Pawelec Graham , Klein Gerd , Koch Sven D. , Pircher Hanspeter , Feyerabend Susan , Wernet Dorothee , Stenzl Arnulf , Rammensee Hans-Georg , Gouttefangeas Cécile
Published: October 2009

Renal cell carcinoma is frequently infiltrated by cells of the immune system. This makes it important to understand interactions between cancer cells and immune cells so they can be manipulated to bring clinical benefit. Here, we analyze subsets and functions of T lymphocytes infiltrating renal cell tumors directly ex vivo following mechanical disaggregation and without any culture step. Subpopulations of memory and effector CD4+ Th1, Th2, and Th17 and CD8+ Tc1 cells were identified based on surface phenotype, activation potential, and multicytokine production. Compared with the same patient's peripheral blood, T lymphocytes present inside tumors were found to be enriched in functional CD4+ cells of the Th1 lineage and in effector memory CD8+ cells. Additionally, several populations of CD4+ and CD8+ regulatory T cells were identified that may synergize to locally dampen antitumor T-cell responses. [Cancer Res 2009;69(21):8412–9]
Deletion of PTEN Promotes Tumorigenic Signaling, Resistance to Anoikis, and Altered Response to Chemotherapeutic Agents in Human Mammary Epithelial Cells
Authors: Vitolo Michele I. , Weiss Michele B. , Szmacinski Marta , Tahir Khola , Waldman Todd , Park Ben Ho , Martin Stuart S. , Weber David J. , Bachman Kurtis E.
Published: October 2009

Many cancers, including breast cancer, harbor loss-of-function mutations in the catalytic domain of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or have reduced PTEN expression through loss of heterozygosity and/or epigenetic silencing mechanisms. However, specific phenotypic effects of PTEN inactivation in human cancer cells remain poorly defined without a direct causal connection between the loss of PTEN function and the development or progression of cancer. To evaluate the biological and clinical relevance of reduced or deleted PTEN expression, a novel in vitro model system was generated using human somatic cell knockout technologies. Targeted homologous recombination allowed for a single and double allelic deletion, which resulted in reduced and deleted PTEN expression, respectively. We determined that heterozygous loss of PTEN in the nontumorigenic human mammary epithelial cell line MCF-10A was sufficient for activation of the phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase pathways, whereas the homozygous absence of PTEN expression led to a further increased activation of both pathways. The deletion of PTEN was able to confer growth factor–independent proliferation, which was confirmed by the resistance of the PTEN−/− MCF-10A cells to small-molecule inhibitors of the epidermal growth factor receptor. However, neither heterozygous nor homozygous loss of PTEN expression was sufficient to promote anchorage-independent growth, but the loss of PTEN did confer apoptotic resistance to cell rounding and matrix detachment. Finally, MCF-10A cells with the reduction or loss of PTEN showed increased susceptibility to the chemotherapeutic drug doxorubicin but not paclitaxel. [Cancer Res 2009;69(21):8275–83]
Intratumoral Cytokines and Tumor Cell Biology Determine Spontaneous Breast Cancer–Specific Immune Responses and Their Correlation to Prognosis
Authors: Domschke Christoph , Schuetz Florian , Ge Yingzi , Seibel Tobias , Falk Christine , Brors Benedikt , Vlodavsky Israel , Sommerfeldt Nora , Sinn Hans-Peter , Kühnle Marie-Christine , Schneeweiss Andreas , Scharf Alexander , Sohn Christof , Schirrmacher Volker , Moldenhauer Gerhard , Momburg Frank , Beckhove Philipp
Published: October 2009

