bluuebunny/crossref_metadata_2025 huggingface dataset:
PRESENT STATUS AND FUTURE DIRECTIONS OF SiGe HBT TECHNOLOGY
Authors: Khater Marwan H. , Adam Thomas N. , Krishnasamy Rajendran , Dahlstrom Mattias E. , Rieh Jae-Sung , Schonenberg Kathryn T. , Orner Bradly A. , Pagette Francois , Stein Kenneth , Ahlgren David C.
Published: July 2007

The implementation of challenging novel materials and process techniques has led to remarkable device improvements in state-of-the-art high-performance SiGe HBTs, rivaling their III-V compound semiconductor counterparts. Vertical scaling, lateral scaling, and device structure innovations required to improve SiGe HBTs performance have benefited from advanced materials and process techniques developed for next generation CMOS technology. In this work, we present a review of recent process and materials development enabling operational speeds of SiGe HBTs approaching 400 GHz. In addition, we present device simulation results that show the extendibility of SiGe HBT technology performance towards half-terahertz and beyond with further scaling and device structure improvements.
FOCUSED THERMAL BEAM DIRECT PATTERNING ON INGAN DURING MOLECULAR BEAM EPITAXY
Authors: CHEN XIAODONG , SCHAFF WILLIAM J. , EASTMAN LESTER F.
Published: July 2007

During InGaN Molecular Beam Epitaxy (MBE) growth, the material surface is exposed to a small diameter pulse laser beam that is controlled by scanning mirrors. Local heating effects are observed at the points of exposure. The materials are characterized by Wavelength Dispersive Spectroscopy (WDS), Scanning Electron Microscopy (SEM), and Photoluminescence (PL). Indium mole fraction of materials is reduced where laser exposure takes place. The effect of local thermal heating appears to enhance surface diffusion while not causing ablation or evaporation under the conditions studied. PL efficiency is significantly increased by focused thermal beam exposure. Laser written regions have 7 times higher PL intensity compared to non-written areas, which might be due to surface texturing that causes higher extraction efficiency.
TERAHERTZ EMISSION FROM ELECTRICALLY PUMPED SILICON GERMANIUM INTERSUBBAND DEVICES
Authors: Sustersic N. , Kim S. , Lv P.-C. , Coppinger M. , Troeger T. , Kolodzey James
Published: July 2007

In this paper, we report on current pumped THz emitting devices based on intersubband transitions in SiGe quantum wells. The spectral lines occurred in a range from 5 to 12 THz depending on the quantum well width, Ge concentration in the well, and device temperature. A time-averaged power of 15 nW was extracted from a 16 period SiGe/Si superlattice with quantum wells 22 Å thick, at a device temperature of 30 K and a drive current of 550 mA. A net quantum efficiency of approximately 3 × 10-4 was calculated from the power and drive current, 30 times higher than reported for comparable quantum cascades utilizing heavy-hole to heavy-hole transitions and, taking into account the number of quantum well periods, approximately four times larger than for electroluminescence reported previously from a device utilizing light-hole to heavy-hole transitions.
HIGH PERFORMANCE SIGEC/SI NEAR-IR ELECTROOPTIC MODULATORS AND PHOTODETECTORS
Authors: SCHUBERT MARTIN , RANA FARHAN
Published: July 2007

Numerical simulations are performed for SiGeC/Si electrooptic modulators and photodetectors operating at near-IR wavelengths. The addition of carbon provides the ability to lattice match layers with high germanium composition to silicon, which is shown to allow structures with a substantial increase in the optical confinement factor. In addition, SiGeC/Si heterostructures provide strong confinement of large electron and hole concentrations. The large optical confinement factor and strong carrier confinement enable broadband electrooptic modulators with sub-100 μm lengths and switching times below 0.5 ns with 25 mA current as well as photodetectors with quantum efficiencies as high as 90% for 300 μm length.
TABU SEARCH STRATEGIES FOR SOLVING JOB SHOP SCHEDULING PROBLEMS
Authors: ESWARAMURTHY V. P. , TAMILARASI A.
Published: July 2007

Scheduling is considered to be a major task to improve shop-floor productivity. The job shop problem is under this category and is combinatorial in nature. Research on optimization of job shop problem is one of the most significant and promising areas of optimization. This paper presents an application of the global optimization technique called tabu search to the job shop scheduling problem. An easily implementable algorithm for the problem of finding a minimum makespan in a job shop is presented. The method employs critical paths and blocks of operations. The algorithm is based on a specific neighborhood and dynamic tabu length strategies. A neighboring solution is a solution obtained by permuting two successive and critical operations that use the same machine. Tabus are useful to help the search move away from previously visited portions of the search space and thus perform more extensive exploration. Experiments using well-known bench mark problems are carried out to check the performance of the proposed method.
Lessons Learned from Studies of Fission Yeast Mating-Type Switching and Silencing
Authors: Klar Amar J.S.
Published: July 2007

Stably maintaining specific states of gene expression during cell division is crucial for cellular differentiation. In fission yeast, such patterns result from directed gene rearrangements and chromosomally inherited epigenetic gene control mechanisms that control mating cell type. Recent advances have shown that a specific DNA strand at the mat1 locus is “differentiated” by a novel strand-specific imprint so that nonequivalent sister chromatids are produced. Therefore, cellular differentiation is a natural consequence of the fact that DNA strands are complementary and nonequivalent. Another epigenetic control that “silences” library copies of mat-information is due to heterochromatin organization. This is a clear case where Mendel’s gene is composed of DNA plus the associated epigenetic moiety. Following up on initial genetic studies with more recent molecular investigations, this system has become one of the prominent models to understand mechanisms of gene regulation, genome integrity, and cellular differentiation. By applying lessons learned from these studies, such epigenetic gene control mechanisms, which must be installed in somatic cells, might explain mechanisms of cellular differentiation and development in higher eukaryotes.
Legal Innovation and the Control of Gang Behavior
Authors: Rosen Eva , Venkatesh Sudhir
Published: July 2007

