bluuebunny/crossref_metadata_2025 huggingface dataset:
Unique Centipede Mechanism of Mycoplasma Gliding
Authors: Miyata Makoto
Published: June 2010

Mycoplasma, a genus of pathogenic bacteria, forms a membrane protrusion at a cell pole. It binds to solid surfaces with this protrusion and then glides. The mechanism is not related to known bacterial motility systems, such as flagella or pili, or to conventional motor proteins, including myosin. We have studied the fastest species, Mycoplasma mobile, and have proposed a working model as follows. The gliding machinery is composed of four huge proteins at the base of the membrane protrusion and supported by a cytoskeletal architecture from the cell inside. Many flexible legs approximately 50 nm long are sticking out from the machinery. The movements generated by the ATP hydrolysis cell inside are transmitted to the “leg” protein through a “gear” protein, resulting in repeated binding, pull, and release of the sialylgalactose fixed on the surface by the legs. The gliding of Mycoplasma pneumoniae, a species distantly related to M. mobile, is also discussed.
Mitochondrion-Related Organelles in Eukaryotic Protists
Authors: Shiflett April M. , Johnson Patricia J.
Published: June 2010

The discovery of mitochondrion-type genes in organisms thought to lack mitochondria led to the demonstration that hydrogenosomes share a common ancestry with mitochondria, as well as the discovery of mitosomes in multiple eukaryotic lineages. No examples of examined eukaryotes lacking a mitochondrion-related organelle exist, implying that the endosymbiont that gave rise to the mitochondrion was present in the first eukaryote. These organelles, known as hydrogenosomes, mitosomes, or mitochondrion-like organelles, are typically reduced, both structurally and biochemically, relative to classical mitochondria. However, despite their diversification and adaptation to different niches, all appear to play a role in Fe-S cluster assembly, as observed for mitochondria. Although evidence supports the use of common protein targeting mechanisms in the biogenesis of these diverse organelles, divergent features are also apparent. This review examines the metabolism and biogenesis of these organelles in divergent unicellular microbes, with a focus on parasitic protists.
Single-cell analysis of insulin-regulated fatty acid uptake in adipocytes
Authors: Varlamov Oleg , Somwar Romel , Cornea Anda , Kievit Paul , Grove Kevin L. , Roberts Charles T.
Published: June 2010

Increased body fat correlates with the enlargement of average fat cell size and reduced adipose tissue insulin sensitivity. It is currently unclear whether adipocytes, as they accumulate more triglycerides and grow in size, gradually become less insulin sensitive or whether obesity-related factors independently cause both the enlargement of adipocyte size and reduced adipose tissue insulin sensitivity. In the first instance, large and small adipocytes in the same tissue would exhibit differences in insulin sensitivity, whereas, in the second instance, adipocyte size per se would not necessarily correlate with insulin response. To analyze the effect of adipocyte size on insulin sensitivity, we employed a new single-cell imaging assay that resolves fatty acid uptake and insulin response in single adipocytes in subcutaneous adipose tissue explants. Here, we report that subcutaneous adipocytes are heterogeneous in size and intrinsic insulin sensitivity. Whereas smaller adipocytes respond to insulin by increasing lipid uptake, adipocytes with cell diameters larger than 80–100 μm are insulin resistant. We propose that, when cell size approaches a critical boundary, adipocytes lose insulin-dependent fatty acid transport. This negative feedback mechanism may protect adipocytes from lipid overload and restrict further expansion of adipose tissue, which leads to obesity and metabolic complications.
Modulation of Voltage-Gated Ion Channels in Rat Retinal Ganglion Cells Mediated by Somatostatin Receptor Subtype 4
Authors: Farrell Spring R. , Raymond Iona D. , Foote Michael , Brecha Nicholas C. , Barnes Steven
Published: June 2010

Somatostatin (somatotropin release-inhibiting factor [SRIF]) is known to modulate the excitability of retinal ganglion cells, but the membrane mechanisms responsible and the extent to which intracellular calcium signaling is affected have not been determined. We show that somatostatin receptor subtype 4 (sst4) is expressed specifically in rat ganglion cells and that the generation of repetitive action potentials by isolated ganglion cells is reduced in the presence of L-803,087, a selective sst4 agonist (10 nM). Under voltage clamp, L-803,087 increased outward K+ currents by 51.1 ± 13.1% at 0 mV and suppressed Ca2+ channel currents by 32.5 ± 9.4% at −10 mV in whole cell patch-clamped ganglion cells. The N-type Ca2+ channel blocker ω-conotoxin GVIA (CTX, 1 μM) reduced L-type Ca2+ current ( ICa) in ganglion cells by 43.5 ± 7.2% at −10 mV, after which addition of L-803,087 further reduced ICa by 28.0 ± 16.0% . In contrast, ganglion cells treated first with nifedipine (NIF, 10 μM), which blocked 46.1 ± 3.5% of the control current at −10 mV, did not undergo any further reduction in ICa in the presence of L-803,087 (−3.5 ± 3.8% vs. NIF), showing that stimulation of sst4 reduces Ca2+ influx through L-type Ca2+ channels. To assess the effects of sst4 stimulation on intracellular Ca2+ levels ([Ca2+]i) in ganglion cells, fura-2 was used to measure changes in [Ca2+]i in response to depolarization induced by elevated [K+]o. [Ca2+]i was increased to a lesser extent (86%) in the presence of L-803,087 compared with recordings made in the absence of the sst4 agonist and this effect was blocked by NIF (10 μM). Suppression of spiking and Ca2+ signaling via sst4 may contribute to the reported neuroprotective actions of somatostatin and promote ganglion cell survival following ischemia and axonal trauma.
In silico structure-function analysis of pathological variation in the HSD11B2 gene sequence
Authors: Manning Jonathan R. , Bailey Matthew A. , Soares Dinesh C. , Dunbar Donald R. , Mullins John J.
Published: June 2010

