bluuebunny/crossref_metadata_2025 huggingface dataset:
The anticipatory regulation of performance: the physiological basis for pacing strategies and the development of a perception-based model for exercise performance
Authors: Tucker R
Published: February 2009

During self-paced exercise, the exercise work rate is regulated by the brain based on the integration of numerous signals from various physiological systems. It has been proposed that the brain regulates the degree of muscle activation and thus exercise intensity specifically to prevent harmful physiological disturbances. It is presently proposed how the rating of perceived exertion (RPE) is generated as a result of the numerous afferent signals during exercise and serves as a mediator of any subsequent alterations in skeletal muscle activation levels and exercise intensity. A conceptual model for how the RPE mediates feedforward, anticipatory regulation of exercise performance is proposed, and this model is applied to previously described research studies of exercise in various conditions, including heat, hypoxia and reduced energy substrate availability. Finally, the application of this model to recent novel studies that altered pacing strategies and performance is described utilising an RPE clamp design, central nervous system drugs and the provision of inaccurate duration or distance feedback to exercising athletes.
Treatment of lateral epicondylitis using skin-derived tenocyte-like cells
Authors: Connell D , Datir A , Alyas F , Curtis M
Published: February 2009

Objectives:

To culture collagen-producing cells derived from skin fibroblasts and o evaluate prospectively the safety and potential use of this cell preparation for treatment of refractory lateral epicondylitis in a pilot study.

Design:

Prospective clinical pilot study.

Setting:

Institution-based clinical research.

Patients:

A total of 12 patients (5 men and 7 women; mean age 39.1 years) with clinical diagnosis of refractory lateral epicondylitis.

Interventions:

Laboratory-prepared collagen-producing cells derived from dermal fibroblasts were injected into the sites of intrasubstance tears and fibrillar discontinuity of the common extensor origin under ultrasonography guidance.

Main outcome measures:

The outcome assessment was performed over 6 months. The Patient-Rated Tennis Elbow Evaluation (PRTEE) scale was used to assess pain severity and functional disability. Tendon healing response was measured using four criteria on ultrasonography: tendon thickness, hypoechogenicity, intrasubstance tears and neovascularity.

Results:

Cell cultures rich in collagen-producing cells was successfully prepared. After injection, the median PRTEE score decreased from 78 before the procedure to 47 at 6 weeks, 35 at 3 months and 12 at 6 months after the procedure (p<0.05). The healing response on ultrasonography showed median decrease in: (1) number of tears, from 5 to 2; (2) number of new vessels, from 3 to 1; and (3) tendon thickness, from 4.35 to 4.2 (p<0.05). Of the 12 patients, 11 had a satisfactory outcome, and only one patient proceeded to surgery after failure of treatment at the end of 3 months.

Conclusions:

Skin-derived tenocyte-like cells can be cultured in the laboratory to yield a rich preparation of collagen-producing cells. Our pilot study suggests that these collagen-producing cells can be injected safely into patients and may have therapeutic value in patients with refractory lateral epicondylitis.
Selecting outcome measures in sports medicine: a guide for practitioners using the example of anterior cruciate ligament rehabilitation
Authors: Bent N P , Wright C C , Rushton A B , Batt M E
Published: February 2009

Using examples from the field of anterior cruciate ligament rehabilitation, this review provides sports and health practitioners with a comprehensive, user-friendly, guide to selecting outcome measures for use with active populations. A series of questions are presented for consideration when selecting a measure: is the measure appropriate for the intended use? (appropriateness); is the measure acceptable to patients? (acceptability); is it feasible to use the measure? (feasibility); does the measure provide meaningful results? (interpretability); does the measure provide reproducible values? (reliability); does the measure assess what it is supposed to assess? (validity); can the measure detect change? (responsiveness); do substantial proportions of patients achieve the worst or best scores? (floor and ceiling effects); is the measure structured and scored correctly? (dimensionality and internal consistency); has the measure been tested with the types of patients with whom it will be used? (sample characteristics). Evaluation of the measure using these questions will assist practitioners in making their judgements.
Cellular mediators of renal vascular dysfunction in hypertension
Authors: Ponnuchamy Bharathy , Khalil Raouf A.
Published: February 2009

The renal vasculature plays a major role in the regulation of renal blood flow and the ability of the kidney to control the plasma volume and blood pressure. Renal vascular dysfunction is associated with renal vasoconstriction, decreased renal blood flow, and consequent increase in plasma volume and has been demonstrated in several forms of hypertension (HTN), including genetic and salt-sensitive HTN. Several predisposing factors and cellular mediators have been implicated, but the relationship between their actions on the renal vasculature and the consequent effects on renal tubular function in the setting of HTN is not clearly defined. Gene mutations/defects in an ion channel, a membrane ion transporter, and/or a regulatory enzyme in the nephron and renal vasculature may be a primary cause of renal vascular dysfunction. Environmental risk factors, such as high dietary salt intake, vascular inflammation, and oxidative stress further promote renal vascular dysfunction. Renal endothelial cell dysfunction is manifested as a decrease in the release of vasodilatory mediators, such as nitric oxide, prostacyclin, and hyperpolarizing factors, and/or an increase in vasoconstrictive mediators, such as endothelin, angiotensin II, and thromboxane A2. Also, an increase in the amount/activity of intracellular Ca2+concentration, protein kinase C, Rho kinase, and mitogen-activated protein kinase in vascular smooth muscle promotes renal vasoconstriction. Matrix metalloproteinases and their inhibitors could also modify the composition of the extracellular matrix and lead to renal vascular remodeling. Synergistic interactions between the genetic and environmental risk factors on the cellular mediators of renal vascular dysfunction cause persistent renal vasoconstriction, increased renal vascular resistance, and decreased renal blood flow, and, consequently, lead to a disturbance in the renal control mechanisms of water and electrolyte balance, increased plasma volume, and HTN. Targeting the underlying genetic defects, environmental risk factors, and the aberrant renal vascular mediators involved should provide complementary strategies in the management of HTN.
Intermediate-duration day lengths unmask reproductive responses to nonphotic environmental cues
Authors: Paul Matthew J. , Galang Jerome , Schwartz William J. , Prendergast Brian J.
Published: February 2009

