bluuebunny/crossref_metadata_2025 huggingface dataset:
Mechanism of Sperm Immobilization byEscherichia coli
Authors: Prabha Vijay , Sandhu Ravneet , Kaur Siftjit , Kaur Kiranjeet , Sarwal Abha , Mavuduru Ravimohan S. , Singh Shravan Kumar
Published: March 2010

Aim. To explore the influence ofEscherichia colion the motility of human spermatozoa and its possible mechanism.Methods. Highly motile preparations of spermatozoa from normozoospermic patients were coincubated withEscherichia colifor 4 hours. At 1, 2 and 4 hours of incubation, sperm motility was determined. The factor responsible for sperm immobilization without agglutination was isolated and purified from filtrates.Results. This report confirms the immobilization of spermatozoa byE. coliand demonstrates sperm immobilization factor (SIF) excreted byE. coli. Further this factor was purified by ammonium sulfate precipitation, gel permeation chromatography, and ion-exchange chromatography. Purified SIF (56 kDa) caused instant immobilization without agglutination of human spermatozoa at 800 μg/mL and death at 2.1 mg/mL. Spermatozoa incubated with SIF revealed multiple and profound alterations involving all superficial structures of spermatozoa as observed by scanning electron microscopy.Conclusion. In conclusion, these results have shown immobilization of spermatozoa byE. coliand demonstrate a factor (SIF) produced and secreted byE. coliwhich causes variable structural damage as probable morphological correlates of immobilization.
A Predator‐Prey Model in the Chemostat with Time Delay
Authors: Fan Guihong , Wolkowicz Gail S. K.
Published: March 2010

The aim of this paper is to study the dynamics of predator‐prey interaction in a chemostat to determine whether including a discrete delay to model the time between the capture of the prey and its conversion to viable biomass can introduce oscillatory dynamics even though there is a globally asymptotically stable equilibrium when the delay is ignored. Hence, Holling type I response functions are chosen so that no oscillatory behavior is possible when there is no delay. It is proven that unlike the analogous model for competition, as the parameter modeling the delay is increased, Hopf bifurcations can occur.
The Data Big Bang and the Expanding Digital Universe: High‐Dimensional, Complex and Massive Data Sets in an Inflationary Epoch
Authors: Pesenson Meyer Z. , Pesenson Isaac Z. , McCollum Bruce
Published: March 2010

Recent and forthcoming advances in instrumentation, and giant new surveys, are creating astronomical data sets that are not amenable to the methods of analysis familiar to astronomers. Traditional methods are often inadequate not merely because of the size in bytes of the data sets, but also because of the complexity of modern data sets. Mathematical limitations of familiar algorithms and techniques in dealing with such data sets create a critical need fornew paradigmsfor the representation, analysis and scientific visualization (as opposed to illustrative visualization) of heterogeneous, multiresolution data across application domains. Some of the problems presented by the new data sets have been addressed by other disciplines such as applied mathematics, statistics and machine learning and have been utilized by other sciences such as space‐based geosciences. Unfortunately, valuable results pertaining to these problems are mostly to be found in publications outside of astronomy. Here we offer brief overviews of a number of concepts, techniques and developments that are vital to the analysis and visualization of complex datasets and images. One of the goals of this paper is to help bridge the gap between applied mathematics and artificial intelligence on the one side and astronomy on the other.
Weyl‐Titchmarsh Theory for Hamiltonian Dynamic Systems
Authors: Sun Shurong , Bohner Martin , Chen Shaozhu
Published: March 2010

We establish the Weyl‐Titchmarsh theory for singular linear
Hamiltonian dynamic systems on a time scale 𝕋, which allows one to treat both continuous
and discrete linear Hamiltonian systems as special cases for 𝕋 = ℝ and 𝕋 = ℤ within one
theory and to explain the discrepancies between these two theories. This paper extends the
Weyl‐Titchmarsh theory and provides a foundation for studying spectral theory of Hamiltonian dynamic systems. These investigations are part of a larger program which includes
the following: (i) M(λ) theory for singular Hamiltonian systems, (ii) on the spectrum
of Hamiltonian systems, (iii) on boundary value problems for Hamiltonian dynamic systems.
Action Recognition for Support of Adaptive Gameplay: A Case Study of a First Person Shooter
Authors: Kazmi S. , Palmer I. J.
Published: March 2010

With games continuously and rapidly evolving to become more complex and sophisticated in their nature and implementation. There is a fundamental need to sustain and deliver a similarly advanced, realistic, and engaging experience for the player. The implementation of “emergence” within games as providing an effective means to sustain this engagement in conjunction with some form of action recognition mechanism for its support. More recently, games have made much of the “adaptive” mechanisms that tailor the player experience during the game, but much of this appears to be implemented by merely making the game harder according to the success of the player. Some go further than this by incorporating adaptive AI that change agent tactics to suit the player's style of play. Whilst these are clearly advances in the approach to providing a player-centric experience to engage the player, the basis and transferability of these approaches is open to question. Here we propose a limited flavour of “emergence” which can be used to support an adaptive game mechanism and so present players with different gameplay experiences based on their actions within the game.
Bone Diseases of the Jaws
Authors: Slootweg Pieter Johannes
Published: March 2010

Lesions specific for the jaws and not occurring in any other bones mostly are related to the teeth or to odontogenic tissues. Moreover, the jaws may harbor nonodontogenic bone lesions not seen in any other part of the skeleton. This paper pays attention to the diseases that are specific for the jaws, odontogenic as well as nonodontogenic. Both neoplastic and nonneoplastic entities will be discussed.
Robust MMSE Transceiver Designs for Downlink MIMO Systems with Multicell Cooperation
Authors: Li Jialing , Lu I-Tai , Lu Enoch
Published: March 2010

