bluuebunny/crossref_metadata_2025_split huggingface dataset:
S100B Promotes Glioma Growth through Chemoattraction of Myeloid-Derived Macrophages
Authors: Wang Huaqing , Zhang Leying , Zhang Ian Y. , Chen Xuebo , Da Fonseca Anna , Wu Shihua , Ren Hui , Badie Sam , Sadeghi Sam , Ouyang Mao , Warden Charles D. , Badie Behnam 
Published: May 2013

AbstractPurpose: S100B is member of a multigenic family of Ca2+-binding proteins, which is overexpressed by gliomas. Recently, we showed that low concentrations of S100B attenuated microglia activation through the induction of Stat3. We hypothesized that overexpression of S100B in gliomas could promote tumor growth by modulating the activity of tumor-associated macrophages (TAM).Experimental Design: We stably transfected GL261 glioma cell lines with constructs that overexpressed (S100Bhigh) or underexpressed (S100Blow) S100B and compared their growth characteristics to intracranial wild-type (S100Bwt) tumors.Results: Downregulation of S100B in gliomas had no impact on cell division in vitro but abrogated tumor growth in vivo. Interestingly, compared to S100Blow tumors, S100Bwt and S100Bhigh intracranial gliomas exhibited higher infiltration of TAMs, stronger inflammatory cytokine expression, and increased vascularity. To identify the potential mechanisms involved, the expression of the S100B receptor, receptor for advanced glycation end products (RAGE), was evaluated in gliomas. Although S100B expression induced RAGE in vivo, RAGE ablation in mice did not significantly inhibit TAM infiltration into gliomas, suggesting that other pathways were involved in this process. To evaluate other mechanisms responsible for TAM chemoattraction, we then examined chemokine pathways and found that C-C motif ligand 2 (CCL2) was upregulated in S100Bhigh tumors. Furthermore, analysis of The Cancer Genome Atlas's glioma data bank showed a positive correlation between S100B and CCL2 expression in human proneural and neural glioma subtypes, supporting our finding.Conclusions: These observations suggest that S100B promotes glioma growth by TAM chemoattraction through upregulation of CCL2 and introduces the potential utility of S100B inhibitors for glioma therapy. Clin Cancer Res; 19(14); 3764–75. ©2013 AACR.
RRM2 Regulates Bcl-2 in Head and Neck and Lung Cancers: A Potential Target for Cancer Therapy
Authors: Rahman Mohammad Aminur , Amin A.R.M. Ruhul , Wang Dongsheng , Koenig Lydia , Nannapaneni Sreenivas , Chen Zhengjia , Wang Zhibo , Sica Gabriel , Deng Xingming , Chen Zhuo (Georgia) , Shin Dong M. 
Published: May 2013

Abstract
Purpose: Ribonucleotide reductase subunit M2 (RRM2) plays an active role in tumor progression. Recently, we reported that depletion of RRM2 by systemic delivery of a nanoparticle carrying RRM2-specific siRNA suppresses head and neck tumor growth. The aim of this study is to clarify the underlying mechanism by which RRM2 depletion inhibits tumor growth.
Experimental Design: siRNA-mediated gene silencing was carried out to downregulate RRM2. Immunoblotting, reverse-transcriptase PCR, confocal microscopy, tissue fractionation, gene overexpression and knockdown were employed to analyze critical apoptosis signaling. Conventional immunohistochemistry and quantum dot-based immunofluorescence were applied to detect RRM2 and Bcl2 expression and localization in tissue samples from patients and mice.
Results: Knockdown of RRM2 led to apoptosis through the intrinsic pathway in head and neck squamous cell carcinoma (HNSCC) and non–small cell lung cancer (NSCLC) cell lines. We showed that Bcl-2 is a key determinant controlling apoptosis, both in vitro and in vivo, and that RRM2 depletion significantly reduces Bcl-2 protein expression. We observed that RRM2 regulates Bcl-2 protein stability, with RRM2 suppression leading to increased Bcl-2 degradation, and identified their colocalization in HNSCC and NSCLC cells. In a total of 50 specimens each from patients with HNSCC and NSCLC, we identified the colocalization of Bcl-2 and RRM2 and found a significant positive correlation between their expression in HNSCC (R = 0.98; P &lt; 0.0001) and NSCLC (R = 0.92; P &lt; 0.0001) tumor tissues.
Conclusions: Our novel findings add to the knowledge of RRM2 in regulating expression of the antiapoptotic protein Bcl-2 and reveal a critical link between RRM2 and Bcl-2 in apoptosis signaling. Clin Cancer Res; 19(13); 3416–28. ©2013 AACR.
TLR4 Is a Novel Determinant of the Response to Paclitaxel in Breast Cancer
Authors: Rajput Sandeep , Volk-Draper Lisa D. , Ran Sophia 
Published: May 2013