This review considers one of the most prominent methods of combating gang activity in the second half of the last century, namely the deployment of legal strategies to prevent gang formation and intervene in existing gang structures. These include highly formalized strategies, such as the enactment of legislative decrees such as injunctions that limit the association of gang members in public space, as well as informal procedures in which communities create an indigenous and localized set of norms and juridical procedures to fight gang activity. Research on legal tactics and gang control in the past few decades has shown that the formative understanding of the city as a social ecology of distinct and separate communities, in which social institutions and residents are largely attuned to activity occurring within their boundaries, remains at the heart of social policy formulation with respect to youth delinquency. The review addresses these major legal innovations and the debates surrounding them.
Carboxy-terminal modulator protein induces Akt phosphorylation and activation, thereby enhancing antiapoptotic, glycogen synthetic, and glucose uptake pathways
Authors: Ono Hiraku , Sakoda Hideyuki , Fujishiro Midori , Anai Motonobu , Kushiyama Akifumi , Fukushima Yasushi , Katagiri Hideki , Ogihara Takehide , Oka Yoshitomo , Kamata Hideaki , Horike Nanao , Uchijima Yasunobu , Kurihara Hiroki , Asano Tomoichiro
Published: July 2007

Carboxy-terminal modulator protein (CTMP) was identified as binding to the carboxy terminus of Akt and inhibiting the phosphorylation and activation of Akt. In contrast to a previous study, we found CTMP overexpression to significantly enhance Akt phosphorylation at both Thr308 and Ser473 as well as the kinase activity of Akt, while phosphatidylinositol 3-kinase (PI3-kinase) activity was unaffected. Translocation of Akt to the membrane fraction was also markedly increased in response to overexpression of CTMP, with no change in the whole cellular content of Akt. Furthermore, the phosphorylations of GSK-3β and Foxo1, well-known substrates of Akt, were increased by CTMP overexpression. On the other hand, suppression of CTMP with small interfering RNA partially but significantly attenuated this Akt phosphorylation. The cellular activities reportedly mediated by Akt activation were also enhanced by CTMP overexpression. UV-B-induced apoptosis of HeLa cells was significantly reversed not only by overexpression of the active mutant of Akt (myr-Akt) but also by that of CTMP. Increases in glucose transport activity and glycogen synthesis were also induced by overexpression of either myr-Akt or CTMP in 3T3-L1 adipocytes. Taking these results into consideration, it can be concluded that CTMP induces translocation of Akt to the membrane and thereby increases the level of Akt phosphorylation. As a result, CTMP enhances various cellular activities that are principally mediated by the PI3-kinase/Akt pathway.
Effects of laxative and N-acetylcysteine on mucus accumulation, bacterial load, transit, and inflammation in the cystic fibrosis mouse small intestine
Authors: De Lisle Robert C. , Roach Eileen , Jansson Kyle
Published: July 2007

The accumulation of mucus in affected organs is characteristic of cystic fibrosis (CF). The CF mouse small intestine has dramatic mucus accumulation and exhibits slower interdigestive intestinal transit. These factors are proposed to play cooperative roles that foster small intestinal bacterial overgrowth (SIBO) and contribute to the innate immune response of the CF intestine. It was hypothesized that decreasing the mucus accumulation would reduce SIBO and might improve other aspects of the CF intestinal phenotype. To test this, solid chow-fed CF mice were treated with an osmotic laxative to improve gut hydration or liquid-fed mice were treated orally with N-acetylcysteine (NAC) to break mucin disulfide bonds. Treatment with laxative or NAC reduced mucus accumulation by 43% and 50%, respectively, as measured histologically as dilation of the intestinal crypts. Laxative and NAC also reduced bacterial overgrowth in the CF intestine by 92% and 63%, respectively. Treatment with laxative normalized small intestinal transit in CF mice, whereas NAC did not. The expression of innate immune response-related genes was significantly reduced in laxative-treated CF mice, whereas there was no significant effect in NAC-treated CF mice. In summary, laxative and NAC treatments of CF mice reduced mucus accumulation to a similar extent, but laxative was more effective than NAC at reducing bacterial load. Eradication of bacterial overgrowth by laxative treatment was associated with normalized intestinal transit and a reduction in the innate immune response. These results suggest that both mucus accumulation and slowed interdigestive small intestinal transit contribute to SIBO in the CF intestine.
Downregulation of p63 upon exposure to bile salts and acid in normal and cancer esophageal cells in culture
Authors: Roman Sabine , Pétré Aurélia , Thépot Amélie , Hautefeuille Agnès , Scoazec Jean-Yves , Mion François , Hainaut Pierre
Published: July 2007

