bluuebunny/crossref_metadata_2025 huggingface dataset:
Locating Outfalls on Meandering Channels to Optimise Transverse Mixing
Authors: Boxall J. B. , Guymer I. , Marion A.
Published: July 2007

Many sources of river pollution approximate steady‐state conditions and, under such conditions, the rate of transverse mixing is critical in determining the impact of pollutants. Results are presented from transverse‐mixing experiments which were carried out on a large‐scale laboratory channel with meander planform geometry of natural cross‐section, generated by flow over a mobile bed. Dye‐tracer measurements below three point sources within one cross‐section are presented and compared, together with hydrodynamic measurements. The results show the importance of locating outfalls to maximise mixing rates, hence minimising pollution impact (depending on the environmental need). A release on the outside of a bend is shown to result in a faster rate of transverse mixing than a release on the inside of a bend.
CHARACTERISTICS AND CONTROLS OF GRAVEL‐BED RIFFLES: AN ANALYSES OF DATA FROM THE RIVER‐HABITAT SURVEY
Authors: Emery J. C. , Gurnel A. M. , Clifford N. J. , Petts G. E.
Published: July 2007

This paper presents an analysis of data from the UK Environment Agency's River Habitat Survey database relating to bedform type and frequency. Emphasis is given to the gravel‐bed riffle which (a) traditionally has been considered to be a fundamental morphological unit diagnostic of river stability, and (b) more recently has become an important design component in channel restoration and rehabilitation schemes. Data were sufficient to support the identification of distinct, catchment‐scale controls determining the circumstances under which step‐pools and riffles occur, and key local‐scale influences upon riffle frequency and spacing. This demonstrates that the database can be used to support a broad geomorphological analysis. Suggestions are made for the interpretation of results obtained from the existing database, and for possible future modifications to enhance its geomorphological value.
NATURAL SEWAGE TREATMENT IN THE UK: SELECTION GUIDELINES
Authors: Mara D. D.
Published: July 2007

The design of septic tanks, constructed wetlands, waste‐stabilisation ponds and rock filters is detailed, and their applicability in the UK is discussed. Septic tanks are a suitable primary treatment system for villages with a population of less than 500. Constructed wetlands, which are secondary or tertiary treatment units, have the disadvantage that their plants do not play any significant role in their performance, except for nitrogen removal. Secondary facultative waste‐stabilisation ponds, with pre‐treatment in septic tanks and post‐treatment in rock filters, provide primary, secondary and tertiary treatment and can produce high‐quality effluents. The costs of these processes for small rural communities in the UK are compared.
Research in School Shootings
Authors: Muschert Glenn W.
Published: July 2007

Studies of school shootings have been conducted in a variety of disciplines, including sociology, psychology, and media studies. However, to date there is no unified body of knowledge about such events. In an effort to synthesize past studies, and to orient future studies in school shootings, this article (i) offers a typology for understanding the varieties of school shooting incidents, including rampages, mass murders, terrorist attacks, targeted attacks, and government shootings; (ii) examines the mass media dynamic of school shootings; and (iii) presents a synthesis of the multilevel causes suggested in the research, including those on the individual, community, and social levels. Suggestions for future studies in school shootings are explored.
PRELIMINARY INVESTIGATION BY RAMAN SPECTROSCOPY OF SOME POLYMERIC MATRIX WITH PHARMACEUTICAL APPLICATIONS
Authors: TODICA M. , POP C. V. , DINTE E. , FARCAU C. , ASTILEAN S.
Published: July 2007

The possibility to use poly(ethylene oxide) as a polymeric matrix for some pharmaceutical products was analyzed. The behavior of the polymer in the aqueous solutions and the possible interactions between the polymer and the clotrimazole were investigated by Raman spectroscopy. Repeated action of the water on the polymeric conformation is a reversible process and the introduction of the clotrimazole in the polymeric gel do not modify the properties of the active substance of the pharmaceutical product.
Extra Low-Temperature SiO2 Deposition Using Aminosilanes
Authors: Suzuki Ikuo , Dussarrat Christian , Yanagita Kazutaka
Published: July 2007

High quality SiO2 thin films were grown by atomic layer deposition using a newly considered silicon precursor, SAM24, an aminosilane, with an ozone/oxygen mixture. SAM24 is a liquid and has sufficient volatility (with a vapor pressure of 2 Torr at R.T.) and is therefore easy to deliver into the reactor. Deposits obtained exhibit a very good thickness control when deposited as low as 100 ºC and up to 400 ºC at 1 Torr in a hot wall reactor.
Comparison of Electromigration in Cu Interconnects with ALD or PVD TaN Liners
Authors: Hu C.-K. , Gignac Lynne , Liniger Eric , Grunow Stephan , Simon Andrew , Liew San Leong
Published: July 2007

Electromigration in 70 nm wide Cu interconnections has been investigated for the sample temperatures from 213oC to 300oC. The effect of atomic layer or physical vapor deposited TaNx and physical vapor deposited Ta liner layers in Cu Damascene lines on electromigration was also studied. A lower lifetime and activation energy for electromigration was observed in tested lines with sidewall voids. Similar electromigration lifetime and activation energy observed from samples with either atomic layer deposited or physical vapor deposited TaNx suggested that the dominant diffusion paths in the Cu lines were not sensitive to the TaNx layer and were along Cu/dielectric interface and/or grain boundaries.
Atomic Layer Deposition for Nano-Fabrication of 3D Optoelectronic Devices
Authors: Graugnard Elton , King Jeffrey S. , Gaillot Davy P. , Summers Christopher J.
Published: July 2007