Abstract
Overexpression of Toll-like receptor-4 (TLR4) in human tumors often correlates with chemoresistance and metastasis. We found that TLR4 is overexpressed in the majority of clinical breast cancer samples and in 68% of the examined breast cancer lines. TLR4 is activated by lipopolysaccharide (LPS) and other ligands including the widely used drug paclitaxel. LPS is frequently used to show a tumor-promoting role of TLR4 although this bacterial component is unlikely to be found in the breast cancer environment. We reasoned that paclitaxel-dependent activation of TLR4 is more relevant to breast cancer chemoresistance that could be mediated by activation of the NF-κB pathway leading to upregulation of prosurvival genes. To test this hypothesis, we correlated TLR4 expression with resistance to paclitaxel in two modified breast cancer lines with either depleted or overexpressed TLR4 protein. Depletion of TLR4 in naturally overexpressing MDA-MB-231 cells downregulated prosurvival genes concomitant with 2- to 3-fold reduced IC50 to paclitaxel in vitro and a 6-fold decrease in recurrence rate in vivo. Conversely, TLR4 overexpression in a negative cell line HCC1806 significantly increased expression of inflammatory and prosurvival genes along with a 3-fold increase of IC50 to paclitaxel in vitro and enhanced tumor resistance to paclitaxel therapy in vivo. Importantly, both tumor models showed that many paclitaxel-upregulated inflammatory cytokines were coinduced with their receptors suggesting that this therapy induces autocrine tumor-promoting loops. Collectively, these results show that paclitaxel not only kills tumor cells but also enhances their survival by activating TLR4 pathway. These findings suggest that blocking TLR4 could significantly improve response to paclitaxel therapy. Mol Cancer Ther; 12(8); 1676–87. ©2013 AACR.
Pten-Null Tumors Cohabiting the Same Lung Display Differential AKT Activation and Sensitivity to Dietary Restriction
Authors: Curry Natasha L. , Mino-Kenudson Mari , Oliver Trudy G. , Yilmaz Ömer H. , Yilmaz Vedat O. , Moon Jade Y. , Jacks Tyler , Sabatini David M. , Kalaany Nada Y. 
Published: May 2013

Abstract
PTEN loss is considered a biomarker for activated phosphoinositide 3-kinase (PI3K)/AKT, a pathway frequently mutated in cancer, and was recently shown to confer resistance to dietary restriction. Here, we show that Pten loss is not sufficient to drive AKT activation and resistance to dietary restriction in tumors with low growth factor receptor levels. We describe a murine Pten-null Kras-driven lung cancer model that harbors both dietary restriction–resistant, higher-grade, bronchiolar tumors with high AKT activity, and dietary restriction–sensitive, lower-grade, alveolar tumors with low AKT activity. We find that this phenotype is cell autonomous and that normal bronchiolar cells express higher levels of insulin-like growth factor-I receptor (IGF-IR) and of ectonucleoside triphosphate diphosphohydrolase 5 (ENTPD5), an endoplasmic reticulum enzyme known to modulate growth factor receptor levels. Suppression of ENTPD5 is sufficient to decrease IGF-IR levels and sensitize bronchiolar tumor cells to serum in vitro and to dietary restriction in vivo. Furthermore, we find that a significant percentage of human non–small cell lung carcinomas (NSCLC) have low AKT activity despite PTEN loss.
Significance: Our studies point to a heterogeneity of AKT activation in the same murine Pten-null lung tissue and in human NSCLC, further underscoring the challenges of personalizing cancer therapy based solely on cancer genotype. Our findings therefore indicate that the tumor response to anticancer therapies, including dietary restriction, needs to be based on PI3K/AKT activity per se, rather than on genetic alterations in the PTEN/PI3K pathway. Cancer Discov; 3(8); 908–21. ©2013 AACR.
This article is highlighted in the In This Issue feature, p. 826
Effects of Synoptic-Scale Control on Long-Term Declining Trends of Summer Fog Frequency over the Pacific Side of Hokkaido Island
Authors: Sugimoto Shiori , Sato Tomonori , Nakamura Kazuki 
Published: May 2013

