bluuebunny/crossref_metadata_2025 huggingface dataset:
The Regularity of Sustained Firing Reveals Two Populations of Slowly Adapting Touch Receptors in Mouse Hairy Skin
Authors: Wellnitz Scott A. , Lesniak Daine R. , Gerling Gregory J. , Lumpkin Ellen A.
Published: April 2010

Touch is initiated by diverse somatosensory afferents that innervate the skin. The ability to manipulate and classify receptor subtypes is prerequisite for elucidating sensory mechanisms. Merkel cell–neurite complexes, which distinguish shapes and textures, are experimentally tractable mammalian touch receptors that mediate slowly adapting type I (SAI) responses. The assessment of SAI function in mutant mice has been hindered because previous studies did not distinguish SAI responses from slowly adapting type II (SAII) responses, which are thought to arise from different end organs, such as Ruffini endings. Thus we sought methods to discriminate these afferent types. We developed an epidermis-up ex vivo skin–nerve chamber to record action potentials from afferents while imaging Merkel cells in intact receptive fields. Using model-based cluster analysis, we found that two types of slowly adapting receptors were readily distinguished based on the regularity of touch-evoked firing patterns. We identified these clusters as SAI (coefficient of variation = 0.78 ± 0.09) and SAII responses (0.21 ± 0.09). The identity of SAI afferents was confirmed by recording from transgenic mice with green fluorescent protein–expressing Merkel cells. SAI receptive fields always contained fluorescent Merkel cells ( n = 10), whereas SAII receptive fields lacked these cells ( n = 5). Consistent with reports from other vertebrates, mouse SAI and SAII responses arise from afferents exhibiting similar conduction velocities, receptive field sizes, mechanical thresholds, and firing rates. These results demonstrate that mice, like other vertebrates, have two classes of slowly adapting light-touch receptors, identify a simple method to distinguish these populations, and extend the utility of skin–nerve recordings for genetic dissection of touch receptor mechanisms.
Multiple Effects of Serotonin and Acetylcholine on Hyperpolarization-Activated Inward Current in Locomotor Activity-Related Neurons in Cfos-EGFP Mice
Authors: Dai Yue , Jordan Larry M.
Published: April 2010

Hyperpolarization-activated inward current ( Ih) has been shown to be involved in production of bursting during various forms of rhythmic activity. However, details of Ihin spinal interneurons related to locomotion remain unknown. Using Cfos-EGFP transgenic mice (P6–P12) we are able to target the spinal interneurons activated by locomotion. Following a locomotor task, whole cell patch-clamp recordings were obtained from ventral EGFP+ neurons in spinal cord slices (T13–L4, 200–250 μm). Ihwas found in 51% of EGFP+ neurons ( n = 149) with almost even distribution in lamina VII (51%), VIII (47%), and X (55%). Ihcould be blocked by ZD7288 (10–20 μM) or cesium (1–1.5 mM) but was insensitive to barium (2–2.5 mM). Ihactivated at −80.1 ± 9.2 mV with half-maximal activation −95.5 ± 13.3 mV, activation rate 10.0 ± 3.2 mV, time constant 745 ± 501 ms, maximal conductance 1.0 ± 0.7 nS, and reversal potential −34.3 ± 3.6 mV. 5-HT (15–20 μM) and ACh (20–30 μM) produced variable effects on Ih. 5-HT increased Ihin 43% of EGFP+ neurons ( n = 37), decreased Ihin 24%, and had no effect on Ihin 33% of the neurons. ACh decreased Ihin 67% of EGFP+ neurons ( n = 18) with unchanged Ihin 33% of the neurons. This study characterizes the Ihin locomotor-related interneurons and is the first to demonstrate the variable effects of 5-HT and ACh on Ihin rodent spinal interneurons. The finding of 5-HT and ACh-induced reduction of Ihin EGFP+ neurons suggests a novel mechanism that the motor system could use to limit the participation of certain neurons in locomotion.
Evidence of a Novel Somatopic Map in the Human Neocerebellum During Complex Actions
Authors: Schlerf J. E. , Verstynen T. D. , Ivry R. B. , Spencer R. M. C.
Published: April 2010

The human neocerebellum has been hypothesized to contribute to many high-level cognitive processes including attention, language, and working memory. Support for these nonmotor hypotheses comes from evidence demonstrating structural and functional connectivity between the lateral cerebellum and cortical association areas as well as a lack of somatotopy in lobules VI and VII, a hallmark of motor representations in other areas of the cerebellum and cerebral cortex. We set out to test whether somatotopy exists in these lobules by using functional magnetic resonance imaging to measure cerebellar activity while participants produced simple or complex movements, using either fingers or toes. We observed a previously undiscovered somatotopic organization in neocerebellar lobules VI and VIIA that was most prominent when participants executed complex movements. In contrast, activation in the anterior lobe showed a similar somatotopic organization for both simple and complex movements. While the anterior somatotopic representation responded selectively during ipsilateral movements, the new cerebellar map responded during both ipsi- and contralateral movements. The presence of a bilateral, task-dependent somatotopic map in the neocerebellum emphasizes an important role for this region in the control of skilled actions.
Sympathetic Nervous System Overactivity and Its Role in the Development of Cardiovascular Disease
Authors: Malpas Simon C.
Published: April 2010