Therobust-generalized iterative approach(Robust-GIA),robust-fast iterative approach(Robust-FIA), androbust-decoder covariance optimization approach(Robust-DCOA) are proposed for designing MMSE transceivers of downlink multicell multiuser MIMO systems with per-cell and per-antenna power constraints and possibly imperfect channel state information. TheRobust-DCOAis the most restrictive but is always optimum, theRobust-GIAis the most general, and theRobust-FIAis the most efficient. When theRobust-DCOAis applicable and the decoder covariance matrices are full rank, the three proposed approaches are equivalent and all provide the optimum solution. Numerical results show that the proposed robust approaches outperform their non-robust counterparts in various single-cell and multicell examples with different system configurations, channel correlations, power constraints, and cooperation scenarios. Moreover, performances of the robust approaches are insensitive to estimation errors of channel statistics (correlations and path loss). With cell-cooperation, cell edge interference problems can be remedied without reducing the number of data streams by using the proposed robust approaches.
The Connectivity Map Links Iron Regulatory Protein-1–Mediated Inhibition of Hypoxia-Inducible Factor-2a Translation to the Anti-inflammatory 15-deoxy-Δ12,14-Prostaglandin J2
Authors: Zimmer Michael , Lamb Justin , Ebert Benjamin L. , Lynch Mary , Neil Christopher , Schmidt Emmett , Golub Todd R. , Iliopoulos Othon
Published: March 2010

Hypoxia-inducible factors 1 and 2 (HIF1 and HIF2) are heterodimeric transcription factors consisting of α regulatory subunits and a constitutively expressed β subunit. The expression of α regulatory subunits is promoted by hypoxia, cancer-associated mutations, and inflammatory cytokines. Thus, HIF1 and HIF2 provide a molecular link between cancer and inflammation. We have recently identified novel small molecules that selectively inhibit translation of the HIF2a message and thereby powerfully inhibit the expression of HIF2a target genes. We report here that Connectivity Map analysis links three of these compounds to the anti-inflammatory cytokine 15-deoxy-Δ12,14-prostaglandin J2 (PGJ2). As with our identified compounds, PGJ2 inhibits translation of the HIF2a message in a mammalian target of rapamycin–independent manner by promoting the binding of iron regulatory protein-1 (IRP1) to a noncanonical iron responsive element (IRE) embedded within the 5′-untranslated region of the HIF2a message. The IRE is necessary and sufficient for mediating the effect. Mutation of the IRE sequence, or downregulation of IRP1 expression, blocks the effect of PGJ2 on HIF2a translation. This is the first report of an endogenous natural molecule regulating HIF2a translation, and it suggests that part of the anti-inflammatory and putative antineoplastic effects of PGJ2 may be mediated through inhibition of HIF2a within tumor epithelial cells themselves and/or mesenchymal cells of the tumor microenvironment. Cancer Res; 70(8); 3071–9. ©2010 AACR.
The c-Jun NH2-Terminal Kinase 2 Plays a Dominant Role in Human Epidermal Neoplasia
Authors: Ke Hengning , Harris Rebecca , Coloff Jonathan L. , Jin Jane Y. , Leshin Benjamin , de Marval Paula Miliani , Tao Shiying , Rathmell Jeffrey C. , Hall Russell P. , Zhang Jennifer Y.
Published: March 2010

The c-Jun NH2-terminal kinase (JNK) signaling cascade has been implicated in a wide range of diseases, including cancer. It is unclear how different JNK proteins contribute to human cancer. Here, we report that JNK2 is activated in more than 70% of human squamous cell carcinoma (SCC) samples and that inhibition of JNK2 pharmacologically or genetically impairs tumorigenesis of human SCC cells. Most importantly, JNK2, but not JNK1, is sufficient to couple with oncogenic Ras to transform primary human epidermal cells into malignancy with features of SCC. JNK2 prevents Ras-induced cell senescence and growth arrest by reducing the expression levels of the cell cycle inhibitor p16 and the activation of NF-κB. On the other hand, JNK, along with phosphoinositide 3-kinase, is essential for Ras-induced glycolysis, an energy-producing process known to benefit cancer growth. These data indicate that JNK2 collaborates with other oncogenes, such as Ras, at multiple molecular levels to promote tumorigenesis and hence represents a promising therapeutic target for cancer. Cancer Res; 70(8); 3080–8. ©2010 AACR.
Induction of Cancer Cell Death by Self-assembling Nanostructures Incorporating a Cytotoxic Peptide
Authors: Standley Stephany M. , Toft Daniel J. , Cheng Hao , Soukasene Stephen , Chen Jing , Raja Srikumar M. , Band Vimla , Band Hamid , Cryns Vincent L. , Stupp Samuel I.
Published: March 2010

Nanotechnology offers novel delivery vehicles for cancer therapeutics. Potential advantages of nanoscale platforms include improved pharmacokinetics, encapsulation of cytotoxic agents, enhanced accumulation of therapeutics in the tumor microenvironment, and improved therapeutic structures and bioactivity. Here, we report the design of a novel amphiphilic molecule that self-assembles into nanostructures for intracellular delivery of cytotoxic peptides. Specifically, a cationic α-helical (KLAKLAK)2 peptide that is known to induce cancer cell death by membrane disruption was integrated into a peptide amphiphile (PA) that self-assembles into bioactive, cylindrical nanofibers. PAs are composed of a hydrophobic alkyl tail, a β-sheet forming peptide, and a bioactive peptide that is displayed on the surface of the nanofiber after self-assembly. PA nanostructures that included (KLAKLAK)2 were readily internalized by breast cancer cells, in contrast to the (KLAKLAK)2 peptide that on its own was not cell permeable. (KLAKLAK)2 nanostructures, but not the peptides alone, also induced breast cancer cell death by caspase-independent and Bax/Bak–independent mechanisms associated with membrane disruption. Significantly, (KLAKLAK)2 nanostructures induced cell death more robustly in transformed breast epithelial cells than in untransformed cells, suggesting a degree of tumor selectivity. Our results provide proof-of-principle that self-assembling PAs can be rationally designed to generate nanostructures that can efficiently deliver cytotoxic peptides to cancer cells. Cancer Res; 70(8); 3020–6. ©2010 AACR.
In vivo Cytotoxicity of Type I CD20 Antibodies Critically Depends on Fc Receptor ITAM Signaling
Authors: de Haij Simone , Jansen J.H. Marco , Boross Peter , Beurskens Frank J. , Bakema Jantine E. , Bos Desiree L. , Martens Anton , Verbeek J. Sjef , Parren Paul W.H.I. , van de Winkel Jan G.J. , Leusen Jeanette H.W.
Published: March 2010