Many animals time their breeding to the seasons, using the changing day length to forecast those months when environmental conditions favor reproductive success; in Siberian hamsters ( Phodopus sungorus), long summer days stimulate, whereas short winter days inhibit, reproductive physiology and behavior. Nonphotic environmental cues are also thought to influence the timing of breeding, but typically their effects on reproduction are minor and more variable under categorically long and short photoperiods. We hypothesized that the influence of nonphotic cues might be more prominent during intermediate photoperiods (early spring and late summer), when day length is an unreliable predictor of year-to-year fluctuations in food availability. In hamsters housed in an intermediate photoperiod (13.5 h light/day), two nonphotic seasonal cues, mild food restriction and same-sex social housing, induced gonadal regression, amplified photoperiod history-dependent reproductive responses to decreasing day lengths, and prevented pubertal development indefinitely. These cues were entirely without effect in hamsters maintained under a long photoperiod (16 h light/day). Thus intermediate photoperiods reveal a heightened responsiveness of the reproductive axis to nonphotic cues. This photoperiod-dependent efficacy of nonphotic cues may explain how animals integrate long-term photic and short-term nonphotic cues in nature: intermediate day lengths open a seasonal window of increased reproductive responsiveness to nonphotic cues at a time when such cues may be of singular relevance, thereby allowing for precise synchronization of the onset and offset of the breeding season to local conditions.
Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time
Authors: Kramer Andrea B. , van Timmeren Mirjan M. , Schuurs Theo A. , Vaidya Vishal S. , Bonventre Joseph V. , van Goor Harry , Navis Gerjan
Published: February 2009

Tubulointerstitial lesions are important in the progression of proteinuric renal disease. Tubular kidney injury molecule-1 (Kim-1) is induced in acute renal injury and reversible as a natural course. Kim-1 is also present in chronic renal damage; however, the dynamics of Kim-1 in chronic renal damage and effects of antiproteinuric treatment on Kim-1 are unknown. We studied Kim-1 in adriamycin nephrosis (AN) before and after renin-angiotensin system blockade. A renal biopsy was taken 6 wk after adriamycin injection to study renal damage and Kim-1 expression. Subsequently, ACE inhibition (ACEi; n = 23), angiotensin II antagonist (AT1A; n = 23), or vehicle ( n = 10) was given for 6 wk; healthy rats served as controls (CON; n = 8). In AN, renal Kim-1 mRNA was induced 26-fold vs. CON at week 6, with further increase in vehicle to week 12 (40-fold) but was reduced by ACEi and AT1Ato 10- and 12-fold vs. CON ( P < 0.05 vs. week 6). Kim-1 protein was undetectable in CON; in AN, it was present in brush border of dilated tubules in areas with adjacent interstitial lesions. Renal Kim-1 protein levels increased from weeks 6–12 in vehicle and decreased in ACEi- and AT1A-treated groups ( P < 0.05). In vehicle, urinary Kim-1 was increased ( P < 0.05 vs. CON), with a reduction by ACEi and AT1A( P < 0.05 vs. vehicle). Renal and urinary Kim-1 correlated with proteinuria and interstitial damage cross-sectionally. Reductions in proteinuria and renal Kim-1 correlated, which was not associated by corresponding changes in tubulointerstitial fibrosis. In conclusion, on longitudinal follow-up during antiproteinuric treatment increased renal Kim-1 expression is reversible in proportion to proteinuria reduction, likely reflecting reversibility of early tubular injury, supporting its potential as a biomarker for tubulointerstitial processes of damage and repair.
Curcumin ameliorates renal failure in 5/6 nephrectomized rats: role of inflammation
Authors: Ghosh S. S. , Massey H. D. , Krieg R. , Fazelbhoy Z. A. , Ghosh S. , Sica D. A. , Fakhry I. , Gehr T. W. B.
Published: February 2009

TNF-α and NF-κB play important roles in the development of inflammation in chronic renal failure (CRF). In hepatic cells, curcumin is shown to antagonize TNF-α-elicited NF-κB activation. In this study, we hypothesized that if inflammation plays a key role in renal failure then curcumin should be effective in improving CRF. The effectiveness of curcumin was compared with enalapril, a compound known to ameliorate human and experimental CRF. Investigation was conducted in Sprague-Dawley rats where CRF was induced by 5/6 nephrectomy (Nx). The Nx animals were divided into untreated (Nx), curcumin-treated (curcumin), and enalapril-treated (enalapril) groups. Sham-operated animals served as a control. Renal dysfunction in the Nx group, as evidenced by elevated blood urea nitrogen, plasma creatinine, proteinuria, segmental sclerosis, and tubular dilatation, was significantly reduced by curcumin and enalapril treatment. However, only enalapril significantly improved blood pressure. Compared with the control, the Nx animals had significantly higher plasma and kidney TNF-α, which was associated with NF-κB activation and macrophage infiltration in the kidney. These changes were effectively antagonized by curcumin and enalapril treatment. The decline in the anti-inflammatory peroxisome proliferator-activated receptor γ (PPARγ) seen in Nx animals was also counteracted by curcumin and enalapril. Studies in mesangial cells were carried out to further establish that the anti-inflammatory effect of curcumin in vivo was mediated essentially by antagonizing TNF-α. Curcumin dose dependently antagonized the TNF-α-mediated decrease in PPARγ and blocked transactivation of NF-κB and repression of PPARγ, indicating that the anti-inflamatory property of curcumin may be responsible for alleviating CRF in Nx animals.
Rho kinase inhibition attenuates LPS-induced renal failure in mice in part by attenuation of NF-κB p65 signaling
Authors: Meyer-Schwesinger Catherine , Dehde Silke , von Ruffer Claudia , Gatzemeier Stefan , Klug Philipp , Wenzel Ulrich O. , Stahl Rolf A. K. , Thaiss Friedrich , Meyer Tobias N.
Published: February 2009