11β-Hydroxysteroid dehydrogenase type 2 (11βHSD2) is a short-chain dehydrogenase/reductase (SDR) responsible for inactivating cortisol and preventing its binding to the mineralocorticoid receptor (MR). Nonfunctional mutations in HSD11B2, the gene encoding 11βHSD2, cause the hypertensive syndrome of apparent mineralocorticoid excess (AME). Like other such Mendelian disorders, AME is rare but has nevertheless helped to illuminate principles fundamental to the regulation of blood pressure. Furthermore, polymorphisms in HSD11B2 have been associated with salt sensitivity, a major risk factor for cardiovascular mortality. It is therefore highly likely that sequence variation in HSD11B2, having subtle functional ramifications, will affect blood pressure in the wider population. In this study, a three-dimensional homology model of 11βHSD2 was created and used to hypothesize the functional consequences in terms of protein structure of published mutations in HSD11B2. This approach underscored the strong genotype-phenotype correlation of AME: severe forms of the disease, associated with little in vivo enzyme activity, arise from mutations occurring in invariant alignment positions. These were predicted to exert gross structural changes in the protein. In contrast, those mutations causing a mild clinical phenotype were in less conserved regions of the protein that were predicted to be relatively more tolerant to substitution. Finally, a number of pathogenic mutations are shown to be associated with regions predicted to participate in dimer formation, and in protein stabilization, which may therefore suggest molecular mechanisms of disease.
Intraspecific Variation in a Scorpionfly Newly Recorded from Texas and the State of Taxonomy of North American Panorpidae (Mecoptera)
Authors: Jones Joshua R.
Published: June 2010

Panorpa vernalisByers is recorded for the first time from Texas, and represents only the second species ofPanorpadocumented from the state. Intraspecific variations between the Texas specimens and Byers' original description are discussed. A synopsis of the principal modern keys for identification of North AmericanPanorpais provided, and an argument for a modern taxonomic review of the Panorpidae of North America is presented.
Nonconvex Optimization of Collaborative Multiband Spectrum Sensing for Cognitive Radios with Genetic Algorithms
Authors: Sanna Michele , Murroni Maurizio
Published: June 2010

Cognitive Radio (CR) is a novel technology that permits secondary users (SUs) to transmit alongside primary users (PUs). PUs retain transparent communications whereas SUs perform spectrum sensing and adaptive transmission to avoid collisions. Ultra-wideband sensing is of primary importance for SU to sense and access opportunistically several bands at a time. Reliable detection in wide geographical regions needs collaborative sensing. Optimal collaborative multiband sensing is not analytically solvable unless some approximations and solution domain restrictions are applied for convexity exploitation. In this paper, we demonstrate that convex constraints are deleterious. We propose an alternative optimization technique based on genetic algorithms. Genetic programming performs a direct search of the optimal solution without approximations and solution domain restrictions. As a consequence, collaborative multiband sensing can be consistently optimized without limitations. Additionally the genetic optimization exploits the correlation of time-varying channels for fast adaptive convergence.
A Hybrid Proximal Point Three-Step Algorithm for Nonlinear Set-Valued Quasi-Variational Inclusions System Involving "Equation missing" -Accretive Mappings
Authors: Li Hong-Gang , Xu AnJian , Jin MaoMing
Published: June 2010

The main purpose of this paper is to introduce and study a new class of generalized nonlinear set-valued quasi-variational inclusions system involving "Equation missing"-accretive mappings in Banach spaces. By using the resolvent operator due to Lan-Cho-Verma associated with "Equation missing"-accretive mappings and the matrix analysis method, we prove the convergence of a new hybrid proximal point three-step iterative algorithm for this system of set-valued variational inclusions and an existence theorem of solutions for this kind of the variational inclusions system. The results presented in this paper generalize, improve, and unify some recent results in this field.
Totally Laparoscopic Gastrectomy for Gastric Cancer Associated with Recklinghausen's Disease
Authors: Sakaguchi Yoshihisa , Ikeda Osamu , Ohgaki Kippei , Oki Eiji , Chinen Yoshiki , Sakamoto Yasuo , Minami Kazuhito , Toh Yasushi , Okamura Takeshi
Published: June 2010

This paper documents the first case of gastric cancer associated with Recklinghausen's disease, which was successfully treated by a totally laparoscopic operation. A 67-year-old woman with Recklinghausen's disease was referred to this department to undergo surgical treatment for early gastric cancer. The physical examination showed multiple cutaneous neurofibromas throughout the body surface, which made an upper abdominal incision impossible. Laparoscopic surgery requiring only small incisions was well indicated, and a totally laparoscopic distal gastrectomy with lymph node dissection was performed. Billroth I reconstruction was done intra-abdominally using a delta-shaped anastomosis. The patient followed a satisfactory postoperative course with no complications. Since the totally laparoscopic gastrectomy has many advantages over open surgery, it should therefore be preferentially used as a less invasive treatment in the field of gastric cancer.
Significant Growth Inhibition of Canine Mammary Carcinoma Xenografts following Treatment with Oncolytic Vaccinia Virus GLV-1h68
Authors: Gentschev Ivaylo , Ehrig Klaas , Donat Ulrike , Hess Michael , Rudolph Stephan , Chen Nanhai , Yu Yong A. , Zhang Qian , Bullerdiek Jörn , Nolte Ingo , Stritzker Jochen , Szalay Aladar A.
Published: June 2010

