bluuebunny/crossref_metadata_2025_split huggingface dataset:
Low cardiorespiratory fitness in young adulthood and future risk of disability pension: a follow-up study until 59 years of age in Swedish men
Authors: Rabiee Rynaz , Agardh Emilie , Kjellberg Katarina , Falkstedt Daniel 
Published: October 2014

BackgroundThere is a strong belief in the potential of increased physical activity to improve the health of populations. The objective of the present study was to estimate the association between low cardiorespiratory fitness in young adulthood and subsequent health impairment until middle age, measured by disability pension.MethodsThe study utilised data on cardiorespiratory fitness and a number of covariates (social background, health behaviours and psychological characteristics) from the Swedish Conscription Cohort of 1969/1970 including 49 321 men born in 1949–1951, and data on disability pension from 1971 to 2008 (20–59 years of age) through record linkage with two national insurance databases. Cox proportional-hazards regressions yielded hazard ratios (HR) with 95% confidence intervals (CI).ResultsHaving low-level or mid-level cardiorespiratory fitness in late adolescence was associated with an increased HR of disability pension across the follow-up (HR for low fitness: 1.85, CI 1.71 to 2.00; HR for mid-level fitness: 1.40, CI 1.31 to 1.50). The association was stronger with earlier disability pensions than with later disability pensions, which was also seen after multiple confounding adjustments. At the same time, these adjustments revealed considerable confounding of the association by individual differences in psychological characteristics in particular.ConclusionsLower levels of cardiorespiratory fitness in young adulthood were found to be associated with an increased HR of disability pension throughout the follow-up until 59 years of age, even after adjustment for important confounding factors measured in late adolescence. Increased physical fitness may thus have a lowering effect on the risk of disability pension.
Vessel sealing versus suture ligation for canine ovarian pedicle haemostasis: a randomised clinical trial
Authors: Schwarzkopf I. , Van Goethem B. , Vandekerckhove P. M. , de Rooster H. 
Published: October 2014

Vessel sealing (VS) is well established in laparoscopic ovariectomy (OVE) in dogs. The objectives of this study were to evaluate the efficacy of ovarian pedicle haemostasis by VS using a commercially available VS tool in open OVE and compare it with suture ligation (SL). A prospective, randomised clinical trial including 20 female dogs was designed. Open OVE was performed via a standard mid‐line celiotomy by a single surgeon using a standardised protocol. At random, the right ovarian pedicle was sealed (VS) or ligated (SL) whereas the left pedicle was treated by the alternative technique. Surgical times for procedural stages and intra‐operative complications were recorded and statistically evaluated. Total surgical time was 29.28±11.13 minutes (range 12.50–62.13 minutes) and time from identification to removal of the ovary was significantly less when sealing (VS 2.22±0.58 minutes) than when ligating (SL 4.10±1.13 minutes P=0.0001). Intra‐operative complications were rare for both techniques (failure of the electrode of the VS device (n=3); ovarian pedicle haemorrhage due to ligature slippage (n=1)). The results of the current study indicate that ovarian pedicle haemostasis achieved by VS is significantly faster than by placement of ligatures without appearing to compromise safety.
Alba Field – how seismic technologies have influenced reservoir characterization and field development
Authors: Moore Ian 
Published: October 2014

Abstract
As giant oil fields mature, the flow of results from development drilling and production history, as well as interpretations of new seismic data, provide an evolving view of in-place volumes, reservoir architecture and fluid movement through the reservoir. Often, such changes can trigger modifications to asset development plans and, together with economic conditions, revisions to estimates of ultimate recovery.
The development of the Alba Field – a relatively heavy oil (19° API) accumulation lying in an Eocene deep-water channel complex in Block 16/26 of the UK's Central North Sea – has followed a similar pattern. With an estimated 900 mmbbl of oil in place, the reservoir is characterized by thick, high net-to-gross (NTG) sands with extremely favourable reservoir properties. Because of the less favourable mobility ratio, Alba has been developed exclusively by horizontal production wells, with pressure support provided by a series of seawater injectors.