Rho kinase signaling regulates inflammatory cell migration and chemokine production. We therefore investigated the mechanisms of Rho-kinase-dependent inflammation in lipopolysaccharide (LPS)-induced renal failure. C57/BL6 mice received intraperitoneal LPS with or without daily treatment with specific Rho kinase inhibitors (Y-27632 or HA-1077; 5 mg/kg). Rho kinase inhibitors were applied in a preventive (12 or 1 h before LPS) or a therapeutic (6 h after LPS) scheme. Both protected renal function and decreased tubular injury in LPS-treated mice. Enhanced Rho kinase activity was inhibited by HA-1077 in capillary endothelial cells, inflammatory cells, and tubuli by analysis of Rho kinase substrate phosphorylation. Early neutrophil influx was reduced by HA-1077 without reduction of the proinflammatory cytokine TNFα. In contrast, HA-1077 decreased the influx of monocytes/macrophages coinciding with reduced expression of the NF-κB-regulated chemokines CCL5 and CCL2. We therefore examined NF-κB signal transduction and found that NF-κB p65 phosphorylation and nuclear translocation were reduced by Rho kinase inhibition. IκBα degradation was not altered during the first 6 h but was reduced by HA-1077 at later time points. NF-κB p50-deficient mice were similarly protected from renal injury by Rho kinase inhibition further supporting the prominent role for p65 in Rho kinase inhibition. Together, these data suggest that Rho kinase inhibition by preventive or therapeutic treatment effectively reduced endotoxic kidney injury in part by attenuation of NF-κB p65 activation.
Multicenter Phase II Study of Lapatinib in Patients with Brain Metastases from HER2-Positive Breast Cancer
Authors: Lin Nancy U. , Diéras Véronique , Paul Devchand , Lossignol Dominique , Christodoulou Christos , Stemmler Hans-Joachim , Roché Henri , Liu Minetta C. , Greil Richard , Ciruelos Eva , Loibl Sibylle , Gori Stefania , Wardley Andrew , Yardley Denise , Brufsky Adam , Blum Joanne L. , Rubin Stephen D. , Dharan Bernie , Steplewski Klaudia , Zembryki Denise , Oliva Cristina , Roychowdhury Debasish , Paoletti Paolo , Winer Eric P.
Published: February 2009

Purpose: Brain metastases develop in one third of patients with advanced HER2+ breast cancer. Effective therapy for patients with central nervous system (CNS) progression after cranial radiation is extremely limited and represents a major clinical challenge. Lapatinib, an epidermal growth factor receptor/HER2 inhibitor, was associated with regressions of CNS lesions in a small phase 2 trial. The current study was done to further evaluate the CNS activity of lapatinib. The study was later amended to allow patients who progressed on lapatinib the option of receiving lapatinib plus capecitabine.

Experimental Design: Eligible patients had HER2+ breast cancer, progressive brain metastases, prior trastuzumab, and cranial radiotherapy. The primary end point was CNS objective response, defined as ≥50% volumetric reduction of CNS lesion(s) in the absence of increasing steroid use, progressive neurologic signs and symptoms, or progressive extra-CNS disease.

Results: Two-hundred and forty-two patients entered the study. CNS objective responses to lapatinib were observed in 6% of patients. In an exploratory analysis, 21% of patients experienced a ≥20% volumetric reduction in their CNS lesions. An association was observed between volumetric reduction and improvement in progression-free survival and neurologic signs and symptoms. Of the 50 evaluable patients who entered the lapatinib plus capecitabine extension, 20% experienced a CNS objective response and 40% experienced a ≥20% volumetric reduction in their CNS lesions.

Conclusions: This study confirms the modest CNS antitumor activity of lapatinib. Additional responses were observed with the combination of lapatinib and capecitabine. Further studies of lapatinib-based regimens for CNS metastases from HER2+ breast cancer are warranted.
Population Pharmacokinetics of Romidepsin in Patients with Cutaneous T-Cell Lymphoma and Relapsed Peripheral T-Cell Lymphoma
Authors: Woo Sukyung , Gardner Erin R. , Chen Xiaohong , Ockers Sandra B. , Baum Caitlin E. , Sissung Tristan M. , Price Douglas K. , Frye Robin , Piekarz Richard L. , Bates Susan E. , Figg William D.
Published: February 2009

Purpose: Romidepsin is a potent histone deacetylase inhibitor under clinical development. The objective of this study was to evaluate the effect of demographic, clinical, and pharmacogenetic covariates on the pharmacokinetics of romidepsin in patients with T-cell lymphoma.