Canine mammary carcinoma is a highly metastatic tumor that is poorly responsive to available treatment. Therefore, there is an urgent need to identify novel agents for therapy of this disease. Recently, we reported that the oncolytic vaccinia virus GLV-1h68 could be a useful tool for therapy of canine mammary adenomain vivo. In this study we analyzed the therapeutic effect of GLV-1h68 against canine mammary carcinoma. Cell culture data demonstrated that GLV-1h68 efficiently infected and destroyed cells of the mammary carcinoma cell line MTH52c. Furthermore, after systemic administration, this attenuated vaccinia virus strain primarily replicated in canine tumor xenografts in nude mice. Finally, infection with GLV-1h68 led to strong inflammatory and oncolytic effects resulting in significant growth inhibition of the tumors. In summary, the data showed that the GLV-1h68 virus strain has promising potential for effective treatment of canine mammary carcinoma.
Neuroinvasion in Prion Diseases: The Roles of Ascending Neural Infection and Blood Dissemination
Authors: Sisó Sílvia , González Lorenzo , Jeffrey Martin
Published: June 2010

Prion disorders are infectious, neurodegenerative diseases that affect humans and animals. Susceptibility to some prion diseases such as kuru or the new variant of Creutzfeldt-Jakob disease in humans and scrapie in sheep and goats is influenced by polymorphisms of the coding region of the prion protein gene, while other prion disorders such as fatal familial insomnia, familial Creutzfeldt-Jakob disease, or Gerstmann-Straussler-Scheinker disease in humans have an underlying inherited genetic basis. Several prion strains have been demonstrated experimentally in rodents and sheep. The progression and pathogenesis of disease is influenced by both genetic differences in the prion protein and prion strain. Some prion diseases only affect the central nervous system whereas others involve the peripheral organs prior to neuroinvasion. Many experiments undertaken in different species and using different prion strains have postulated common pathways of neuroinvasion. It is suggested that prions access the autonomic nerves innervating peripheral organs and tissues to finally reach the central nervous system. We review here published data supporting this view and additional data suggesting that neuroinvasion may concurrently or independently involve the blood vascular system.
Aspect of Dynamic Simulation and Experimental Research Studies on Hybrid Pneumatic Power System
Authors: Huang K. David , Nguyen Hoai-Nam
Published: June 2010

A Hybrid Pneumatic Power System (HPPS) has been developed for several years with the major aim of reducing the vehicle fuel consumption, environment pollution and enhancing the vehicle performance as well. Comparing with the conventional hybrid system, HPPS replaces the battery's electrochemical energy with a high-pressure air storage tank and enables the internal combustion engine (ICE) to function at its sweet spot. Besides, the HPPS, which effectively merges both the high-pressure air flow from the storage tank and the recycled exhaust flow from the ICE, thereby increases the thermal efficiency of the ICE and transforms the merged flow energy into mechanical energy using a high-efficiency turbine. This paper focuses on the major research process into HPPSs, including overall dynamic simulation and experimental validation. By using the simulation tool ITI-Sim, this research demonstrates an experiment which can be operated precisely according to the requirements of various driving conditions under which a car actually runs on the road in accordance with the regulated running vehicle test mode. HPPS is expected to increase the performance of the entire system from 15% to 39%, and is likely to replace the traditional system in the coming years.
Solution of the Dynamic Interaction Problem between a Framed Structure and an Acoustic Cavity Using Imposed Deformation Functions at the Interface
Authors: Ribeiro Paulo Marcelo Vieira , Pedroso Lineu José
Published: June 2010

This article presents an analytical procedure for solution of the dynamic interaction problem of a vibrating framed structure connected to a bidimensional cavity, containing an acoustic fluid. Initially the pressure solution for the fluid domain is developed, using the separation of variables technique. In a next step, this solution is applied to an entirely open cavity and to a closed cavity in the transversal direction, both containing a vibrating boundary with an arbitrary deformation. The generalized parameters of the structure (mass, rigidity, and force) are obtained by means of the virtual work principle, with the generalized force represented by the dynamic pressures acting on the interface. The dynamic equilibrium equation of the system is established for an imposed deformation, making a parametric study of the involved variables possible. Finally, it is demonstrated that this procedure can be generalized, allowing the construction of practical abacuses for other boundary conditions of both the structure and the cavity, and that these results allow a reasonable interpretation of the coupling regions, including the prediction of added mass and added stiffness effects, as well as corresponding frequencies and mode shapes of the coupled problem.
On a Max‐Type Difference Inequality and Its Applications
Authors: Stević Stevo , Iričanin Bratislav D.
Published: June 2010

We prove a useful max‐type difference inequality which can be applied
in studying of some max‐type difference equations and give an application
of it in a recent problem from the research area. We also give a representation
of solutions of the difference equation .
Tetraspanin CD151 Regulates Transforming Growth Factor β Signaling: Implication in Tumor Metastasis
Authors: Sadej Rafał , Romanska Hanna , Kavanagh Dean , Baldwin Gouri , Takahashi Takashi , Kalia Neena , Berditchevski Fedor
Published: June 2010