This review examines how the sympathetic nervous system plays a major role in the regulation of cardiovascular function over multiple time scales. This is achieved through differential regulation of sympathetic outflow to a variety of organs. This differential control is a product of the topographical organization of the central nervous system and a myriad of afferent inputs. Together this organization produces sympathetic responses tailored to match stimuli. The long-term control of sympathetic nerve activity (SNA) is an area of considerable interest and involves a variety of mediators acting in a quite distinct fashion. These mediators include arterial baroreflexes, angiotensin II, blood volume and osmolarity, and a host of humoral factors. A key feature of many cardiovascular diseases is increased SNA. However, rather than there being a generalized increase in SNA, it is organ specific, in particular to the heart and kidneys. These increases in regional SNA are associated with increased mortality. Understanding the regulation of organ-specific SNA is likely to offer new targets for drug therapy. There is a need for the research community to develop better animal models and technologies that reflect the disease progression seen in humans. A particular focus is required on models in which SNA is chronically elevated.
The Ventilatory Response to Hypoxia in Mammals: Mechanisms, Measurement, and Analysis
Authors: Teppema Luc J. , Dahan Albert
Published: April 2010

The respiratory response to hypoxia in mammals develops from an inhibition of breathing movements in utero into a sustained increase in ventilation in the adult. This ventilatory response to hypoxia (HVR) in mammals is the subject of this review. The period immediately after birth contains a critical time window in which environmental factors can cause long-term changes in the structural and functional properties of the respiratory system, resulting in an altered HVR phenotype. Both neonatal chronic and chronic intermittent hypoxia, but also chronic hyperoxia, can induce such plastic changes, the nature of which depends on the time pattern and duration of the exposure (acute or chronic, episodic or not, etc.). At adult age, exposure to chronic hypoxic paradigms induces adjustments in the HVR that seem reversible when the respiratory system is fully matured. These changes are orchestrated by transcription factors of which hypoxia-inducible factor 1 has been identified as the master regulator. We discuss the mechanisms underlying the HVR and its adaptations to chronic changes in ambient oxygen concentration, with emphasis on the carotid bodies that contain oxygen sensors and initiate the response, and on the contribution of central neurotransmitters and brain stem regions. We also briefly summarize the techniques used in small animals and in humans to measure the HVR and discuss the specific difficulties encountered in its measurement and analysis.
Ancillary Subunits Associated With Voltage-Dependent K+Channels
Authors: Pongs Olaf , Schwarz Jürgen R.
Published: April 2010

Since the first discovery of Kvβ-subunits more than 15 years ago, many more ancillary Kv channel subunits were characterized, for example, KChIPs, KCNEs, and BKβ-subunits. The ancillary subunits are often integral parts of native Kv channels, which, therefore, are mostly multiprotein complexes composed of voltage-sensing and pore-forming Kvα-subunits and of ancillary or β-subunits. Apparently, Kv channels need the ancillary subunits to fulfill their many different cell physiological roles. This is reflected by the large structural diversity observed with ancillary subunit structures. They range from proteins with transmembrane segments and extracellular domains to purely cytoplasmic proteins. Ancillary subunits modulate Kv channel gating but can also have a great impact on channel assembly, on channel trafficking to and from the cellular surface, and on targeting Kv channels to different cellular compartments. The importance of the role of accessory subunits is further emphasized by the number of mutations that are associated in both humans and animals with diseases like hypertension, epilepsy, arrhythmogenesis, periodic paralysis, and hypothyroidism. Interestingly, several ancillary subunits have in vitro enzymatic activity; for example, Kvβ-subunits are oxidoreductases, or modulate enzymatic activity, i.e., KChIP3 modulates presenilin activity. Thus different modes of β-subunit association and of functional impact on Kv channels can be delineated, making it difficult to extract common principles underlying Kvα- and β-subunit interactions. We critically review present knowledge on the physiological role of ancillary Kv channel subunits and their effects on Kv channel properties.
Molecular Background of Leak K+Currents: Two-Pore Domain Potassium Channels
Authors: Enyedi Péter , Czirják Gábor
Published: April 2010

Two-pore domain K+(K2P) channels give rise to leak (also called background) K+currents. The well-known role of background K+currents is to stabilize the negative resting membrane potential and counterbalance depolarization. However, it has become apparent in the past decade (during the detailed examination of the cloned and corresponding native K2Pchannel types) that this primary hyperpolarizing action is not performed passively. The K2Pchannels are regulated by a wide variety of voltage-independent factors. Basic physicochemical parameters (e.g., pH, temperature, membrane stretch) and also several intracellular signaling pathways substantially and specifically modulate the different members of the six K2Pchannel subfamilies (TWIK, TREK, TASK, TALK, THIK, and TRESK). The deep implication in diverse physiological processes, the circumscribed expression pattern of the different channels, and the interesting pharmacological profile brought the K2Pchannel family into the spotlight. In this review, we focus on the physiological roles of K2Pchannels in the most extensively investigated cell types, with special emphasis on the molecular mechanisms of channel regulation.
NF-κB Signaling: A Tale of Two Pathways in Skeletal Myogenesis
Authors: Bakkar Nadine , Guttridge Denis C.
Published: April 2010

