bluuebunny/crossref_metadata_2025 huggingface dataset:
Pmchexpression during early development is critical for normal energy homeostasis
Authors: Mul Joram D. , Yi Chun-Xia , van den Berg Sjoerd A. A. , Ruiter Marieke , Toonen Pim W. , van der Elst Martine C. J. , Voshol Peter J. , Ellenbroek Bart A. , Kalsbeek Andries , la Fleur Susanne E. , Cuppen Edwin
Published: November 2009

Postnatal development and puberty are times of strong physical maturation and require large quantities of energy. The hypothalamic neuropeptide melanin-concentrating hormone (MCH) regulates nutrient intake and energy homeostasis, but the underlying mechanisms are not completely understood. Here we use a novel rat knockout model in which the MCH precursor Pmch has been inactivated to study the effects of loss of MCH on energy regulation in more detail. Pmch−/−rats are lean, hypophagic, osteoporotic, and although endocrine parameters were changed in pmch−/−rats, endocrine dynamics were normal, indicating an adaptation to new homeostatic levels rather than disturbed metabolic mechanisms. Detailed body weight growth and feeding behavior analysis revealed that Pmch expression is particularly important during early rat development and puberty, i.e., the first 8 postnatal weeks. Loss of Pmch resulted in a 20% lower set point for body weight that was determined solely during this period and remained unchanged during adulthood. Although the final body weight is diet dependent, the Pmch-deficiency effect was similar for all diets tested in this study. Loss of Pmch affected energy expenditure in both young and adult rats, although these effects seem secondary to the observed hypophagia. Our findings show an important role for Pmch in energy homeostasis determination during early development and indicate that the MCH receptor 1 system is a plausible target for childhood obesity treatment, currently a major health issue in first world countries.
Effect of a cyclooxygenase-2 inhibitor on postexercise muscle protein synthesis in humans
Authors: Burd Nicholas A. , Dickinson Jared M. , LeMoine Jennifer K. , Carroll Chad C. , Sullivan Bridget E. , Haus Jacob M. , Jemiolo Bozena , Trappe Scott W. , Hughes Gordon M. , Sanders Charles E. , Trappe Todd A.
Published: November 2009

Nonselective blockade of the cyclooxygenase (COX) enzymes in skeletal muscle eliminates the normal increase in muscle protein synthesis following resistance exercise. The current study tested the hypothesis that this COX-mediated increase in postexercise muscle protein synthesis is regulated specifically by the COX-2 isoform. Sixteen males (23 ± 1 yr) were randomly assigned to one of two groups that received three doses of either a selective COX-2 inhibitor (celecoxib; 200 mg/dose, 600 mg total) or a placebo in double-blind fashion during the 24 h following a single bout of knee extensor resistance exercise. At rest and 24 h postexercise, skeletal muscle protein fractional synthesis rate (FSR) was measured using a primed constant infusion of [2H5]phenylalanine coupled with muscle biopsies of the vastus lateralis, and measurements were made of mRNA and protein expression of COX-1 and COX-2. Mixed muscle protein FSR in response to exercise ( P < 0.05) was not suppressed by the COX-2 inhibitor (0.056 ± 0.004 to 0.108 ± 0.014%/h) compared with placebo (0.074 ± 0.004 to 0.091 ± 0.005%/h), nor was there any difference ( P > 0.05) between the placebo and COX-2 inhibitor postexercise when controlling for resting FSR. The COX-2 inhibitor did not influence COX-1 mRNA, COX-1 protein, or COX-2 protein levels, whereas it did increase ( P < 0.05) COX-2 mRNA (3.0 ± 0.9-fold) compared with placebo (1.3 ± 0.3-fold). It appears that the elimination of the postexercise muscle protein synthesis response by nonselective COX inhibitors is not solely due to COX-2 isoform blockade. Furthermore, the current data suggest that the COX-1 enzyme is likely the main isoform responsible for the COX-mediated increase in muscle protein synthesis following resistance exercise in humans.
Protein kinase C: poised to signal
Authors: Newton Alexandra C.
Published: November 2009

Nestled at the tip of a branch of the kinome, protein kinase C (PKC) family members are poised to transduce signals emanating from the cell surface. Cell membranes provide the platform for PKC function, supporting the maturation of PKC through phosphorylation, its allosteric activation by binding specific lipids, and, ultimately, promoting the downregulation of the enzyme. These regulatory mechanisms precisely control the level of signaling-competent PKC in the cell. Disruption of this regulation results in pathophysiological states, most notably cancer, where PKC levels are often grossly altered. This review introduces the PKC family and then focuses on recent advances in understanding the cellular regulation of its diacylglycerol-regulated members.
Impairment of fat oxidation under high- vs. low-glycemic index diet occurs before the development of an obese phenotype
Authors: Isken F. , Klaus S. , Petzke K. J. , Loddenkemper C. , Pfeiffer A. F. H. , Weickert M. O.
Published: November 2009