p63 is a member of the p53 protein family that regulates differentiation and morphogenesis in epithelial tissues and is required for the formation of squamous epithelia. Barrett's mucosa is a glandular metaplasia of the squamous epithelium that develops in the lower esophagus in the context of chronic, gastroesophageal reflux and is considered as a precursor for adenocarcinoma. Normal or squamous cancer esophageal cells were exposed to deoxycholic acid (DCA, 50, 100, or 200 μM) and chenodeoxycholic and taurochenodeoxycholic acid at pH 5. p63 and cyclooxygenase-2 (COX-2) expressions were studied by Western blot and RT-PCR. DCA exposure at pH 5 led to a spectacular decrease in the levels of all isoforms of the p63 proteins. This decrease was observed within minutes of exposure, with a synergistic effect between DCA and acid. Within the same time frame, levels of p63 mRNA were relatively unaffected, whereas levels of COX-2, a marker of stress responses often induced in Barrett's mucosa, were increased. Similar results were obtained with chenodeoxycholic acid but not its taurine conjugate at pH 5. Proteasome inhibition by lactacystin or MG-132 partially blocked the decrease in p63, suggesting a posttranslational degradation mechanism. These results show that combined exposure to bile salt and acid downregulates a critical regulator of squamous differentiation, providing a mechanism to explain the replacement of squamous epithelium by a glandular metaplasia upon exposure of the lower esophagus to gastric reflux.
Sex differences in forebrain and cardiovagal responses at the onset of isometric handgrip exercise: a retrospective fMRI study
Authors: Wong Savio W. , Kimmerly Derek S. , Massé Nicholas , Menon Ravi S. , Cechetto David F. , Shoemaker J. Kevin
Published: July 2007

In general, cardiac regulation is dominated by the sympathetic and parasympathetic nervous systems in men and women, respectively. Our recent study had revealed sex differences in the forebrain network associated with sympathoexcitatory response to baroreceptor unloading. The present study further examined the sex differences in forebrain modulation of cardiovagal response at the onset of isometric exercise. Forebrain activity in healthy men ( n = 8) and women ( n = 9) was measured using functional magnetic resonance imaging during 5 and 35% maximal voluntary contraction handgrip exercise. Heart rate (HR), mean arterial pressure (MAP), and muscle sympathetic nerve activity (MSNA) were collected in a separate recording session. During the exercise, HR and MAP increased progressively, while MSNA was suppressed ( P < 0.05). Relative to men, women demonstrated smaller HR (8 ± 2 vs. 18 ± 3 beats/min) and MAP (3 ± 2 vs. 11 ± 2 mmHg) responses to the 35% maximal voluntary contraction trials ( P < 0.05). Although a similar forebrain network was activated in both groups, the smaller cardiovascular response in women was reflected in a weaker insular cortex activation. Nevertheless, men did not show a stronger deactivation at the ventral medial prefrontal cortex, which has been associated with modulating cardiovagal activity. In contrast, the smaller cardiovascular response in women related to their stronger suppression of the dorsal anterior cingulate cortex activity, which has been associated with sympathetic control of the heart. Our findings revealed sex differences in both the physiological and forebrain responses to isometric exercise.
A novel method of measuring reduction of nitrite-induced methemoglobin applied to fetal and adult blood of humans and sheep
Authors: Power Gordon G. , Bragg Shannon L. , Oshiro Bryan T. , Dejam Andre , Hunter Christian J. , Blood Arlin B.
Published: July 2007

The reaction of nitrite with deoxyhemoglobin results in the production of nitric oxide and methemoglobin, a reaction recently proposed as an important oxygen-sensitive source of vasoactive nitric oxide during hypoxic and anoxic stress, with several animal studies suggesting that nitrite may have therapeutic potential. Accumulation of toxic levels of methemoglobin is suppressed by reductase enzymes present within the erythrocyte. Using a novel method of measuring methemoglobin reductase activity in intact erythrocytes, we compared fetal and adult sheep and human blood. After nitrite-induced production of 20% methemoglobin, the blood was equilibrated with carbon monoxide, which effectively stopped further production. Methemoglobin disappearance was first order in nature with specific rate constants ( k × 1,000) of 12.9 ± 1.3 min−1for fetal sheep, 5.88 ± 0.26 min−1for adult sheep, 4.27 ± 0.34 for adult humans, and 3.30 ± 0.15 for newborn cord blood, all statistically different from one another. The effects of oxygen tensions, pH, hemolysis, and methylene blue are reported. Studies of temperature dependence indicated an activation energy of 8,620 ± 1,060 calories/mol (2.06 kJ/mol), appreciably higher than would be characteristic of processes limited by passive membrane diffusion. In conclusion, the novel methodology permits absolute quantification of the reduction of nitrite-induced methemoglobin in whole blood.
Preconditioning and postconditioning: innate cardioprotection from ischemia-reperfusion injury
Authors: Vinten-Johansen Jakob , Zhao Zhi-Qing , Jiang Rong , Zatta Amanda J. , Dobson Geoffrey P.
Published: July 2007

Reperfusion is the definitive treatment to salvage ischemic myocardium from infarction. A primary determinant of infarct size is the duration of ischemia. In myocardium that has not been irreversibly injured by ischemia, reperfusion induces additional injury in the area at risk. The heart has potent innate cardioprotective mechanisms against ischemia-reperfusion that reduce infarct size and other presentations of postischemic injury. Ischemic preconditioning (IPC) applied before the prolonged ischemia exerts the most potent protection observed among known strategies. It has been assumed that IPC exerts protection during ischemia. However, recent data suggest that cardioprotection is also exerted during reperfusion. Postconditioning (PoC), defined as brief intermittent cycles of ischemia alternating with reperfusion applied after the ischemic event, has been shown to reduce infarct size, in some cases equivalent to that observed with IPC. Although there are similarities in mechanisms of cardioprotection by these two interventions, there are key differences that go beyond simply exerting these mechanisms before or after ischemia. A significant limitation of IPC has been the inability to apply this maneuver clinically except in situations where the ischemic event can be predicted. On the other hand, PoC is applied at the point of service in the hospital (cath-lab for percutaneous coronary intervention, coronary artery bypass grafting, and other cardiac surgery) where and when reperfusion is initiated. Initial clinical studies are in agreement with the success and extent to which PoC reduces infarct size and myocardial injury, even in the presence of multiple comorbidities.
Ketamine and Xylazine Depress Sensory-Evoked Parallel Fiber and Climbing Fiber Responses
Authors: Bengtsson Fredrik , Jörntell Henrik
Published: July 2007