Spontaneous immune responses in cancer patients have been described. Yet their clinical relevance and the conditions for their generation remain unclear. We characterized conditions that determine immune responses in primary breast cancer patients. We used tetramer analysis, ex vivo IFN-γ ELISPOT, cytotoxicity assays, and ELISA in 207 untreated patients and 12 Her-2/neu–specific CD8 T-cell lines to evaluate tumor-specific T cells (TC) in the bone marrow or MUC1-specific antibodies in the blood. Multiplex analysis was performed to quantify 27 intratumoral cytokines, chemokines, and growth factors. Results were compared with multiple pathologic and clinical parameters of the patients and tumors. Forty percent of the patients showed tumor-specific TC responses. These correlated with tumors of high differentiation, estrogen receptor expression, and low proliferative activity, and with a reduced cancer mortality risk. High tumor cell differentiation correlated with increased intratumoral, but not plasma, concentrations of IFN-α and reduced transforming growth factor (TGF)β1. In an in vitro priming experiment these two cytokines increased or inhibited, respectively, the capacity of dendritic cells to induce tumor-reactive TC. Tumor-specific B-cell responses, mainly of IgM isotype, were detectable in 50% of the patients and correlated with advanced tumor stage, increased TGFβ1, reduced IFN-α, and absence of TC responses. We show here that different types of immune responses are linked to distinct cytokine microenvironments and correlate with prognosis-relevant differences in tumor pathobiology. These findings shed light on the relation between immune response and cancer prognosis. [Cancer Res 2009;69(21):8420–8]
Activation of the PI3K/AKT Pathway Induces Urothelial Carcinoma of the Renal Pelvis: Identification in Human Tumors and Confirmation in Animal Models
Authors: Qian Chao-Nan , Furge Kyle A. , Knol Jared , Huang Dan , Chen Jindong , Dykema Karl J. , Kort Eric J. , Massie Aaron , Khoo Sok Kean , Vanden Beldt Kristin , Resau James H. , Anema John , Kahnoski Richard J. , Morreau Hans , Camparo Philippe , Comperat Eva , Sibony Mathilde , Denoux Yves , Molinie Vincent , Vieillefond Annick , Eng Charis , Williams Bart O. , Teh Bin Tean
Published: October 2009

Urothelial carcinoma of the renal pelvis is a deadly disease with an unclear tumorigenic mechanism. We conducted gene expression profiling on a set of human tumors of this type and identified a phosphatidylinositol 3-kinase (PI3K)/AKT activation expression signature in 76.9% (n = 13) of our samples. Sequence analysis found both activating mutations of PIK3CA (13.6%, n = 22) and loss of heterozygosity at the PTEN locus (25%, n = 8). In contrast, none of the other subtypes of kidney neoplasms (e.g., clear-cell renal cell carcinoma) harbored PIK3CA mutations (n = 87; P < 0.001). Immunohistochemical analysis of urothelial carcinoma samples found loss of PTEN protein expression (36.4%, n = 11) and elevation of phosphorylated mammalian target of rapamycin (mTOR; 63.6%, n = 11). To confirm the role of the PI3K/AKT pathway in urothelial carcinoma, we generated mice containing biallelic inactivation of Pten in the urogenital epithelia. These mice developed typical renal pelvic urothelial carcinomas, with an incidence of 57.1% in mice older than 1 year. Laser capture microdissection followed by PCR confirmed the deletion of Pten exons 4 and 5 in the animal tumor cells. Immunohistochemical analyses showed increased phospho-mTOR and phospho-S6K levels in the animal tumors. Renal lymph node metastases were found in 15.8% of the animals with urothelial carcinoma. In conclusion, we identified and confirmed an important role for the PI3K/AKT pathway in the development of urothelial carcinoma and suggested that inhibitors of this pathway (e.g., mTOR inhibitor) may serve as effective therapeutic agents. [Cancer Res 2009;69(21):8256–64]
Eukaryotic Initiation Factor 4E Binding Protein Family of Proteins: Sentinels at a Translational Control Checkpoint in Lung Tumor Defense
Authors: Kim Yong Y. , Von Weymarn Linda , Larsson Ola , Fan Danhua , Underwood Jon M. , Peterson Mark S. , Hecht Stephen S. , Polunovsky Vitaly A. , Bitterman Peter B.
Published: October 2009