By mid-2012, after 18 years of production, more than 390 mmbbl of oil had been recovered. During production, several key seismic and drilling technologies were applied to address reservoir complexities and reservoir management concerns that emerged as field development progressed. The most significant of these include the following:

a dramatic uplift in imaging the depositional architecture was provided by converted shear wave seismic data (1998), revealing an extremely irregular top reservoir and hinting at greater internal complexity than initially modelled;

advances in extended reach drilling technology enabled a greater number of infill targets to be accessed, while geosteering techniques allowed better well placement, and horizontal completions using gravel packs improved well reliability;

spectacular images of production cones beneath horizontal production wells extracted from a dedicated 4D monitor survey (2008) addressed the field's key dynamic uncertainty – where is the remaining oil?

A challenge for Alba has been to fully understand a 4D seismic signal that originates from long horizontal producers where vertical rather than lateral sweep dominates. Ultimately, reliable reservoir models that capture these valuable dynamic insights, based on geologically reasonable interpretations, will be the key tool that enables bypassed oil to be targeted and recovered, as fields such as Alba advance towards their development vision.
Quantitative In Vivo Immunohistochemistry of Epidermal Growth Factor Receptor Using a Receptor Concentration Imaging Approach
Authors: Samkoe Kimberley S. , Tichauer Kenneth M. , Gunn Jason R. , Wells Wendy A. , Hasan Tayyaba , Pogue Brian W. 
Published: October 2014

Abstract
As receptor-targeted therapeutics become increasingly used in clinical oncology, the ability to quantify protein expression and pharmacokinetics in vivo is imperative to ensure successful individualized treatment plans. Current standards for receptor analysis are performed on extracted tissues. These measurements are static and often physiologically irrelevant; therefore, only a partial picture of available receptors for drug targeting in vivo is provided. Until recently, in vivo measurements were limited by the inability to separate delivery, binding, and retention effects, but this can be circumvented by a dual-tracer approach for referencing the detected signal. We hypothesized that in vivo receptor concentration imaging (RCI) would be superior to ex vivo immunohistochemistry (IHC). Using multiple xenograft tumor models with varying EGFR expression, we determined the EGFR concentration in each model using a novel targeted agent (anti-EGFR affibody-IRDye800CW conjugate) along with a simultaneously delivered reference agent (control affibody-IRDye680RD conjugate). The RCI-calculated in vivo receptor concentration was strongly correlated with ex vivo pathologist-scored IHC and computer-quantified ex vivo immunofluorescence. In contrast, no correlation was observed with ex vivo Western blot analysis or in vitro flow-cytometry assays. Overall, our results argue that in vivo RCI provides a robust measure of receptor expression equivalent to ex vivo immunostaining, with implications for use in noninvasive monitoring of therapy or therapeutic guidance during surgery. Cancer Res; 74(24); 7465–74. ©2014 AACR.
Harnessing the Fcμ Receptor for Potent and Selective Cytotoxic Therapy of Chronic Lymphocytic Leukemia
Authors: Vire Bérengère , Skarzynski Martin , Thomas Joshua D. , Nelson Christopher G. , David Alexandre , Aue Georg , Burke Terrence R. , Rader Christoph , Wiestner Adrian 
Published: October 2014

AbstractChronic lymphocytic leukemia (CLL) is a B-cell malignancy in need of new, effective, and safe therapies. The recently identified IgM receptor FcμR is overexpressed on malignant B cells in CLL and mediates the rapid internalization and lysosomal shuttling of IgM via its Fc fragment (Fcμ). To exploit this internalization and trafficking pathway for targeted drug delivery, we engineered an IgM-derived protein scaffold (Fcμ) and linked it with the cytotoxic agent monomethylauristatin F. This Fcμ–drug conjugate was selectively toxic for FcμR-expressing cell lines in vitro and for CLL cells but not autologous normal T cells ex vivo. Notably, the cytotoxic activity of the Fcμ–drug conjugate was maintained in CLL cells carrying a 17p deletion, which predicts resistance to standard chemotherapy. Next, we tested the possible therapeutic application of the Fcμ–drug conjugate in immunodeficient NOD/SCID/IL-2Rγnull (NSG) mice engrafted with peripheral blood cells from patients with leukemia. Three intravenous injections of the Fcμ–drug conjugate over a 10-day period were well tolerated and selectively killed the human CLL cells but not the coengrafted autologous human T cells. In summary, we developed a novel strategy for targeted cytotoxic therapy of CLL based on the unique properties of FcμR. FcμR-targeted drug delivery showed potent and specific therapeutic activity in CLL, thus providing proof of concept for FcμR as a valuable therapeutic target in CLL and for IgM-based antibody–drug conjugates as a new targeting platform. Cancer Res; 74(24); 7510–20. ©2014 AACR.
Tumor-Associated Macrophages in SHH Subgroup of Medulloblastomas
Authors: Margol Ashley S. , Robison Nathan J. , Gnanachandran Janahan , Hung Long T. , Kennedy Rebekah J. , Vali Marzieh , Dhall Girish , Finlay Jonathan L. , Erdreich-Epstein Anat , Krieger Mark D. , Drissi Rachid , Fouladi Maryam , Gilles Floyd H. , Judkins Alexander R. , Sposto Richard , Asgharzadeh Shahab 
Published: October 2014