Exposure to high vs. low glycemic index (GI) diets increases fat mass and insulin resistance in obesity-prone C57BL/6J mice. However, the longer-term effects and potentially involved mechanisms are largely unknown. We exposed four groups of male C57BL/6J mice ( n = 10 per group) to long-term (20 wk) or short-term (6 wk) isoenergetic and macronutrient matched diets only differing in starch type and as such GI. Body composition, liver fat, molecular factors of lipid metabolism, and markers of insulin sensitivity and metabolic flexibility were investigated in all four groups of mice. Mice fed the high GI diet showed a rapid-onset (from week 5) marked increase in body fat mass and liver fat, a gene expression profile in liver consistent with elevated lipogenesis, and, after long-term exposure, significantly reduced glucose clearance following a glucose load. The long-term high-GI diet also led to a delayed switch to both carbohydrate and fat oxidation in the postprandial state, indicating reduced metabolic flexibility. In contrast, no difference in carbohydrate oxidation was observed after short-term high- vs. low-GI exposure. However, fatty acid oxidation was significantly blunted as early as 3 wk after beginning of the high-GI intervention, at a time where most measured phenotypic markers including body fat mass were comparable between groups. Thus long-term high-GI feeding resulted in an obese, insulin-resistant, and metabolically inflexible phenotype in obesity-prone C57BL/6J mice. Early onset and significantly impaired fatty acid oxidation preceded these changes, thereby indicating a potentially causal involvement.
Chlorophylls and Phycoerythrins as Markers of Environmental Forcings Including Cyclone Erica Effect (March 2003) on Phytoplankton in the Southwest Lagoon of New Caledonia and Oceanic Adjacent Area
Authors: Neveux J. , Tenório M. M. B. , Jacquet S. , Torréton J.-P. , Douillet P. , Ouillon S. , Dupouy C.
Published: November 2009

Spatio-temporal variations of chlorophylls and phycoerythrins, inferred by spectrofluorometric methods, were studied from April 2002 to June 2003 in the southwest lagoon and oceanic waters of New Caledonia. Trade winds blew 75% of the time and appeared as the main factor influencing surface Tchla (sum of monovinyl- and divinyl-chlorophyll a) variations in the ocean, near the barrier reef. Lagoon and oceanic waters differed in the composition of picoplanktonic cyanobacteria with a relative dominance of Prochlorococcus and high-phycourobilin Synechococcus in the ocean, and a relative dominance of high-phycoerythrobilin Synechococcus in the lagoon. Main pigment variations in the lagoon were associated with cyclone Erica in March 2003 and showed a 5-6 fold Tchla increase around Nouméa. The cyclone stimulated mainly diatom growth as indicated by the high chlorophyll (c1+c2)/chlorophyll a ratio and by the lowest values for the other pigment ratios. The relative importance of divinyl-chlorophyll a concentration and fluorescence excitation spectra of phycoerythrins appeared as useful tools for characterizing lagoon-ocean exchanges.
Undiagnosed Patent Foramen Ovale Presenting as Retinal Artery Occlusion—An Emerging Association
Authors: Sheth Hiten G. , Laverde-Konig Tania , Raina Jyoti
Published: November 2009

Purpose. To report patent foramen ovale (PFO) as the cause of retinal artery occlusion in a young and previously fit male and discuss the appropriate medical and surgical management options.Methods. Interventional case report with serial fundus photographs of an 18-year-old male presenting to the eye casualty with sudden onset left visual loss.Results. Visual acuities were 6/24 left and 6/4 right with a left afferent pupillary defect. Slitlamp examination confirmed a left hemiretinal artery occlusion and subsequent cardiology review with transoesophageal echocardiography revealed patent foramen ovale which was closed surgically.Conclusions. PFO is not uncommon and is often covert but predisposes individuals to embolic events. These events may be ophthalmic with visual sequelae and so ophthalmologists, physicians, and other healthcare personnel should be aware of this important and emerging association.
A Critical Assessment of Geographic Clusters of Breast and Lung Cancer Incidences among Residents Living near the Tittabawassee and Saginaw Rivers, Michigan, USA
Authors: Guajardo Olga A. , Oyana Tonny J.
Published: November 2009

Objectives. To assess previously determined geographic clusters of breast and lung cancer incidences among residents living near the Tittabawassee and Saginaw Rivers, Michigan, using a new set of environmental factors.Materials and Methods. Breast and lung cancer data were acquired from the Michigan Department of Community Health, along with point source pollution data from the U.S. Environmental Protection Agency. The datasets were used to determine whether there is a spatial association between disease risk and environmental contamination. GIS and spatial techniques were combined with statistical analysis to investigate local risk of breast and lung cancer.Results and Conclusion. The study suggests that neighborhoods in close proximity to the river were associated with a high risk of breast cancer, while increased risk of lung cancer was detected among neighborhoods in close proximity to point source pollution and major highways. Statistically significant(P≤.001)clusters of cancer incidences were observed among residents living near the rivers. These findings are useful to researchers and governmental agencies for risk assessment, regulation, and control of environmental contamination in the floodplains.
Effects of Power Lines on Area Use and Behaviour of Semi-Domestic Reindeer in Enclosures
Authors: Flydal K. , Korslund L. , Reimers E. , Johansen F. , Colman J. E.
Published: November 2009

We conducted large-scale, replicated experiments to test the effects of two parallel power lines on area use, behaviour, and activity of semidomestic reindeer in enclosures. Yearling female reindeer were released into four50×400 m enclosures; two treatment enclosures with power lines and two control enclosures. Reindeer from two herds, one from Kautokeino (domestic tame) and one from Vågå, (domestic wild) were tested separately and compared. Individual location within the enclosures was not affected by the power lines. Effects on restless behaviour were ambiguous, with slightly more restless behaviour in the treatment enclosures for the domestic tame reindeer, while the domestic wild reindeer maintained a stable level in the treatment enclosures, increasing with time in the control enclosures. Activity changes were slightly more common among animals within treatment enclosures for both herds, with no indication of habituation during the experiment. The domestic wild reindeer had more than three times the amount of restless behaviour than the domestic tame reindeer. Our study indicates that for reindeer in enclosures, the disturbance from a power line construction is negligible. This suggests that power lines are a minor disturbing factor compared to human handling when using fenced in areas like grazing gardens in reindeer husbandry.
Heisenberg Uncertainty Relation in Quantum Liouville Equation
Authors: Valenti Davide
Published: November 2009