NF-κB is a ubiquitiously expressed transcription factor that plays vital roles in innate immunity and other processes involving cellular survival, proliferation, and differentiation. Activation of NF-κB is controlled by an IκB kinase (IKK) complex that can direct either canonical (classical) NF-κB signaling by degrading the IκB inhibitor and releasing p65/p50 dimers to the nucleus, or causes p100 processing and nuclear translocation of RelB/p52 via a noncanonical (alternative) pathway. Under physiological conditions, NF-κB activity is transiently regulated, whereas constitutive activation of this transcription factor typically in the classical pathway is associated with a multitude of disease conditions, including those related to skeletal muscle. How NF-κB functions in muscle diseases is currently under intense investigation. Insight into this role of NF-κB may be gained by understanding at a more basic level how this transcription factor contributes to skeletal muscle cell differentiation. Recent data from knockout mice support that the classical NF-κB pathway functions as an inhibitor of skeletal myogenesis and muscle regeneration acting through multiple mechanisms. In contrast, alternative NF-κB signaling does not appear to be required for myofiber conversion, but instead functions in myotube homeostasis by regulating mitochondrial biogenesis. Additional knowledge of these signaling pathways in skeletal myogenesis should aid in the development of specific inhibitors that may be useful in treatments of muscle disorders.
The Solution of Embedding Problems in the Framework of GAPs with Applications on Nonlinear PDEs
Authors: Starkl Reinhard
Published: April 2010

The paper presents a special class of embedding problems whoes solutions are important for the explicit solution of nonlinear partial differential equations. It is shown that these embedding problems are solvable and explicit solutions are given. Not only are the solutions new but also the mathematical framework of their
construction which is defined by a nonstandard function theory built over nonstandard algebraical structures, denoted as “GAPs”. These GAPs must not be neither associative nor division algebras, but the corresponding function theories built over them preserve the most important symmetries from the classical complex function theory in a generalized form: a generalization of the Cauchy‐Riemannian differential equations exists as well as a generalization of the classical Cauchy Integral Theorem.
Initial Experience of the Feasibility of Single-Incision Laparoscopic Appendectomy in Different Clinical Conditions
Authors: Kössi Jyrki , Luostarinen Markku
Published: April 2010

Introduction. Single-incision laparoscopic surgery (SILS) is a new technique developed for performing operations without a visible scar. Preliminary studies have reported the use of the technique mainly in cholecystectomy and appendectomy. We evaluated the feasibility of the technique in various appendicitis conditions including children, fertile women and obese patients. Materials and Methods. SILS technique was used in a random sample of patients hospitalised for suspected appendicitis. The ordinary diagnostic laparoscopy was performed and the appendix was removed if needed. The ligation of appendix was performed by thread loop, absorbable clip or endoscopic stapler. The details regarding the recovery of patients were collected prospectively. Results. Ten SILS procedures were performed without conversions or complications. The patient series included uncomplicated and complicated appendicitis patients. The mean age of the patients was 37 years (range 13–63), mean BMI was 26 (range 18–31), mean operative time was 40 minutes (range 18–31), and mean postoperative stay was 2 days (range 1–5). Conclusions. SILS technique is feasible for obese patients, uncomplicated and complicated appendicitis as well as for exploratory laparoscopy. Most common methods to ligate appendix are feasible with SILS technique. The true benefit of the technique should be assessed by randomised controlled trials.
Evaluation of Hepcidin Isoforms in Hemodialysis Patients by a Proteomic Approach Based on SELDI-TOF MS
Authors: Campostrini Natascia , Castagna Annalisa , Zaninotto Federica , Bedogna Valeria , Tessitore Nicola , Poli Albino , Martinelli Nicola , Lupo Antonio , Olivieri Oliviero , Girelli Domenico
Published: April 2010

The hepatic iron regulator hormone hepcidin consists, in its mature form, of 25 amino acids, but two other isoforms, hepcidin-20 and hepcidin-22, have been reported, whose biological meaning remains poorly understood. We evaluated hepcidin isoforms in sera from 57 control and 54 chronic haemodialysis patients using a quantitative proteomic approach based on SELDI-TOF-MS. Patients had elevated serum levels of both hepcidin-25 and hepcidin-20 as compared to controls (geometric means: 7.52 versus 4.69 nM, and 4.06 versus 1.76 nM, resp.,P<.05for both). The clearance effects of a single dialysis session by different dialysis techniques and membranes were also investigated, showing an average reduction by51.3%±29.2% for hepcidin-25 and34.2%±28.4% for hepcidin-20 but only minor differences among the different dialysis modalities. Measurement of hepcidin isoforms through MS-based techniques can be a useful tool for better understanding of their biological role in hemodialysis patients and other clinical conditions.
Analysis of Adiponectin Gene Polymorphisms in Chinese Population with Systemic Lupus Erythematosus
Authors: Fang Wen Liang , Zhou Bin , Wang Yan Yun , Chen Yu , Zhang Lin
Published: April 2010

Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease. Adiponectin is an adipocyte-derived cytokine with anti-inflammatory, antidiabetic, and antiatherogenic properties. No study has reported on the association between adiponectin (ADIPOQ) gene and SLE. Our aim is to investigate the association between single-nucleotide polymorphisms in ADIPOQ gene and SLE. We examined 179 SLE patients and 237 age- and gender-matched controls from Sichuan province in China. Genotypes were determined using polymerase chain reaction-restriction fragment length polymorphism and DNA sequencing. Results show that there was no significant difference in the allele frequencies of rs1501299 (P=.311,OR=1.17, 95% CI: 0.86–1.59) and rs2241766 (P=.929,OR=0.99, 95% CI: 0.74–1.33) in ADIPOQ gene between SLE patients and controls. The same results were seen in their genotypes (P<.05). The allele frequencies of rs1501299 and rs2241766 polymorphisms of ADIPOQ may not be associated with SLE risk.
Inflammatory and Autoimmune Reactions in Atherosclerosis and Vaccine Design Informatics
Authors: Jan Michael , Meng Shu , Chen Natalie C. , Mai Jietang , Wang Hong , Yang Xiao-Feng
Published: April 2010