The last few years have seen an increase in the variety of in vivo experiments used for studying cerebellar physiological mechanisms. A combination of ketamine and xylazine has become a particularly popular form of anesthesia. However, because nonanesthetized control conditions are lacking in these experiments, so far there has been no evaluation of the effects of these drugs on the physiological activity in the cerebellar neuronal network. In the present study, we used the mossy fiber, parallel fiber, and climbing fiber field potentials evoked in the nonanesthetized, decerebrated rat to serve as a control condition against which the effects of intravenous drug injections could be compared. All anesthetics were applied at doses required for normal maintenance of anesthesia. We found that ketamine substantially depressed the evoked N3 field potential, which is an indicator of the activity in the parallel fiber synapses (−40%), and nearly completely abolished evoked climbing fiber field potentials (−90%). Xylazine severely depressed the N3 field (−75%) and completely abolished the climbing fiber field (−100%). In a combination commonly used for general anesthesia (20:1), ketamine–xylazine injections also severely depressed the N3 field (−75%) and nearly completely abolished the climbing fiber field (−90%). We also observed that lowered body and surface temperatures (<34°C) resulted in a substantial depression of the N3 field (−50%). These results urge for some caution in the interpretations of studies on cerebellar network physiology performed in animals anesthetized with these drugs.
Afferent Input, Efference Copy, Signal Noise, and Biases in Perception of Joint Angle During Active Versus Passive Elbow Movements
Authors: Gritsenko V. , Krouchev N. I. , Kalaska J. F.
Published: July 2007

Psychophysical studies have reported an overestimation of limb position in the direction of movement during the early part of active movements. The main hypothesis tested in this study is that the overestimation results from a process of forward prediction of limb state driven by an efference copy of the outgoing motor command. This hypothesis predicts that position overestimation should decrease or disappear during passive movements, for which there should be no efference copy. Seven subjects were asked to remember and to report the perceived angle of their elbow joint at different times during active and passive movements. They showed a highly velocity-dependent overestimation of the elbow joint angle near the beginning of the movement in both active and passive trials. Toward the end of the movement, subjects showed a relatively velocity-independent underestimation of their elbow angle in all trials. Contrary to the prediction of the efference copy hypothesis, the amplitude and the velocity-dependent slope of the elbow angle overestimation were both greater during the early part of passive movements than active movements. This indicates that psychophysical evidence of early overestimation of arm position on its own is not a sufficient proof of forward prediction based on an efference copy, at least under the conditions of this study. Decreased errors during active movements suggest that an efference copy can improve the accuracy of state estimation during active movements. Error patterns seem to parallel the likely level of sensorimotor noise, suggesting a probabilistic mechanism for position estimation.
Muscarinic Receptors Control Frequency Tuning Through the Downregulation of an A-Type Potassium Current
Authors: Ellis Lee D. , Krahe Rüdiger , Bourque Charles W. , Dunn Robert J. , Chacron Maurice J.
Published: July 2007

The functional role of cholinergic input in the modulation of sensory responses was studied using a combination of in vivo and in vitro electrophysiology supplemented by mathematical modeling. The electrosensory system of weakly electric fish recognizes different environmental stimuli by their unique alteration of a self-generated electric field. Variations in the patterns of stimuli are primarily distinguished based on their frequency. Pyramidal neurons in the electrosensory lateral line lobe (ELL) are often tuned to respond to specific input frequencies. Alterations in the tuning of the pyramidal neurons may allow weakly electric fish to preferentially select for certain stimuli. Here we show that muscarinic receptor activation in vivo enhances the excitability, burst firing, and subsequently the response of pyramidal cells to naturalistic sensory input. Through a combination of in vitro electrophysiology and mathematical modeling, we reveal that this enhanced excitability and bursting likely results from the down-regulation of an A-type potassium current. Further, we provide an explanation of the mechanism by which these currents can mediate frequency tuning.
Molecular Physiology of Pituitary Development: Signaling and Transcriptional Networks
Authors: Zhu Xiaoyan , Gleiberman Anatoli S. , Rosenfeld Michael G.
Published: July 2007

The pituitary gland is a central endocrine organ regulating basic physiological functions, including growth, the stress response, reproduction, metabolic homeostasis, and lactation. Distinct hormone-producing cell types in the anterior pituitary arise from a common ectodermal primordium during development by extrinsic and intrinsic mechanisms, providing a powerful model system for elucidating general principles in mammalian organogenesis. The central purpose of this review is to inspect the integrated signaling and transcriptional events that affect precursor proliferation, cell lineage commitment, terminal differentiation, and physiological regulation by hypothalamic tropic factors.
Histone Deacetylase Inhibitors Induce Premature Sister Chromatid Separation and Override the Mitotic Spindle Assembly Checkpoint
Authors: Magnaghi-Jaulin Laura , Eot-Houllier Grégory , Fulcrand Géraldine , Jaulin Christian
Published: July 2007