Antibody–Fc receptor (FcR) interactions play an important role in the mechanism of action of most therapeutic antibodies against cancer. Effector cell activation through FcR triggering may induce tumor cell killing via antibody-dependent cellular cytotoxicity (ADCC). Reciprocally, FcR cross-linking of antibody may lead to the induction of apoptotic signaling in tumor cells. The relative importance of these bisecting pathways to in vivo antibody activity is unknown. To unravel these roles, we developed a novel mouse model with normal FcR expression but in which FcR signaling was inactivated by mutation of the associated γ-chain. Transgenic mice showed similar immune complex binding compared with wild-type mice. In contrast, ADCC of cells expressing frequently used cancer targets, such as CD20, epidermal growth factor receptor, Her2, and gp75, was abrogated. Using the therapeutic CD20 antibodies ofatumumab and rituximab, we show that FcR cross-linking of antibody-antigen immune complexes in the absence of γ-chain signaling is insufficient for their therapeutic activity in vivo. ADCC therefore represents an essential mechanism of action for immunotherapy of lymphoid tumors. Cancer Res; 70(8); 3209–17. ©2010 AACR.
A Population-Based Prospective Study of Carcinogenic Human Papillomavirus Variant Lineages, Viral Persistence, and Cervical Neoplasia
Authors: Schiffman Mark , Rodriguez Ana Cecilia , Chen Zigui , Wacholder Sholom , Herrero Rolando , Hildesheim Allan , Desalle Rob , Befano Brian , Yu Kai , Safaeian Mahboobeh , Sherman Mark E. , Morales Jorge , Guillen Diego , Alfaro Mario , Hutchinson Martha , Solomon Diane , Castle Philip E. , Burk Robert D.
Published: March 2010

Human papillomavirus (HPV) types differ profoundly in cervical carcinogenicity. For the most carcinogenic type HPV16, variant lineages representing further evolutionary divergence also differ in cancer risk. Variants of the remaining 10 to 15 carcinogenic HPV types have not been well studied. In the first prospective, population-based study of HPV variants, we explored whether, on average, the oldest evolutionary branches within each carcinogenic type predicted different risks of >2-year viral persistence and/or precancer and cancer [cervical intraepithelial neoplasia grade 3+ (CIN3+)]. We examined the natural history of HPV variants in the 7-year, 10,049-woman Guanacaste Cohort Study, using a nested case-control design. Infections were assigned to a variant lineage determined by phylogenetic parsimony methods based on URR/E6 sequences. We used the Fisher's combination test to evaluate significance of the risk associations, cumulating evidence across types. Globally, for HPV types including HPV16, the P value was 0.01 for persistence and 0.07 for CIN3+. Excluding HPV16, the P values were 0.04 and 0.37, respectively. For HPV16, non-European viral variants were significantly more likely than European variants to cause persistence [odds ratio (OR), 2.6; P = 0.01] and CIN3+ (OR, 2.4; P = 0.004). HPV35 and HPV51 variant lineages also predicted CIN3+. HPV variants generally differ in risk of persistence. For some HPV types, especially HPV16, variant lineages differ in risk of CIN3+. The findings indicate that continued evolution of HPV types has led to even finer genetic discrimination linked to HPV natural history and cervical cancer risk. Larger viral genomic studies are warranted, especially to identify the genetic basis for HPV16's unique carcinogenicity. Cancer Res; 70(8); 3159–69. ©2010 AACR.
p66Shc Is Indispensable for Phenethyl Isothiocyanate–Induced Apoptosis in Human Prostate Cancer Cells
Authors: Xiao Dong , Singh Shivendra V.
Published: March 2010

Naturally occurring phenethyl isothiocyanate (PEITC) selectively inhibits growth of cancer cells by causing apoptosis, but the mechanism of cell death induction is not fully understood. We now show, for the first time, that growth factor adapter protein p66Shc is indispensable for PEITC-induced apoptosis. Mouse embryonic fibroblasts derived from p66Shc knockout mice were significantly more resistant to PEITC-mediated growth inhibition, cytoplasmic histone-associated apoptotic DNA fragmentation, and caspase-3 activation compared with wild-type fibroblasts. The PEITC treatment resulted in induction as well as increased Ser36 phosphorylation of p66Shc in PC-3 and LNCaP human prostate cancer cells. Knockdown of p66Shc protein conferred significant protection against PEITC-mediated cytoplasmic histone-associated DNA fragmentation as well as production of reactive oxygen species in both PC-3 and LNCaP cells. The PEITC-treated PC-3 and LNCaP cells exhibited increased binding of p66Shc with prolyl isomerase Pin1, a protein implicated in translocation of p66Shc to mitochondria. Consistent with these results, treatment of PC-3 cells with PEITC resulted in translocation of p66Shc to the mitochondria as judged by immunoblotting using cytosolic and mitochondrial fractions and immunofluorescence microscopy. Growth suppression and apoptosis induction in tumor xenografts in vivo by oral administration of PEITC to the PC-3 tumor-bearing male athymic mice were accompanied by statistically significant increase in the level of Ser36-phosphorylated p66Shc. Collectively, these results provide novel insight into the critical role of p66Shc in regulation of PEITC-induced apoptotic cell death in human prostate cancer cells. Cancer Res; 70(8); 3150–8. ©2010 AACR.
Pharmacologic Inhibition of Cyclin-Dependent Kinases 4 and 6 Arrests the Growth of Glioblastoma Multiforme Intracranial Xenografts
Authors: Michaud Karine , Solomon David A. , Oermann Eric , Kim Jung-Sik , Zhong Wei-Zhu , Prados Michael D. , Ozawa Tomoko , James C. David , Waldman Todd
Published: March 2010