We present recent investigations of the atomic layer deposition (ALD) of high transparency, high index, luminescent, and optoelectronic materials into self-assembled opal, lithographic, and biologically derived templates. Investigations on inverse opal based structures, which have the potential to sustain a complete photonic band gap, are presented and have been infiltrated with depositions of TiO2, Al2O3, ZnS:Mn and GaP. It is demonstrated that derivatives of the opal structure can be obtained by the use of a sacrificial buffer layer technique. Consequently, structures can be inverted, precisely replicated, and formed from composite or multilayered materials that allow a high degree of functionality. Additionally, this process enables temperature-sensitive polymer structures to be inverted by low temperature ALD to a high temperature compatible material that then serves as a high temperature template. Recent work is presented on the application of this technique to tune the properties of 2D photonic crystal slab waveguides and for the coating of biological scaffolds.
Reflex Inhibition of Normal Cramp Following Electrical Stimulation of the Muscle Tendon
Authors: Khan Serajul I. , Burne John A.
Published: July 2007

Muscle cramp was induced in one head of the gastrocnemius muscle (GA) in eight of thirteen subjects using maximum voluntary contraction when the muscle was in the shortened position. Cramp in GA was painful, involuntary, and localized. Induction of cramp was indicated by the presence of electromyographic (EMG) activity in one head of GA while the other head remained silent. In all cramping subjects, reflex inhibition of cramp electrical activity was observed following Achilles tendon electrical stimulation and they all reported subjective relief of cramp. Thus muscle cramp can be inhibited by stimulation of tendon afferents in the cramped muscle. When the inhibition of cramp-generated EMG and voluntary EMG was compared at similar mean EMG levels, the area and timing of the two phases of inhibition (I1, I2) did not differ significantly. This strongly suggests that the same reflex pathway was the source of the inhibition in both cases. Thus the cramp-generated EMG is also likely to be driven by spinal synaptic input to the motorneurons. We have found that the muscle conditions that appear necessary to facilitate cramp, a near to maximal contraction of the shortened muscle, are also the conditions that render the inhibition generated by tendon afferents ineffective. When the strength of tendon inhibition in cramping subjects was compared with that in subjects that failed to cramp, it was found to be significantly weaker under the same experimental conditions. It is likely that reduced inhibitory feedback from tendon afferents has an important role in generating cramp.
Contrast and Assimilation in Motion Perception and Smooth Pursuit Eye Movements
Authors: Spering Miriam , Gegenfurtner Karl R.
Published: July 2007

The analysis of visual motion serves many different functions ranging from object motion perception to the control of self-motion. The perception of visual motion and the oculomotor tracking of a moving object are known to be closely related and are assumed to be controlled by shared brain areas. We compared perceived velocity and the velocity of smooth pursuit eye movements in human observers in a paradigm that required the segmentation of target object motion from context motion. In each trial, a pursuit target and a visual context were independently perturbed simultaneously to briefly increase or decrease in speed. Observers had to accurately track the target and estimate target speed during the perturbation interval. Here we show that the same motion signals are processed in fundamentally different ways for perception and steady-state smooth pursuit eye movements. For the computation of perceived velocity, motion of the context was subtracted from target motion (motion contrast), whereas pursuit velocity was determined by the motion average (motion assimilation). We conclude that the human motion system uses these computations to optimally accomplish different functions: image segmentation for object motion perception and velocity estimation for the control of smooth pursuit eye movements.
Pulse-to-Pulse Changes in the Frequency of Deep Brain Stimulation Affect Tremor and Modeled Neuronal Activity
Authors: Birdno Merrill J. , Cooper Scott E. , Rezai Ali R. , Grill Warren M.
Published: July 2007

The effectiveness of deep brain stimulation (DBS) in relieving the symptoms of movement disorders is dependent on the average frequency of stimulation. However, no one has yet examined whether the effectiveness of DBS in relieving tremor is dependent on the pulse-to-pulse (instantaneous) frequency of DBS. We examined the effects of paired-pulse thalamic DBS on tremor in subjects with essential tremor and on the firing of model neurons in a biophysically based computational model of DBS. DBS with an average rate of 130 Hz was more effective at reducing tremor when pulses were evenly spaced than when there were large differences between intrapair and interpair pulse intervals. Similar correlations were observed in the firing patterns of model neurons: increasing the difference between the intrapair and interpair intervals rendered model neurons more likely to fire synchronous bursts, more likely to fire irregularly, and less likely to entrain to the stimulus. The tremor responses provide evidence that the pulse-to-pulse frequency of DBS, not just its average rate, plays an important role in DBS function. Modeling results also suggest that effective DBS overrides oscillatory pathological activity and replaces it with more regularized neuronal firing patterns.
Physical activity modifies the effect of SNPs in theSLC2A2(GLUT2) andABCC8(SUR1) genes on the risk of developing type 2 diabetes
Authors: Kilpeläinen T. O. , Lakka T. A. , Laaksonen D. E. , Laukkanen O. , Lindström J. , Eriksson J. G. , Valle T. T. , Hämäläinen H. , Aunola S. , Ilanne-Parikka P. , Keinänen-Kiukaanniemi S. , Tuomilehto J. , Uusitupa M. , Laakso M.
Published: July 2007