We consider the quantum Liouville equation and give a characterization of the solutions which satisfy the Heisenberg uncertainty relation. We analyze three cases. Initially we consider a particular solution of the quantum Liouville equation: the Wigner transform f(x,v,t) of a generic solution ψ(x;t) of the Schrödinger equation. We give a representation of ψ(x, t) by the Hermite functions. We show that the values of the variances of x and v calculated by using the Wigner function f(x,v,t) coincide, respectively, with the variances of position operator and conjugate momentum operator obtained using the wave function ψ(x,t). Then we consider the
Fourier transform of the density matrix ρ(z,y,t) = ψ∗(z,t)ψ(y,t). We find again that the variances of x and v obtained by using ρ(z, y,t) are respectively equal to the variances of and calculated in ψ(x,t). Finally we introduce the matrix and we show that a generic square‐integrable function g(x,v,t) can be written as Fourier transform of a density matrix, provided that the matrix is diagonalizable.
Nodular Regenerative Hyperplasia Secondary to Neoadjuvant Chemotherapy for Colorectal Liver Metastases
Authors: van den Broek Maartje A. J. , Olde Damink Steven W. M. , Driessen Ann , Dejong Cornelis H. C. , Bemelmans Marc H. A.
Published: November 2009

Liver resection is the only curative treatment for patients with colorectal liver metastases (CLMs). Neoadjuvant chemotherapy can improve resectability but has a potential harmful effect on the nontumorous liver. Patients with chemotherapy-induced hepatic injury undergoing liver surgery have higher risks of post-resectional morbidity. We present two cases of patients without pre-existent liver disease treated with oxaliplatin-based chemotherapy followed by surgical resection of their CLMs. Their intra-operative liver specimen showed morphologic abnormalities characteristic of nodular regenerative hyperplasia (NRH). NRH led to portal hypertension in both patients that resulted in deleterious post-resectional complications and death of one patient. Interestingly, the other patient underwent two repeat nonanatomic liver resections because of recurrent CLMs. The intra-operative liver specimen still showed signs of NRH and sinusoidal congestion, but the post-resectional courses were uneventful. Nevertheless, caution is recommended in patients with suspected NRH. Careful volumetric analysis should guide the operative strategy. When future remnant liver volume is regarded insufficient, portal vein embolization or restrictive surgery should be considered.
Concentrations of H1-Receptor Antagonist in the Human Nasal Mucosa
Authors: Takasaki Kenji , Enatsu Kaori , Kumagami Hidetaka , Takahashi Haruo
Published: November 2009

Aims. To measure blood and tissue concentrations of the H1-receptor antagonist, bepotastine besilate (BB).Methods. Participants included 14 men and six women, whose age ranged from 13 to 76 years, with chronic rhinosinusitis, who underwent endoscopic sinus surgery at our university hospital. Among them, 10 participants had allergic rhinitis (AR) (Group I), and others did not have AR (Group II). Nasal mucosa and blood were collected 55 to 130 minutes after oral administration of BB 10 mg. Concentrations of the agent in the serum and nasal mucosa were measured by high-performance liquid chromatography.Results. Concentrations of BB of the serum in Group I and II were  ng/mL and  ng/mL. Those of the nasal mucosa tissue in Groups I and II were  ng/g and  ng/g. There was no significant difference in the values of concentration of BB between the serum and the nasal mucosa in either Group I or II ( and , resp., Pairedt-test).Conclusion. This preliminary study is considered the first report on the concentration of H1-receptor antagonists in nasal mucosa. The prompt absorption and transition to the nasal mucosa of BB seems to have an effect on allergic rhinitis.
Systems Engineering in Terms of Exergy
Authors: Camberos José A. , Moorhouse David J.
Published: November 2009

We address the design of a flight vehicle from the viewpoint of a system of systems and we discuss the integration of the individual technical disciplines. Then a conceptual fundamental methodology and tools required for the analysis, design, and optimization of aerospace vehicles in terms of the efficient use of on‐board energy are discussed. This suggests changing the design paradigm to the optimization of a system of energy systems. We propose a foundation for system‐level design with optimization based on minimum exergy destruction.
Modification of Low Refractive Index Polycarbonate for High Refractive Index Applications
Authors: Suri Gunjan , Jha Gouri Shankar , Seshadri Geetha , Khandal Rakesh Kumar
Published: November 2009

Polycarbonates and polythiourethanes are the most popular materials in use today, for optical applications. Polycarbonates are of two types which fall in the category of low refractive index and medium refractive index. The present paper describes the conversion of low refractive index polycarbonates into high refractive index material by the use of a high refractive index monomer, polythiol, as an additive. Novel polycarbonates, where the properties of refractive index and Abbe number can be tailor made, have been obtained. Thermal studies and refractive index determination indicate the formation of a new polymer with improved properties and suitable for optical applications.
First Hitting Place Probabilities for a Discrete Version of the Ornstein‐Uhlenbeck Process
Authors: Lefebvre Mario , Guilbault Jean-Luc
Published: November 2009