Histone deacetylase inhibitors (HDACI) are powerful antiproliferative drugs, and are currently undergoing clinical trials as antitumor agents. It would be valuable for both cancer therapy and our knowledge of basic cellular processes to understand the mechanisms by which HDACIs block cell proliferation. Most current models postulate that HDACIs allow the reexpression of tumor suppressor genes silenced in cancer cells. However, other mechanisms, distinct from transcription regulation, may participate in HDACI antiproliferative properties. We report that HDACI treatment induces premature sister chromatid separation in cells in which the mitotic spindle assembly checkpoint (SAC) has already been activated. This effect was transcription-independent. In addition, HDACI-treated mitotic cells displayed SAC inactivation characteristics, including anaphase-promoting complex/cyclosome target degradation, cyclin-dependent kinase 1 inactivation, histone H3 dephosphorylation, and loss of the SAC component MAD2 from the kinetochore. Thus, HDAC inhibition renders the SAC ineffective. Our findings help elucidate the molecular mechanisms of proliferative cell death induced by HDACI treatment and may allow new HDACI-based preclinical and clinical trial protocols to be redesigned so as to target mitosis. [Cancer Res 2007;67(13):6360–7]
Protein Kinase Cε Is Overexpressed in Primary Human Non–Small Cell Lung Cancers and Functionally Required for Proliferation of Non–Small Cell Lung Cancer Cells in a p21/Cip1-Dependent Manner
Authors: Bae Kyung-Mi , Wang Heiman , Jiang Guohua , Chen Melissa G. , Lu Li , Xiao Lei
Published: July 2007

The protein kinase C (PKC) family of proteins plays important roles in growth regulation and is implicated in tumorigenesis. It has become clear that the role of PKC in tumorigenesis is cell context dependent and/or isoform specific. In this study, we showed for the first time by immunohistochemistry that overexpression of PKCε was detected in the vast majority (>90%) of primary human non–small cell lung cancers (NSCLC) compared with normal lung epithelium. Inhibition of the PKCε pathway using a kinase-inactive, dominant-negative PKCε, PKCε(KR), led to a significant inhibition of proliferation and anchorage-independent growth of human NSCLC cells in a p53-independent manner. This was accompanied by a specific induction of the cyclin-dependent kinase (cdk) inhibitor p21/Cip1 but not p27/Kip1. In response to serum stimulation, PKCε(KR)-expressing cells showed a prolonged G1-S transition and delayed and reduced activation of cdk2 complexes, which was likely attributed to the increased binding of p21/Cip1 to cdk2. Furthermore, inhibition of PKCε function either by expressing PKCε(KR) or by small interfering RNA (siRNA)–mediated gene knockdown resulted in c-Myc down-regulation, which, in turn, regulated p21/Cip1 expression. Knockdown of PKCε or c-Myc expression using siRNA led to induction of p21/Cip1 and attenuation of G1-S transition in NSCLC cells. Using p21+/+ and p21−/− HCT116 isogenic cell lines, we further showed that growth inhibition by PKCε(KR) required the function of p21/Cip1. Collectively, these results reveal an important role for PKCε signaling in lung cancer and suggest that one potential mechanism by which PKCε exerts its oncogenic activity is through deregulation of the cell cycle via a p21/Cip1–dependent mechanism. [Cancer Res 2007;67(13):6053–63]
Inhibition of Heat Shock Protein 27–Mediated Resistance to DNA Damaging Agents by a Novel PKCδ-V5 Heptapeptide
Authors: Kim Eun-Ho , Lee Hae-June , Lee Dae-Hoon , Bae Sangwoo , Soh Jae-Won , Jeoung Dooil , Kim Joon , Cho Chul-Koo , Lee Yoon-Jin , Lee Yun-Sil
Published: July 2007

Heat shock protein 27 (HSP27), which is highly expressed in human lung and breast cancer tissues, induced resistance to cell death against various stimuli. Treatment of NCI-H1299 cells, which express a high level of HSP27, with small interference RNA specifically targeting HSP27 resulted in inhibition of their resistance to radiation or cisplatin, suggesting that HSP27 contributed to cellular resistance in these lung cancer cells. Furthermore, because HSP27 interacts directly with the COOH terminus of the protein kinase Cδ (PKCδ)-V5 region with ensuing inhibition of PKCδ activity and PKCδ-mediated cell death, we wished to determine amino acid residues in the V5 region that mediate its interaction with HSP27. Investigation with various deletion mutants of the region revealed that amino acid residues 668 to 674 of the V5 region mediate its interaction with HSP27. When NCI-H1299 cells were treated with biotin or with FITC-tagged heptapeptide of the residues 668 to 674 (E-F-Q-F-L-D-I), the cells exhibited dramatically increased cisplatin or radiation-induced cell death with the heptapeptide having efficient interaction with HSP27, which in turn restored the PKCδ activity that had been inhibited by HSP27. In vivo nude mice grafting data also suggested that NCI-H1299 cells were sensitized by this heptapeptide. The above data strongly show that the heptapeptide of the PKCδ-V5 region sensitized human cancer cells through its interaction with HSP27, thereby sequestering HSP27. The heptapeptide may provide a novel strategy for selective neutralization of HSP27. [Cancer Res 2007;67(13):6333–9]
Indole-3-carbinol Inhibits 4-(Methylnitrosamino)-1-(3-pyridyl)-1-butanone Plus Benzo(a)pyrene–Induced Lung Tumorigenesis in A/J Mice and Modulates Carcinogen-Induced Alterations in Protein Levels
Authors: Kassie Fekadu , Anderson Lorraine B. , Scherber Robyn , Yu Nanxiong , Lahti David , Upadhyaya Pramod , Hecht Stephen S.
Published: July 2007