Single nucleotide polymorphisms (SNPs) in two genes regulating insulin secretion, SLC2A2 (encoding GLUT2) and ABCC8 (encoding SUR1), were associated with the conversion from impaired glucose tolerance (IGT) to type 2 diabetes (T2D) in the Finnish Diabetes Prevention Study (DPS). We determined whether physical activity (PA), assessed annually with a questionnaire, modified the association of SNPs in SLC2A2 and ABCC8 with the conversion to T2D in the combined intervention and control groups of the DPS. Finnish overweight subjects with IGT ( N = 479) were followed for an average of 4.1 yr. The interaction of the SNPs with the change in PA on the conversion to T2D was assessed using Cox regression with adjustments for the other components of the intervention (dietary changes, weight reduction). The carriers of the common homozygous genotype of rs5393, rs5394, or rs5404 of SLC2A2 and rs3758947 of ABCC8 who were in the lower third of the change in moderate-to-vigorous PA during the follow-up had a 2.6- to 3.7-fold increased risk of developing T2D compared with the upper third, whereas the rare allele carriers seemed to be unresponsive to changes in moderate-to-vigorous PA (for the interaction of genotype with change in PA, P = 0.022–0.027 for the SNPs in SLC2A2, and P = 0.007 for rs3758947). We conclude that moderate-to-vigorous PA may modify the risk of developing T2D associated with genes regulating insulin secretion ( SLC2A2, ABCC8) in persons with IGT.
Angiopoietin: A TIE(d) Balance in Tumor Angiogenesis
Authors: Shim Winston S.N. , Ho Ivy A.W. , Wong Philip E.H.
Published: July 2007

Angiopoietins (ANG-1 and ANG-2) and their TIE-2 receptor tyrosine kinase have wide-ranging effects on tumor malignancy that includes angiogenesis, inflammation, and vascular extravasation. These multifaceted pathways present a valuable opportunity in developing novel inhibition strategies for cancer treatment. However, the regulatory role of ANG-1 and ANG-2 in tumor angiogenesis remains controversial. There is a complex interplay between complementary yet conflicting roles of both the ANGs in shaping the outcome of angiogenesis. Embryonic vascular development suggests that ANG-1 is crucial in engaging interaction between endothelial and perivascular cells. However, recruitment of perivascular cells by ANG-1 has recently been implicated in its antiangiogenic effect on tumor growth. It is becoming clear that TIE-2 signaling may function in a paracrine and autocrine manner directly on tumor cells because the receptor has been increasingly found in tumor cells. In addition, α5β1 and αvβ5 integrins were recently recognized as functional receptors for ANG-1 and ANG-2. Therefore, both the ligands may have wide-ranging functions in cellular activities that affect overall tumor development. Collectively, these TIE-2–dependent and TIE-2–independent activities may account for the conflicting findings of ANG-1 and ANG-2 in tumor angiogenesis. These uncertainties have impeded development of a clear strategy to target this important angiogenic pathway. A better understanding of the molecular basis of ANG-1 and ANG-2 activity in the pathophysiologic regulation of angiogenesis may set the stage for novel therapy targeting this pathway. (Mol Cancer Res 2007;5(7):655–65)
Elder Crime: Patterns and Current Trends, 1980—2004
Authors: Feldmeyer Ben , Steffensmeier Darrell
Published: July 2007

Using the Federal Bureau of Investigation (FBI)'s Uniform Crime Reports (UCR) arrest statistics for the 1980 to 2004 period, we use age-standardization and Dickey-Fuller time-series techniques to examine recent trends in elderly crime (age 55+), both alone and compared to younger age groups. We find that (1) elderly arrest rates have either declined or remained essentially stable across the majority of UCR offense categories; (2) proportionate criminal involvement of the elderly is about the same now as 25 years ago, but where change has occurred, the trend is toward a smaller elderly share of criminal offending; (3) there has been very little change in the profile of the elderly offender, with elder arrests continuing to be overwhelmingly for minor offenses and alcohol-related violations. Shifts in elderly crime have generally been paralleled by similar trends among the nonelderly, indicating that recent social, economic, and legal changes have had similar impacts on arrest patterns across age groups.
Wrist Actigraphy Validation of Exercise Movement in COPD
Authors: Bauldoff Gerene S. , Ryan-Wenger Nancy A. , Diaz Philip T.
Published: July 2007

A wrist actigraph is a device used in sleep research studies to measure whole body movements. The purpose of this study was to evaluate the feasibility, sensitivity, and validity of wrist actigraphy during pulmonary rehabilitation (PR) upper-extremity exercise in chronic obstructive pulmonary disease (COPD) patients. In this study, 20 patients wore Octagonal Basic Motionlogger® actigraphs during two 90-minute PR sessions while the investigator recorded details of the subject's upper-extremity movements. Concurrent validity with supervised exercise records was supported for upper-extremity endurance (UEE) intensity at baseline ( r = .885, p < .001) and 1 week ( r = .935, p < .001). Criterion validity was supported for UEE ( r = .56, p = .01) and combined lower- and upper-extremity resistance ( r = .72, p < .01) compared with rank-ordered type of exercise. Wrist actigraphy is shown to be a feasible, sensitive, and valid instrument to measure upper-extremity movement during PR in COPD patients.
Evidence of a Gene X Environment Interaction in the Creation of Victimization
Authors: Beaver Kevin M. , Wright John Paul , DeLisi Matt , Daigle Leah E. , Swatt Marc L. , Gibson Chris L.
Published: July 2007

A large body of research has revealed that aggressive personality traits and violent criminal behaviors are influenced by genetic factors. Surprisingly, however, no research has been devoted to investigating the potential genetic origins to adolescent victimization. In the current study, the authors address this gap in the literature by using data from the National Longitudinal Study of Adolescent Health (Add Health) to examine whether different variants of the dopamine D2 receptor gene ( DRD2) are related to victimization, net of the effects of environmental measures. The results of the multivariate models revealed a significant gene X environment interaction in the creation of victimization for White males. Specifically, DRD2 interacted with delinquent peers to predict victimization. The authors discuss the implications of these findings.
The Masculinity of the Governator: Muscle and Compassion in American Politics
Authors: Messner Michael A.
Published: July 2007