A Markov chain with state space {0, …, N} and transition probabilities depending on the current state is studied. The chain can be
considered as a discrete Ornstein‐Uhlenbeck process. The probability that the process hits N before 0 is computed explicitly. Similarly, the
probability that the process hits N before −M is computed in the case when the state space is {−M, …, 0, …, N} and the transition probabilities pi,i+1 are not necessarily the same when i is positive and i is negative.
Synthesis of Poly(L-lactide) via Solvothermal Method
Authors: Fang Ling , Qi Rongrong , Liu Linbo , Juan Gongwen , Huang Suangwu
Published: November 2009

Poly(L-lactide) was obtained from the ring-opening polymerization of L-lactide through a solvothermal process. Tin (II) chloride (SnC12) was used as the catalyst for the polymerization reaction. The focus of this paper was on the effect of solvents, catalyst usage, temperature, time, and antioxidants on the ring-opening reaction in the solvothermal synthesis. Ubbelohde viscometer, FTIR, GPC, and DSC were used to characterize the products. It is found that the optimal reaction condition for the highest molecular weight of PLA is at160∘Cfor 10 hour with 0.4% SnCl2in 10 mL toluene as solvent, and the high crystallinity can be obtained. The addition of antioxidant prior to the polymerization is conducive to obtaining high molecular weight and augmentTm,TcandXcvalues of PLA.
On Convexity of Composition and Multiplication Operators on Weighted Hardy Spaces
Authors: Hedayatian Karim , Karimi Lotfollah
Published: November 2009

A bounded linear operator T on a Hilbert space ℋ, satisfying for every h ∈ ℋ, is called a convex operator. In this paper, we give necessary and sufficient conditions under which a convex
composition operator on a large class of weighted Hardy spaces is an isometry. Also, we discuss convexity of multiplication operators.
Infinitely Many Solutions for a Robin Boundary Value Problem
Authors: Qian Aixia , Li Chong
Published: November 2009

By combining the embedding arguments and the variational methods, we obtain infinitely many
solutions for a class of superlinear elliptic problems with the Robin boundary value under weaker conditions.
The Mysterious Unfoldome: Structureless, Underappreciated, Yet Vital Part of Any Given Proteome
Authors: Uversky Vladimir N.
Published: November 2009

Contrarily to the general believe, many biologically active proteins lack stable tertiary and/or secondary structure under physiological conditions in vitro. These intrinsically disordered proteins (IDPs) are highly abundant in nature and many of them are associated with various human diseases. The functional repertoire of IDPs complements the functions of ordered proteins. Since IDPs constitute a significant portion of any given proteome, they can be combined in an unfoldome; which is a portion of the proteome including all IDPs (also known as natively unfolded proteins, therefore, unfoldome), and describing their functions, structures, interactions, evolution, and so forth. Amino acid sequence and compositions of IDPs are very different from those of ordered proteins, making possible reliable identification of IDPs at the proteome level by various computational means. Furthermore, IDPs possess a number of unique structural properties and are characterized by a peculiar conformational behavior, including their high stability against low pH and high temperature and their structural indifference toward the unfolding by strong denaturants. These peculiarities were shown to be useful for elaboration of the experimental techniques for the large-scale identification of IDPs in various organisms. Some of the computational and experimental tools for the unfoldome discovery are discussed in this review.
Constraints of Biological Neural Networks and Their Consideration in AI Applications
Authors: Stafford Richard
Published: November 2009

Biological organisms do not evolve to perfection, but to out compete others in their ecological niche, and therefore survive and reproduce. This paper reviews the constraints imposed on imperfect organisms, particularly on their neural systems and ability to capture and process information accurately. By understanding biological constraints of the physical properties of neurons, simpler and more efficient artificial neural networks can be made (e.g., spiking networks will transmit less information than graded potential networks, spikes only occur in nature due to limitations of carrying electrical charges over large distances). Furthermore, understanding the behavioural and ecological constraints on animals allows an understanding of the limitations of bio-inspired solutions, but also an understanding of why bio-inspired solutions may fail and how to correct these failures.
Strongly Enhanced Antitumor Activity of Trastuzumab and Pertuzumab Combination Treatment on HER2-Positive Human Xenograft Tumor Models
Authors: Scheuer Werner , Friess Thomas , Burtscher Helmut , Bossenmaier Birgit , Endl Josef , Hasmann Max
Published: November 2009

The human epidermal growth factor receptor (HER) family plays an important role in cell survival and proliferation, and is implicated in oncogenesis. Overexpression of HER2 is associated with aggressive disease and poor prognosis. Trastuzumab is a humanized monoclonal antibody targeting HER2 and has proven survival benefit for women with HER2-positive early and metastatic breast cancer. Pertuzumab, another monoclonal antibody, is a HER2 dimerization inhibitor that binds to a different epitope on HER2 than trastuzumab and inhibits HER2 dimer formation with other HER family members such as HER3 and HER1. We investigated the antitumor activity of these agents alone and in combination in HER2-positive breast and non–small cell lung cancer xenografts. Our data show that the combination of trastuzumab and pertuzumab has a strongly enhanced antitumor effect and induces tumor regression in both xenograft models, something that cannot be achieved by either monotherapy. The enhanced efficacy of the combination was also observed after tumor progression during trastuzumab monotherapy. Near-IR fluorescence imaging experiments confirm that pertuzumab binding to tumors is not impaired by trastuzumab pretreatment. Furthermore, we show by in vitro assay that both trastuzumab and pertuzumab potently activate antibody-dependent cellular cytotoxicity. However, our data suggest that the strongly enhanced antitumor activity is mainly due to the differing but complementary mechanisms of action of trastuzumab and pertuzumab, namely inhibition of HER2 dimerization and prevention of p95HER2 formation. [Cancer Res 2009;69(24):9330–6]
Imatinib Mesylate Induces Cisplatin Hypersensitivity in Bcr-Abl+ Cells by Differential Modulation of p53 Transcriptional and Proapoptotic Activity
Authors: Skorta Ioanna , Oren Moshe , Markwardt Christiane , Gutekunst Matthias , Aulitzky Walter E. , van der Kuip Heiko
Published: November 2009