Atherosclerosis is the leading pathological contributor to cardiovascular morbidity and mortality worldwide. As its complex pathogenesis has been gradually unwoven, the regime of treatments and therapies has increased with still much ground to cover. Active research in the past decade has attempted to develop antiatherosclerosis vaccines with some positive results. Nevertheless, it remains to develop a vaccine against atherosclerosis with high affinity, specificity, efficiency, and minimal undesirable pathology. In this review, we explore vaccine development against atherosclerosis by interpolating a number of novel findings in the fields of vascular biology, immunology, and bioinformatics. With recent technological breakthroughs, vaccine development affords precision in specifying the nature of the desired immune response—useful when addressing a disease as complex as atherosclerosis with a manifold of inflammatory and autoimmune components. Moreover, our exploration of available bioinformatic tools for epitope-based vaccine design provides a method to avoid expenditure of excess time or resources.
A Cluster of Legionnaires' Disease and Associated Pontiac Fever Morbidity in Office Workers, Dublin, June-July 2008
Authors: Ward M. , Boland M. , Nicolay N. , Murphy H. , McElhiney J. , Collins C. , Lynch M. , McCarthy M. , O' Donnell J.
Published: April 2010

In June and July 2008, two office workers were admitted to a Dublin hospital with Legionnaires' disease. Investigations showed that cooling towers in the basement car park were the most likely source of infection. However, positive results from cooling tower samples by polymerase chain reaction (PCR) did not correlate with subsequent culture results. Also, many employees reported Pontiac fever-like morbidity following notification of the second case of Legionnaires' disease. In total, 54 employees attended their general practitioner or emergency department with symptoms of Legionnaires' disease or Pontiac fever. However, all laboratory tests for Legionnaires' disease or Pontiac fever were negative. In this investigation, email was used extensively for active case finding and provision of time information to employees and medical colleagues. We recommend clarification of the role of PCR in the diagnosis of legionellosis and also advocate for a specific laboratory test for the diagnosis of the milder form of legionellosis as in Pontiac fever.
Level of CYP4G19 Expression Is Associated with Pyrethroid Resistance inBlattella germanica
Authors: Guo Guang-zhou , Geng Yi-jie , Huang Da-na , Xue Cai-fang , Zhang Ren-li
Published: April 2010

German cockroaches have become a large problem in the Shenzhen area because of their pesticide resistance, especially to pyrethroid. A pyrethroid called “Jia Chong Qing” to prevent pests for a long time were found to be resistant to “Jia Chong Qing” with resistance index of 3.88 measured using RT-PCR and immunohistochemistry analysis showed that both CYP4G19 mRNA and CYP4G19 protein expression levels in the wild strain were substantially higher than that of a sensitive strain. dsRNA segments derived from the target gene CYP4G19 were prepared using in vitro transcription and were microinjected into abdomens of the wild strain. Two to eight days after injection, the result showed that CYP4G19 mRNA expressions were significantly reduced in the groups injected with dsRNAs.
Clinical Implications of Power Toothbrushing on Fluoride Delivery: Effects on Biofilm Plaque Metabolism and Physiology
Authors: Aspiras M. , Stoodley P. , Nistico L. , Longwell M. , de Jager M.
Published: April 2010

Dental biofilms are implicated in the formation of caries and periodontal disease. A major constituent of the supragingival biofilm isStreptococcus mutans, which produces lactic acid from sucrose fermentation, enhancing enamel demineralization and eventual caries development. Caries prevention through F inhibits enamel demineralization and promotes remineralization. Fluoride also exerts effects on metabolic activities in the supragingival biofilm such as aerobic respiration, acid fermentation and dentrification. In experimentalS. mutansbiofilms, adding 1000 ppm F to an acidogenic biofilm resulting from 10% sucrose addition increased pH to pre-sucrose levels, suggesting inhibition of acid fermentation. F effects on metabolic activity and sucrose utilization in interproximal plaque biofilms were also recorded. Addition of 10% sucrose reduced pH from neutral to 4.2, but subsequent addition of 1000 ppm F increased pH by 1 unit, inhibiting acid fermentation. 10% Sucrose addition also stimulated denitrification, increasing production of nitrous oxide (N2O). Addition of 1000 ppm F suppressed denitrification, indicating an additional mechanism by which F exerts effects in the active interproximal biofilm. Finally, fluid dynamic activity by power tooth brushing enhanced F delivery and retention in an experimentalS. mutansbiofilm, suggesting a potential novel benefit for this intervention beyond mechanical plaque removal.
Cytokine Networks in Systemic Lupus Erythematosus
Authors: Lee Hooi-Ming , Sugino Hidehiko , Nishimoto Norihiro
Published: April 2010