Arnold Schwarzenegger's celebrity status allowed him to project a symbolic masculine persona that was effective in gaining political power as California governor. The well-known violent tough-guy persona that Schwarzenegger developed in the mid-1980s contributed to a post—Vietnam era cultural remasculinization of the American man. But this narrow hyper-masculinity was often caricatured in popular culture and delegitimized. In the 1990s and 2000s, Schwarzenegger forged a credible masculine imagery by introducing characters who were humorously self-mocking and focused on care and protection of children. Schwarzenegger's resultant hybrid masculinity, the “Kindergarten Commando,” represents an ascendant hegemonic masculinity always foregrounding muscle, toughness, and the threat of violence and following with situationally appropriate symbolic displays of compassion. The equation of toughness plus compassion composing the Kindergarten Commando is asymmetrical, with toughness eclipsing compassion; this has implications for the kinds of policies that U.S. elected leaders advocate. Republicans utilize this masculine imagery in national politics to gain voters' trust in times of fear and insecurity and continue to employ a strategy that projects a devalued feminized stigma onto more liberal candidates.
Co-expression of cytokine and suicide genes to enhance the activity and safety of tumor-specific cytotoxic T lymphocytes
Authors: Quintarelli Concetta , Vera Juan F. , Savoldo Barbara , Giordano Attianese Greta M. P. , Pule Martin , Foster Aaron E. , Heslop Helen E. , Rooney Cliona M. , Brenner Malcolm K. , Dotti Gianpietro
Published: July 2007

The antitumor effect of adoptively transferred tumor-specific cytotoxic T lymphocytes (CTLs) is impaired by the limited capacity of these cells to expand within the tumor microenvironment. Administration of interleukin 2 (IL-2) has been used to overcome this limitation, but the systemic toxicity and the expansion of unwanted cells, including regulatory T cells, limit the clinical value of this strategy. To discover whether transgenic expression of lymphokines by the CTLs themselves might overcome these limitations, we evaluated the effects of transgenic expression of IL-2 and IL-15 in our model of Epstein Barr Virus–specific CTLs (EBV-CTLs). We found that transgenic expression of IL-2 or IL-15 increased the expansion of EBV-CTLs both in vitro and in vivo in a severe combined immunodeficiency disease (SCID) mouse model and enhanced antitumor activity. Although the proliferation of these cytokine genes transduced CTLs remained strictly antigen dependent, clinical application of this approach likely requires the inclusion of a suicide gene to deal with the potential development of T-cell mutants with autonomous growth. We found that the incorporation of an inducible caspase-9 suicide gene allowed efficient elimination of transgenic CTLs after exposure to a chemical inducer of dimerization, thereby increasing the safety and feasibility of the approach.
Association of oestrogen receptor beta 2 (ERβ2/ERβcx) with outcome of adjuvant endocrine treatment for primary breast cancer – a retrospective study
Authors: Vinayagam Raman , Sibson D Ross , Holcombe Christopher , Aachi Vijay , Davies Michael PA
Published: July 2007

Background

Oestrogen receptor beta (ERβ) modulates ERα activity; wild type ERβ (ERβ1) and its splice variants may therefore impact on hormone responsiveness of breast cancer. ERβ2/ERβcx acts as a dominant negative inhibitor of ERα and expression of ERβ2 mRNA has been proposed as a candidate marker for outcome in primary breast cancer following adjuvant endocrine therapy. We therefore now assess ERβ2 protein by immunostaining and mRNA by quantitative RT-PCR in relation to treatment outcome.

Methods

ERβ2-specific immunostaining was quantified in 141 primary breast cancer cases receiving adjuvant endocrine therapy, but no neoadjuvant therapy or adjuvant chemotherapy. The expression of mRNA for ERβ2/ERβcx was measured in 100 cases by quantitative RT-PCR. Statistical analysis of breast cancer relapse and breast cancer survival was performed using Kaplan Meier log-rank tests and Cox's univariate and multivariate survival analysis.

Results

High ERβ2 immunostaining (Allred score >5) and high ERβ2 mRNA levels were independently associated with significantly better outcome across the whole cohort, including both ERα positive and negative cases (Log-Rank P < 0.05). However, only ERβ2 mRNA levels were significantly associated with better outcome in the ERα + subgroup (Log-Rank P = 0.01) and this was independent of grade, size, nodal status and progesterone receptor status (Cox hazard ratio 0.31 P = 0.02 for relapse; 0.17 P = 0.01 for survival). High ERβ2 mRNA was also associated with better outcome in node negative cases (Log Rank P < 0.001).

ERβ2 protein levels were greater in ERα positive cases (T-test P = 0.00001), possibly explaining the association with better outcome. Levels of ERβ2 protein did not correlate ERβ2 mRNA levels, but 34% of cases had both high mRNA and protein and had a significantly better outcome (Log-Rank relapse P < 0.005).