Imatinib is highly effective in inducing remission in chronic myelogenous leukemia (CML). However, complete eradication of the malignant clone by imatinib is rare. We investigated the efficacy of combining imatinib with cisplatin. Inhibition of Bcr-Abl by imatinib induced a hypersensitive phenotype both in Bcr-Abl+ cell lines and in CD34+ cells from CML patients. Importantly, cisplatin sensitivity of leukemic cells harboring an inactive Bcr-Abl greatly exceeded that of Bcr-Abl− parental cells. The cisplatin response of Bcr-Abl+ cells treated with imatinib was characterized by an impaired G2-M arrest and by rapid induction of mitochondrial cell death after the first passage through G2. Imatinib abrogated ATM activation on cisplatin selectively in Bcr-Abl+ cells. As a consequence, phosphorylation of p53 on Ser15 and its activity as a transcription factor was significantly diminished. Furthermore, p53 accumulated predominantly in the cytoplasm in Bcr-Abl+ cells treated with imatinib and cisplatin. Silencing of p53 significantly reduced sensitivity to cisplatin in imatinib-treated Bcr-Abl+ cells, indicating that p53 retains its proapoptotic activity. Simultaneous downregulation of Bcl-xL was an additional requirement for cisplatin hypersensitivity, as p53-dependent cell death could be antagonized by exogenous Bcl-xL. We conclude that imatinib sensitizes Bcr-Abl+ cells to cisplatin by simultaneous inhibition of p53 transactivation, induction of p53 accumulation predominantly in the cytoplasm, and reduction of Bcl-xL. [Cancer Res 2009;69(24):9337–45]
Testing the Circadian Gene Hypothesis in Prostate Cancer: A Population-Based Case-Control Study
Authors: Zhu Yong , Stevens Richard G. , Hoffman Aaron E. , FitzGerald Liesel M. , Kwon Erika M. , Ostrander Elaine A. , Davis Scott , Zheng Tongzhang , Stanford Janet L.
Published: November 2009

Circadian genes are responsible for maintaining the ancient adaptation of a 24-hour circadian rhythm and influence a variety of cancer-related biological pathways, including the regulation of sex hormone levels. However, few studies have been undertaken to investigate the role of circadian genes in the development of prostate cancer, the most common cancer type among men (excluding nonmelanoma skin cancer). The current genetic association study tested the circadian gene hypothesis in relation to prostate cancer by genotyping a total of 41 tagging and amino acid–altering single nucleotide polymorphisms (SNP) in 10 circadian-related genes in a population-based case-control study of Caucasian men (n = 1,308 cases and 1,266 controls). Our results showed that at least one SNP in nine core circadian genes (rs885747 and rs2289591 in PER1; rs7602358 in PER2; rs1012477 in PER3; rs1534891 in CSNK1E; rs12315175 in CRY1; rs2292912 in CRY2; rs7950226 in ARNTL; rs11133373 in CLOCK; and rs1369481, rs895521, and rs17024926 in NPAS2) was significantly associated with susceptibility to prostate cancer (either overall risk or risk of aggressive disease), and the risk estimate for four SNPs in three genes (rs885747 and rs2289591 in PER1, rs1012477 in PER3, and rs11133373 in CLOCK) varied by disease aggressiveness. Further analyses of haplotypes were consistent with these genotyping results. Findings from this candidate gene association study support the hypothesis of a link between genetic variants in circadian genes and prostate cancer risk, warranting further confirmation and mechanistic investigation of circadian biomarkers in prostate tumorigenesis. [Cancer Res 2009;69(24):9315–22]
Loss of ΔNp63α Promotes Invasion of Urothelial Carcinomas via N-Cadherin/Src Homology and Collagen/Extracellular Signal-Regulated Kinase Pathway
Authors: Fukushima Hiroshi , Koga Fumitaka , Kawakami Satoru , Fujii Yasuhisa , Yoshida Soichiro , Ratovitski Edward , Trink Barry , Kihara Kazunori
Published: November 2009