Tetraspanin CD151 is associated with laminin-binding integrins and controls tumor cell migration and invasion. By analyzing responses of breast cancer cells to various growth factors, we showed that depletion of CD151 specifically attenuates transforming growth factor β1 (TGFβ1)–induced scattering and proliferation of breast cancer cells in three-dimensional Matrigel. CD151-dependent cell scattering requires its association with either α3β1 or α6 integrins, but it is independent of the recruitment of CD151 to tetraspanin-enriched microdomains. We also found that CD151 regulates the compartmentalization of TGF-β type I receptor (TβRI/ALK-5) and specifically controls the TGFβ1-induced activation of p38. In contrast, signaling leading to activation of Smad2/3, c-Akt, and Erk1/2 proteins was comparable in CD151(+) and CD151(−) cells. Attenuation of TGFβ1-induced responses correlated with reduced retention in the lung vascular bed, inhibition of pneumocyte-induced scattering of breast cancer cells in three-dimensional Matrigel, and decrease in experimental metastasis to the lungs. These results identify CD151 as a positive regulator of TGFβ1-initiated signaling and highlight the important role played by this tetraspanin in TGFβ1-induced breast cancer metastasis. Cancer Res; 70(14); 6059–70. ©2010 AACR.
Compensatory Upregulation of Tyrosine Kinase Etk/BMX in Response to Androgen Deprivation Promotes Castration-Resistant Growth of Prostate Cancer Cells
Authors: Dai Bojie , Chen Hege , Guo Shengjie , Yang Xi , Linn Douglas E. , Sun Feng , Li Wei , Guo Zhiyong , Xu Kexin , Kim Oekyung , Kong Xiangtian , Melamed Jonathan , Qiu Shaopeng , Chen Hegang , Qiu Yun
Published: June 2010

We previously showed that targeted expression of non–receptor tyrosine kinase Etk/BMX in mouse prostate induces prostate intraepithelial neoplasia, implying a possible causal role of Etk in prostate cancer development and progression. Here, we report that Etk is upregulated in both human and mouse prostates in response to androgen ablation. Etk expression seems to be differentially regulated by androgen and interleukin 6 (IL-6), which is possibly mediated by the androgen receptor (AR) in prostate cancer cells. Our immunohistochemical analysis of tissue microarrays containing 112 human prostate tumor samples revealed that Etk expression is elevated in hormone-resistant prostate cancer and positively correlated with tyrosine phosphorylation of AR (Pearson correlation coefficient ρ = 0.71, P < 0.0001). AR tyrosine phosphorylation is increased in Etk-overexpressing cells, suggesting that Etk may be another tyrosine kinase, in addition to Src and Ack-1, which can phosphorylate AR. We also showed that Etk can directly interact with AR through its Src homology 2 domain, and such interaction may prevent the association of AR with Mdm2, leading to stabilization of AR under androgen-depleted conditions. Overexpression of Etk in androgen-sensitive LNCaP cells promotes tumor growth while knocking down Etk expression in hormone-insensitive prostate cancer cells by a specific shRNA that inhibits tumor growth under androgen-depleted conditions. Taken together, our data suggest that Etk may be a component of the adaptive compensatory mechanism activated by androgen ablation in prostate and may play a role in hormone resistance, at least in part, through direct modulation of the AR signaling pathway. Cancer Res; 70(13); 5587–96. ©2010 AACR.
Characterization of a Novel Mechanism of Genomic Instability Involving the SEI1/SET/NM23H1 Pathway in Esophageal Cancers
Authors: Li Yan , Nie Chang-Jun , Hu Liang , Qin Yanru , Liu Hai-bo , Zeng Ting-Ting , Chen Leilei , Fu Li , Deng Wen , Chen Shu-Peng , Jia Wei-Hua , Zhang Chunyu , Xie Dan , Guan Xin-Yuan
Published: June 2010

Amplification of 19q is a frequent genetic alteration in many solid tumors, and SEI1 is a candidate oncogene within the amplified region. Our previous study found that the oncogenic function of SEI1 was associated with chromosome instability. In this study, we report a novel mechanism of genomic instability involving the SEI1-SET-NM23H1 pathway. Overexpression of SEI1 was observed in 57 of 100 of esophageal squamous cell carcinoma cases. Functional study showed that SEI1 had strong tumorigenic ability, and overexpression of SEI1 could induce the genomic instability by increasing micronuclei formation and reducing the number of chromosomes. Further study found that SEI1 was able to upregulate SET expression and subsequently promote the translocation of a small amount of NM23H1 from the cytoplasm to the nucleus. Nuclear NM23H1 can induce DNA damage through its DNA nick activity. Unlike CTL attack, only a small amount of NM23H1 translocated into the nucleus (<10%) induced by the overexpression of SEI1. Further study found that the small amount of NM23H1 only induced minor DNA damage and subsequently increased genomic instability, rather than inducing irreparable DNA damage and initiating apoptosis by CTL attack. Sister chromatid exchange experiment found that the translocation of small amount of NM23H1 into the nucleus induced by the overexpressions of SEI1/SET could increase the frequency of sister chromatid exchange. In addition, overexpression of SEI1 was associated with poor prognosis of esophageal squamous cell carcinoma. Taken together, these findings define a novel mechanism of genomic instability and malignant progression in esophageal cancers, a deadly disease of increasing incidence in developed countries. Cancer Res; 70(14); 5695–705. ©2010 AACR.
Alternatively Spliced RAGEv1 Inhibits Tumorigenesis through Suppression of JNK Signaling
Authors: Kalea Anastasia Z. , See Fiona , Harja Evis , Arriero Maria , Schmidt Ann Marie , Hudson Barry I.
Published: June 2010