Conclusion

High ERβ2 protein levels were associated with ERα expression. Although most cases with high ERβ2 mRNA had strong ERβ2 immunostaining, mRNA levels but not protein levels were independently predictive of outcome in tamoxifen-treated ERα + tumours. Post-transcriptional control needs to be considered when assessing the biological or clinical importance of ERβ proteins.
Expression of thymidine phosphorylase in peripheral blood cells of breast cancer patients is not increased by paclitaxel
Authors: Bartsch Rupert , Steger Guenther G , Forstner Birgit , Wenzel Catharina , Pluschnig Ursula , Rizovski Blanka , Altorjai Gabriela , Zielinski Christoph C , Mader Robert M
Published: July 2007

Background

A synergistic cytotoxic effect has been hypothesized for taxanes and capecitabine, a prodrug of 5-fluorouracil. Based on preclinical studies, this synergism has been attributed to an up-regulation of the enzyme thymidine phosphorylase (TP). Beside tumour tissue, TP is highly expressed in white blood cells, possibly causing increased hematotoxicity, when taxanes are combined with capecitabine. So far, this hypothesis has not been investigated in humans.

Methods

A total of 128 consecutive blood samples were collected from eight patients with advanced breast cancer receiving paclitaxel weekly at a dose of 80 mg/m2. To assess the expression of TP in blood cells, samples were collected prior to first therapy, at the end of infusion, and up to 15 days thereafter. This procedure was repeated during the sixth application of paclitaxel. After isolation of the peripheral mononuclear blood cells, the expression of TP was assessed by ELISA. In parallel, paclitaxel level in plasma was evaluated at three selected time points as pharmacokinetic control parameter.

Results

Paclitaxel concentrations at the end of infusion did not change significantly from week 1 to week 6. The expression of TP in peripheral mononuclear blood cells decreased significantly after infusion below pretherapeutic values (p = 0.023; n = 8). After the nadir on day 3, the expression of TP increased moderately returning to baseline levels within one week. The overall picture in week 6 was similar to week 1. Using a trend analysis, neither a short-term nor a long-term induction of TP was observed.

Conclusion

TP in peripheral mononuclear blood cells was hardly regulated under therapy with paclitaxel. Therefore, no increased haematotoxicity due to TP upregulation is expected from the combination of taxanes and capecitabine.
Absence of a relationship between immunophenotypic and colony enumeration analysis of endothelial progenitor cells in clinical haematopoietic cell sources
Authors: Tura Olga , Barclay G Robin , Roddie Huw , Davies John , Turner Marc L
Published: July 2007

Background

The discovery of adult endothelial progenitor cells (EPC) offers potential for vascular regenerative therapies. The expression of CD34 and VEGFR2 by EPC indicates a close relationship with haematopoietic progenitor cells (HPC), and HPC-rich sources have been used to treat cardiac and limb ischaemias with apparent clinical benefit. However, the laboratory characterisation of the vasculogenic capability of potential or actual therapeutic cell autograft sources is uncertain since the description of EPC remains elusive. Various definitions of EPC based on phenotype and more recently on colony formation (CFU-EPC) have been proposed.

Methods

We determined EPC as defined by proposed phenotype definitions (flow cytometry) and by CFU-EPC in HPC-rich sources: bone marrow (BM); cord blood (CB); and G-CSF-mobilised peripheral blood (mPB), and in HPC-poor normal peripheral blood (nPB).

Results

As expected, the highest numbers of cells expressing the HPC markers CD34 or CD133 were found in mPB and least in nPB. The proportions of CD34+ cells co-expressing CD133 is of the order mPB>CB>BM≈nPB. CD34+ cells co-expressing VEGFR2 were also most frequent in mPB. In contrast, CFU-EPC were virtually absent in mPB and were most readily detected in nPB, the source lowest in HPC.

Conclusion

HPC sources differ in their content of putative EPC. Normal peripheral blood, poor in HPC and in HPC-related phenotypically defined EPC, is the richest source of CFU-EPC, suggesting no direct relationship between the proposed EPC immunophenotypes and CFU-EPC potential. It is not apparent whether either of these EPC measurements, or any, is an appropriate indicator of the therapeutic vasculogenic potential of autologous HSC sources.
New Approaches to Diagnosis and Therapy of Tularemia
Authors: TÄRNVIK ARNE , CHU MAY C.
Published: July 2007

Abstract: Francisella tularensisis a potent pathogen and a cause of severe human disease. The outcome of tularemia will depend on rapid insertion of appropriate antibiotics. Until recently, effective clinical handling was hampered by shortcomings in laboratory diagnostics. No suitable direct methods were available and, because of risks and isolate recovery difficulties associated with laboratory work, culture has been rarely practiced. Due to achievements from work on modern technology, however, tularemia can now be rapidly and specifically diagnosed. Conventional PCR has been successfully applied on wound specimens of patients acquiring tularemia, and prospects for application on other human specimens are promising. Besides allowing diagnostics at high sensitivity and specificity, the PCR technology will also facilitate the identification of cases of tularemia presenting with aberrant signs and symptoms. Antibiotics for efficacious treatment of tularemia have been available for several decades. Although highly valuable, these drugs are afflicted with adverse effects and/or are available only for parenteral therapy. Recently, quinolones have been shown to afford a new valuable option for treatment of tularemia caused byF. tularensissubsp.holarctica(type B). Experience in treating more severe disease caused byF. tularensissubsp.tularensis(type A) is currently limited. In essence, the clinical handling of tularemia is currently facilitated by new achievements in molecular diagnostics and, at least with regard to type B tularemia, by the introduction of quinolones for therapy.
Prediction of Prostate Cancer for Patients Receiving Finasteride: Results From the Prostate Cancer Prevention Trial
Authors: Thompson Ian M. , Pauler Ankerst Donna , Chi Chen , Goodman Phyllis J. , Tangen Catherine M. , Lippman Scott M. , Lucia M. Scott , Parnes Howard L. , Coltman Charles A.
Published: July 2007

Purpose

Using data from men in the finasteride group of the Prostate Cancer Prevention Trial (PCPT), we evaluated the impact of prostate-specific antigen (PSA) and other risk factors on the risk of prostate cancer.