Experimental Design: Pharmacokinetic assessment was done in 98 patients enrolled in a phase II study who received 14 or 18 mg/m2 of romidepsin as a 4-hour infusion on day 1 during their first treatment cycle. Population modeling was done using a nonlinear mixed effects modeling approach to explore the effects of polymorphic variations in CYP3A4, CYP3A5, SLCO1B3, and ABCB1, all of which encode genes thought to be involved in romidepsin disposition.

Results: A two-compartment model with linear kinetics adequately described the romidepsin disposition. Population clearance was 15.9 L/h with between-patient variability of 37%. ABCB1 2677G>T/A variant alleles tended toward a reduced clearance and lower volume of tissue distribution, but this was not supported by a statistical significance. Genetic variations in CYP3A4/5 and SCLO1B3 had no effect on the systemic exposure.

Conclusion: The population pharmacokinetic analysis indicates moderate interindividual variability in romidepsin pharmacokinetics and no clinically relevant covariates associated with the unexplained pharmacokinetic variability of romidepsin in this population.
Cytogenetic and Molecular Tumor Profiling for Type 1 and Type 2 Papillary Renal Cell Carcinoma
Authors: Klatte Tobias , Pantuck Allan J. , Said Jonathan W. , Seligson David B. , Rao Nagesh P. , LaRochelle Jeffrey C. , Shuch Brian , Zisman Amnon , Kabbinavar Fairooz F. , Belldegrun Arie S.
Published: February 2009

Purpose: The goal of this study was to evaluate immunohistochemical and cytogenetic features and their prognostic value in papillary renal cell carcinoma (PRCC) subtypes.

Experimental Design: One hundred fifty-eight cases of PRCC were identified and reclassified by subtype. Tumoral expression of 29 molecular markers was determined by immunohistochemistry. Cytogenetic analyses were done on a prospective series of 65 patients. Associations with clinicopathologic information and disease-specific survival were assessed.

Results: Fifty-one patients (32%) had type 1 and 107 (68%) type 2 PRCC. Type 2 patients had worse Eastern Cooperative Oncology Group performance status, higher T stages, nodal and distant metastases, higher grades, and a higher frequency of necrosis, collecting system invasion and sarcomatoid features. Type 2 showed greater expression of vascular endothelial growth factor (VEGF)-R2 in the tumor epithelium, and of VEGF-R3 in both tumor epithelium and endothelium. Loss of chromosome 1p, loss of 3p, and gain of 5q were exclusively observed in type 2, whereas type 1 more frequently had trisomy 17. Type 2 PRCC was associated with worse survival than type 1, but type was not retained as an independent prognostic factor. Lower PTEN, lower EpCAM, lower gelsolin, higher CAIX, and higher VEGF-R2 and VEGF-R3 expression, loss of 1p, 3p, or 9p, and absence trisomy 17 were all associated with poorer prognosis.

Conclusions: Type 2 PRCC is associated with more aggressive clinicopathologic features and worse outcome. Molecular and chromosomal alterations can distinguish between PRCC subtypes and influence their prognosis. The effect of 3p loss on survival in PRCC is opposite to the relationship seen in clear cell RCC.
Phase I Trial of 2-Methoxyestradiol NanoCrystal Dispersion in Advanced Solid Malignancies
Authors: Tevaarwerk Amye J. , Holen Kyle D. , Alberti Dona B. , Sidor Carolyn , Arnott Jamie , Quon Check , Wilding George , Liu Glenn
Published: February 2009

Purpose: 2-Methoxyestradiol (2ME2; Panzem) is an endogenous, estradiol-17β metabolite that at pharmacologic doses exerts antimitotic and antiangiogenic activities. Studies with a 2ME2 capsule formulation showed limited oral bioavailability. We report the results of a phase I study using a NanoCrystal Dispersion formulation of 2ME2 (2ME2 NCD).

Experimental Design: Patients with refractory solid tumors received 2ME2 NCD orally. Patients received drug either every 6 hours (part A) or every 8 hours (part B). Doses were escalated in successive cohorts until the maximum tolerated dose (MTD) was identified. The primary objective was identifying the MTD. Secondary objectives were to evaluate the plasma pharmacokinetics of 2ME2 and efficacy.

Results: In part A, 16 patients received a median of 4 cycles of 2ME2 NCD. Dose-limiting toxicities (DLT) included fatigue (2), hypophosphatemia (2), increased alanine aminotransferase (1), and muscle weakness (1). Trough levels at steady-state reached the minimum effective concentration in all cohorts. The MTD was determined to be 1,000 mg orally every 6 hours. In part B, 10 patients received a median of 1 cycle. DLTs included elevated γ-glutamyltransferase (1), hyponatremia (1), fatigue (1), and anorexia (1). An MTD could not be defined for part B because 4 of 10 patients had DLTs at the initial dose level and dose reduction was not pursued. Thirteen patients had stable disease (A, 11; B, 2); there were no confirmed responses.

Conclusion: For 2ME2 NCD, the MTD and recommended phase II regimen is 1,000 mg orally every 6 hours. Treatment was generally well-tolerated.
Pharmacodynamic Effects of Seliciclib, an Orally Administered Cell Cycle Modulator, in Undifferentiated Nasopharyngeal Cancer
Authors: Hsieh Wen-Son , Soo Ross , Peh Bee-Keow , Loh Thomas , Dong Difeng , Soh Donny , Wong Lim-Soon , Green Simon , Chiao Judy , Cui Chun-Ying , Lai Yoke-Fong , Lee Soo-Chin , Mow Benjamin , Soong Richie , Salto-Tellez Manuel , Goh Boon-Cher
Published: February 2009

Purpose: Cell cycle dysregulation resulting in expression of antiapoptotic genes and uncontrolled proliferation is a feature of undifferentiated nasopharyngeal carcinoma. The pharmacodynamic effects of seliciclib, a cyclin-dependent kinase (CDK) inhibitor, were studied in patients with nasopharyngeal carcinoma.