AbstractIn this study, long-term visibility data for the Pacific Ocean side of Hokkaido Island, northeast Japan, are investigated to clarify the relationship between interannual variation in summer fog frequency (FF) and large-scale circulation patterns. At Kushiro, a significant FF decrease is found during 1931–2010 even without the influence of the observatory's relocation after 2000. In particular, since the late 1970s, a linear declining trend has accelerated, as evidenced by an increased number of years with very low FF in July and August. To clarify the climatological factor causing the summer FF declining trend at Kushiro, atmospheric vertical conditions in the planetary boundary layer and large-scale circulation are examined during 1989–2009 and 1958–2002, respectively, using available datasets. Composite analyses that are based on radiosonde observations reveal that the shallow fog layer is covered with a strong inversion layer during fog days whereas the inversion layer is absent during nonfog days. Composite circulation anomalies for the low-FF years at Kushiro show an intensified Okhotsk high (OH) pressure feature and southward shrinking of the North Pacific high (NPH) in July, in addition to the eastward displacement or shrinking of the NPH in August. These anomalous synoptic circulation patterns cause weakening in the southerly–southeasterly wind, which reduces sea-fog advection toward Kushiro and prevents the formation of stable stratification over the sea-fog layer. The authors suggest that the interannual variation in summer FF with the recent accelerated decline at Kushiro is primarily controlled by changes in the synoptic circulation associated with the OH and NPH development.
Dynamical Downscaling Projections of Twenty-First-Century Atlantic Hurricane Activity: CMIP3 and CMIP5 Model-Based Scenarios
Authors: Knutson Thomas R. , Sirutis Joseph J. , Vecchi Gabriel A. , Garner Stephen , Zhao Ming , Kim Hyeong-Seog , Bender Morris , Tuleya Robert E. , Held Isaac M. , Villarini Gabriele 
Published: May 2013

Abstract
Twenty-first-century projections of Atlantic climate change are downscaled to explore the robustness of potential changes in hurricane activity. Multimodel ensembles using the phase 3 of the Coupled Model Intercomparison Project (CMIP3)/Special Report on Emissions Scenarios A1B (SRES A1B; late-twenty-first century) and phase 5 of the Coupled Model Intercomparison Project (CMIP5)/representative concentration pathway 4.5 (RCP4.5; early- and late-twenty-first century) scenarios are examined. Ten individual CMIP3 models are downscaled to assess the spread of results among the CMIP3 (but not the CMIP5) models. Downscaling simulations are compared for 18-km grid regional and 50-km grid global models. Storm cases from the regional model are further downscaled into the Geophysical Fluid Dynamics Laboratory (GFDL) hurricane model (9-km inner grid spacing, with ocean coupling) to simulate intense hurricanes at a finer resolution.
A significant reduction in tropical storm frequency is projected for the CMIP3 (−27%), CMIP5-early (−20%) and CMIP5-late (−23%) ensembles and for 5 of the 10 individual CMIP3 models. Lifetime maximum hurricane intensity increases significantly in the high-resolution experiments—by 4%–6% for CMIP3 and CMIP5 ensembles. A significant increase (+87%) in the frequency of very intense (categories 4 and 5) hurricanes (winds ≥ 59 m s−1) is projected using CMIP3, but smaller, only marginally significant increases are projected (+45% and +39%) for the CMIP5-early and CMIP5-late scenarios. Hurricane rainfall rates increase robustly for the CMIP3 and CMIP5 scenarios. For the late-twenty-first century, this increase amounts to +20% to +30% in the model hurricane’s inner core, with a smaller increase (~10%) for averaging radii of 200 km or larger. The fractional increase in precipitation at large radii (200–400 km) approximates that expected from environmental water vapor content scaling, while increases for the inner core exceed this level.
Lidar-Observed Stress Vectors and Veer in the Atmospheric Boundary Layer
Authors: Berg Jacob , Mann Jakob , Patton Edward G. 
Published: May 2013

Abstract
This study demonstrates that a pulsed wind lidar is a reliable instrument for measuring angles between horizontal vectors of significance in the atmospheric boundary layer. Three different angles are considered: the wind turning, the angle between the stress vector and the mean wind direction, and the angle between the stress vector and the vertical gradient of the mean velocity vector. The latter is assumed to be zero by the often applied turbulent-viscosity hypothesis, so that the stress vector can be described through the vertical gradient of velocity. In the atmospheric surface layer, where the Coriolis force is negligible, this is supposedly a good approximation. High-resolution large-eddy simulation data show that this is indeed the case even beyond the surface layer. In contrast, through analysis of WindCube lidar measurements supported by sonic measurements, the study shows that it is only valid very close to the surface. The deviation may be significant even at 100 m. This behavior is attributed to mesoscale effects.
Clinical features and axis I comorbidity of Australian adolescent pathological Internet and video game users
Authors: King Daniel L , Delfabbro Paul H , Zwaans Tara , Kaptsis Dean 
Published: May 2013