We tested the chemopreventive efficacy of indole-3-carbinol (I3C), a constituent of Brassica vegetables, and its major condensation product, 3,3′-diindolylmethane (DIM), against lung tumorigenesis induced by a mixture of 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and benzo[a]pyrene (BaP) in A/J mice. The mixture of NNK plus BaP (2 μmol each) was administered by gavage as eight weekly doses, whereas I3C (112 μmol/g diet) and DIM (2 and 30 μmol/g diet in experiments 1 and 2, respectively) were given in the diet for 23 weeks beginning at 50% of carcinogen treatment. I3C reduced NNK plus BaP–induced tumor multiplicity by 78% in experiment 1 and 86% in experiment 2; the respective reductions in tumor multiplicity by DIM were 5% and 66%. Using a quantitative proteomics method, isobaric tags for relative and absolute quantitation (iTRAQ) coupled with mass spectrometry, we identified and quantified at least 250 proteins in lung tissues. Of these proteins, nine showed differences in relative abundance in lung tissues of carcinogen-treated versus untreated mice: fatty acid synthase, transketolase, pulmonary surfactant-associated protein C (SP-C), l-plastin, annexin A1, and haptoglobin increased, whereas transferrin, α-1-antitrypsin, and apolipoprotein A-1 decreased. Supplementation of the diet of carcinogen-treated mice with I3C reduced the level of SP-C, l-plastin, annexin A1, and haptoglobin to that of untreated controls. These results were verified using immunoblotting. We show here that tumor-associated signature proteins are increased during NNK plus BaP–induced lung carcinogenesis, and I3C inhibits this effect, suggesting that the lung tumor chemopreventive activity of I3C might be related to modulation of carcinogen-induced alterations in protein levels. [Cancer Res 2007;67(13):6502–11]
Critical Role for TrkB Kinase Function in Anoikis Suppression, Tumorigenesis, and Metastasis
Authors: Geiger Thomas R. , Peeper Daniel S.
Published: July 2007

Anoikis, or cell death induced by cell detachment, provides protection against the metastatic spread of tumor cells. We have previously shown that the neurotrophic receptor tyrosine kinase TrkB suppresses anoikis in rat intestinal epithelial cells and renders them highly tumorigenic and metastatic. Because TrkB is overexpressed in several aggressive human cancers, first attempts are being made to target TrkB in cancer therapy. However, the mechanisms underlying TrkB-mediated anoikis suppression, tumorigenesis, and metastasis still remain largely elusive. Although, to date, most attempts to neutralize TrkB in tumors aim to inactivate its kinase activity, it is unclear whether TrkB kinase activity is required for its oncogenic functions. Indeed, it has been suggested that also other properties of the receptor contribute to functions that are relevant to tumor cell survival. Specifically, several adhesion motifs reside within the extracellular domains of TrkB. In line with this, TrkB-expressing epithelial cells form large cellular aggregates in suspension cultures, possibly facilitating tumor cell survival. Therefore, we set out to study the relative contributions of TrkB's kinase activity and its adhesion domains to anoikis suppression and oncogenicity. On the basis of a structure-function analysis, we report that TrkB kinase activity is required and, unexpectedly, also sufficient for anoikis suppression, tumor formation, and experimental metastasis. Thus, TrkB can act tumorigenically independent of its adhesion motifs. These results suggest that targeting the enzymatic activity of TrkB might be beneficial in cancer therapy. [Cancer Res 2007;67(13):6221–30]
Born to Be Exported: COOH-Terminal Nuclear Export Signals of Different Strength Ensure Cytoplasmic Accumulation of Nucleophosmin Leukemic Mutants
Authors: Bolli Niccolò , Nicoletti Ildo , De Marco M. Felicetta , Bigerna Barbara , Pucciarini Alessandra , Mannucci Roberta , Martelli Maria Paola , Liso Arcangelo , Mecucci Cristina , Fabbiano Francesco , Martelli Massimo F. , Henderson Beric R. , Falini Brunangelo
Published: July 2007

Creation of a nuclear export signal (NES) motif and loss of tryptophans (W) 288 and 290 (or 290 only) at the COOH terminus of nucleophosmin (NPM) are both crucial for NPM aberrant cytoplasmic accumulation in acute myelogenous leukemia (AML) carrying NPM1 mutations. Hereby, we clarify how these COOH-terminal alterations functionally cooperate to delocalize NPM to the cytoplasm. Using a Rev(1.4)-based shuttling assay, we measured the nuclear export efficiency of six different COOH-terminal NES motifs identified in NPM mutants and found significant strength variability, the strongest NES motifs being associated with NPM mutants retaining W288. When artificially coupled with a weak NES, W288-retaining NPM mutants are not exported efficiently into cytoplasm because the force (W288) driving the mutants toward the nucleolus overwhelms the force (NES) exporting the mutants into cytoplasm. We then used this functional assay to study the physiologic NH2-terminal NES motifs of wild-type NPM and found that they are weak, which explains the prominent nucleolar localization of wild-type NPM. Thus, the opposing balance of forces (tryptophans and NES) seems to determine the subcellular localization of NPM. The fact that W288-retaining mutants always combine with the strongest NES reveals mutational selective pressure toward efficient export into cytoplasm, pointing to this event as critical for leukemogenesis. [Cancer Res 2007;67(13):6230–7]
Androgen Withdrawal in Patients Reduces Prostate Cancer Hypoxia: Implications for Disease Progression and Radiation Response
Authors: Milosevic Michael , Chung Peter , Parker Chris , Bristow Robert , Toi Ants , Panzarella Tony , Warde Padraig , Catton Charles , Menard Cynthia , Bayley Andrew , Gospodarowicz Mary , Hill Richard
Published: July 2007