The usurping of translational control by sustained activation of translation initiation factors is oncogenic. Here, we show that the primary negative regulators of these oncogenic initiation factors—the 4E-BP protein family—operate as guardians of a translational control checkpoint in lung tumor defense. When challenged with the tobacco carcinogen 4-(methylnitrosamino)-I-(3-pyridyl)-1-butanone (NNK), 4ebp1−/−/4ebp2−/− mice showed increased sensitivity to tumorigenesis compared with their wild-type counterparts. The 4E-BP–deficient state per se creates pro-oncogenic, genome-wide skewing of the molecular landscape, with translational activation of genes governing angiogenesis, growth, and proliferation, and translational activation of the precise cytochrome p450 enzyme isoform (CYP2A5) that bioactivates NNK into mutagenic metabolites. Our study provides in vivo proof for a translational control checkpoint in lung tumor defense. [Cancer Res 2009;69(21):8455–62]
Regulation of Protein Citrullination through p53/PADI4 Network in DNA Damage Response
Authors: Tanikawa Chizu , Ueda Koji , Nakagawa Hidewaki , Yoshida Nobuaki , Nakamura Yusuke , Matsuda Koichi
Published: October 2009

Upon a wide range of cellular stresses, p53 is activated and inhibits malignant transformation through the transcriptional regulation of its target genes related to apoptosis, cell cycle arrest, and DNA repair. However, its involvement in posttranslational modifications of proteins has not yet been well characterized. Here, we report the novel role of p53 in the regulation of protein citrullination. p53 transactivated peptidylarginine deiminase type 4 (PADI4) through an intronic p53-binding site. The PADI4 gene encodes an enzyme catalyzing the citrullination of arginine residues in proteins, and ectopic expression of p53 or PADI4 induced protein citrullination. In addition, various proteins were citrullinated in response to DNA damage, but knockdown of PADI4 or p53 remarkably inhibited their citrullination, indicating the regulation of protein citrullination in a p53/PADI4-dependent manner. We found that PADI4 citrullinated the histone chaperone protein, nucleophosmin (NPM1), at the arginine 197 residue in vivo under physiologic conditions. Citrullination of NPM1 by PADI4 resulted in its translocation from the nucleoli to the nucleoplasm, whereas PADI4 did not alter the localization of mutant NPM1 (R197K). Furthermore, ectopic expression of PADI4 inhibited tumor cell growth, and concordantly, the knockdown of PADI4 attenuated p53-mediated growth-inhibitory activity, demonstrating the significance of PADI4-mediated protein citrullination in the p53 signaling pathway.[Cancer Res 2009;69(22):8761–9]
Identification of Key Regions and Genes Important in the Pathogenesis of Sézary Syndrome by Combining Genomic and Expression Microarrays
Authors: Caprini Elisabetta , Cristofoletti Cristina , Arcelli Diego , Fadda Paolo , Citterich Mauro Helmer , Sampogna Francesca , Magrelli Armando , Censi Federica , Torreri Paola , Frontani Marina , Scala Enrico , Picchio Maria Cristina , Temperani Paola , Monopoli Alessandro , Lombardo Giuseppe Alfonso , Taruscio Domenica , Narducci Maria Grazia , Russo Giandomenico
Published: October 2009