Activation of cyclin-dependent kinases 4 and 6 (cdk4/6) occurs in the majority of glioblastoma multiforme (GBM) tumors, and represents a promising molecular target for the development of small molecule inhibitors. In the current study, we investigated the molecular determinants and in vivo response of diverse GBM cell lines and xenografts to PD-0332991, a cdk4/6-specific inhibitor. In vitro testing of PD-0332991 against a panel of GBM cell lines revealed a potent G1 cell cycle arrest and induction of senescence in each of 16 retinoblastoma protein (Rb)–proficient cell lines regardless of other genetic lesions, whereas 5 cell lines with homozygous inactivation of Rb were completely resistant to treatment. Short hairpin RNA depletion of Rb expression conferred resistance of GBM cells to PD-0332991, further demonstrating a requirement of Rb for sensitivity to cdk4/6 inhibition. PD-0332991 was found to efficiently cross the blood-brain barrier and proved highly effective in suppressing the growth of intracranial GBM xenograft tumors, including those that had recurred after initial therapy with temozolomide. Remarkably, no mice receiving PD-0332991 died as a result of disease progression while on therapy. Additionally, the combination of PD-0332991 and radiation therapy resulted in significantly increased survival benefit compared with either therapy alone. In total, our results support clinical trial evaluation of PD-0332991 against newly diagnosed as well as recurrent GBM, and indicate that Rb status is the primary determinant of potential benefit from this therapy. Cancer Res; 70(8); 3228–38. ©2010 AACR.
A Therapeutic Anti–VEGF Antibody with Increased Potency Independent of Pharmacokinetic Half-life
Authors: Yeung Yik Andy , Wu Xiumin , Reyes Arthur E. , Vernes Jean-Michel , Lien Samantha , Lowe John , Maia Mauricio , Forrest William F. , Meng Y. Gloria , Damico Lisa A. , Ferrara Napoleone , Lowman Henry B.
Published: March 2010

Bevacizumab [Avastin; anti–vascular endothelial growth factor (VEGF) antibody] is an antiangiogenic IgG approved for treating patients with certain types of colon, breast, and lung cancer. In these indications, bevacizumab is administered every 2 to 3 weeks, prompting us to study ways to reduce the frequency of administration. Increasing affinity to neonatal Fc receptor (FcRn) may extend the pharmacokinetic half-life of an antibody, but the quantitative effect of FcRn affinity on clearance has not been clearly elucidated. To gain further insight into this relationship, we engineered a series of anti-VEGF antibody variants with minimal amino acid substitutions and showed a range of half-life improvements in primates. These results suggest that, if proven clinically safe and effective, a modified version of bevacizumab could potentially provide clinical benefit to patients on long-term anti-VEGF therapy through less-frequent dosing and improved compliance with drug therapy. Moreover, despite having half-life similar to that of wild-type in mice due to the species-specific FcRn binding effects, the variant T307Q/N434A exhibited superior in vivo potency in slowing the growth of certain human tumor lines in mouse xenograft models. These results further suggest that FcRn variants may achieve increased potency through unidentified mechanisms in addition to increased systemic exposure. Cancer Res; 70(8); 3269–77. ©2010 AACR.
Pretargeted Immuno–Positron Emission Tomography Imaging of Carcinoembryonic Antigen–Expressing Tumors with a Bispecific Antibody and a 68Ga- and 18F-Labeled Hapten Peptide in Mice with Human Tumor Xenografts
Authors: Schoffelen Rafke , Sharkey Robert M. , Goldenberg David M. , Franssen Gerben , McBride William J. , Rossi Edmund A. , Chang Chien-Hsing , Laverman Peter , Disselhorst Jonathan A. , Eek Annemarie , van der Graaf Winette T.A. , Oyen Wim J.G. , Boerman Otto C.
Published: March 2010