Methods

Four thousand four hundred forty men in the finasteride group of the PCPT underwent prostate biopsy, had at least one PSA and a digital rectal exam (DRE) during the year before biopsy, had at least two PSA values from the 3 years before biopsy, and were on finasteride at the time of PSA evaluation. Logistic regression was conducted using the variables age, race, family history of prostate cancer, PSA, PSA velocity, and DRE adjusting for history of prior prostate biopsy.

Results

Six hundred forty-nine (14.6%) of 4,440 men were diagnosed with prostate cancer; 250 had Gleason 7 or higher cancer. Factors associated with an increased risk of prostate cancer included high PSA value and a rising PSA (24.9% risk for PSA value of 1.0 ng/mL and 24.8% risk for a rising PSA), family history of prostate cancer, abnormal DRE result, African American race, and older age. Factors associated with an increased risk of Gleason 7 or higher grade prostate cancer included PSA, abnormal DRE, and older age. A prior negative biopsy was associated with decreased risk of prostate cancer and high-grade prostate cancer.

Conclusion

Risk factors for prostate cancer on biopsy for men receiving finasteride include PSA, DRE, age, race, family history, and history of a prior negative biopsy. With the exception of the approximate reduction of PSA by half with finasteride, the impact of these risk factors is similar to men who do not receive finasteride.
18Fluorodeoxyglucose Positron Emission Tomography in the Prediction of Relapse in Patients With High-Risk, Clinical Stage I Nonseminomatous Germ Cell Tumors: Preliminary Report of MRC Trial TE22—The NCRI Testis Tumour Clinical Study Group
Authors: Huddart Robert A. , O'Doherty Michael J. , Padhani Anwar , Rustin Gordon J.S. , Mead Graham M. , Joffe Johnathan K. , Vasey Paul , Harland Stephen J. , Logue John , Daugaard Gedske , Hain Sharon F. , Kirk Sarah J. , MacKewn Jane E. , Stenning Sally P.
Published: July 2007

Purpose

There are several management options for patients with clinical stage I (CS1) nonseminomatous germ cell tumors (NSGCT); this study examined whether an 18fluorodeoxyglucose positron emission tomography (18FDG PET) scan could identify patients without occult metastatic disease for whom surveillance is an attractive option.

Methods

High-risk (lymphovascular invasion positive) patients with CS1 NSGCT underwent 18FDG PET scanning within 8 weeks of orchidectomy or marker normalization. PET-positive patients went off study; PET-negative patients were observed on a surveillance program. The primary outcome measure was the 2-year relapse-free rate (RFR) in patients with a negative PET scan (the negative predictive value). Assuming an RFR of 90% to exclude an RFR less than 80% with approximately 90% power, 100 PET-negative patients were required; 135 scanned patients were anticipated.

Results

Patients were registered between May 2002 and January 2005, when the trial was stopped by the independent data monitoring committee due to an unacceptably high relapse rate in the PET-negative patients. Of 116 registered patients, 111 underwent PET scans, and 88 (79%) were PET-negative (61% of preorchidectomy marker–negative patients v 88% of marker-positive patients; P = .002); 87 proceeded to surveillance, and one requested adjuvant chemotherapy. With a median follow-up of 12 months, 33 of 87 patients on surveillance relapsed (1-year RFR, 63%; 90% CI, 54% to 72%).

Conclusion

Though PET identified some patients with disease not detected by computed tomography scan, the relapse rate among PET negative patients remains high. The results show that 18FDG PET scanning is not sufficiently sensitive to identify patients at low risk of relapse in this setting.
Phase I and Pharmacokinetic Study of the Oral Farnesyltransferase Inhibitor Lonafarnib Administered Twice Daily to Pediatric Patients With Advanced Central Nervous System Tumors Using a Modified Continuous Reassessment Method: A Pediatric Brain Tumor Consortium Study
Authors: Kieran Mark W. , Packer Roger J. , Onar Arzu , Blaney Susan M. , Phillips Peter , Pollack Ian F. , Geyer J. Russell , Gururangan Sri , Banerjee Anu , Goldman Stewart , Turner Christopher D. , Belasco Jean B. , Broniscer Alberto , Zhu Yali , Frank Emily , Kirschmeier Paul , Statkevich Paul , Yver Antoine , Boyett James M. , Kun Larry E.
Published: July 2007

Purpose

A dose-escalation phase I and pharmacokinetic study of the farnesyltransferase inhibitor lonafarnib ( SCH66336 ) was conducted in children with recurrent or progressive CNS tumors. Primary objectives were to estimate the maximum-tolerated dose (MTD) and to describe the dose-limiting toxicities (DLTs) and pharmacokinetics of lonafarnib. Farnesylation inhibition of HDJ-2 in peripheral blood was also measured.

Patients and Methods

Lonafarnib was administered orally twice daily at dose levels of 70, 90, 115, 150, and 200 mg/m2/dose bid. A modified continual reassessment method (CRM) was used to estimate the MTD based on actual dosages of lonafarnib administered and toxicities observed during the initial 4 weeks of treatment.

Results

Fifty-three children with progressive or recurrent brain tumors were enrolled, with a median age of 12.2 years (range, 3.9 to 19.5 years). Dose-limiting pneumonitis or myelosuppression was observed in three of three patients at the 200 mg/m2/dose level. A relatively constant DLT rate at the 70, 90, and 115 mg/m2/dose levels resulted in a recommended phase II dose of 115 mg/m2/dose. Significant diarrhea did not occur with prophylactic loperamide. Both radiographic response (one anaplastic astrocytoma) and stable disease (one medulloblastoma, two high-grade and four low-grade gliomas, one ependymoma, and one sarcoma) were noted, and seven patients remained on treatment for 1 year or longer.