Hypoxia is a feature of many human malignancies, and leads to aggressive clinical behavior and recurrence after treatment. Here, we show for the first time that androgen withdrawal reduces prostate cancer hypoxia in patients. Oxygen measurements were done in 248 patients with clinically localized prostate cancer prior to radiotherapy, and showed hypoxia of potential biological and clinical significance. In 22 of these patients, prostate oxygen levels were measured both before and after 30 to 145 days of the androgen antagonist bicalutamide. There was a significant reduction in tumor hypoxia with androgen withdrawal (P = 0.005). The median pO2 increased from 6.4 to 15 mm Hg, and the hypoxic proportion decreased from 40% to 31%. However, the response was heterogeneous, with improvement in 12 patients, stable oxygen readings in 9 patients and worsening hypoxia in 1 patient. Among the responding patients, the median pO2 increased from 4.9 to 33 mm Hg, and the hypoxic proportion decreased from 51% to 23%. There was no apparent relationship between the change in oxygenation and baseline prostatic volume, T category, Gleason score, prostate-specific antigen levels, the duration of treatment with bicalutamide, or the change in prostate-specific antigen levels with bicalutamide. These results might, in part, explain the improved patient outcome that has been observed in clinical trials of radiotherapy and hormones, and suggest a role for novel therapeutic agents that block the molecular response to hypoxia in prostate cancer either alone or in combination with other established treatments. [Cancer Res 2007;67(13):6022–5]
Repression of BCL2 by the Tumor Suppressor Activity of the Lysyl Oxidase Propeptide Inhibits Transformed Phenotype of Lung and Pancreatic Cancer Cells
Authors: Wu Min , Min Chengyin , Wang Xiaobo , Yu Ziyang , Kirsch Kathrin H. , Trackman Philip C. , Sonenshein Gail E.
Published: July 2007

The gene encoding lysyl oxidase (LOX) was identified as the ras recision gene (rrg), with the ability to revert Ras-mediated transformation of NIH 3T3 fibroblasts. Mutations in RAS genes have been found in ∼25% of lung cancers and in 85% of pancreatic cancers. In microarray analysis, these cancers were found to display reduced LOX gene expression. Thus, the ability of the LOX gene to repress the transformed phenotype of these cancer cells was tested. LOX is synthesized as a 50-kDa secreted precursor Pro-LOX that is processed to the 32-kDa active enzyme (LOX) and to an 18-kDa propeptide (LOX-PP). Recently, we mapped the rrg activity of Pro-LOX to the LOX-PP in Ras-transformed NIH 3T3 cells. Ectopic Pro-LOX and LOX-PP expression in H1299 lung cancer cells inhibited growth in soft agar and invasive colony formation in Matrigel and reduced activation of extracellular signal-regulated kinase (ERK) and Akt, with LOX-PP showing substantially higher activity. Similarly, LOX-PP expression in PANC-1 pancreatic cancer cells effectively reduced ERK and Akt activity and inhibited growth in soft agar and ability of these cells to migrate. Nuclear Factor-κB (NF-κB) and its target gene BCL2, which are overexpressed in 70% to 75% of pancreatic cancers, have recently been implicated in invasive phenotype. LOX-PP substantially reduced NF-κB and Bcl-2 levels. Reintroduction of Bcl-2 into PANC-1 or H1299 cells expressing LOX-PP restored the transformed phenotype, suggesting that Bcl-2 is an essential target. Thus, LOX-PP potently inhibits invasive phenotype of lung and pancreatic cancer cells, suggesting potential therapeutic applications in treatment of these cancers. [Cancer Res 2007;67(13):6278–85]
Combined Targeting of Endothelin A Receptor and Epidermal Growth Factor Receptor in Ovarian Cancer Shows Enhanced Antitumor Activity
Authors: Rosanò Laura , Di Castro Valeriana , Spinella Francesca , Tortora Giampaolo , Nicotra Maria Rita , Natali Pier Giorgio , Bagnato Anna
Published: July 2007

Ovarian carcinomas overexpress endothelin A receptors (ETAR) and epidermal growth factor (EGF) receptor (EGFR). In these cells, endothelin-1 (ET-1) triggers mitogenic and invasive signaling pathways that are in part mediated by EGFR transactivation. Combined targeting of ETAR, by the specific ETAR antagonist ZD4054, and of EGFR by the EGFR inhibitor gefitinib (IRESSA), may offer improvements in ovarian carcinoma treatment. In HEY and OVCA 433 ovarian carcinoma cells, ET-1 or EGF induced rapid activation of EGFR, p42/44 mitogen-activated protein kinase (MAPK), and AKT. ZD4054 was able to reduce the ET-1–induced EGFR transactivation. Gefitinib significantly inhibited EGF- and ET-1–induced EGFR phosphorylation, but incompletely reduced the ET-1–induced activation of downstream targets. ZD4054 plus gefitinib resulted in a greater inhibition of EGFR, MAPK, and AKT phosphorylation, indicating the critical role of these interconnected signaling proteins. ZD4054 effectively inhibited cell proliferation, invasiveness, and vascular endothelial growth factor (VEGF) secretion. Concomitantly, ZD4054 enhanced apoptosis and E-cadherin promoter activity and expression. In both cell lines, the drug combination resulted in a significant decrease in cell proliferation (65%), invasion (52%), and VEGF production (50%), accompanied by a 2-fold increase in apoptosis. The coadministration of ZD4054 enhanced the efficacy of gefitinib leading to partial (82%) or complete tumor regression on HEY ovarian carcinoma xenografts. Antitumor effects were paralleled by biochemical and immunohistologic evidence of decreased vascularization, Ki-67, matrix metalloproteinase-2 (MMP-2), VEGF, MAPK and EGFR, and enhanced E-cadherin expression. The cross-signaling between the EGFR/ETAR pathways provides a rationale to combine EGFR inhibitors with ETAR antagonists, identifying new effective therapeutic opportunities for ovarian cancer. [Cancer Res 2007;67(13):6351–9]
Human Papillomavirus 16 E5 Oncogene Contributes to Two Stages of Skin Carcinogenesis
Authors: Maufort John P. , Genther Williams Sybil M. , Pitot Henry C. , Lambert Paul F.
Published: July 2007