Experimental Design: Patients with treatment-naïve locally advanced nasopharyngeal carcinoma received seliciclib at 800 mg or 400 mg twice daily on days 1 to 3 and 8 to 12. Paired tumor samples obtained at baseline and on day 13 were assessed by light microscopy, immunohistochemistry, and transcriptional profiling using real-time PCR low-density array consisting of a panel of 380 genes related to cell cycle inhibition, apoptosis, signal transduction, and cell proliferation.

Results: At 800 mg bd, one patient experienced grade 3 liver toxicity and another had grade 2 vomiting; no significant toxicities were experienced in 13 patients treated at 400 mg bd. Seven of fourteen evaluable patients had clinical evidence of tumor reduction. Some of these responses were associated with increased tumor apoptosis, necrosis, and decreases in plasma EBV DNA posttreatment. Reduced protein expression of Mcl-1, cyclin D1, phosphorylated retinoblastoma protein pRB (T821), and significant transcriptional down-regulation of genes related to cellular proliferation and survival were shown in some patients posttreatment, indicative of cell cycle modulation by seliciclib, more specifically inhibition of cdk2/cyclin E, cdk7/cyclin H, and cdk9/cyclin T.

Conclusions: Brief treatment with this regimen of seliciclib in patients with nasopharyngeal carcinoma is tolerable at 400 mg bd and associated with tumor pharmacodynamic changes consistent with cdk inhibition, and warrants further efficacy studies in this tumor.
Fascin Regulates Prostate Cancer Cell Invasion and Is Associated with Metastasis and Biochemical Failure in Prostate Cancer
Authors: Darnel Andrew D. , Behmoaram Emy , Vollmer Robin T. , Corcos Jacques , Bijian Krikor , Sircar Kanishka , Su Jie , Jiao Jinsong , Alaoui-Jamali Moulay A. , Bismar Tarek A.
Published: February 2009

Purpose: Prostate cancer metastasis to secondary organs is considered an initial event in the development of hormone refractory disease and remains the major cause of death among prostate cancer patients. In this study, we investigated the role of fascin, a cytoskeleton actin–bundling protein involved in the formation of filopodia and cell migration, in prostate cancer progression.

Experimental Design: Fascin protein expression was examined by immunohistochemistry in a cohort of 196 patients with localized prostate cancer and across several stages of disease progression, including hormone refractory disease. Cellular changes were also assessed in vitro and in vivo in DU145 prostate cancer cell line using fascin gene silencing.

Results: Fascin epithelial expression was significantly up-regulated in localized and hormone refractory prostate cancer compared with benign prostate tissue (P < 0.05). Furthermore, high fascin expression was associated with an increased rate of prostate-specific antigen recurrence following radical prostatectomy (P = 0.075), signifying more aggressive clinical course, thus supporting a function for fascin in prostate cancer progression. In cellular models, fascin gene silencing using small interfering RNA in the androgen-independent prostate cancer cell line DU145 decreased cell motility and invasiveness while increasing cell adhesive properties. In addition, fascin small interfering RNA–expressing DU145 cells implanted orthotopically in mouse prostate showed significantly decreased growth (P < 0.005) and drastically prevented the formation of lymph node metastases (P < 0.001) compared with their matched controls.

Conclusions: Our data show a function of fascin in the regulation of prostate cancer progression and emphasize the importance of fascin as a prognostic marker for aggressive disease and as a potential therapeutic target for advanced androgen independent disease.
AKT/mTOR Pathway Activation and BCL-2 Family Proteins Modulate the Sensitivity of Human Small Cell Lung Cancer Cells to RAD001
Authors: Marinov Marin , Ziogas Algirdas , Pardo Olivier E. , Tan Liwen Terence , Dhillon Tony , Mauri Francesco A. , Lane Heidi A. , Lemoine Nicholas R. , Zangemeister-Wittke Uwe , Seckl Michael J. , Arcaro Alexandre
Published: February 2009

Purpose: The Akt/mammalian target of rapamycin (mTOR) pathway is frequently activated in human cancers and plays an important role in small cell lung cancer (SCLC) biology. We investigated the potential of targeting mTOR signaling as a novel antitumor approach in SCLC.

Experimental Design: The expression of mTOR in patient specimens and in a panel of SCLC cell lines was analyzed. The effects on SCLC cell survival and downstream signaling were determined following mTOR inhibition by the rapamycin derivative RAD001 (Everolimus) or down-regulation by small interfering RNA.

Results: We found elevated expression of mTOR in patient specimens and SCLC cell lines, compared with normal lung tissue and normal lung epithelial cells. RAD001 treatment impaired basal and growth factor–stimulated cell growth in a panel of SCLC cell lines. Cells with increased Akt pathway activation were more sensitive to RAD001. Accordingly, a constitutive activation of the Akt/mTOR pathway was sufficient to sensitize resistant SCLC cells to the cytotoxic effect of RAD001. In the sensitive cells, RAD001 showed a strong additive effect to the proapoptotic action of the chemotherapeutic agent etoposide. Intriguingly, we observed low Bcl-2 family proteins levels in the SCLC cells with a constitutive Akt pathway activation, whereas an increased expression was detected in the RAD001-resistant SCLC cells. An antisense construct targeting Bcl-2 or a Bcl-2–specific inhibitor was able to sensitize resistant SCLC cells to RAD001. Moreover, SCLC tumor growth in vivo was significantly inhibited by RAD001.