18F-Fluorodeoxyglucose (18F-FDG) is the most common molecular imaging agent in oncology, with a high sensitivity and specificity for detecting several cancers. Antibodies could enhance specificity; therefore, procedures were developed for radiolabeling a small (∼1451 Da) hapten peptide with 68Ga or 18F to compare their specificity with 18F-FDG for detecting tumors using a pretargeting procedure. Mice were implanted with carcinoembryonic antigen (CEA; CEACAM5)–expressing LS174T human colonic tumors and a CEA-negative tumor, or an inflammation was induced in thigh muscle. A bispecific monoclonal anti-CEA × anti-hapten antibody was given to mice, and 16 hours later, 5 MBq of 68Ga- or 18F-labeled hapten peptides were administered intravenously. Within 1 hour, tissues showed high and specific targeting of 68Ga-IMP-288, with 10.7 ± 3.6% ID/g uptake in the tumor and very low uptake in normal tissues (e.g., tumor-to-blood ratio of 69.9 ± 32.3), in a CEA-negative tumor (0.35 ± 0.35% ID/g), and inflamed muscle (0.72 ± 0.20% ID/g). 18F-FDG localized efficiently in the tumor (7.42 ± 0.20% ID/g) but also in the inflamed muscle (4.07 ± 1.13% ID/g) and in several normal tissues; thus, pretargeted 68Ga-IMP-288 provided better specificity and sensitivity. Positron emission tomography (PET)/computed tomography images reinforced the improved specificity of the pretargeting method. 18F-labeled IMP-449 distributed similarly in the tumor and normal tissues as the 68Ga-labeled IMP-288, indicating that either radiolabeled hapten peptide could be used. Thus, pretargeted immuno-PET does exceptionally well with short-lived radionuclides and is a highly sensitive procedure that is more specific than 18F-FDG-PET. Mol Cancer Ther; 9(4); 1019–27. ©2010 AACR.
PF-03814735, an Orally Bioavailable Small Molecule Aurora Kinase Inhibitor for Cancer Therapy
Authors: Jani Jitesh P. , Arcari Joel , Bernardo Vincent , Bhattacharya Samit K. , Briere David , Cohen Bruce D. , Coleman Kevin , Christensen James G. , Emerson Erling O. , Jakowski Amy , Hook Kenneth , Los Gerrit , Moyer James D. , Pruimboom-Brees Ingrid , Pustilnik Leslie , Rossi Ann Marie , Steyn Stefan J. , Su Chunyan , Tsaparikos Konstantinos , Wishka Donn , Yoon Kwansik , Jakubczak John L.
Published: March 2010

The Aurora family of highly related serine/threonine kinases plays a key role in the regulation of mitosis. Aurora1 and Aurora2 play important but distinct roles in the G2 and M phases of the cell cycle and are essential for proper chromosome segregation and cell division. Overexpression and amplification of Aurora2 have been reported in different tumor types, including breast, colon, pancreatic, ovarian, and gastric cancer. PF-03814735 is a novel, potent, orally bioavailable, reversible inhibitor of both Aurora1 and Aurora2 kinases that is currently in phase I clinical trials for the treatment of advanced solid tumors. In intact cells, the inhibitory activity of PF-03814735 on the Aurora1 and Aurora2 kinases reduces levels of phospho-Aurora1, phosphohistone H3, and phospho-Aurora2. PF-03814735 produces a block in cytokinesis, resulting in inhibition of cell proliferation and the formation of polyploid multinucleated cells. Although PF-03814735 produces significant inhibition of several other protein kinases, the predominant biochemical effects in cellular assays are consistent with inhibition of Aurora kinases. Once-daily oral administration of PF-03814735 to mice bearing human xenograft tumors produces a reduction in phosphohistone H3 in tumors at doses that are tolerable and that result in significant inhibition of tumor growth. The combination of PF-03814735 and docetaxel in xenograft mouse tumor models shows additive tumor growth inhibition. These results support the clinical evaluation of PF-03814735 in cancer patients. Mol Cancer Ther; 9(4); 883–94. ©2010 AACR.
AT7519, a Cyclin-Dependent Kinase Inhibitor, Exerts Its Effects by Transcriptional Inhibition in Leukemia Cell Lines and Patient Samples
Authors: Squires Matthew S. , Cooke Laurence , Lock Victoria , Qi Wenqing , Lewis E. Jonathan , Thompson Neil T. , Lyons John F. , Mahadevan Daruka
Published: March 2010

AT7519 is a potent inhibitor of several cyclin-dependent kinases and is currently in early phase clinical development. Recently, cyclin-dependent kinases 7, 8, and 9 have been shown to regulate transcription through phosphorylation of RNA polymerase II. B-cell lymphoproliferative disorders, including chronic lymphocytic leukemia, rely on the expression of transcripts with a short half-life, such as Mcl-1, Bcl-2, and XIAP, for survival. Here, we describe the characterization of AT7519 in leukemia cell lines, and compare and contrast the response in cell lines derived from solid tumors. Finally, we use these mechanistic insights to show activity in peripheral blood mononuclear cells isolated from 16 chronic lymphocytic leukemia patients. AT7519 induced apoptosis at concentrations of 100 to 700 nmol/L and was equally effective regardless of Rai stage or known prognostic markers. Short-term treatments (4-6 hours) resulted in inhibition of phosphorylation of the transcriptional marker RNA polymerase II and downregulation of the antiapoptotic protein Mcl-1, with no effect on either XIAP or Bcl-2 levels. The reduction in Mcl-1 protein level was associated with an increase in cleaved poly(ADP-ribose) polymerase. Together the data suggest AT7519 offers a promising treatment for patients with advanced B-cell leukemia. Mol Cancer Ther; 9(4); 920–8. ©2010 AACR.
TAF4b and Jun/Activating Protein-1 Collaborate to Regulate the Expression of Integrin α6 and Cancer Cell Migration Properties
Authors: Kalogeropoulou Margarita , Voulgari Angeliki , Kostourou Vassiliki , Sandaltzopoulos Raphael , Dikstein Rivka , Davidson Irwin , Tora Laszlo , Pintzas Alexander
Published: March 2010