Objectives: Although there is growing international recognition of pathological technology use (PTU) in adolescence, there has been a paucity of empirical research conducted in Australia. This study was designed to assess the clinical features of pathological video gaming (PVG) and pathological Internet use (PIU) in a normative Australian adolescent population. A secondary objective was to investigate the axis I comorbidities associated with PIU and video gaming. Method: A total of 1287 South Australian secondary school students aged 12–18 years were recruited. Participants were assessed using the PTU checklist, Revised Children’s Anxiety and Depression Scale, Social Anxiety Scale for Adolescents, revised UCLA Loneliness Scale, and Teenage Inventory of Social Skills. Adolescents who met the criteria for PVG or PIU or both were compared to normal adolescents in terms of axis I comorbidity. Results: The prevalence rates of PIU and PVG were 6.4% and 1.8%, respectively. A subgroup with co-occurring PIU and PVG was identified (3.3%). The most distinguishing clinical features of PTU were withdrawal, tolerance, lies and secrecy, and conflict. Symptoms of preoccupation, inability to self-limit, and using technology as an escape were commonly reported by adolescents without PTU, and therefore may be less useful as clinical indicators. Depression, panic disorder, and separation anxiety were most prevalent among adolescents with PIU. Conclusions: PTU among Australian adolescents remains an issue warranting clinical concern. These results suggest an emerging trend towards the greater uptake and use of the Internet among female adolescents, with associated PIU. Although there exists an overlap of PTU disorders, adolescents with PIU appear to be at greater risk of axis I comorbidity than adolescents with PVG alone. Further research with an emphasis on validation techniques, such as verified identification of harm, may enable an informed consensus on the definition and diagnosis of PTU.
Anemia increases the risk of renal cortical and medullary hypoxia during cardiopulmonary bypass
Authors: Darby PJ , Kim N , Hare GMT , Tsui A , Wang Z , Harrington A , Mazer CD 
Published: May 2013

Introduction: Anemia is an independent predictor of acute kidney injury (AKI) following cardiopulmonary bypass (CPB), possibly due to inadequate renal oxygen delivery. The objective of this study was to investigate the effects of CPB and anemia on tissue oxygen tension (pO2) and blood flow in the renal cortex and medulla. Methods: Rats (n=6/group) underwent 1hr of normothermic cardiopulmonary bypass (CPB), with target hemoglobin concentrations (Hb) of 10g/dL (CPB) or 6.5g/dL (anemia-CPB). Renal blood flow (RBF) and tissue PO2 were measured before, during and after 1hr of CPB. To confirm the observed differences in renal cortical and medullary PO2, HIF-1α (ODD) luciferase mice were exposed to 8% O2 (hypoxia) and HIF-1α dependent luminescence was measured in the renal cortex and medulla (n=5). Results: Renal tissue PO2 values decreased initially and returned towards baseline, however, values at the end of CPB. Anemia-CPB resulted in a significant increase in both renal cortical and medullary blood flow, PO2 remained significantly reduced throughout anemia-CPB. Renal medullary HIF-1α-dependent luminescence confirmed a greater degree of hypoxia in the renal medulla. Discussion: During CPB, renal O2 delivery was transiently jeopardized, but recovered after 1hr. Anemia-CPB resulted in a dramatic and sustained reduction in renal cortical and medullary PO2, which suggests an increased risk of renal hypoxic injury with anemia. Conclusion: The clear difference in the degree of hypoxia in the renal cortex and medulla may be useful in understanding the progress of medullary hypoxia during CPB with anemia and the potential development of AKI. Further studies should aim at identifying early markers of medullary hypoxia and potential agents that may decrease the work and O2 consumption in the renal medulla to reduce the risk of hypoxic damage during CPB and anemia.
Preventive treatment for migraine in primary care, a population-based study in the Netherlands
Authors: Dekker F , Dieleman JP , Neven A Knuistingh , Ferrari MD , Assendelft WJJ 
Published: May 2013