Conclusion: Together, our data show that inhibiting mTOR signaling with RAD001 potently disrupts growth and survival signaling in human SCLC cells.
Genetic and Epigenetic SLC18A2 Silencing in Prostate Cancer Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy
Authors: Sørensen Karina Dalsgaard , Wild Peter Johannes , Mortezavi Ashkan , Adolf Katja , Tørring Niels , Heebøll Sara , Ulhøi Benedicte Parm , Ottosen Peter , Sulser Tullio , Hermanns Thomas , Moch Holger , Borre Michael , Ørntoft Torben Falck , Dyrskjøt Lars
Published: February 2009

Purpose: This study investigates SLC18A2 (vesicular monoamine transporter 2) expression in prostate adenocarcinoma and examines its potential as a predictive marker for prostate cancer patient outcome after radical prostatectomy.

Experimental Design: Expression and single nucleotide polymorphism microarray analyses identified SLC18A2 as both down-regulated and subject to common loss-of-heterozygosity in prostate cancer. Down-regulated SLC18A2 expression was validated on tissue microarrays containing benign and malignant prostate specimens from an independent patient group (n = 738). Furthermore, SLC18A2 immunoreactivity in radical prostatectomy tumor specimens (n = 506) was correlated to clinicopathologic characteristics and recurrence-free survival. The possibility of SLC18A2 silencing by aberrant DNA methylation in prostate cancer cells was investigated by bisulfite sequencing.

Results: Tissue microarray analysis revealed markedly lower cytoplasmic SLC18A2 staining in cancer compared with nonmalignant prostate tissue samples, confirming RNA expression profiling results. Furthermore, multivariate analysis identified cytoplasmic SLC18A2 immunoreactivity as a novel predictor of biochemical recurrence following prostatectomy (hazard ratio, 0.485; 95% confidence interval, 0.333-0.709; P < 0.001) independent of prostate-specific antigen, Gleason score, tumor stage, and surgical margin status. SLC18A2 showed loss-of-heterozygosity in 23% of the tumors and was densely hypermethylated in 15 of 17 (88%) prostate cancer samples plus 6 of 6 prostate cancer cell lines. In contrast, SLC18A2 was unmethylated in 4 of 4 adjacent nonmalignant prostate and 3 of 5 benign prostatic hyperplasia tissue samples, whereas 2 of 5 benign prostatic hyperplasia samples had monoallelic hypermethylation. Methylation and histone deacetylase inhibitory agents rescued SLC18A2 expression in three prostate cancer cell lines.

Conclusions: SLC18A2 silencing by DNA hypermethylation and/or allelic loss is a frequent event in prostate cancer and a novel independent predictor of biochemical recurrence after prostatectomy.
Revelations of a Missing Paragraph: Zhu Changwen (1039-1098) and the Compilation of Local Gazetteers in Northern Song China
Authors: Sue Takashi
Published: February 2009

The Supplement to the Illustrated Record of Wu Commandery (Wujun tujing xuji), compiled in 1084 by Zhu Changwen (1039-1098), is one of only two extant Northern Song local gazetteers. An examination of biographical materials reveals that Zhu Changwen wrote his gazetteer in opposition to the New Policies of Wang Anshi (1021-1086); it was intended as a contribution toward a new empire-wide gazetteer that would be required after the abolition of Wang's administrative reorganizations. The detail of Zhu's Supplement anticipates the more comprehensive gazetteers of the late Northern and the Southern Song. Les Notes supplémentaires à la géographie de la commanderie Wu (Wujun tujing xuji), compilées par Zhu Changwen (1039-1098) en 1084, sont l'une des deux seules monographies locales qui nous soient parvenues des Song du Nord. Un examen des matériaux biographiques montre que Zhu Changwen l'avait écrite en adversaire des réformes de Wang Anshi (1021-1086) pour contribuer à une nouvelle monographie nationale devenue nécessaire du fait de l'abolition attendue des réorganisations administratives de Wang Anshi. Par leur contenu, les Notes supplémentaires anticipent les monographies locales plus complètes des derniers Song du Nord et des Song du Sud.
Quantitative description of collagen structure in the articular cartilage of the young and adult equine distal metacarpus
Authors: van Turnhout Mark , Haazelager Monique , Gijsen Merel , Schipper Henk , Kranenbarg Sander , van Leeuwen Johan
Published: February 2009

The orientation and organisation of collagen fibrils play an important role in the mechanical functioning of the articular cartilage (AC) that covers the surfaces in the diarthrodial joints. In the adult animal, typically an arcade like 'Benninghoff structure' is found. Because the remodelling capacity of the collagen network in the adult animal is limited, this Benninghoff structure needs to develop before the animal reaches maturity, and it needs to develop correctly. The aim of this study is to use quantitative polarised light microscopy (qPLM) and scanning electron microscopy (SEM) techniques to investigate if this Benninghoff structure is already present in the young animal, and to quantitatively investigate possible differences in collagen structure in the equine distal metacarpus of the young and adult animal. In total, 21 forelimbs of 13 horses are used. In animals of age 10 months and older, we find an arcade like Benninghoff structure for the collagen fibril network in both the qPLM and SEM study. The qPLM study shows that the collagen's predominant orientation is parallel to the articular surface throughout the entire cartilage depth in two animals directly after birth. These findings are supported by SEM results on a foal. We conclude that structural remodelling of the collagen network in AC occurs in the first months after birth. Because animals start with collagen parallel to the articular surface and need to remodel this structure to a Benninghoff architecture, and because collagen structure is an important parameter for AC mechanics and mechanobiology, these results suggest implications for AC epigenetics.
Looking for the ants: selection of oviposition sites by two myrmecophilous butterfly species
Authors: Wynhoff Irma , Grutters Mark , van Langevelde Frank
Published: February 2009