In this study, we used single nucleotide polymorphism and comparative genomic hybridization array to study DNA copy number changes and loss of heterozygosity for 28 patients affected by Sézary syndrome (SS), a rare form of cutaneous T-cell lymphoma (CTCL). Our data identified, further confirming previous studies, recurrent losses of 17p13.2-p11.2 and 10p12.1-q26.3 occurring in 71% and 68% of cases, respectively; common gains were detected for 17p11.2-q25.3 (64%) and chromosome 8/8q (50%). Moreover, we identified novel genomic lesions recurring in >30% of tumors: loss of 9q13-q21.33 and gain of 10p15.3-10p12.2. Individual chromosomal aberrations did not show a significant correlation with prognosis; however, when more than three recurrent chromosomal alterations (gain or loss) were considered, a statistical association was observed using Kaplan-Meier survival analysis. Integrating mapping and transcriptional data, we were able to identify a total of 113 deregulated transcripts in aberrant chromosomal regions that included cancer-related genes such as members of the NF-κB pathway (BAG4, BTRC, NKIRAS2, PSMD3, and TRAF2) that might explain its constitutive activation in CTCL. Matching this list of genes with those discriminating patients with different survival times, we identify several common candidates that might exert critical roles in SS, such as BUB3 and PIP5K1B. Altogether, our study confirms and maps more precisely the regions of gain and loss and, combined to transcriptional profiles, suggests a novel set of genes of potential interest in SS. [Cancer Res 2009;69(21):8438–46]
A Phase I Study of the Mammalian Target of Rapamycin Inhibitor Sirolimus and MEC Chemotherapy in Relapsed and Refractory Acute Myelogenous Leukemia
Authors: Perl Alexander E. , Kasner Margaret T. , Tsai Donald E. , Vogl Dan T. , Loren Alison W. , Schuster Stephen J. , Porter David L. , Stadtmauer Edward A. , Goldstein Steven C. , Frey Noelle V. , Nasta Sunita D. , Hexner Elizabeth O. , Dierov Jamil K. , Swider Cezary R. , Bagg Adam , Gewirtz Alan M. , Carroll Martin , Luger Selina M.
Published: October 2009

Purpose: Inhibiting mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) blasts and leukemic stem cells may enhance their sensitivity to cytotoxic agents. We sought to determine the safety and describe the toxicity of this approach by adding the mTOR inhibitor, sirolimus (rapamycin), to intensive AML induction chemotherapy.

Experimental Design: We performed a phase I dose escalation study of sirolimus with the chemotherapy regimen MEC (mitoxantrone, etoposide, and cytarabine) in patients with relapsed, refractory, or untreated secondary AML.

Results: Twenty-nine subjects received sirolimus and MEC across five dose levels. Dose-limiting toxicities were irreversible marrow aplasia and multiorgan failure. The maximum tolerated dose (MTD) of sirolimus was determined to be a 12 mg loading dose on day 1 followed by 4 mg/d on days 2 to 7, concurrent with MEC chemotherapy. Complete or partial remissions occurred in 6 (22%) of the 27 subjects who completed chemotherapy, including 3 (25%) of the 12 subjects treated at the MTD. At the MTD, measured rapamycin trough levels were within the therapeutic range for solid organ transplantation. However, direct measurement of the mTOR target p70 S6 kinase phosphorylation in marrow blasts from these subjects only showed definite target inhibition in one of five evaluable samples.

Conclusions: Sirolimus and MEC is an active and feasible regimen. However, as administered in this study, the synergy between MEC and sirolimus was not confirmed. Future studies are planned with different schedules to clarify the clinical and biochemical effects of sirolimus in AML and to determine whether target inhibition predicts chemotherapy response. (Clin Cancer Res 2009;15(21):6732–9)
Crosstalk to Stromal Fibroblasts Induces Resistance of Lung Cancer to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors
Authors: Wang Wei , Li Qi , Yamada Tadaaki , Matsumoto Kunio , Matsumoto Isao , Oda Makoto , Watanabe Go , Kayano Yoshiyuki , Nishioka Yasuhiko , Sone Saburo , Yano Seiji
Published: October 2009

Purpose: Lung cancers with epidermal growth factor receptor (EGFR)–activating mutations show good clinical response to gefitinib and erlotinib, selective tyrosine kinase inhibitors (TKI) to EGFR, but these tumors invariably develop drug resistance. Host stromal cells have been found to have a considerable effect on the behavior of cancer cells. Little is known, however, about the role of host cells on the sensitivity of cancer cells to receptor TKIs. We have therefore assessed the effect of crosstalk between stromal cells and lung cancer cells harboring EGFR mutations on susceptibility to EGFR-TKIs.

Experimental Design: We evaluated the gefitinib sensitivity of lung cancer cells with EGFR-activating mutations, PC-9 and HCC827, when cocultured with fibroblasts and coinjected into severe combined immunodeficient mice. We also examined the effect of lung cancer cells to fibroblast recruitment.