Conclusion

Although the estimated MTD by the CRM model was 98.5 mg/m2/dose, because of the relatively constant observed DLT rate at the lower four dose levels, the recommended phase II dose of lonafarnib is 115 mg/m2/dose administered twice daily by mouth with concurrent loperamide.
Phase III Trial of Two Investigational Schedules of Ifosfamide Compared With Standard-Dose Doxorubicin in Advanced or Metastatic Soft Tissue Sarcoma: A European Organisation for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study
Authors: Lorigan Paul , Verweij Jaap , Papai Zsuzsa , Rodenhuis Sjoerd , Le Cesne Axel , Leahy Michael G. , Radford John A. , Van Glabbeke Martine M. , Kirkpatrick Anne , Hogendoorn Pancras C.W. , Blay Jean-Yves
Published: July 2007

Purpose

Single-agent doxorubicin remains the standard treatment for advanced soft tissue sarcomas. Combining doxorubicin with standard-dose ifosfamide has not been shown to improve survival and is associated with a significantly increased toxicity; it is not known whether higher dose single-agent ifosfamide is superior to doxorubicin.

Patients and Methods

This randomized prospective multicenter phase III trial was designed to compare progression-free survival of patients with advanced soft tissue sarcoma receiving either regimen of standard doxorubicin 75 mg/m2 every 21 days, ifosfamide 9 g/m2 over 3 days continuous infusion, or ifosfamide 3 g/m2 per day in 3 hours over 3 days. The primary end point was progression-free survival. Secondary end points included overall survival, response rate, and toxicity.

Results

The study included 326 patients. Grade 4 leukopenia, neutropenia, febrile neutropenia, and encephalopathy were more frequent in the ifosfamide arms. Progression-free survival, overall survival, and response rates were not significantly different between the three arms. An independent data monitoring committee reviewed the interim data and recommended early closure of the trial for futility (ie, no significant difference would be shown).

Conclusion

Single-agent doxorubicin remains the treatment of choice for patients with advanced soft tissue sarcoma.
A Pilot Study of [18F]Fluorodeoxyglucose Positron Emission Tomography Scans During and After Radiation-Based Therapy in Patients With Non–Small-Cell Lung Cancer
Authors: Kong Feng-Ming Spring , Frey Kirk A. , Quint Leslie E. , Haken Randall K. Ten , Hayman James A. , Kessler Marc , Chetty Indrin J. , Normolle Daniel , Eisbruch Avraham , Lawrence Theodore S.
Published: July 2007

Purpose

To study whether changes of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) during treatment correlate with post-treatment responses in tumor and normal lung in patients with non–small-cell lung cancer (NSCLC).

Patients and Methods

Patients with stage I to III NSCLC requiring a definitive dose of fractionated radiation therapy (RT) were eligible. FDG-PET/computed tomography scans were acquired before, during, and after RT. Tumor and lung metabolic responses were assessed qualitatively by physicians and quantitatively by normalized peak FDG activity (the ratio of the maximum FDG activity divided by the mean of the aortic arch background).

Results

The study reached the goal of recruiting 15 patients between February 2004 and August 2005. Of these, 11 patients had partial metabolic response, two patients had complete metabolic response, and two patients had stable disease at approximately 45 Gy during RT. The mean peak tumor FDG activity was 5.2 (95% CI, 4.0 to 6.4), 2.5 (95% CI, 2.0 to 3.0), and 1.7 (95% CI, 1.3 to 2.0) on pre-, during, and post-RT scans, respectively. None of the patients had appreciable changes in the lung during RT. The peak FDG activity of the lung was 0.47 (95% CI, 0.36 to 0.59), 0.52 (95% CI, 0.40 to 0.64), and 1.29 (95% CI, 0.82 to 1.76), on pre-, during-, and post-RT scans, respectively. The qualitative response during RT correlated with the overall response post-RT (P = .03); the peak tumor FDG activity during RT correlated with those 3 months post-RT (R2 = 0.7; P < .001).

Conclusion

This pilot study suggests a significant correlation in tumor metabolic response and no association in lung FDG activity between during RT scans and 3 months post-RT scans in patients with NSCLC. Additional study with a large number of patients is needed to validate these findings.
Prostaglandin E2 Increases Transforming Growth Factor-β Type III Receptor Expression through CCAAT Enhancer-Binding Protein δ in Osteoblasts
Authors: McCarthy Thomas L. , Pham Tony H. , Knoll Bianca I. , Centrella Michael
Published: July 2007