Abstract
Purpose: Medulloblastoma in children can be categorized into at least four molecular subgroups, offering the potential for targeted therapeutic approaches to reduce treatment-related morbidities. Little is known about the role of tumor microenvironment in medulloblastoma or its contribution to these molecular subgroups. Tumor microenvironment has been shown to be an important source for therapeutic targets in both adult and pediatric neoplasms. In this study, we investigated the hypothesis that expression of genes related to tumor-associated macrophages (TAM) correlates with the medulloblastoma molecular subgroups and contributes to a diagnostic signature.
Methods: Gene-expression profiling using human exon array (n = 168) was analyzed to identify medulloblastoma molecular subgroups and expression of inflammation-related genes. Expression of 45 tumor-related and inflammation-related genes was analyzed in 83 medulloblastoma samples to build a gene signature predictive of molecular subgroups. TAMs in medulloblastomas (n = 54) comprising the four molecular subgroups were assessed by immunohistochemistry (IHC).
Results: A 31-gene medulloblastoma subgroup classification score inclusive of TAM-related genes (CD163 and CSF1R) was developed with a misclassification rate of 2%. Tumors in the Sonic Hedgehog (SHH) subgroup had increased expression of inflammation-related genes and significantly higher infiltration of TAMs than tumors in the Group 3 or Group 4 subgroups (P &lt; 0.0001 and P &lt; 0.0001, respectively). IHC data revealed a strong association between location of TAMs and proliferating tumor cells.
Conclusions: These data show that SHH tumors have a unique tumor microenvironment among medulloblastoma subgroups. The interactions of TAMs and SHH medulloblastoma cells may contribute to tumor growth revealing TAMs as a potential therapeutic target. Clin Cancer Res; 21(6); 1457–65. ©2014 AACR.
The Effect of Disintegrin–Metalloproteinase ADAM9 in Gastric Cancer Progression
Authors: Kim Jeong Min , Jeung Hei-Cheul , Rha Sun Young , Yu Eun Jeong , Kim Tae Soo , Shin You Keun , Zhang Xianglan , Park Kyu Hyun , Park Seung Woo , Chung Hyun Cheol , Powis Garth 
Published: October 2014

AbstractAdvanced gastric cancer is one of the most aggressive gastrointestinal malignancies, and ADAM (A disintegrin and metalloproteinase)-9 is a cell-surface membrane glycoprotein with oncogenic properties that is overexpressed in several cancers. Herein, we investigated the biologic mechanism of ADAM9 in the progression, proliferation, and invasion of gastric cancer. First, we detected ADAM's expression, processing, and protease activity in gastric cancer cells. Protease activity was moderately correlated with ADAM9 protein expression, but was better related to a processed smaller molecular weight (84 kDa) form of ADAM9. Knockdown of ADAM9 or specifically targeted monoclonal antibody (RAV-18) suppressed cancer cell proliferation and invasion in high ADAM9-expressing cells, not in low ADAM9-expressing cells. RAV-18 showed in vivo antitumor activity in a gastric cancer xenograft model. Hypoxia (1% oxygen) induced ADAM9 expression and functional activity in low ADAM9-expressing gastric cancer cells that was inhibited by siRNA knockdown or RAV-18 antibody to levels in normoxic cells. Overall, our studies show that ADAM9 plays an important role in gastric cancer proliferation and invasion, and that while expressed in some gastric cancer cells at high levels that are responsive to functional inhibition and antitumor activity of a catalytic site–directed antibody, other gastric cancer cells have low levels of expression and only when exposed to hypoxia do ADAM9 levels increase and the cells become responsive to ADAM9 antibody inhibition. Therefore, our findings suggest that ADAM9 could be an effective therapeutic target for advanced gastric cancer. Mol Cancer Ther; 13(12); 3074–85. ©2014 AACR.
Small Molecule Inhibitor YM155-Mediated Activation of Death Receptor 5 Is Crucial for Chemotherapy-Induced Apoptosis in Pancreatic Carcinoma
Authors: Zhao Xiangxuan , Puszyk William M. , Lu Zaiming , Ostrov David A. , George Thomas J. , Robertson Keith D. , Liu Chen 
Published: October 2014