Results: Both human fibroblast cell lines and primary cultured fibroblasts produced various levels of hepatocyte growth factor (HGF). Lung cancer cells markedly recruited fibroblasts. The lung cancer cells became resistant to EGFR-TKIs when cocultured in vitro with HGF-producing fibroblasts and coinjected into severe combined immunodeficient mice. Importantly, combined use of gefitinib plus anti-HGF antibody or the HGF antagonist, NK4, successfully overcame the fibroblast-induced EGFR-TKI resistance both in vitro and in vivo. Colocalization of fibroblasts and HGF was detected in both xenograft tumors in mouse model and lung cancer patient specimens.

Conclusions: These findings indicate that crosstalk to stromal fibroblasts plays a critical role in lung cancer resistance to EGFR-TKIs and may be an ideal therapeutic target in lung cancer with EGFR-activating mutations. (Clin Cancer Res 2009;15(21):6630–8)
UNC45A Confers Resistance to Histone Deacetylase Inhibitors and Retinoic Acid
Authors: Epping Mirjam T. , Meijer Lars A.T. , Bos Johannes L. , Bernards René
Published: October 2009

To identify potential biomarkers of therapy response, we have previously done a large-scale gain-of-function genetic screen to identify genes whose expression confers resistance to histone deacetylase inhibitors (HDACI). This genetic screen identified two genes with a role in retinoic acid signaling, suggesting that HDACIs target retinoic acid signaling as part of their anticancer effect. We study here a third gene identified in this genetic screen, UNC45A, and assess its role in retinoic acid signaling and responses to HDACIs using cell-based proliferation and differentiation assays and transcriptional reporter gene assays. The vertebrate Unc45 genes are known for their roles in muscle development and the assembly and cochaperoning of the muscle motor protein myosin. Here, we report that human UNC45A (GCUNC45) can render transformed cells resistant to treatment with HDACIs. We show that UNC45A also inhibits signaling through the retinoic acid receptor α. Expression of UNC45A inhibits retinoic acid–induced proliferation arrest and differentiation of human neuroblastoma cells and inhibits the induction of endogenous retinoic acid receptor target genes. These data establish an unexpected role for UNC45A in causing resistance to both HDACI drugs and retinoic acid. Moreover, our data lend further support to the notion that HDACIs exert their anticancer effect, at least in part, through an effect on retinoic acid signaling. (Mol Cancer Res 2009;7(11):1861–70)
Elevated Levels of Urinary Prostaglandin E Metabolite Indicate a Poor Prognosis in Ever Smoker Head and Neck Squamous Cell Carcinoma Patients
Authors: Kekatpure Vikram D. , Boyle Jay O. , Zhou Xi Kathy , Duffield-Lillico Anna J. , Gross Neil D. , Lee Nancy Y. , Subbaramaiah Kotha , Morrow Jason D. , Milne Ginger , Lippman Scott M. , Dannenberg Andrew J.
Published: October 2009