Receptor for advanced glycation end products (RAGE) and its ligands are overexpressed in multiple cancers. RAGE has been implicated in tumorigenesis and metastasis, but little is known of the mechanisms involved. In this study, we define a specific functional role for an alternate splice variant termed RAGE splice variant 1 (RAGEv1), which encodes a soluble endogenous form of the receptor that inhibits tumorigenesis. RAGEv1 was downregulated in lung, prostate, and brain tumors relative to control matched tissues. Overexpressing RAGEv1 in tumor cells altered RAGE ligand stimulation of several novel classes of genes that are critical in tumorigenesis and metastasis. Additionally, RAGEv1 inhibited tumor formation, cell invasion, and angiogenesis induced by RAGE ligand signaling. Analysis of signal transduction pathways underlying these effects revealed marked suppression of c-jun-NH2-kinase (JNK) pathway signaling, and JNK inhibition suppressed signaling through the RAGE pathway. Tumors expressing RAGEv1 were significantly smaller than wild-type tumors and displayed prominently reduced activation of JNK. Our results identify RAGEv1 as a novel suppressor, the study of which may offer new cancer therapeutic directions. Cancer Res; 70(13); 5628–38. ©2010 AACR.
The Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Vatalanib and Pazopanib Potently Induce Apoptosis in Chronic Lymphocytic Leukemia Cells In vitro and In vivo
Authors: Paesler Julian , Gehrke Iris , Gandhirajan Rajesh Kumar , Filipovich Alexandra , Hertweck Magdalena , Erdfelder Felix , Uhrmacher Sabrina , Poll-Wolbeck Simon Jonas , Hallek Michael , Kreuzer Karl-Anton
Published: June 2010

Purpose: There is evidence that vascular endothelial growth factor (VEGF) is a critical microenvironmental factor that exerts angiogenesis-independent effects on the survival of chronic lymphocytic leukemia (CLL) cells. Vatalanib and pazopanib are potent orally available VEGF receptor tyrosine kinase inhibitors. We investigated the efficacy and selectivity of both compounds in CLL cells, simulated potential combination with conventional cytostatics, and tested the effect of both substances on CLL-like tumor xenografts.

Experimental Design: Primary CLL and normal peripheral blood cells were tested for viability after incubation with varying concentrations of both inhibitors. Further, phosphorylation status of VEGF receptor on treatment, caspase activation, and poly(ADP-ribose) polymerase cleavage were assessed. Combinations of each inhibitor with fludarabine, vincristine, and doxorubicin were analyzed for possible synergistic effects in vitro. For in vivo testing, mice grafted with the CLL-like cell line JVM-3 were treated orally with each inhibitor.

Results: Vatalanib and pazopanib decreased phosphorylation of the VEGF receptor, along with induction of apoptosis in CLL cells in clinically achievable concentrations. Healthy B cells were only mildly affected. Immunoblots showed downregulation of the antiapoptotic proteins XIAP and MCL1, whereas poly(ADP-ribose) polymerase cleavage was increased. Combinations with conventional cytostatic agents resulted in synergistic effects. Treatment of xenografted mice with 100 mg/kg of body weight for 21 days resulted in tumor inhibition rates of 76% (vatalanib) and 77% (pazopanib). In two mice, a total tumor eradication could be observed. No gross systemic toxicity occurred.

Conclusion: We conclude that VEGF inhibition is a promising new therapeutic approach in CLL. Vatalanib and pazopanib seem to be effective and safe candidates to be further evaluated for this purpose. Clin Cancer Res; 16(13); 3390–8. ©2010 AACR.
ADAM-17: A Target to Increase Chemotherapeutic Efficacy in Colorectal Cancer?
Authors: Lee Adam M. , Diasio Robert B.
Published: June 2010

Chemotherapy-induced activation of ADAM-17 results in increased growth factor shedding and activation of growth factor receptor-mediated pro-survival response. Enhanced ADAM-17 activity and HER ligand shedding results in resistance to chemotherapy in CRC. Therapies that decrease ADAM-17 activity in conjunction with current treatments may enhance response rates in advanced CRC patients. Clin Cancer Res; 16(13); 3319–21. ©2010 AACR.
Telomerase as an Important Target of Androgen Signaling Blockade for Prostate Cancer Treatment
Authors: Liu Shuang , Qi Yanfeng , Ge Yubin , Duplessis Tamika , Rowan Brian G. , Ip Clement , Cheng Helen , Rennie Paul S. , Horikawa Izumi , Lustig Arthur J. , Yu Qun , Zhang Haitao , Dong Yan
Published: June 2010

As the mainstay treatment for advanced prostate cancer, androgen deprivation therapy (ADT) targets the action of androgen receptor (AR) by reducing androgen level and/or by using anti-androgen to compete with androgens for binding to AR. Albeit effective in extending survival, ADT is associated with dose-limiting toxicity and the development of castration-resistant prostate cancer (CRPC) after prolonged use. Because CRPC is lethal and incurable, developing effective strategies to enhance the efficacy of ADT and circumvent resistance becomes an urgent task. Continuous AR signaling constitutes one major mechanism underlying the development of CRPC. The present study showed that methylseleninic acid (MSA), an agent that effectively reduces AR abundance, could enhance the cancer-killing efficacy of the anti-androgen bicalutamide in androgen-dependent and CRPC cells. We found that the combination of MSA and bicalutamide produced a robust downregulation of prostate-specific antigen and a recently identified AR target, telomerase, and its catalytic subunit, human telomerase reverse transcriptase. The downregulation of hTERT occurs mainly at the transcriptional level, and reduced AR occupancy of the promoter contributes to downregulation. Furthermore, apoptosis induction by the two agents is significantly mitigated by the restoration of hTERT. Our findings thus indicate that MSA in combination with anti-androgen could represent a viable approach to improve the therapeutic outcome of ADT. Given the critical role of hTERT/telomerase downregulation in mediating the combination effect and the fact that hTERT/telomerase could be measured in blood and urine, hTERT/telomerase could serve as an ideal tumor-specific biomarker to monitor the efficacy of the combination therapy noninvasively. Mol Cancer Ther; 9(7); 2016–25. ©2010 AACR.
Targeted Therapies for Non–Small Cell Lung Cancer: An Evolving Landscape
Authors: Pal Sumanta Kumar , Figlin Robert A. , Reckamp Karen
Published: June 2010