Background Preventive treatment of migraine contributes to reducing the impact of migraine but its extent of use in routine care is unknown. Objective The objective of this article is to assess current use, previous use, duration and course of preventive treatment of migraine in Dutch general practice. Methods We conducted a retrospective cohort study, for the period between 1997 and 2007, in the Interdisciplinary Processing of Clinical Information (IPCI) database, a GP research database in the Netherlands (source population of more than half a million subjects). All prevalent and incident migraine patients ( N = 7367) were included. Results About 13% of all migraine patients currently use preventive therapy and almost half of migraine patients have prior use. Of those starting with preventive treatment, 56% (95% CI: 54.3–64.7) still used it after nine months. There was a long delay between migraine diagnosis and preventive treatment start. Forty-four percent (95% CI 43.0–45.7) started preventive therapy in the study period. Conclusion This large primary-care database study shows that a limited number of patients are current users of preventive treatment, but many patients have prior use. After diagnosis there is often an extended time before preventive treatment is applied. Also there is often only one attempt. The continuation in time seems appropriate. Preventive therapy in migraine still deserves focus.
Occipital nerve stimulation in medically intractable, chronic cluster headache. The ICON study: Rationale and protocol of a randomised trial
Authors: Wilbrink Leopoldine A , Teernstra Onno PM , Haan Joost , van Zwet Erik W , Evers Silvia MAA , Spincemaille Geert H , Veltink Peter H , Mulleners Wim , Brand Ronald , Huygen Frank JPM , Jensen Rigmor H , Paemeleire Koen , Goadsby Peter J , Visser-Vandewalle Veerle , Ferrari Michel D 
Published: May 2013

Background About 10% of cluster headache patients have the chronic form. At least 10% of this chronic group is intractable to or cannot tolerate medical treatment. Open pilot studies suggest that occipital nerve stimulation (ONS) might offer effective prevention in these patients. Controlled neuromodulation studies in treatments inducing paraesthesias have a general problem in blinding. We have introduced a new design in pain neuromodulation by which we think we can overcome this problem. Methods/design We propose a prospective, randomised, double-blind, parallel-group international clinical study in medically intractable, chronic cluster headache patients of high- versus low-amplitude ONS. Primary outcome measure is the mean number of attacks over the last four weeks. After a study period of six months there is an open extension phase of six months. Alongside the randomised trial an economic evaluation study is performed. Discussion The ICON study will show if ONS is an effective preventive therapy for patients suffering medically intractable chronic cluster headache and if there is a difference between high- and low-amplitude stimulation. The innovative design of the study will, for the first time, assess efficacy of ONS in a blinded way.
Posterolateral Corner Reconstruction Using the Single Fibular Sling Method for Posterolateral Rotatory Instability of the Knee
Authors: Yang Byoung Se , Bae Woo Han , Ha Jeong Ku , Lee Dhong Won , Jang Hyoung Won , Kim Jin Goo 
Published: May 2013

Background: Recently, posterolateral corner (PLC) reconstruction techniques have been developed based on an anatomic study of cadaveric dissections. However, the best operative method for various anatomic reconstructions remains controversial. Hypothesis: The anatomic single fibular sling method for PLC reconstruction would be sufficiently strong to control posterolateral rotatory instability without an additional tibial sling. Study Design: Case series; Level of evidence, 4. Methods: This retrospective cohort study analyzed 60 knees in 60 patients who underwent anatomic PLC reconstruction using the single fibular sling method with a tibialis anterior allograft, with a minimum follow-up period of 2 years. Ninety percent of the patients had concomitant reconstruction of one or both cruciate ligaments. Preoperative and postoperative dial test, varus stress test, and subjective clinical outcomes including Lysholm score, International Knee Documentation Committee (IKDC) subjective scores, and stress radiographs, including varus and posterior stress, were compared. In addition, intraoperative arthroscopic findings were analyzed. Results: The mean length of clinical follow-up was 35.6 months (range, 24-65 months). Forty-two (70%) patients showed no rotational instability postoperatively. Varus laxity improved, with 96.7% of the patients assessed as grade 0 or 1. The mean side-to-side difference in varus stress test was reduced from 2.32 ± 1.33 mm preoperatively to 0.37 ± 1.48 mm postoperatively. Posterior stress radiography in combined posterior cruciate ligament reconstruction showed a mean posterior tibial translation of 14.7 ± 2.83 mm preoperatively and 4.06 ± 1.40 mm at final follow-up. The Lysholm and IKDC subjective scores improved from 52 ± 6.7 to 87.7 ± 12.3 and from 44.8 ± 6.3 to 77.6 ± 14.2 ( P < .001), respectively. There were no significant differences in clinical outcome or varus laxity between isolated PLC and combined injuries. Conclusion: Anatomic PLC reconstruction using a single fibular sling method is an effective and relatively simple procedure for most patients with posterolateral rotatory instability, with the exception of those with severe multiple injuries.