Obligate myrmecophilous butterfly species, such as Maculinea teleius and M. nausithous that hibernate as caterpillar in nests of the ant species Myrmica scabrinodis and M. rubra respectively, have narrowly defined habitat requirements. One would expect that these butterflies are able to select for sites that meet all their requirements. Both butterfly species occur in habitats where their initial larval resource, the host plant Sanguisorba officinalis, is abundant, while the ant nests are relatively less abundant. With ants in the proximity of a host plant, caterpillars have a chance of being found by their host ant species, while the host plant could become a sink as caterpillars will die when there are no ants close to the host plant. We tested whether females oviposit on host plants in the close proximity of host ants (ant-mediated oviposition) or whether there is random oviposition, using 587 1-m2 plots in and around a nature reserve in The Netherlands where both species were reintroduced. We found that females of both species indeed more often deposit eggs on host plants nearby ants than on host plants without ants. Visits of adult butterflies to plots with the host plant but without the host ants only occurred in years with high butterfly densities. We argue that understanding site selection for oviposition is important for these highly endangered butterfly species with a specialised life cycle, especially after disturbances or reintroductions.
Plasticity in flood-avoiding behaviour in two congeneric riparian wolf spiders
Authors: Lambeets Kevin , Maelfait Jean-Pierre , Bonte Dries
Published: February 2009

The ecological effects of disrupted flooding are known to be pernicious for the occurring riparian fauna. As flooding disturbance is argued to structure species assemblages, behavioural aspects may be affected just as well. Generally, eurytopic inhabitants possess a well-developed dispersal ability allowing frequent recolonization, whereas specialized stenotopic species are expected to be adapted to these stress regimes. This study aims at determining whether flooding induces different behavioural responses in two congeneric wolf spider species. Variation in flood-avoiding behaviour was evaluated by means of individual tests performed under different ambient conditions. We considered sheltering behaviour preceding flooding, a direct flight reflex induced by the flood event, an escape reaction away from the rising water and submersion tolerance. Our findings indicated clear flood-avoiding behaviour for both species, yet a higher degree of plasticity in individual behaviour for a riparian wolf spider (Pardosa agricola) in contrast to a generalist species (P. amentata). Nonetheless the former species systematically reacted under different ambient conditions, a generalist shifts responses, displaying a higher degree of between-individual variation. Submersion tolerance was equivalent, emphasizing similar morphological characteristics. We argue habitat specialization and/or experience with local conditions to influence behavioural responses in order to optimize long-term persistence under flood stress. Future studies of behavioural variation should consider temporal variation in species condition, thus employing distinct populations thriving under different local stress regimes.
Armenia in Chinese Sources
Authors: Yingsheng Liu , Kauz Ralph
Published: February 2009

This paper discusses several toponyms in Chinese sources, which may possibly be identified with Armenia. First, Aman country, which can be found in the "History of the Later Han" (compiled 3rd–5th centuries) and in the "Account of the Wei Dynasty" (compiled between 239 and 265), is discussed, and it is suggested that there are reasons for an identification, though doubts remain. Armenia was well known by the Mongols and the "Korean Worldmap", which originates in Chinese geographical scholarship during the Mongol period and depicts possibly even Greater and Lesser Armenia. Another source of that period that mentions Armenia is "Muslim Prescriptions" (Huihui yaofang), which names Armenian materia medica known in China. Finally, two other Chinese geographical texts of the 16th and early 18th century that deal with Armenia and the Caucasus region are discussed. This paper shows that Armenia was described in Chinese texts since at least the Mongol period, and that China had a profound knowledge of the geographical situation in Western Asia.
The Lost Sanjaq
Authors: Nicolaus Peter
Published: February 2009

The seven sanjaqs, or sacred images of Malak Tawus, are the most concrete expression of Yezidism and considered the holiest of the holy ritual objects of that religion. Only a handful of non-Yezidis have ever seen one, and very little is known about them. The latter holds, in particular, true with regard to the so-called Moskovi-sanjaq. Before World War I it was sent to the Russian Empire (East Anatolia and the Transcaucasus) every year, but was reported lost in 1914.Based on numerous interviews with Yezidis in Armenia, as well as on official correspondence between British, Iraqi, and Soviet authorities, the first part of the article reconstructs the odyssey of the Moskovi-sanjaq and the seven priests (qewwals) carrying it. It confirms that after 16 years of wandering through the Transcaucasus, five of the seven qewwals were eventually able to return via Odessa and London to the Yezidi heartland in Northern Iraq, but concludes that the Moskovi-sanjaq was ultimately lost in Georgia—confiscated by the Soviet authorities.The second part of the paper describes the history of a second sanjaq, which the author discovered in a village near Yerevan, secretly kept and protected from the prying eyes of non-Yezidis by a sheikhly family. Although all tales and myths, explaining how this second sanjaq arrived in Armenia, are examined and analysed, the origin of that sacred image remains mysterious. The article further paints a detailed picture of the cult, which evolved around the sacred image in Armenia as well as of the—sometimes savage—fights over its possession and the struggle of the keepers of the sanjaq with the Soviet authorities. In addition to interviews with eyewitnesses, the author bases his findings on court decisions and minutes of the councils of Yezidi elders, as well as information found at Yezidi graveyards.
Rituals of Birth among the Adyghes
Authors: Djandar Mariet
Published: February 2009