High-risk human papillomaviruses (HPVs), which cause the vast majority of cervical cancer, other anogenital cancers, and a subset of head and neck squamous cell carcinomas, encode three oncogenes: E5, E6, and E7. To determine the oncogenic properties of HPV16 E5 in vivo, we previously generated K14E5 transgenic mice, in which expression of E5 was directed to the basal compartment of stratified squamous epithelia. In these mice, E5 induced epidermal hyperplasia and spontaneous skin tumors. In the current study, we determined how E5 contributes to tumor formation in the skin using a multistage model for skin carcinogenesis that specifies the role of genes in three stages: initiation, promotion, and malignant progression. Both initiation and promotion are required steps for papilloma formation. K14E5 mice treated with the initiating agent 7,12-dimethylbenz(a)anthracene (DMBA) developed more papillomas than like-treated nontransgenic mice, whereas neither K14E5 nor nontransgenic mice treated with the promoting agent 12-O-tetradecanoylphorbol-13-acetate (TPA) developed papillomas. K14E5 mice treated with both DMBA and TPA to induce large numbers of papillomas had a higher incidence and earlier onset of carcinoma progression compared with like-treated nontransgenic mice. Thus, HPV16 E5 contributes to two stages of skin carcinogenesis: promotion and progression. The progressive neoplastic disease in K14E5 mice differed from that in nontransgenic mice in that benign tumors converted from exophytic to endophytic papillomas before progressing to carcinomas. Initial genetic and immunohistopathologic analyses did not determine the underlying basis for this distinct morphology, which correlates with a highly penetrant neoplastic phenotype. [Cancer Res 2007;67(13):6106–7]
Regulation of Mammalian Target of Rapamycin Activity in PTEN-Inactive Prostate Cancer Cells by IκB Kinase α
Authors: Dan Han C. , Adli Mazhar , Baldwin Albert S.
Published: July 2007

The mammalian target of rapamycin (mTOR) is a mediator of cell growth, survival, and energy metabolism at least partly through its ability to regulate mRNA translation. mTOR is activated downstream of growth factors, insulin, and Akt-dependent signaling associated with oncoprotein expression or loss of the tumor-suppressor PTEN. In this regard, mTOR activity is associated with cancer cell growth and survival. Here, we have explored an involvement of the IκB kinase (IKK) pathway, associated with nuclear factor-κB activation, in controlling mTOR activity. The experiments show that IKKα controls mTOR kinase activity in Akt-active, PTEN-null prostate cancer cells, with less involvement by IKKβ. In these cells, IKKα associates with mTOR, as part of the TORC1 complex, in an Akt-dependent manner. Additionally, IKKα is required for efficient induction of mTOR activity downstream of constitutively active Akt expression. The results indicate a novel role for IKKα in controlling mTOR function in cancer cells with constitutive Akt activity. [Cancer Res 2007;67(13):6263–9]
Role of Beta-3-Adrenoceptor in Catecholamine-Induced Relaxations in Gastric Fundus from Control and Diabetic Rats
Authors: Ozakca Isil , Arioglu Ebru , Guner Sahika , Altan V. Melih , Ozcelikay A. Tanju
Published: July 2007

The contribution of β-adrenoceptor subtypes to the catecholamine-mediated relaxations in gastric fundus from control and streptozotocin (STZ)-induced diabetic rats were investigated. Isolated organ bath studies and molecular techniques were used to characterize the β-adrenoceptor subtypes mediating relaxation of rat gastric fundus. Isoprenaline-mediated relaxation was not significantly changed by nadolol (β1-/β2-adrenoceptor antagonist; 1 µmol/l) but only shifted to the right by SR59230A (3-(2-ethylphenoxy)-1-[[(1S)-1,2,3,4-tetrahydronaphth-1-yl]amino]-(2S)-2-propanol oxalate salt, 0.1–1 µmol/l), a selective β3-adrenoceptor antagonist, in a competitive manner. Relaxant responses to noradrenaline were antagonized in a concentration-dependent manner by SR59230A (0.1–1 µmol/l), but not by metoprolol (selective β1-adrenoceptor antagonist; 0.1–1 µmol/l) and ICI-118551 (1-[2,3-(dihydro-7-methyl-1Hinden- 4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol hydrochloride, selective β2-adrenoceptor antagonist; 0.1–1 µmol/l). SR59230A (1 µmol/l) also caused a significant rightward shift in fenoterol-induced relaxation while ICI-118551 (1 µmol/l) did not have any effect. Selective β3-adrenoceptor agonist, BRL37344 ([4-[2-[[2-(3-chlorophenyl)-2-hydroxyethyl]amino]propyl]phenoxy]acetic acid), caused biphasic relaxation which was not affected by nadolol (1 µmol/l). SR59230A (1 µmol/l) abolished only the first phase of BRL37344 response. β1-, β2- and β3-adrenoceptor mRNA expressions have been detected in a similar intensity in gastric fundus from control rats. Experimental diabetes caused a significant decrease in Emax and pD2 values of isoprenaline and noradrenaline. Diabetes also reduced Emax but not pD2 value of the first component of BRL37344-induced relaxation response. The band intensity of mRNA transcript of β3-adrenoceptor was reduced in diabetics while no alteration has been found for β1- and β2-adrenoceptor mRNA transcripts between groups. These results show that functional β-adrenoceptor subtype involved in catecholamine-mediated relaxations is β3-adrenoceptor, and its function and mRNA expression are decreased in diabetes.