The TAF4b subunit of the transcription factor IID, which has a central role in transcription by polymerase II, is involved in promoter recognition by selective recruitment of activators. The activating protein-1 (AP-1) family members participate in oncogenic transformation via gene regulation. Utilizing immunoprecipitation of endogenous protein complexes, we documented specific interactions between Jun family members and TATA box binding protein–associated factors (TAF) in colon HT29 adenocarcinoma cells. Particularly, TAF4b and c-Jun were found to colocalize and interact in the nucleus of advanced carcinoma cells and in cells with epithelial-to-mesenchymal transition (EMT) characteristics. TAF4b was found to specifically regulate the AP-1 target gene involved in EMT integrin α6, thus altering related cellular properties such as migration potential. Using a chromatin immunoprecipitation approach in colon adenocarcinoma cell lines, we further identified a synergistic role for TAF4b and c-Jun and other AP-1 family members on the promoter of integrin α6, underlining the existence of a specific mechanism related to gene expression control. We show evidence for the first time of an interdependence of TAF4b and AP-1 family members in cell type–specific promoter recognition and initiation of transcription in the context of cancer progression and EMT. Mol Cancer Res; 8(4); 554–68. ©2010 AACR.
The MicroRNA Profile of Prostate Carcinoma Obtained by Deep Sequencing
Authors: Szczyrba Jaroslaw , Löprich Elke , Wach Sven , Jung Volker , Unteregger Gerhard , Barth Stephanie , Grobholz Rainer , Wieland Wolf , Stöhr Robert , Hartmann Arndt , Wullich Bernd , Grässer Friedrich
Published: March 2010

Prostate cancer is a leading cause of tumor mortality. To characterize the underlying molecular mechanisms, we have compared the microRNA (miRNA) profile of primary prostate cancers and noncancer prostate tissues using deep sequencing. MiRNAs are small noncoding RNAs of 21 to 25 nucleotides that regulate gene expression through the inhibition of protein synthesis. We find that 33 miRNAs were upregulated or downregulated >1.5-fold. The deregulation of selected miRNAs was confirmed by both Northern blotting and quantitative reverse transcription-PCR in established prostate cancer cell lines and clinical tissue samples. A computational search indicated the 3′-untranslated region (UTR) of the mRNA for myosin VI (MYO6) as a potential target for both miR-143 and miR-145, the expression of which was reduced in the tumor tissues. Upregulation of myosin VI in prostate cancer was previously shown by immunohistochemistry. The level of MYO6 mRNA was significantly induced in all primary tumor tissues compared with the nontumor tissue from the same patient. This finding was matched to the upregulation of myosin VI in established prostate cancer cell lines. In luciferase reporter analysis, we find a significant negative regulatory effect on the MYO6 3′UTR by both miR-143 and miR-145. Mutation of the potential binding sites for miR-143 and miR-145 in the MYO6 3′UTR resulted in a loss of responsiveness to the corresponding miRNA. Our data indicate that miR-143 and miR-145 are involved in the regulation of MYO6 expression and possibly in the development of prostate cancer. Mol Cancer Res; 8(4); 529–38. ©2010 AACR.
Fiberoptic Resonance Raman Spectroscopy to Measure Carotenoid Oxidative Breakdown in Live Tissues
Authors: Bentz Brandon G. , Diaz Jason , Ring Terry A. , Wade Mark , Kennington Konrad , Burnett David M. , McClane Robert , Fitzpatrick Frank A.
Published: March 2010

Based on compelling epidemiologic and corroboratory in vitro studies, carotenoids are thought to have great potential as dietary prevention against cancer. Yet, carotenoid-based chemopreventive trials have found very contradictory results. Definitive conclusions from these trials are hampered by an inability to accurately and safely measure carotenoids in specific tissues at risk of cancer development. Raman spectroscopy has been proposed as an optical technology with which to analyze various molecules in live tissues. One major obstacle that impedes the clinical use of this powerful technology is the lack of a fiberoptic Raman probe suitable for endoscopic tissue evaluation. A single-fiber resonance Raman Spectroscope capable of noninvasive “optical biopsies” to measure carotenoid concentrations in live tissues has been developed. The accuracy of this Raman instrument was confirmed by comparison with more standard methods of spectrophotometry and high-pressure liquid chromatography using solubilized β-carotene (BC) and BC-loaded cells before use in a small patient cohort. This Raman instrument detected intact BC as well as BC oxidative breakdown as a decrement of its Raman signal in cells. Use of the Raman instrument in our small cohort study showed its feasibility for measuring human tissues and raised some potentially intriguing possibilities about BC tissue pharmacokinetics and oxidative biology. Based on these results, our newly developed single fiberoptic resonance Raman instrument may provide a very useful method of measuring carotenoids and their oxidative breakdown within live tissue during future carotenoid chemopreventive trials. This proof-of-concept study provides the foundation to justify future validation of our Raman prototype. Cancer Prev Res; 3(4); 529–38. ©2010 AACR.
Knockout of the Tumor Suppressor Gene Gprc5a in Mice Leads to NF-κB Activation in Airway Epithelium and Promotes Lung Inflammation and Tumorigenesis
Authors: Deng Jiong , Fujimoto Junya , Ye Xiao-Feng , Men Tao-Yan , Van Pelt Carolyn S. , Chen Yu-Long , Lin Xiao-Feng , Kadara Humam , Tao Qingguo , Lotan Dafna , Lotan Reuben
Published: March 2010

Mouse models can be useful for increasing the understanding of lung tumorigenesis and assessing the potential of chemopreventive agents. We explored the role of inflammation in lung tumor development in mice with knockout of the tumor suppressor Gprc5a. Examination of normal lung tissue and tumors from 51 Gprc5a+/+ (adenoma incidence, 9.8%; adenocarcinoma, 0%) and 38 Gprc5a−/− mice (adenoma, 63%; adenocarcinoma, 21%) revealed macrophage infiltration into lungs of 45% of the Gprc5a−/− mice and 8% of Gprc5a+/+ mice and the direct association of macrophages with 42% of adenomas and 88% of adenocarcinomas in the knockout mice. Gprc5a−/− mouse lungs contained higher constitutive levels of proinflammatory cytokines and chemokines and were more sensitive than lungs of Gprc5a+/+ mice to stimulation of NF-κB activation by lipopolysaccharide in vivo. Studies with epithelial cells cultured from tracheas of Gprc5a−/− and Gprc5a+/+ mice revealed that Gprc5a loss is associated with increased cell proliferation, resistance to cell death in suspension, and increased basal, tumor necrosis factor α–induced, and lipopolysaccharide-induced NF-κB activation, which were reversed partially in Gprc5a−/− adenocarcinoma cells by reexpression of Gprc5a. Compared with Gprc5a+/+ cells, the Gprc5a−/− cells produced higher levels of chemokines and cytokines and their conditioned medium induced more extensive macrophage migration. Silencing Gprc5a and the p65 subunit of NF-κB in Gprc5a+/+ and Gprc5a−/− cells, respectively, reversed these effects. Thus, Gprc5a loss enhances NF-κB activation in lung epithelial cells, leading to increased autocrine and paracrine interactions, cell autonomy, and enhanced inflammation, which may synergize in the creation of a tumor-promoting microenvironment. Cancer Prev Res; 3(4); 424–37. ©2010 AACR.
Management of Congenital Bile Duct Cysts
Authors: Mabrut Jean-Yves , Bozio Guillaume , Hubert Catherine , Gigot Jean-François
Published: March 2010