p63 plays a critical role in normal development and maintenance of stratified epithelia, including the urothelium. In the normal urothelium, urothelial cells in the basal layers abundantly express the predominant p63 isoform ΔNp63α. We previously showed that (a) ΔNp63α expression at the similar level to the normal urothelium is retained in most low-grade papillary noninvasive (LPN) tumors, whereas frequently lost in high-grade invasive carcinomas, and that (b) loss of ΔNp63α is associated with poor prognosis of invasive bladder urothelial carcinoma patients. However, a functional role of ΔNp63α in progression of urothelial carcinomas remains to be elucidated. Here, we show that loss of ΔNp63α expression promotes invasion of urothelial carcinoma cells. In 5637 cells substantially expressing only ΔNp63α isoform at the protein level, knockdown of endogenous p63 upregulated N-cadherin, which recruited more Src homology and collagen to N-cadherin and activated extracellular signal-regulated kinase (ERK) signaling, and consequently potentiated cell motility, excretion of matrix metalloproteinase-9, and invasion. In T24 cells originally lacking endogenous ΔNp63α expression, exogenous expression of ΔNp63α attenuated invasion by downregulating N-cadherin expression and ERK activity, confirming an invasion-suppressive role of ΔNp63α in urothelial carcinoma cells. We further documented loss of ΔNp63 expression accompanied by N-cadherin upregulation during muscle-invasive recurrence in patients whose bladder cancer had progressed from LPN tumors to muscle-invasive disease. These results suggest that loss of ΔNp63α and subsequent upregulation of N-cadherin is one of the mechanisms underlying progression of bladder cancer. [Cancer Res 2009;69(24):9263–70]
Gonadotropin-Regulated Lymphangiogenesis in Ovarian Cancer Is Mediated by LEDGF-Induced Expression of VEGF-C
Authors: Sapoznik Stav , Cohen Batya , Tzuman Yael , Meir Gila , Ben-Dor Shifra , Harmelin Alon , Neeman Michal
Published: November 2009

The risk and severity of ovarian carcinoma, the leading cause of gynecologic malignancy death, are significantly elevated in postmenopausal women. Ovarian failure at menopause, associated with a reduction in estrogen secretion, results in an increase of the gonadotropic luteinizing hormone (LH) and follicle-stimulating hormone (FSH), suggesting a role for these hormones in facilitating the progression of ovarian carcinoma. The current study examined the influence of hormonal stimulation on lymphangiogenesis in ovarian cancer cells. In vitro stimulation of ES2 ovarian carcinoma cells with LH and FSH induced expression of vascular endothelial growth factor (VEGF)-C. In vivo, ovariectomy of mice resulted in activation of the VEGF-C promoter in ovarian carcinoma xenografts, increased VEGF-C mRNA level, and enhanced tumor lymphangiogenesis and angiogenesis. Seeking the molecular mechanism, we examined the role of lens epithelium-derived growth factor (LEDGF/p75) and the possible contribution of its putative target, a conserved stress-response element identified in silico in the VEGF-C promoter. Using chromatin immunoprecipitation, we showed that LEDGF/p75 indeed binds the VEGF-C promoter, and binding is augmented by FSH. A corresponding hormonally regulated increase in the LEDGF/p75 mRNA and protein levels was observed. Suppression of LEDGF/p75 expression using small interfering RNA, suppression of LH and FSH production using the gonadotropin-releasing hormone antagonist cetrorelix, or mutation of the conserved stress-response element suppressed the hormonally induced expression of VEGF-C. Overall, our data suggest a possible role for elevated gonadotropins in augmenting ovarian tumor lymphangiogenesis in postmenopausal women. [Cancer Res 2009;69(24):9306–14]
hnRNP A2 Regulates Alternative mRNA Splicing of TP53INP2 to Control Invasive Cell Migration
Authors: Moran-Jones Kim , Grindlay Joan , Jones Marc , Smith Ross , Norman Jim C.
Published: November 2009

Largely owing to widespread deployment of microarray analysis, many of the transcriptional events associated with invasive cell migration are becoming clear. However, the transcriptional drives to invasive migration are likely modified by alternative splicing of pre-mRNAs to produce functionally distinct patterns of protein expression. Heterogenous nuclear ribonucleoprotein (hnRNP A2) is a known regulator of alternative splicing that is upregulated in a number of invasive cancer types. Here, we report that although siRNA of hnRNP A2 had little influence on the ability of cells to migrate on plastic surfaces, the splicing regulator was clearly required for cells to move effectively on three-dimensional matrices and to invade into plugs of extracellular matrix proteins. We used exon-tiling microarrays to determine that hnRNP A2 controlled approximately six individual splicing events in a three-dimensional matrix-dependent fashion, one of which influenced invasive migration. Here, we show that alternative splicing of an exon in the 5′ untranslated region of a gene termed TP53INP2 is a key event downstream of hnRNP A2 that is necessary for cells to invade the extracellular matrix. Furthermore, we report that the consequences of altered TP53INP2 splicing on invasion are likely mediated via alterations in Golgi complex integrity during migration on three-dimensional matrices. [Cancer Res 2009;69(24):9219–27]
Reduced Tumor Necrosis Factor Receptor–Associated Death Domain Expression Is Associated with Prostate Cancer Progression
Authors: Wang Diping , Montgomery R. Bruce , Schmidt Lucy J. , Mostaghel Elahe A. , Huang Haojie , Nelson Peter S. , Tindall Donald J.
Published: November 2009

By using LNCaP and its derivative cell lines, we first observed an association between tumor necrosis factor-α (TNF-α) resistance and hormone independence. Moreover, we found that the expression of tumor necrosis factor receptor–associated death domain (TRADD) was reduced in androgen deprivation–independent cells compared with that in androgen deprivation–dependent cells. TRADD is a crucial transducer for TNF-α–induced nuclear factor-κB (NF-κB) activation. Knocking down TRADD expression in LNCaP cells impaired TNF-α–induced NF-κB activation and androgen receptor repression, whereas overexpression of TRADD in C4-2B cells restored their sensitivity to TNF-α. Finally, we found that androgen deprivation reduces TRADD expression in vitro and in vivo, suggesting that androgen deprivation therapy may promote the development of TNF-α resistance by reducing TRADD expression during prostate cancer progression. [Cancer Res 2009;69(24):9448–56]
The Role of Myc-Induced Protein Synthesis in Cancer
Authors: Ruggero Davide
Published: November 2009