Abstract
Despite much effort, pancreatic cancer survival rates are still dismally low. Novel therapeutics may hold the key to improving survival. YM155 is a small molecule inhibitor that has shown antitumor activity in a number of cancers by reducing the expression of survivin. The aim of our study is to understand the mechanisms by which YM155 functions in pancreatic cancer cells. We established the antitumor effect of YM155 with in vitro studies in cultured cells, and in vivo studies using a mouse xenograft model. Our data demonstrated that YM155 reduced the expression of survivin; however, downregulation of survivin itself is insufficient to induce apoptosis in pancreatic cancer cells. We showed for the first time that treatment with YM155 increased death receptor 5 (DR5) expression in pancreatic cancer cells. We found that YM155 induced apoptosis by broad-spectrum inhibition of IAP family member proteins (e.g., CIAP1/2 and FLIP) and induced proapoptotic Bak protein upregulation and activation; the antitumor effect of YM155 treatment with either the DR5 agonist lexatumumab or gemcitabine on pancreatic cancer cells was synergistic. Our data also revealed that YM155 inhibits tumor growth in vivo, without apparent toxicity to the noncancerous human pancreatic ductal epithelial cell line. Together, these findings suggest that YM155 could be a novel therapeutic agent for pancreatic cancer. Mol Cancer Ther; 14(1); 80–89. ©2014 AACR.
Pharmacological Profiling of Kinase Dependency in Cell Lines across Triple-Negative Breast Cancer Subtypes
Authors: Fink Lauren S. , Beatty Alexander , Devarajan Karthik , Peri Suraj , Peterson Jeffrey R. 
Published: October 2014

Abstract
Triple-negative breast cancers (TNBC), negative for estrogen receptor, progesterone receptor, and ERBB2 amplification, are resistant to standard targeted therapies and exhibit a poor prognosis. Furthermore, they are highly heterogeneous with respect to genomic alterations, and common therapeutic targets are lacking though substantial evidence implicates dysregulated kinase signaling. Recently, six subtypes of TNBC were identified based on gene expression and were proposed to predict sensitivity to a variety of therapeutic agents including kinase inhibitors. To test this hypothesis, we screened a large collection of well-characterized, small molecule kinase inhibitors for growth inhibition in a panel of TNBC cell lines representing all six subtypes. Sensitivity to kinase inhibition correlated poorly with TNBC subtype. Instead, unsupervised clustering segregated TNBC cell lines according to clinically relevant features including dependence on epidermal growth factor signaling and mutation of the PTEN tumor suppressor. We further report the discovery of kinase inhibitors with selective toxicity to these groups. Overall, however, TNBC cell lines exhibited diverse sensitivity to kinase inhibition consistent with the lack of common driver mutations in this disease. Although our findings support specific kinase dependencies in subsets of TNBC, they are not associated with gene expression–based subtypes. Instead, we find that mutation status can be an effective predictor of sensitivity to inhibition of particular kinase pathways for subsets of TNBC. Mol Cancer Ther; 14(1); 298–306. ©2014 AACR.
Direct Binding of Arsenic Trioxide to AMPK and Generation of Inhibitory Effects on Acute Myeloid Leukemia Precursors
Authors: Beauchamp Elspeth M. , Kosciuczuk Ewa M. , Serrano Ruth , Nanavati Dhaval , Swindell Elden P. , Viollet Benoit , O'Halloran Thomas V. , Altman Jessica K. , Platanias Leonidas C. 
Published: October 2014