Bile duct cysts (BDC) are rare congenital anomalies of the biliary tree that are characterized by cystic dilatation of the extrahepatic and/or intrahepatic bile ducts. Presence of an anomalous bilio-pancreatic junction allowing pancreatic juice to reflux into the biliary tree is the most widely aetiopathogenic concept currently accepted. BDC are associated with biliary stasis and lithiasis, and the whole biliary epithelium is considered at risk of malignant transformation. Magnetic resonance cholangio-pancreatography is currently the most accurate preoperative imaging study to assess cyst anatomy and classify the disease according to the standard Todani classification. Complete cyst excision with cholecystectomy followed by biliary reconstruction using a Roux-en-Y hepatico-jejunostomy is the treatment of choice for the extrahepatic component of the disease (type I and IV BDC), but cystic involvement up to the roof of the main biliary convergence represents a real surgical challenge to perform complete resection. The optimal treatment of intrahepatic bile duct dilatations remains controversial, especially for type IV-A BDC. In type V BDC (Caroli’s disease), extent of the liver resection is tailored to intrahepatic disease extent and takes into consideration the presence and severity of underlying chronic liver (congenital hepatic fibrosis) and kidney disease. Late postoperative cholangitis secondary to intrahepatic strictures and lithiasis, as well as the risk of metachronous cholangiocarcinoma that can occur throughout the whole biliary tree even after complete cyst excision, represent serious complications justifying careful long-term follow-up.
Management of Ruptured Hepatocellular Adenoma
Authors: Huurman Volkert A.L. , Schaapherder Alexander F.M.
Published: March 2010

Hepatocellular adenoma (HA) is an increasingly prevalent benign liver tumor that is strongly associated with use of oral contraceptive medication. The diagnosis is often made after abdominal imaging in female patients with sudden abdominal pain, with or without signs of hemorrhage. Especially larger adenomas are of potential hazard to patients, because of the increased likelihood of rupture or malignant degeneration. Standard treatment of larger adenomas has since long consisted in surgical resection, both for non-ruptured and for ruptured tumors. Although resection is still considered the gold standard, recent reports have advocated initial conservative management. Recently, newer and less invasive methods using selective transarterial embolization have been described that can successfully stop bleeding and even lead to tumor regression. This review addresses different treatment options and recent advances regarding this relatively new condition, focusing mainly on treatment of bleeding and ruptured tumors in an acute setting. A possible algorithm for optimal treatment is presented.
Liver Transplantation for Benign Hepatic Tumors: A Systematic Review
Authors: Ercolani Giorgio , Grazi Gian Luca , Pinna Antonio Daniele
Published: March 2010

Orthotopic liver transplantation (OLT) has been performed for several benign hepatic tumors. Most of these diseases are usually managed conservatively, or treated by liver resection. OLT might be required when the lesions are symptomatic, diffuse in hepatic parenchyma, causing life-threatening complications or malignant transformation cannot be ruled out. Polycystic liver disease is the most common indication for OLT. We present a review of transplantable benign hepatic lesions to evaluate the need of OLT for these diseases, to summarize in which OLT is a good therapeutic option, and to show the early and long-term survival which might be expected.
Dopamine D2 Receptor Genotype (C957T) and Habitual Consumption of Sugars in a Free-Living Population of Men and Women
Authors: Eny Karen M. , Corey Paul N. , El-Sohemy Ahmed
Published: March 2010

Background/Aims: The dopamine D2 receptor (DRD2) has been implicated in modulating the rewarding effects of foods high in sugar. The purpose of this study was to determine whether a variation in the DRD2 gene affects habitual consumption of sugars in a free-living population. Methods: Caucasian men (n = 96) and women (n = 217) 20–29 years of age completed a 1-month food frequency questionnaire and were genotyped for the C957T polymorphism in the DRD2 gene. Analyses of covariance with post-hoc Tukey tests were used to compare nutrient intakes between genotypes adjusting for potential confounders. Results: Among men, consumption of sucrose was 60 ± 6, 48 ± 4, and 39 ± 5 g/day for those with the CC, CT and TT genotypes, respectively, with a significant difference between the homozygotes (p = 0.03), suggesting an additive mode of inheritance. Among women, sucrose consumption was 42 ± 4, 53 ± 2, and 44 ± 4 g/day for the CC, CT and TT genotypes, respectively, with CC and CT differing significantly (p = 0.02), suggesting a partial heterosis mode of inheritance. No differences were observed for protein or fat. Conclusions: These findings suggest that genetic variation in DRD2 influences food selection and may explain some of the interindividual differences in sugar consumption.
C-Peptide as a Therapeutic Tool in Diabetic Nephropathy
Authors: Hills Claire E. , Brunskill Nigel J. , Squires Paul E.
Published: March 2010