Variations in individual TGF-β receptors (TβRs) may modify TGF-β activity and significantly alter its effects on connective tissue growth or repair. Differences in the amount of TβR type III (TβRIII) relative to signal transducing TβRI occur on bone cells during differentiation or in response to other growth regulators. Here we investigated prostaglandin (PG) E2, a potent effector during trauma, inflammation, or mechanical load, on TβR expression in primary osteoblast-enriched cultures. PGE2 rapidly increased TβRIII mRNA and protein expression and enhanced TβRIII gene promoter activity through a discrete region within 0.4 kb of the transcription start site. PGE2 alters osteoblast function through multiple signal-inducing pathways. In this regard, protein kinase A (PKA) activators, PGE1 and forskolin, also enhanced gene expression through the TβRIII gene promoter, whereas protein kinase C activators, PGF2α and phorbol myristate acetate, did not. The stimulatory effect of PGE2 on TβRIII promoter activity was suppressed by a dominant negative PKA-regulatory subunit, but not by dominant negative protein kinase C. PGE2 specifically increased nuclear factor CCAAT enhancer-binding protein δ (C/EBPδ) binding to a half-binding site upstream of the basal TβRIII promoter region, and promoter activity was sensitive to C/EBPδ overexpression and to dominant-negative C/EBPδ competition. In parallel with their effect on TβRIII expression, activators of PKA decreased TGF-β-induced activity. In summary, high levels of PGE2 that occur with inflammation or trauma may, through PKA-activated C/EBPδ, preferentially increase TβRIII expression and in this way delay TGF-β-dependent activation of osteoblasts during the early stabilization phase of bone repair.
The neuronal Arf GAP centaurin α1 modulates dendritic differentiation
Authors: Moore Carlene D. , Thacker Erin E. , Larimore Jennifer , Gaston David , Underwood Alison , Kearns Brian , Patterson Sean I. , Jackson Trevor , Chapleau Chris , Pozzo-Miller Lucas , Theibert Anne
Published: July 2007

Centaurin α1 is an Arf GTPase-activating protein (GAP) that is highly expressed in the nervous system. In the current study, we show that endogenous centaurin α1 protein is localized in the synaptosome fraction, with peak expression in early postnatal development. In cultured dissociated hippocampal neurons, centaurin α1 localizes to dendrites, dendritic spines and the postsynaptic region. siRNA-mediated knockdown of centaurin α1 levels or overexpression of a GAP-inactive mutant of centaurin α1 leads to inhibition of dendritic branching, dendritic filopodia and spine-like protrusions in dissociated hippocampal neurons. Overexpression of wild-type centaurin α1 in cultured hippocampal neurons in early development enhances dendritic branching, and increases dendritic filopodia and lamellipodia. Both filopodia and lamellipodia have been implicated in dendritic branching and spine formation. Following synaptogenesis in cultured neurons, wild-type centaurin α1 expression increases dendritic filopodia and spine-like protrusions. Expression of a GAP-inactive mutant diminishes spine density in CA1 pyramidal neurons within cultured organotypic hippocampal slice cultures. These data support the conclusion that centaurin α1 functions through GAP-dependent Arf regulation of dendritic branching and spines that underlie normal dendritic differentiation and development.
Dynamic in vivo interaction of DDB2 E3 ubiquitin ligase with UV-damaged DNA is independent of damage-recognition protein XPC
Authors: Luijsterburg Martijn S. , Goedhart Joachim , Moser Jill , Kool Hanneke , Geverts Bart , Houtsmuller Adriaan B. , Mullenders Leon H. F. , Vermeulen Wim , van Driel Roel
Published: July 2007

Damage DNA binding protein 2 (DDB2) has a high affinity for UV-damaged DNA and has been implicated in the initial steps of global genome nucleotide excision repair (NER) in mammals. DDB2 binds to CUL4A and forms an E3 ubiquitin ligase. In this study, we have analyzed the properties of DDB2 and CUL4A in vivo. The majority of DDB2 and CUL4A diffuse in the nucleus with a diffusion rate consistent with a high molecular mass complex. Essentially all DDB2 binds to UV-induced DNA damage, where each molecule resides for ∼2 minutes. After the induction of DNA damage, DDB2 is proteolytically degraded with a half-life that is two orders of magnitude larger than its residence time on a DNA lesion. This indicates that binding to damaged DNA is not the primary trigger for DDB2 breakdown. The bulk of DDB2 binds to and dissociates from DNA lesions independently of damage-recognition protein XPC. Moreover, the DDB2-containing E3 ubiquitin ligase is bound to many more damaged sites than XPC, suggesting that there is little physical interaction between the two proteins. We propose a scenario in which DDB2 prepares UV-damaged chromatin for assembly of the NER complex.
The Microtubule-Associated Protein Tumor Overexpressed Gene/Cytoskeleton-Associated Protein 5 Is Necessary for Myelin Basic Protein Expression in Oligodendrocytes
Authors: Francone Victor P. , Maggipinto Michael J. , Kosturko Linda D. , Barbarese Elisa
Published: July 2007

Tumor overexpressed gene (TOG) protein, encoded by cytoskeleton-associated protein CKAP5, is a microtubule-associated protein that binds to heterogeneous nuclear ribonucleoprotein (hnRNP) A2. hnRNP A2 is an RNA trafficking factor that associates with myelin basic protein (MBP) mRNA. In oligodendrocytes, TOG, hnRNP A2, and MBP mRNA colocalize in granules that assemble in the perikaryon and are transported to the peripheral network of processes that extends from it. MBP accumulates preferentially in the membrane of the medial and distal portions of these cellular processes. MBP expression was reduced when TOG level was lowered by short-hairpin (sh) RNA. The reduction in TOG did not affect overall cell morphology or the assembly, transport, localization, or number of MBP mRNA-containing granules. Reduced levels of TOG did not affect another oligodendrocyte-specific component, myelin oligodendrocyte glycoprotein, which is expressed at the same time as MBP but translated from mRNA localized in the cell body. Expression in a neural cell line of a green fluorescent protein (GFP)–MBP fusion protein derived from a construct containing GFP and the full-length cDNA for the rat 14 kDa MBP was reduced when TOG level was lowered by shRNA treatment. Expression of GFP, derived from GFP mRNA containing the hnRNP A2 binding element of MBP mRNA, was similarly reduced in cells with low TOG levels. These data indicate that TOG is necessary for efficient translation of MBP mRNA and suggest that this role is mediated by its interaction with hnRNP A2.