Cyclooxygenase (COX)-derived prostaglandin E2 (PGE2) plays a role in the development and progression of several tumor types including head and neck squamous cell carcinoma (HNSCC). Measurements of urinary PGE metabolite (PGE-M) can be used as an index of systemic PGE2 production. In ever smokers, increased levels of urinary PGE-M reflect increased COX-2 activity. In this study, we determined whether baseline levels of urinary PGE-M were prognostic for ever smoker HNSCC patients. A retrospective chart review of ever smoker HNSCC patients treated with curative intent was done. Fifteen of 31 evaluable patients developed progressive disease (recurrence or a second primary tumor) after a median follow-up of 38 months. There were no statistically significant differences between patients with (n = 15) or without disease progression (n = 16) with regard to stage, site, treatment received, smoking status, and aspirin use during follow-up. Median urinary PGE-M levels were significantly higher in HNSCC patients with disease progression (21.7 ng/mg creatinine) compared with patients without (13.35 ng/mg creatinine; P = 0.03). Importantly, patients with high baseline levels of urinary PGE-M had a significantly greater risk of disease progression (hazard ratio, 4.76, 95% CI, 1.31-17.30; P < 0.01) and death (hazard ratio, 9.54; 95% CI, 1.17-77.7; P = 0.01) than patients with low baseline levels of urinary PGE-M. These differences were most evident among patients with early-stage disease. Taken together, our findings suggest that high baseline levels of urinary PGE-M indicate a poor prognosis in HNSCC patients. Possibly, HNSCC patients with high COX-2 activity manifested by elevated urinary PGE-M will benefit from treatment with a COX-2 inhibitor.
Identification of Actively Translated mRNA Transcripts in a Rat Model of Early-Stage Colon Carcinogenesis
Authors: Davidson Laurie A. , Wang Naisyin , Ivanov Ivan , Goldsby Jennifer , Lupton Joanne R. , Chapkin Robert S.
Published: October 2009

With respect to functional mapping of gene expression signatures, the steady-state mRNA expression level does not always accurately reflect the status of critical signaling proteins. In these cases, control is exerted at the epigenetic level of recruitment of mRNAs to polysomes, the factories of ribosomes that mediate efficient translation of many cellular messages. However, to date, a genome-wide perspective of the effect of carcinogen and chemoprotective bioactive diets on actively translated (polysomal) mRNA populations has not been done. Therefore, we used an established colon cancer model, i.e., the azoxymethane (AOM)-treated rat, in combination with a chemoprotective diet extensively studied in our laboratory, i.e., n-3 polyunsaturated fatty acids, to characterize the molecular processes underlying the transformation of normal colonic epithelium. The number of genes affected by AOM treatment 10 weeks after carcinogen injection was significantly greater in the polysome RNA fraction compared with the total RNA fraction as determined using a high-density microarray platform. In particular, polysomal loading patterns of mRNAs associated with the Wnt-β catenin, phospholipase A2-eicosanoid and the mitogen-activated protein kinase signaling axes were significantly upregulated at a very early period of tumor development in the colon. These data indicate that translational alterations are far more extensive relative to transcriptional alterations in mediating malignant transformation. In contrast, transcriptional alterations were found to be more extensive relative to translational alterations in mediating the effects of diet. Therefore, during early stage colonic neoplasia, diet and carcinogen seem to predominantly regulate gene expression at multiple levels via unique mechanisms.
Management of Reflux Symptoms with Over-the-Counter Proton Pump Inhibitors: Issues and Proposed Guidelines
Authors: Haag Sebastian , Andrews Jane M. , Katelaris Peter H. , Gapasin Judith , Galmiche Jean Paul , Hunt Richard , Layer Peter , Malfertheiner Peter , Holtmann Gerald
Published: October 2009

Background: Symptoms of gastroesophageal reflux are widely prevalent. There is a continuum between subjects with mild reflux symptoms and those severely affected by gastroesophageal reflux disease (GERD). Both groups may at times access over-the-counter (OTC) therapies. For the purpose of this review, relevant papers, including national and international guidelines were reviewed and recommendations made for appropriate use of OTC proton pump inhibitor (PPI) therapy. Results: PPIs are the gold standard for treatment of reflux symptoms. OTC therapy with histamine2 receptor antagonists (H2RAs) also plays a role. For the majority affected by reflux symptoms, effective symptom control is the most important outcome, as only a subgroup requires investigations or interventions. However, patients with alarm features (i.e. troublesome dysphagia, weight loss, predominant upper abdominal pain) are not recommended for OTC therapy and need prompt medical referral. Frequent relapses or failure to adequately respond to OTC therapy are additional triggers for medical assessment. Conclusions: OTC treatment of typical reflux symptoms (acid regurgitation, heartburn) with antacids and H2RAs is now accepted as safe and results in short-term relief of symptoms. There is no evidence of additional risk with OTC PPIs compared to these existing OTC therapies and PPIs are significantly more efficacious.