Systemic lupus erythematosus (SLE) is an autoimmune disease more prominent in women and characterized by multiple organ damage. Imbalance in cytokine production and cytokine levels correlates with SLE progression, making the understanding of SLE cytokine networks very important for SLE treatment strategy and drug development. In this article, we review cytokine networks that may be involved in the pathogenesis of SLE by briefly describing abnormal cytokine production and serum cytokine levels in SLE patients. We also focus on the pathological roles of cytokines and their interactions in immunoregulatory networks and suggest how their disturbances may implicate in pathological conditions in SLE. Finally, we further discuss the influence of estrogen on these cytokine networks.
A High Molecular Weight Melanoma-Associated Antigen–Specific Chimeric Antigen Receptor Redirects Lymphocytes to Target Human Melanomas
Authors: Burns William R. , Zhao Yangbing , Frankel Timothy L. , Hinrichs Christian S. , Zheng Zhili , Xu Hui , Feldman Steven A. , Ferrone Soldano , Rosenberg Steven A. , Morgan Richard A.
Published: April 2010

Immunotherapy, particularly the adoptive cell transfer (ACT) of tumor-infiltrating lymphocytes (TIL), is a very promising therapy for metastatic melanoma. Some patients unable to receive TIL have been successfully treated with autologous peripheral blood lymphocytes (PBL), genetically modified to express human leukocyte antigen (HLA) class I antigen–restricted, melanoma antigen–reactive T-cell receptors; however, substantial numbers of patients remain ineligible due to the lack of expression of the restricting HLA class I allele. We sought to overcome this limitation by designing a non–MHC-restricted, chimeric antigen receptor (CAR) targeting the high molecular weight melanoma-associated antigen (HMW-MAA), which is highly expressed on more than 90% of human melanomas but has a restricted distribution in normal tissues. HMW-MAA–specific CARs containing an antigen recognition domain based on variations of the HMW-MAA–specific monoclonal antibody 225.28S and a T-cell activation domain based on combinations of CD28, 4-1BB, and CD3ζ activation motifs were constructed within a retroviral vector to allow stable gene transfer into cells and their progeny. Following optimization of the HMW-MAA–specific CAR for expression and function in human PBL, these gene-modified T cells secreted cytokines, were cytolytic, and proliferated in response to HMW-MAA–expressing cell lines. Furthermore, the receptor functioned in both CD4+ and CD8+ cells, was non–MHC restricted, and reacted against explanted human melanomas. To evaluate this HMW-MAA–specific CAR in patients with metastatic melanoma, we developed a clinical-grade retroviral packaging line. This may represent a novel means to treat the majority of patients with advanced melanoma, most notably those unable to receive current ACT therapies. Cancer Res; 70(8); 3027–33. ©2010 AACR.
Common Botanical Compounds Inhibit the Hedgehog Signaling Pathway in Prostate Cancer
Authors: Ślusarz Anna , Shenouda Nader S. , Sakla Mary S. , Drenkhahn Sara K. , Narula Acharan S. , MacDonald Ruth S. , Besch-Williford Cynthia L. , Lubahn Dennis B.
Published: April 2010

Many botanical compounds have been proposed to prevent cancer. We investigated the cancer treatment and prevention abilities of apigenin, baicalein, curcumin, epigallocatechin 3-gallate (EGCG), genistein, quercetin, and resveratrol both in vivo in transgenic adenocarcinoma of the mouse prostate (TRAMP) mice as well as in vitro in prostate cancer cell lines. In our experiments, these seven compounds act similarly to the Hedgehog antagonist cyclopamine, a teratogenic plant alkaloid, which had been previously shown to “cure” prostate cancer in a mouse xenograft model. With IC50 values ranging from <1 to 25 μmol/L, these compounds can inhibit Gli1 mRNA concentration by up to 95% and downregulate Gli reporter activity by 80%. We show that four compounds, genistein, curcumin, EGCG, and resveratrol, inhibit Hedgehog signaling as monitored by real-time reverse transcription-PCR analysis of Gli1 mRNA concentration or by Gli reporter activity. Three compounds, apigenin, baicalein, and quercetin, decreased Gli1 mRNA concentration but not Gli reporter activity. Our results show that these compounds are also able to reduce or delay prostate cancer in vivo in TRAMP mice. All seven compounds, when fed in combination as pure compounds or as crude plant extracts, inhibit well-differentiated carcinoma of the prostate by 58% and 81%, respectively. In vitro, we show that all seven compounds also inhibit growth in human and mouse prostate cancer cell lines. Mechanistically, we propose the Hedgehog signaling pathway to be a direct or indirect target of these compounds. These botanicals at pharmacologic concentrations are potentially safer and less expensive alternatives to cyclopamine and its pharmaceutical analogues for cancer therapy. Cancer Res; 70(8); 3382–90. ©2010 AACR.
A Second Genetic Variant on Chromosome 15q24-25.1 Associates with Lung Cancer
Authors: Liu Pengyuan , Yang Ping , Wu Xifeng , Vikis Haris G. , Lu Yan , Wang Yian , Schwartz Ann G. , Pinney Susan M. , de Andrade Mariza , Gazdar Adi , Gaba Colette , Mandal Diptasri , Lee Juwon , Kupert Elena , Seminara Daniela , Minna John , Bailey-Wilson Joan E. , Spitz Margaret , Amos Christopher I. , Anderson Marshall W. , You Ming
Published: April 2010