Over the past decade, a multitude of targeted agents have been explored in the treatment of advanced non–small cell lung cancer (NSCLC). Thus far, two broad classes of agents have been implemented in clinical practice: (a) vascular endothelial growth factor (VEGF)-directed therapies and (b) antagonists of the epidermal growth factor receptor (EGFR). In the former category, the agent bevacizumab (a monoclonal antibody) has shown landmark improvements in survival when added to cytotoxic therapy. Small molecule tyrosine kinase inhibitors (TKI) targeting the VEGF receptor (i.e., sunitinib, sorafenib, and vandetanib) show activity in phase II clinical studies. With respect to EGFR-directed therapies, the TKIs gefitinib and erlotinib have shown significant benefit, and have uncovered valuable information about the biology of lung cancer. Outside of therapies directed specifically at VEGF- and EGFR-mediated signaling, trials evaluating insulin-like growth factor-1 receptor (IGF-IR)-targeting agents, cyclooxygenase-2 (COX-2) inhibitors, c-met inhibitors, irreversible pan-HER inhibitors, mammalian target of rapamycin (mTOR) inhibitors, and histone deacetylase (HDAC) inhibitors are ongoing. Inhibitors of ALK show great promise in patients with the relevant gene translocation. Herein, the clinical development of novel therapies for NSCLC is described, including some discussion of relevant biomarkers and determination of synergy with both cytotoxic therapy and other targeted agents. Mol Cancer Ther; 9(7); 1931–44. ©2010 AACR.
Profiling Lipoxygenase Metabolism in Specific Steps of Colorectal Tumorigenesis
Authors: Shureiqi Imad , Chen Dongning , Day R. Sue , Zuo Xiangsheng , Hochman Fredric Lyone , Ross William A. , Cole Rhonda A. , Moy Ofie , Morris Jeffrey S. , Xiao Lianchun , Newman Robert A. , Yang Peiying , Lippman Scott M.
Published: June 2010

Lipoxygenases (LOX) are key enzymes for the oxidative metabolism of polyunsaturated fatty acids into biologically active products. Clinical data on comparative levels of various LOX products in tumorigenesis are lacking. Therefore, we examined the profiles of several LOX products (5-LOX, 12-LOX, 15-LOX-1, and 15-LOX-2) by liquid chromatography/tandem mass spectrometry in the major steps of colorectal tumorigenesis (normal, polyp, and cancer) in a clinical study of 125 subjects (49 with normal colon, 36 with colorectal polyps, and 40 with colorectal cancer) who underwent prospective colorectal biopsies to control for various potential confounding factors (e.g., diet, medications). Mean 13-hydroxyoctadecadienoic acid (13-HODE) levels were significantly higher in normal colon [mean, 36.11 ng/mg protein; 95% confidence interval (95% CI), 31.56-40.67] than in paired colorectal cancer mucosa (mean, 27.01 ng/mg protein; 95% CI, 22.00-32.02; P = 0.0002), and in normal colon (mean, 37.15 ng/mg protein; 95% CI, 31.95-42.34) than in paired colorectal polyp mucosa (mean, 28.07 ng/mg protein; 95% CI, 23.66-32.48; P < 0.001). Mean 13-HODE levels, however, were similar between the left (mean, 37.15 ng/mg protein; 95% CI, 31.95-42.35) and the right normal colon (mean, 32.46 ng/mg protein; 95% CI, 27.95-36.98; P = 0.09). No significant differences with regard to 12- or 15-hydroxyeicosatetraenoic acid or leukotriene B4 levels were detected between normal, polyp, and cancer mucosae. 15-LOX-1 inhibited interleukin-1β expression. This study establishes that reduced 13-HODE levels are a specific alteration in the LOX product profile associated with human colorectal tumorigenesis. Cancer Prev Res; 3(7); 829–38. ©2010 AACR.
Molecular Basis of Phenylketonuria: From Genotype to Clinical Management
Authors: Zschocke Johannes
Published: June 2010

In the age of neonatal screening and the presymptomatic treatment of individuals with phenylketonuria, disease definition has shifted from a set of clinical symptoms observed in untreated patients to an inherited predisposition that requires dietary intervention to avoid brain damage and intellectual impairment. The analysis of correlations between genotype and phenotype must thus be targeted to the need and modalities of preventive treatment. In phenylketonuria, mutation analysis is not a prerequisite to correct diagnosis and therapy including treatment with the cofactor tetrahydrobiopterin (BH4). Nevertheless, the functional impact of individual mutations has been extensively investigated over the last years, and there are well-studied correlations between the genotype and various phenotypic aspects. Knowing and understanding the genotype at a very early stage often allows a prediction of the severity of phenylalanine hydroxylase deficiency and provides a better picture of the disease characteristics in the individual patient. This may assist in the clinical management. Identification of homozygosity or compound heterozygosity for null mutations indicates that this patient will not benefit from BH4 treatment, whilst identification of a well-known BH4-sensitive mutation in a patient who has been classified as non-responsive in a BH4 test should be an indication to re-examine the classification and, if necessary, repeat the test. Care must be taken to recognize potential errors in the results of molecular studies, and to interpret them in relation to clinical and biochemical findings in the individual.
Neuropsychological Functioning in Early-Treated Phenylketonuria – A Review
Authors: Crossley Louise H. , Anderson Peter J.
Published: June 2010