Deregulation in different steps of translational control is an emerging mechanism for cancer formation. One example of an oncogene with a direct role in control of translation is the Myc transcription factor. Myc directly increases protein synthesis rates by controlling the expression of multiple components of the protein synthetic machinery, including ribosomal proteins and initiation factors of translation, Pol III and rDNA. However, the contribution of Myc-dependent increases in protein synthesis toward the multistep process leading to cancer has remained unknown. Recent evidence strongly suggests that Myc oncogenic signaling may monopolize the translational machinery to elicit cooperative effects on cell growth, cell cycle progression, and genome instability as a mechanism for cancer initiation. Moreover, new genetic tools to restore aberrant increases in protein synthesis control are now available, which should enable the dissection of important mechanisms in cancer that rely on the translational machinery. [Cancer Res 2009;69(23):8839–43]
Comparative Analysis of Normal versus CLL B-Lymphocytes Reveals Patient-Specific Variability in Signaling Mechanisms Controlling LFA-1 Activation by Chemokines
Authors: Montresor Alessio , Bolomini-Vittori Matteo , Simon Scott I. , Rigo Antonella , Vinante Fabrizio , Laudanna Carlo
Published: November 2009

Activation of lymphocyte function–associated antigen-1 (LFA-1) by chemokines is fine-tuned by inside-out signaling mechanisms responsible for integrin-mediated adhesion modulation. In the present study, we investigated the possibility of qualitative variability of signaling mechanisms controlling LFA-1 activation in chronic lymphocytic leukemia (CLL) cells. We pursued a multiplexed comparative analysis of the role of the recently described chemokine-triggered rho-signaling module in human normal versus CLL B-lymphocytes. We found that the rho-module of LFA-1 affinity triggering is functionally conserved in normal B-lymphocytes. In contrast, in malignant B-lymphocytes isolated from patients with B-CLL, the role of the rho-module was not maintained, showing remarkable differences and variability. Specifically, RhoA and phospholipase D1 were crucially involved in LFA-1 affinity triggering by CXCL12 in all analyzed patients. In contrast, Rac1 and CDC42 involvement displayed a consistent patient-by-patient variability, with a group of patients showing LFA-1 affinity modulation totally independent of Rac1 and CDC42 signaling activity. Finally, phosphatidylinositol-4-phosphate 5-kinase isoform 1γ (PIP5KC) was found without any regulatory role in all patients. The data imply that the neoplastic progression may completely bypass the regulatory role of Rac1, CDC42, and PIP5KC, and show a profound divergence in the signaling mechanisms controlling integrin activation in normal versus neoplastic lymphocytes, suggesting that patients with CLL can be more accurately evaluated on the basis of the analysis of signaling mechanisms controlling integrin activation. Our findings could potentially affect the diagnosis, prognosis, and therapy of CLL disorders. [Cancer Res 2009;69(24):9281–90]
Global Changes in Processing of mRNA 3′ Untranslated Regions Characterize Clinically Distinct Cancer Subtypes
Authors: Singh Priyam , Alley Travis L. , Wright Sarah M. , Kamdar Sonya , Schott William , Wilpan Robert Y , Mills Kevin D. , Graber Joel H.
Published: November 2009

Molecular cancer diagnostics are an important clinical advance in cancer management, but new methods are still needed. In this context, gene expression signatures obtained by microarray represent a useful molecular diagnostic. Here, we describe novel probe-level microarray analyses that reveal connections between mRNA processing and neoplasia in multiple tumor types, with diagnostic potential. We now show that characteristic differences in mRNA processing, primarily in the 3′-untranslated region, define molecular signatures that can distinguish similar tumor subtypes with different survival characteristics, with at least 74% accuracy. Using a mouse model of B-cell leukemia/lymphoma, we find that differences in transcript isoform abundance are likely due to both alternative polyadenylation (APA) and differential degradation. While truncation of the 3′-UTR is the most common observed pattern, genes with elongated transcripts were also observed, and distinct groups of affected genes are found in related but distinct tumor types. Genes with elongated transcripts are overrepresented in ontology categories related to cell-cell adhesion and morphology. Analysis of microarray data from human primary tumor samples revealed similar phenomena. Western blot analysis of selected proteins confirms that changes in the 3′-UTR can correlate with changes in protein expression. Our work suggests that alternative mRNA processing, particularly APA, can be a powerful molecular biomarker with prognostic potential. Finally, these findings provide insights into the molecular mechanisms of gene deregulation in tumorigenesis. [Cancer Res 2009;69(24):9422–30]
Embryonic Lethality after Combined Inactivation ofFancd2andMlh1in Mice
Authors: van de Vrugt Henri J. , Eaton Laura , Hanlon Newell Amy , Al-Dhalimy Mushen , Liskay R. Michael , Olson Susan B. , Grompe Markus
Published: November 2009