Rituals of childbirth make up an important part of life in traditional Adyghe society. The author provides a detailed description of these rituals, paying special attention not only to the birth itself, but also to the rituals and ceremonies practiced during the entire period of pregnancy, the behaviour of the mother-to-be, and her social status before and after the birth in the house of her husband. In a number of cases original ritual songs with translation are also included. The research is predominantly based on field-records of the author and archive materials.Of all the rituals associated with childhood in this survey, only some of them are practiced now, though sporadically. Others have been consigned to oblivion.
Some Laki Demons
Authors: Yusefvand Reza
Published: February 2009

The Laks are a West Iranian ethnic group linguistically closely related to the Lurs and the Kurds. They mainly inhabit the provinces of Luristan, Kirmanshah, Ilam, and Hamadan in the Islamic Republic of Iran, as well as Kirkuk and Khanaqin in Iraq. The paper presents some imaginary figures from the folk beliefs of the Laks, recorded by the author within the framework of a larger project on the ethnography and folklore of the Laks.
Parthisch uzbar(i) und georgisch zvari
Authors: Bielmeier Roland
Published: February 2009

This paper shows that Georgian zvari, Old Georgian zwari "large vineyard, wine-growing estate" is a direct loan, without Armenian transmission, from Sasanian Parthian *(i)zßar going back to Arsacid Parthian uzbar(i) with the meaning "subject to taxation, profitable" and denoting a certain category of vineyard of an estate in the Parthian Economic Documents from Nisa of the 1st century B.C. Its Old Persian correspondence was also current as a loan in Late Babylonian with the meaning "crown land". The Georgian form is documented twice in the Old Testament: 1 Samuel 22,7 showing that a zwari consisted of several venaq'i "vineyard"; and in 1 Samuel 8,12 mezware "guard or keeper of a zwari", misread in the Mc'xet'a Bible but correct in the Oški Bible. A further mistake in the Mc'xet'a Bible shows that its Georgian translator misinterpreted the Armenian model. Again, the differring text in the Oški Bible is correct. The word is mentioned by Sulxan-Saba Orbeliani in the 17th century and was explained by Niko Č'ubinašvili and his nephew Davit' Č'ubinašvili by a folk etymology connecting it with mzvare "sunny place", an erroneous explanation, which has also crept into modern publications.
Words from Kelārdašt
Authors: Mir-Sadeqi Mehdi
Published: February 2009

The paper introduces some lexical items, with etymological notes and comparative material, recorded during linguistic fieldwork carried out in the villages of Lāhū, Majal, and Ojābeyt of the Kelārdašt region in Māzandarān, Iran.
Culture, Policy, and Scholarship in the Subcaucasian Region: (Some Critical Remarks and a Methodological Survey)
Authors: Zekiyan Boghos Levon
Published: February 2009

The mutual interaction of culture and policy, and its influence on scholarship is attested in history. Even today this influence is often remarkable in the various fields of humanities, especially in extra-European contexts.The topics, which most frequently became the object of analogous polemics in Caucasian and Subcaucasian studies, can be summed up as follows: a) the question of identities, that is how to define the ethnic, cultural, political, and religious belonging of persons, regions, and objects; b) the question of cultural influences and interactions, that is the question, who and which side influenced the other in those cases in which similar historical phenomena or artistic expressions are discernible in different ethnic or religious groups, or state structures.Obviously, in all these questions strong predicaments of various natures, which can be combined under the common denominator of extra-scholarly factors, play a big role: namely they do not allow or make very difficult a passionless approach and a balanced discussion of the subject.Since the field of discussion is extremely large, the present inquiry takes into consideration only some specific cases in which the role of extra-scholarly factors seems to have major relevance. Moreover, these cases put in a clearer light the gaps of the conceptual frame and of the methodological procedures used in approaching the subject.
Turkish Views on Christians: Implications for Armenian-Turkish Relations
Authors: Kluge Pascal
Published: February 2009

Samuel Huntington argues in The Clash of Civilizations that a principal cultural fault line is to be found between the Muslim world and the Western non-Muslim world. In this context it is not surprising that the Christian West often assumes Muslims to be suspicious or even hostile towards Christians. Periodic cases of anti-Christian public statements and actions support this impression and are indicative of profound inter-religious tensions. This notion also influences the relations between peoples and nations. In the South-Caucasian case, the Armenian-Turkish relations are affected most by this phenomenon. When conflicts arise, religion plays a role in the perception of the Other. What is needed, therefore, is more inter-religious understanding on all societal levels. Although politics play a key role in establishing friendly ties between nations, it is the grassroots of the population upon which fruitful relations stand and which secure a more consistent quality to the results of political efforts. When considering Turkish views on Christians, field research indicates that the average Turk harbours an overall benevolent view of Christians and, therefore, that there exists considerable potential for successful inter-religious dialogue. Christians are generally regarded with respect, and most Turkish participants showed little to no negative attitudes towards them. The Christians of Turkey, notably Armenians and Greeks, were, furthermore, perceived as part of Turkey's society. The reason for these predominantly positive attitudes may be sought in the institutional incorporation of Christians and Jews into the broader context of Islamic society or, more inherent to Turkish history, in the positive remembrance of the multi-religious and multi-ethnic face of the Ottoman Empire—and thus in the appreciation of religious diversity as an asset and historical obligation.