A common variant on chromosomal region 15q24-25.1, marked by rs1051730, was found to be associated with lung cancer risk. Here, we attempted to confirm the second variant on 15q24-25.1 in several large sporadic lung cancer populations and determined what percentage of additional risk for lung cancer is due to the genetic effect of the second variant. SNPs rs1051730 and rs481134 were genotyped in 2,818 lung cancer cases and 2,766 controls from four populations. Joint analysis of these two variants (rs1051730 and rs481134) on 15q24-25.1 identified three major haplotypes (G_T, A_C, and G_C) and provided stronger evidence for association of 15q24-25.1 with lung cancer (P = 9.72 × 10−9). These two variants represent three levels of risk associated with lung cancer. The most common haplotype G_T is neutral; the haplotype A_C is associated with increased risk for lung cancer with 5.0% higher frequency in cases than in controls [P = 1.68 × 10−7; odds ratio (OR), 1.24; 95% confidence interval (95% CI), 1.14–1.35]; whereas the haplotype G_C is associated with reduced risk for lung cancer with 4.4% lower frequency in cases than in controls (P = 7.39 × 10−7; OR, 0.80; 95% CI, 0.73–0.87). We further showed that these two genetic variants on 15q24-25.1 independently influence lung cancer risk (rs1051730: P = 4.42 × 10−11; OR, 1.60; 95% CI, 1.46–1.74; rs481134: P = 7.01 × 10−4; OR, 0.81; 95% CI, 0.72–0.92). The second variant on 15q24-25.1, marked by rs481134, explains an additional 13.2% of population attributable risk for lung cancer. Cancer Res; 70(8); 3128–35. ©2010 AACR.
Immune Promotion of Epithelial-mesenchymal Transition and Generation of Breast Cancer Stem Cells
Authors: Reiman Jennifer M. , Knutson Keith L. , Radisky Derek C.
Published: April 2010

Elements of the immune system act as intimate regulators of cancer progression, inhibiting early stages of tumor growth, through immunosurveillance while facilitating later stages of tumor progression. Recent findings have revealed that activated CD8 T cells can stimulate mammary epithelial tumor cells to undergo epithelial-mesenchymal transition (EMT) and to acquire the greatly increased tumorigenic capability and chemotherapeutic resistance of breast cancer stem cells (BCSC). These studies provide a window to understanding how BCSC arise and are maintained within tumors, and how to best target these processes for therapeutic benefit. Cancer Res; 70(8); 3005–8. ©2010 AACR.
Blockade of CCN6 (WISP3) Activates Growth Factor–Independent Survival and Resistance to Anoikis in Human Mammary Epithelial Cells
Authors: Huang Wei , Gonzalez Maria E. , Toy Kathy A. , Banerjee Mousumi , Kleer Celina G.
Published: April 2010

CCN6 is a secreted cysteine-rich matricellular protein (36.9 kDa) that exerts growth-inhibitory functions in breast cancer. Reduction or loss of CCN6 protein has been reported in invasive carcinomas of the breast with lymph node metastasis and in inflammatory breast cancer. However, the mechanism by which CCN6 loss promotes breast cancer growth remains to be defined. In the present study, we developed lentiviral-mediated short hairpin RNA CCN6 knockdown (KD) in nontumorigenic mammary epithelial cells MCF10A and HME. We discovered that CCN6 KD protects mammary epithelial cells from apoptosis and activates growth factor–independent survival. In the absence of exogenous growth factors, CCN6 KD was able to promote growth under anchorage-independent conditions and triggered resistance to detachment-induced cell death (anoikis). On serum starvation, CCN6 KD was sufficient for activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway. Growth factor–independent cell survival was stunted in CCN6 KD cells when treated with either human recombinant CCN6 protein or the PI3K inhibitor LY294002. Targeted inhibition of Akt isoforms revealed that the survival advantage rendered by CCN6 KD requires specific activation of Akt-1. The relevance of our studies to human breast cancer is highlighted by the finding that low CCN6 protein levels are associated with upregulated expression of phospho-Akt-1 (Ser473) in 21% of invasive breast carcinomas. These results enable us to pinpoint one mechanism by which CCN6 controls survival of breast cells mediated by the PI3K/Akt-1 pathway. Cancer Res; 70(8); 3340–50. ©2010 AACR.
Cancer Inhibition through Circadian Reprogramming of Tumor Transcriptome with Meal Timing
Authors: Li Xiao-Mei , Delaunay Franck , Dulong Sandrine , Claustrat Bruno , Zampera Sinisa , Fujii Yoshiro , Teboul Michèle , Beau Jacques , Lévi Francis
Published: April 2010

Circadian disruption accelerates cancer progression, whereas circadian reinforcement could halt it. Mice with P03 pancreatic adenocarcinoma (n = 77) were synchronized and fed ad libitum (AL) or with meal timing (MT) from Zeitgeber time (ZT) 2 to ZT6 with normal or fat diet. Tumor gene expression profiling was determined with DNA microarrays at endogenous circadian time (CT) 4 and CT16. Circadian mRNA expression patterns were determined for clock genes Rev-erbα, Per2, and Bmal1, cellular stress genes Hspa8 and Cirbp, and cyclin A2 gene Ccna2 in liver and tumor. The 24-hour patterns in telemetered rest-activity and body temperature and plasma corticosterone and insulin-like growth factor-I (IGF-I) were assessed. We showed that MT inhibited cancer growth by ∼40% as compared with AL (P = 0.011) irrespective of calorie intake. Clock gene transcription remained arrhythmic in tumors irrespective of feeding schedule or diet. Yet, MT upregulated or downregulated the expression of 423 tumor genes, according to CT. Moreover, 36 genes involved in cellular stress, cell cycle, and metabolism were upregulated at one CT and downregulated 12 h apart. MT induced >10-fold circadian expression of Hspa8, Cirbp, and Ccna2 in tumors. Corticosterone or IGF-I patterns played no role in tumor growth inhibition. In contrast, MT consistently doubled the circadian amplitude of body temperature. Peak and trough respectively corresponded to peak expressions of Hspa8 and Cirbp in tumors. The reinforcement of the host circadian timing system with MT induced 24-hour rhythmic expression of critical genes in clock-deficient tumors, which translated into cancer growth inhibition. Targeting circadian clocks represents a novel potential challenge for cancer therapeutics. Cancer Res; 70(8); 3351–60. ©2010 AACR.
Debating Clinical Utility
Authors: Burke W. , Laberge A.-M. , Press N.
Published: April 2010