Phenylketonuria (PKU) is an inborn error of metabolism involving a deficiency of the enzyme phenylalanine hydroxylase. This condition results in elevated levels of phenylalanine and low levels of tyrosine. If left untreated, severe neuropathology and neurobehavioral sequelae manifest. The implementation of newborn screening and early dietary treatment has significantly reduced such morbidity. Despite relatively preserved general intellectual functioning, in early-treated PKU individuals subtle cognitive and behavioral deficits are still apparent. This paper provides a review of the evidence for impairment in information processing, executive function, memory and learning, academic achievement and behavior. This paper also reviews the two primary theories proposed to date relating to the underlying mechanisms for the cognitive and behavioral deficits encountered in treated PKU patients, namely prefrontal dysfunction and white matter abnormalities. Although more research is required, the literature to date suggests that early-treated PKU individuals are at risk of subtle neurobehavioral deficits across a range of neuropsychological domains. Thus, PKU patients should be closely monitored so that problems are detected early and appropriate interventions are put in place to ensure that individuals reach their full potential.
Occurrence of PARK2 Mutations in a Never-Smoker Population with Parkinson’s Disease in North India
Authors: Prabhakar Sudesh , Vinish Monika , Das C.P. , Anand Akshay
Published: June 2010

Background: Parkinson’s disease (PD) is a complex neurological disorder without any well-documented genotype-demography associations among sporadic variants. We recently reported PARK2 mutations to be constituting 40% of PD in this region and thus analysed how demographic variables associate with PARK2 mutations in 70 of these patients. Methods: PD samples were screened by PCR single-strand conformation polymorphism (SSCP) and sequencing and their demographic data collected. Demographic and religion data was obtained from 1,010 randomly selected individuals of 120,000 patients visiting the Neurology Clinic and was compared with state database and PD patients. Results: Sikhs from a rural background exhibited the majority of PARK2 mutations. The frequency of PARK2 mutations among females was significantly higher as compared to males (p < 0.015). The age of onset of PD patients with a rural background was found to be significantly lower as compared to patients with an urban background (p < 0.004). The demographic spectrum of the 1,010 randomly selected patients and the background population was found to be comparable. Conclusions: As PD patients with PARK2 mutations were found to be of sporadic origin and never-smokers, a non-redundant inverse relationship between founder PARK2 mutations and smoking is implicated to account for its high frequency. The predisposition of Sikhs to PARK2 mutations necessitates a larger study among its familial variants and a control smoker PD population. The spectrum of PARK2 mutations among Sikh smokers is difficult to study because of the religion-based aversion to smoking.
Charcot-Marie-Tooth Disease in Cyprus: Epidemiological, Clinical and Genetic Characteristics
Authors: Nicolaou Paschalis , Zamba-Papanicolaou Eleni , Koutsou Pantelitsa , Kleopa Kleopas A. , Georghiou Anthi , Hadjigeorgiou Georgios , Papadimitriou Alexandros , Kyriakides Theodoros , Christodoulou Kyproula
Published: June 2010

Background: Charcot-Marie-Tooth disease (CMT) is the most common inherited neuropathy. CMT is classified into 2 main subgroups: a demyelinating and an axonal type. Further subdivisions within these 2 main categories exist and intermediate forms have more recently been described. Inheritance can be autosomal dominant, recessive or X-linked. CMT is associated with more than 30 loci, and about 25 causative genes have been described thus far. Methods: We studied epidemiological, clinical and genetic characteristics of CMT in the Cypriot population. Results: The prevalence of CMT in Cyprus on January 15, 2009, is estimated to be 16 per 100,000. Thirty-three families and 8 sporadic patients were ascertained. CMT was demyelinating in 52%, axonal in 33% and intermediate in 15% of the patients. Thirteen families had PMP22 duplication, 3 families had the PMP22 S22F mutation, 4 families had GJB1/Cx32 mutations, 2 families had different MPZ mutations, 1 of them novel, and 2 families had different MFN2 mutations. Nine families and 8 sporadic patients were excluded from the common CMT genes. Conclusion: The most frequent CMT mutation worldwide, the PMP22 duplication, is also the most frequent CMT mutation in the Cypriot population. Five out of the 8 other mutations are novel, not reported in other populations.
Low-Flow Polytetrafluoroethylene Accesses: Ultrasound Surveillance and Preemptive Interventions Ensure Long-Term Patency
Authors: Malik Jan , Tuka Vladimir , Chytilova Eva , Mokrejsova Magdalena , Masek Martin , Slavikova Marcela
Published: June 2010

Background: Vascular accesses (especially polytetrafluoroethylene grafts) with a permanently low flow (Qa <600 ml/min) are prone to thrombosis and thus have short patency. The reason for a permanently low flow is usually medial calcinosis of the inflow artery in diabetics. We retrospectively studied the long-term patency of low-flow grafts with careful ultrasound surveillance and preemptive interventions. Methods: Twenty subjects with Qa permanently <600 ml/min were included. Ultrasound surveillance was performed every 3 months in addition to classical monitoring techniques. Significant stenosis was strictly defined as the combination of B-mode narrowing >50% + >2-fold peak systolic velocity increase + 1 additional criterion (residual diameter <2.0 mm or flow volume decrease by >20%). Such stenoses were treated by preemptive percutaneous intervention. Primary and secondary patencies were calculated. Results: The primary patency was 357 ± 316 days and the secondary (cumulative) patency was 996 ± 702 days. The number of interventions was 2.09/patient year, but >10 in 6 (33%) subjects. 93 and 80% of grafts were patent 1 and 2 years after access creation, respectively. Conclusion: Low-flow accesses undergoing ultrasound surveillance with strict diagnostic criteria and preemptive interventions had patencies similar to accesses with normal Qa in our study. This was enabled by a relatively high rate of interventions.
Role of Fosinopril and Valsartan on Klotho Gene Expression Induced by Angiotensin II in Rat Renal Tubular Epithelial Cells
Authors: Zhou Q. , Lin S. , Tang R. , Veeraragoo P. , Peng W. , Wu R.
Published: June 2010