Background/Aims: Insulin is synthesised as a pro-hormone with an interconnecting C-peptide, cleaved during post-translational modification. This review discusses growing evidence which indicates that C-peptide is biologically active, benefiting microvascular complications associated with diabetes. Methods: To explore the renoprotective role of C-peptide in diabetic nephropathy (DN), we reviewed the literature using PubMed for English language articles that contained key words related to C-peptide, kidney and DN. Results: Numerous studies have demonstrated that C-peptide ameliorates a number of the structural and functional renal disturbances associated with uncontrolled hyperglycaemia in human and animal models of type 1 diabetes mellitus that lead to the development and progression of nephropathy, including abrogation of glomerular hyperfiltration, reduced microalbuminuria, decreased mesangial expansion and increased endothelial nitric oxide synthase levels. The in vitro exposure of kidney proximal tubular cells to physiological concentrations of C-peptide activates extracellular signal-regulated kinase, phosphatidylinositol 3-kinase, protein kinase C, elevates intracellular calcium, and stimulates transcription factors NF-ĸB and peroxisome proliferator-activated receptor-γ. Conclusion: Burgeoning studies suggest that C-peptide is more than merely a link between the A and B chains of the proinsulin molecule and represents a future therapeutic tool in reducing complications of DN.
Hepatitis E Virus Infection: A General Review with a Focus on Hemodialysis and Kidney Transplant Patients
Authors: Hosseini-Moghaddam Seyed Mohammadmehdi , Zarei Afagh , Alavian Seyed Moayed , Mansouri Mehdi
Published: March 2010

Background: Hepatitis E virus (HEV) infection is a self-limited viral disease that causes acute hepatitis epidemics in developing countries. The common route of transmission for HEV is supposedly fecal-oral. Serological evidence may be unexpectedly found in hemodialysis (HD) patients and kidney transplant recipients. Although the route of HEV transmission is not usually determined in HD subjects, this virus seems to be transmitted either directly through HD or nosocomially. In this study, we gathered the published information on HEV infection in HD patients and kidney transplant recipients. Methods: For this review, we collected the relevant articles by searching through Medline and Google Scholar from January 1980 up to September 2009. Results: Some variables including older age, low education, living in rural versus urban areas and the duration of HD seem to be risk factors for HEV infection in HD patients. Compared with non-HD subjects, HEV infection may be specifically associated with poor outcome in HD patients. Specific considerations seem to be required to prevent transmission of HEV to HD patients. Conclusion: More extensive investigations are required to determine the disease burden of HEV infection in HD subjects in countries which experience outbreaks of HEV infection.
Feasible and Successful: Genome-Wide Interaction Analysis Involving All 1.9 × 1011 Pair-Wise Interaction Tests
Authors: Steffens Michael , Becker Tim , Sander Thomas , Fimmers Rolf , Herold Christine , Holler Daniela A. , Leu Costin , Herms Stefan , Cichon Sven , Bohn Bastian , Gerstner Thomas , Griebel Michael , Nöthen Markus M. , Wienker Thomas F. , Baur Max P.
Published: March 2010

The Genome-Wide Association Study (GWAS) is the study design of choice for detecting common genetic risk factors for multifactorial diseases. The performance of full Genome-Wide Interaction Analyses (GWIA) has always been considered computationally challenging. Two-stage strategies to reduce the amount of numerical analysis require the detection of single marker effects or prior pathophysiological hypotheses before the analysis of interaction. This prevents the detection of pure epistatic effects. Our case-control study in idiopathic generalized epilepsy demonstrates that a full GWIA is feasible through use of data compression, specific data representation, interleaved data organization, and parallelization of the analysis on a multi-processor system. Following extensive quality control of the genotypes, our final list of top interaction hits contains only pairs of interacting SNPs with negligible marginal effects. The TOP HIT interaction was between a SNP-pair intragenic to gene DNER (chr 2) and gene CTNNA3 (chr 10). Both of these genes are functionally involved in neuronal migration, synaptogenesis, and the formation of neuronal circuits. Our results therefore indicate a possible interaction between these two genes in epileptogenesis. Results from GWAS are beginning to reveal a ‘missing heritability’ in complex traits and diseases. Systematic, hypothesis-free analysis of epistatic interaction (GWIA) may help to close this increasingly recognized gap in heritability.
Airborne Fungi Induce Nasal Polyp Epithelial Cell Activation and Toll-Like Receptor Expression
Authors: Shin Seung-Heon , Lee Young-Ho
Published: March 2010

Background: The nasal epithelium is the first barrier encountered by airborne allergens and is an active participant in airway inflammation. Fungi have been increasingly recognized as important pathogens in sinusitis and airway diseases. The aim of the study was to evaluate fungal protease activity during cytokine production in nasal polyp epithelial cells and to determine the expression of Toll-like receptor (TLR) mRNA by fungi. Methods: Nasal polyp epithelial cells were obtained from patients and stimulated with Alternaria and Aspergillus. Interleukin-8 (IL-8) and granulocyte macrophage colony-stimulating factor (GM-CSF) were measured to determine the activation of epithelial cells. Reverse transcriptase polymerase chain reaction for the TLR mRNA expression of the nasal epithelial cells was performed. Cytokine production was inhibited with protease inhibitors and anti-human TLR antibodies. Results: The fungi enhanced the production of IL-8 and GM-CSF from nasal epithelial cells. When nasal epithelial cells were activated by the fungi, TLR2, TLR3 and TLR4 mRNAs were more strongly expressed than in the nonactivated cells. Cytokine production was inhibited by protease inhibitors and anti-human TLR4 antibodies. Conclusions: The results of this study showed that fungi interacted with nasal epithelial cells and enhanced the production of cytokines and TLR mRNA expression. The cytokine production was related to the protease in fungi and TLR4.