The clinical utility of genetic tests is determined by the outcomes following test use. Like other measures of value, it is often contested. Stakeholders may have different views about benefits and risks and about the importance of social versus health outcomes. They also commonly disagree about the evidence needed to determine whether a test is effective in achieving a specific outcome. Questions may be presented as factual disagreements, when they are actually debates about what information matters or how facts should be interpreted and used in clinical decision-making. Defining the different issues at stake is therefore an important element of policy-making. Key issues include evidence standards for test use, and in particular, the circumstances under which prospective controlled data should be required, as well as evidence on feasibility, cost and equitable delivery of testing; the goals of population-based screening programs, and in particular, the role of social outcomes in evaluating test value; and the appropriate uses and funding of tests that inform non-medical actions. Addressing each of these issues requires attention to stakeholder values and methods for effective deliberation that incorporate consumer as well as health professional perspectives.
Mainstreaming Genetics: A Comparative Review of Clinical Services for Inherited Cardiovascular Conditions in the UK
Authors: Burton H. , Alberg C. , Stewart A.
Published: April 2010

Inherited cardiovascular conditions (ICCs) are a group of monogenic disorders caused by mutations in the components of the electrical and contractile system of the heart or its vasculature. ICCs include arrhythmias, cardiomyopathies, inherited arteriopathies such as Marfan syndrome, muscular dystrophies, and familial hypercholesterolaemia. Epidemiological data on ICCs are sparse but a survey of the available literature suggests that there are approximately 340,000 prevalent cases of these conditions in the UK (population 61 million). As a result of dramatic advances in understanding of the molecular pathology of ICCs, more than 50 ICCs have been recognised, and diagnostic genetic tests are increasingly available. As part of a needs assessment and review of provision of ICC services, a survey of all UK ICC services was undertaken focusing on both quantitative and qualitative aspects. Service provision was found to be highly inequitable, with typically a 10–20-fold variation in referral and genetic testing rates between different UK regions. Service levels per million population are much higher in London than in all but one of the regions. The review concluded that capacity of services is inadequate to meet current or future demand and many services lack the critical mass to provide the full range of services. Recommendations are made for the development of services appropriate for the future. Services should be led by cardiology but have close links with clinical genetics services, which should provide support with specialist genetics advice and cascade testing. Finally, the international relevance of this review is considered.
Low-Shear Modelled Microgravity Environment Maintains Morphology and Differentiated Functionality of Primary Porcine Hepatocyte Cultures
Authors: Nelson Leonard J. , Walker Simon W. , Hayes Peter C. , Plevris John N.
Published: April 2010

Hepatocytes cultured in conventional static culture rapidly lose polarity and differentiated function. This could be explained by gravity-induced sedimentation, which prevents formation of complete three-dimensional (3D) cell-cell/cell-matrix interactions and disrupts integrin-mediated signals (including the most abundant hepatic integrin α5β1), important for cellular polarity and differentiation. Cell culture in a low fluid shear modelled microgravity (about 10–2g) environment promotes spatial colocation/self-aggregation of dissociated cells and induction of 3D differentiated liver morphology. Previously, we demonstrated the utility of a NASA rotary bioreactor in maintaining key metabolic functions and 3D aggregate formation of high-density primary porcine hepatocyte cultures over 21 days. Using serum-free chemically defined medium, without confounding interactions of exogenous bioscaffolding or bioenhancing surface materials, we investigated features of hepatic cellular polarity and differentiated functionality, including expression of hepatic integrin α5, as markers of functional morphology. We report here that in the absence of exogenous biomatrix scaffolding, hepatocytes cultured in serum-free chemically defined medium in a microgravity environment rapidly (<24 h) form macroscopic (2–5 mm), compacted 3D hepatospheroid structures consisting of a shell of glycogen-positive viable cells circumscribing a core of eosinophilic cells. The spheroid shell layers exhibited ultrastructural, morphological and functional features of differentiated, polarized hepatic tissue including strong expression of the integrin α5 subunit, functional bile canaliculi, albumin synthesis, and fine ultrastructure reminiscent of in vivo hepatic tissue. The low fluid shear microgravity environment may promote tissue-like self-organization of dissociated cells, and offer advantages over spheroids cultured in conventional formats to delineate optimal conditions for enhanced directed tissue self-assembly.
Receptive Reason: Alexander of Aphrodisias on Material Intellect
Authors: Tuominen Miira
Published: April 2010

According to Alexander of Aphrodisias, our potential intellect is a purely receptive capacity. Alexander also claims that, in order for us to actualise our intellectual potentiality, the intellect needs to abstract what is intelligible from enmattered perceptible objects. Now a problem emerges: How is it possible for a purely receptive capacity to perform such an abstraction? It will be argued that even though Alexander’s reaction to this question causes some tension in his theory, the philosophical motivation for it is a sound one. Rather than a calculation of actualities and potentialities, the doctrine of receptivity is supposed to explain how human beings come to grasp universal aspects of reality in an accurate manner.
The bay'a: Modern Political Uses of Islamic Ritual in the Arab World
Authors: Podeh Elie
Published: April 2010