Background/Aims: Klotho gene, a new anti-aging gene, is mainly expressed in the kidney tubules. Several studies have found the relationship between klotho and emergence and development of renal diseases. This study set out to explore the role of fosinopril (Fos) and valsartan (Val) on klotho expression induced by angiotensin II (Ang II) in rat renal tubular epithelial cells (NRK-52E). Methods: NRK-52E cells were divided into five groups according to the treatment of Ang II, Fos and Val. Transforming growth factor-β1 (TGF-β1), p38, phospho-p38 (p-p38), p53, and Sp1 protein expression were determined by immunohistochemical and Western blotting analysis. Klotho expression was detected by reverse transcription-polymerase chain reaction and Western blotting analysis. Results: Ang II upregulated TGF-β1, p-p38 and p53 expression, and inhibited Sp1 and klotho expression in NRK-52E cells. After the intervention of Fos and/or Val, TGF-β1, p-p38 and p53 expression were downregulated, Sp1 and klotho expression were upregulated. TGF-β1 and p53, Sp1 and klotho expression exhibited a positive linear correlation, respectively. Conclusion: We conclude that Fos and Val have a protective role in Ang II-induced renal damage, and it may be through mechanism of inhibiting TGF-β1, p-p38 and p53 expression, thus upregulating Sp1 and klotho expression.
Fine-Mapping in African Americans of 8 Recently Discovered Genetic Loci for Plasma Lipids
Authors: Keebler Mary E. , Deo Rahul C. , Surti Aarti , Konieczkowski David , Guiducci Candace , Burtt Noel , Buxbaum Sarah G. , Sarpong Daniel F. , Steffes Michael W. , Wilson James G. , Taylor Herman A. , Kathiresan Sekar
Published: June 2010

Background—

Genome-wide association studies in cohorts of European descent have identified novel genomic regions as associated with lipids, but their relevance in African Americans remains unclear.

Methods and Results—

We genotyped 8 index single nucleotide polymorphisms (SNPs) and 488 tagging SNPs across 8 novel lipid loci in the Jackson Heart Study, a community-based cohort of 4605 African Americans. For each trait, we calculated residuals adjusted for age, sex, and global ancestry and performed multivariable linear regression to detect genotype-phenotype association with adjustment for local ancestry. To explore admixture effects, we conducted stratified analyses in individuals with a high probability of 2 African ancestral alleles or at least 1 European allele at each locus. We confirmed 2 index SNPs as associated with lipid traits in African Americans, with suggestive association for 3 more. However, the effect sizes for 4 of the 5 associated SNPs were larger in the European local ancestry subgroup compared with the African local ancestry subgroup, suggesting that the replication is driven by European ancestry segments. Through fine-mapping, we discovered 3 new SNPs with significant associations, 2 with consistent effect on triglyceride levels across ancestral groups: rs636523 near
DOCK7
/
ANGPTL3
and rs780093 in
GCKR
. African linkage disequilibrium patterns did not assist in narrowing association signals.

Conclusions—

We confirm that 5 genetic regions associated with lipid traits in European-derived populations are relevant in African Americans. To further evaluate these loci, fine-mapping in larger African American cohorts and/or resequencing will be required.
A Two-Layer Model of Natural Stimuli Estimated with Score Matching
Authors: Köster Urs , Hyvärinen Aapo
Published: June 2010

We consider a hierarchical two-layer model of natural signals in which both layers are learned from the data. Estimation is accomplished by score matching, a recently proposed estimation principle for energy-based models. If the first-layer outputs are squared and the second-layer weights are constrained to be nonnegative, the model learns responses similar to complex cells in primary visual cortex from natural images. The second layer pools a small number of features with similar orientation and frequency, but differing in spatial phase. For speech data, we obtain analogous results. The model unifies previous extensions to independent component analysis such as subspace and topographic models and provides new evidence that localized, oriented, phase-invariant features reflect the statistical properties of natural image patches.
Topographic Mapping of Large Dissimilarity Data Sets
Authors: Hammer Barbara , Hasenfuss Alexander
Published: June 2010

Topographic maps such as the self-organizing map (SOM) or neural gas (NG) constitute powerful data mining techniques that allow simultaneously clustering data and inferring their topological structure, such that additional features, for example, browsing, become available. Both methods have been introduced for vectorial data sets; they require a classical feature encoding of information. Often data are available in the form of pairwise distances only, such as arise from a kernel matrix, a graph, or some general dissimilarity measure. In such cases, NG and SOM cannot be applied directly. In this article, we introduce relational topographic maps as an extension of relational clustering algorithms, which offer prototype-based representations of dissimilarity data, to incorporate neighborhood structure. These methods are equivalent to the standard (vectorial) techniques if a Euclidean embedding exists, while preventing the need to explicitly compute such an embedding. Extending these techniques for the general case of non-Euclidean dissimilarities makes possible an interpretation of relational clustering as clustering in pseudo-Euclidean space. We compare the methods to well-known clustering methods for proximity data based on deterministic annealing and discuss how far convergence can be guaranteed in the general case. Relational clustering is quadratic in the number of data points, which makes the algorithms infeasible for huge data sets. We propose an approximate patch version of relational clustering that runs in linear time. The effectiveness of the methods is demonstrated in a number of examples.