DNA repair defects are frequently encountered in human cancers. These defects are utilized by traditional therapeutics but also offer novel cancer treatment strategies based on synthetic lethality. To determine the consequences of combined Fanconi anemia (FA) and mismatch repair pathway inactivation, defects in Fancd2 and Mlh1 were combined in one mouse model. Fancd2/Mlh1 double-mutant embryos displayed growth retardation resulting in embryonic lethality and significant underrepresentation among progeny. Additional inactivation of Trp53 failed to improve the survival of Fancd2/Mlh1–deficient embryos. Mouse fibroblasts were obtained and challenged with cross-linking agents. Fancd2-deficient cells displayed the FA-characteristic growth inhibition after mitomycin C (MMC) exposure. In primary fibroblasts, the absence of Mlh1 did not greatly affect the MMC sensitivity of Fancd2-deficient and Fancd2-proficient cells. However, in Trp53 mutant immortalized fibroblasts, Mlh1 deficiency reduced the growth-inhibiting effect of MMC in Fancd2 mutant and complemented cells. Similar data were obtained using psoralen/UVA, signifying that MLH1 influences the cellular sensitivity to DNA interstrand cross-links. Next, the effect of MLH1 deficiency on the formation of chromosomal aberrations in response to cross-linking agents was determined. Surprisingly, Mlh1 mutant fibroblasts displayed a modest but noticeable decrease in induced chromosomal breakage and interchange frequencies, suggesting that MLH1 promotes interstrand cross-link repair catastrophe. In conclusion, the combined inactivation of Fancd2 and Mlh1 did not result in synthetic lethality at the cellular level. Although the absence of Fancd2 sensitized Mlh1/Trp53 mutant fibroblasts to MMC, the differential survival of primary and immortalized fibroblasts advocates against systemic inactivation of FANCD2 to enhance treatment of MLH1-deficient tumors. [Cancer Res 2009;69(24):9431–8]
Disruption of Transforming Growth Factor-β Signaling by Five Frequently Methylated Genes Leads to Head and Neck Squamous Cell Carcinoma Pathogenesis
Authors: Bennett Kristi L. , Romigh Todd , Eng Charis
Published: November 2009

Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with low survival rates in advanced stages. To facilitate timely diagnosis and improve outcome, early detection markers (e.g., DNA methylation) are crucial for timely cancer diagnosis. In a recent publication, an epigenome-wide screen revealed a set of genes that are commonly methylated and downregulated in head and neck cancers (SEPT9, SLC5A8, FUSSEL18, EBF3, and IRX1). Interestingly, these candidates are potentially involved in the transforming growth factor-β (TGF-β) signaling pathway, which is often disrupted in HNSCC. Therefore, we sought to determine coordinated epigenetic silencing of these candidate genes in HNSCC as potential key disruptors of TGF-β signaling, which could ultimately result in HNSCC progression. Through immunoprecipitation studies, all five of the investigated candidate genes were found to interact with components of the TGF-β pathway. Overexpression of SLC5A8, EBF3, and IRX1 resulted in decreased mitotic activity and increased apoptosis. In addition, EBF3 was found to increase p21 promoter activity, and SMAD2 significantly increased IRX1 promoter activity. These findings are significant because they reveal a set of genes that interact with components of the TGF-β pathway, and their silencing via methylation in HNSCC results in coordinated decrease in apoptosis, increased proliferation, and decreased differentiation. [Cancer Res 2009;69(24):9301–5]
Signaling in Malignant Astrocytomas: Role of Neural Stem Cells and Its Therapeutic Implications
Authors: Alcantara Llaguno Sheila R. , Chen Jian , Parada Luis F.
Published: November 2009

Malignant astrocytomas are infiltrative and aggressive brain tumors. Conventional forms of therapy have not been effective in controlling this incurable disease. Recent advances in understanding the molecular biology of these tumors have revealed potential mechanisms by which astrocytoma cells undergo tumor initiation, progression, and maintenance, as well as possible avenues for targeted therapeutics. Studies on the role of neural stem cells as cells of origin and tumor-propagating cells have also greatly increased our understanding of the biology and clinical behavior of these tumors. An integrated view of the genetics, signal transduction, and cell biology of astrocytomas, as well as clinical data from patients, will provide a more useful approach in designing novel therapies for this devastating disease. (Clin Cancer Res 2009;15(23):7124–9)
Antiangiogenic Tetrathiomolybdate Protects against Her2/neu-Induced Breast Carcinoma by Hypoplastic Remodeling of the Mammary Gland
Authors: Pan Quintin , Rosenthal Devin T. , Bao Liwei , Kleer Celina G. , Merajver Sofia D.
Published: November 2009

Purpose: The objective of the present study was to delineate the efficacy of tetrathiomolybdate (TM), a novel antiangiogenic anticancer agent, as a chemopreventative agent.

Experimental Design: Nulliparous Her2/neu transgenic mice were treated with water or TM for 180 days and observed for tumor development during treatment and for 180 days after treatment. Mammary gland composition and architecture were also observed following TM treatment of Her2/neu transgenic and normal FVB mice.

Results: At the 1-year follow-up, 86.7% of control and 40% of TM-treated Her2/neu mice had palpable mammary tumors with a median time to tumor development of 234 days (95% confidence interval, 202-279 days) for control and >460 days for TM-treated mice (P < 0.0005, n = 15). The mammary glands from TM-treated Her2/neu and FVB mice showed a blunted epithelial ductal branching system due to a significant decrease in the number of secondary branches and total number of differentiated mammary epithelial cells. Microvessel density in Her2/neu and FVB mammary glands was lowered by 65.6 ± 6.2% and 50.9 ± 4.5% (P < 0.005), respectively, following TM therapy, consistent with the antiangiogenic effect of TM. Lastly, TM treatment resulted in a 2-fold increase in the absolute number of aldehyde dehydrogenase–positive mammary stem cells in Her2/neu and FVB mammary glands.

Conclusion: Taken together, these results strongly support that TM is a potent chemopreventative agent as a consequence of hypoplastic remodeling of the mammary gland through modulation of the mammary stem cell compartment. (Clin Cancer Res 2009;15(23):7441–6)