According to Islamic tradition, the bay'a (translated as investiture or an oath of allegiance) is an act by which a certain number of persons, acting individually or collectively, recognize the authority of another person as the head of a Muslim state. This article analyzes the different modern political uses of the bay'a in the Arab world. Based on research of seven Arab case studies—the Kingdom of Hijaz, Iraq, Syria, Jordan, Egypt, Lebanon and Saudi Arabia, the article presents three arguments: First, the bay'a evolved into an elastic term politically used in a variety of ways by different Arab regimes. Second, the evoking of the bay'a ritual has often been a response to a domestic necessity or crisis. Finally, the use of this traditional ritual, along modern Western symbolic artifacts, is an indication of the evolving hybrid nature of the Arab political culture, based on a market of a mixed reservoir of foreign and local rituals and symbols. The interplay between foreign and local artifacts depends on the state's specific historical circumstances, which include also the impact of the colonial period. Ultimately, the modern uses of the bay'a demonstrate that modernity, in its Western version, has not been adopted wholesale. The bay'a ritual has been kept almost intact only in Saudi Arabia—a territory which did not go through the colonial experience. In contrast, Iraq, Syria and Jordan, which were under colonial rule, used an adapted version of this instrument on a temporary and utilitarian basis.
Sales Tax Law in Jordan: Questions of Legality and Propriety
Authors: Al-Shawabkah Ibrahim Kamil
Published: April 2010

Despite consecutive amendments over 15 years, the Jordanian Sales Tax Law of 1994 still raises questions about the legality of a number of its provisions as well as the propriety or appropriateness of others. Is it in conformance with the Constitution to determine in a Regulation, rather than an Act of Parliament, those who shall pay, collect and forward the sales tax to the treasury? Does it ensure equality under the law that the sales tax puts certain businesses at a disadvantage compared to other similar ones? As regards propriety, the procedure for filing and reviewing self-assessment statements begs questions of clarity and fairness. All these questions will be examined in this article.
Narrative Construction as Sensemaking: How a Central Bank Thinks
Authors: Abolafia Mitchel Y.
Published: April 2010

How do elite policy-making groups make sense of complex and ambiguous environments while remaining consistent with the group’s institutionalized operating model? This paper identifies a sensemaking process based in shared narrative construction. It is a social process of pattern recognition involving abduction, the comparison of culturally approved models to the current conditions to establish relevant facts and events; plotting, the reordering of those facts and events into a plausible narrative; and selective retention, the collective negotiation of a policy choice that fits the emerging narrative. This paper uses verbatim transcripts of meetings at the Federal Reserve to explore how policy makers use a logic of appropriateness to identify relevant cues and integrate them with existing models by weaving sensible plots. These plots are designed to control the supply of money and credit and maintain the legitimacy of the central bank.
Polyphony and its Other
Authors: Letiche Hugo
Published: April 2010

A post-deconstruction ethics of honoring, respecting, and/or theorizing anOther via a concept of polyphony seems very attractive to organizational studies (De Cock and Jeanes 2006; Clegg et al. 2006). Many organizational studies intellectuals prefer ‘reasonableness’ and/or ‘historical meanings’ as an object of study to a more empirical one. This rhetorical strategy (amongst others) has claimed polyphony as a leading concept, celebrating dialogue, diversity, and intertextuality. But, as Gayatri Spivak has indicated, it is necessary to ask if anOther speaks at all in such practices. Spivak (1999) explores polyphony in terms of the subaltern and her (his) representation, making use of différance to clarify what a many-voiced perspective actually could imply. In this article, I deconstruct two organizational studies articles on polyphony, making use of Spivak’s insights.
“I’ll See You on IM, Text, or Call You”: A Social Network Approach of Adolescents’ Use of Communication Media
Authors: Van Cleemput Katrien
Published: April 2010

This study explores some possibilities of social network analysis for studying adolescents’ communication patterns. A full network analysis was conducted on third-grade high school students (15 year olds, 137 students) in Belgium. The results pointed out that face-to-face communication was still the most prominent way for information to flow through the network. Interactions through communication media (e-mail, instant messaging, text messaging, mobile phone, and landline phone), however, supplemented this flow of information in a substantive way. Communication media use patterns were characterized by multiplexity and could be placed on a unidimensional scale indicating a media hierarchy. Close friends (strong ties) used all communication media at their disposal to connect with each other; students who were just friends (weak ties) preferred face-to-face communication and social network sites. In the discussion, some other possibilities of social network analysis for studying adolescents’ communication media are discussed.
An Evaluation of the Importance of Military Associations at Civil Airports
Authors: Clark Patti J.
Published: April 2010

Today there are over 1,500 public-use airports in the United States. Each of these airports provides a service to the surrounding community, whether in the form of a general aviation or commercial air service facility. An airport is dependent on many facets of the local government infrastructure for support services. Also, the airports have ties to neighboring or resident military installations. A military installation has similar missions and objectives to an airport, a situation that enables a working relationship that is complementary to each party. For example, airports and military installations alike must provide such services as emergency response, fire protection, airspace control, environmental protection, and a safe infrastructure for aircraft operations. While many aspects of the relationships are intangible and subjective, others are easily measured.