Abstract
Arsenic trioxide (As2O3) exhibits potent antineoplastic effects and is used extensively in clinical oncology for the treatment of a subset of patients with acute myeloid leukemia (AML). Although As2O3 is known to regulate activation of several signaling cascades, the key events, accounting for its antileukemic properties, remain to be defined. We provide evidence that arsenic can directly bind to cysteine 299 in AMPKα and inhibit its activity. This inhibition of AMPK by arsenic is required in part for its cytotoxic effects on primitive leukemic progenitors from patients with AML, while concomitant treatment with an AMPK activator antagonizes in vivo the arsenic-induced antileukemic effects in a xenograft AML mouse model. A consequence of AMPK inhibition is activation of the mTOR pathway as a negative regulatory feedback loop. However, when AMPK expression is lost, arsenic-dependent activation of the kinase RSK downstream of MAPK activity compensates the generation of regulatory feedback signals through phosphorylation of downstream mTOR targets. Thus, therapeutic regimens with As2O3 will need to include inhibitors of both the mTOR and RSK pathways in combination to prevent engagement of negative feedback loops and maximize antineoplastic responses. Mol Cancer Ther; 14(1); 202–12. ©2014 AACR.
ERG Oncoprotein Inhibits ANXA2 Expression and Function in Prostate Cancer
Authors: Griner Nicholas B. , Young Denise , Chaudhary Pankaj , Mohamed Ahmed A. , Huang Wei , Chen Yongmei , Sreenath Taduru , Dobi Albert , Petrovics Gyorgy , Vishwanatha Jamboor K. , Sesterhenn Isabell A. , Srivastava Shiv , Tan Shyh-Han 
Published: October 2014

Abstract
Overexpression of ERG in the prostate epithelium, due to chromosomal translocations, contributes to prostate tumorigenesis. Here, genomic analysis of ERG siRNA-treated prostate cells harboring the endogenous TMPRSS2–ERG fusion revealed an inverse relationship between ERG and Annexin A2 (ANXA2) expression at both the RNA and protein level. ANXA2, a Ca2+-dependent and phospholipid-binding protein, is involved in various cellular functions, including maintenance of epithelial cell polarity. Mechanistic studies defined the prostate-specific transcription start site of ANXA2 and showed that the recruitment of ERG to the ANXA2 promoter is required for transcriptional repression by ERG. Knockdown of ERG enhanced the apical localization of ANXA2, the bundling of actin filaments at cell–cell junctions and formation of a polarized epithelial phenotype. ERG overexpression disrupted ANXA2-mediated cell polarity and promoted epithelial–mesenchymal transition (EMT) by inhibiting CDC42 and RHOA, and by activating cofilin. Immunohistochemistry demonstrated a reciprocal relationship of ANXA2 and ERG expression in a large fraction of primary prostate cancer clinical specimens. ANXA2 was absent or markedly reduced in ERG(+) tumors, which were mostly well differentiated. ERG(−) tumors, meanwhile, expressed moderate to high levels of ANXA2, and were either poorly differentiated or displayed subsets of poorly differentiated cells. Taken together, the transcriptional repression of ANXA2 by ERG in prostate epithelial cells plays a critical role in abrogating differentiation, promoting EMT, and in the reciprocal correlation of ERG and ANXA2 expression observed in human prostate cancer.
Implications: ANXA2 is a new component of the ERG network with potential to enhance biologic stratification and therapeutic targeting of ERG-stratified prostate cancers. Mol Cancer Res; 13(2); 368–79. ©2014 AACR.
Mechanisms of Exercise Intolerance in Heart Failure With Preserved Ejection Fraction
Authors: Dhakal Bishnu P. , Malhotra Rajeev , Murphy Ryan M. , Pappagianopoulos Paul P. , Baggish Aaron L. , Weiner Rory B. , Houstis Nicholas E. , Eisman Aaron S. , Hough Stacyann S. , Lewis Gregory D. 
Published: October 2014

Background—

Exercise capacity as measured by peak oxygen uptake (V
o
2
) is similarly impaired in patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with reduced ejection fraction (HFrEF). However, characterization of how each component of V
o
2
changes in response to incremental exercise in HFpEF versus HFrEF has not been previously defined. We hypothesized that abnormally low peripheral o
2
extraction (arterio-mixed venous o
2
content difference, [C(a-v)o
2
]) during exercise significantly contributes to impaired exercise capacity in HFpEF.

Methods and Results—

We performed maximum incremental cardiopulmonary exercise testing with invasive hemodynamic monitoring on 104 patients with symptomatic NYHA II to IV heart failure (HFpEF, n=48, peak V
o
2
=13.9±0.5 mL kg
−1
min
−1
, mean±SEM, and HFrEF, n=56, peak V
o
2
=12.1±0.5 mL kg
−1
min
−1
) and 24 control subjects (peak V
o
2
27.0±1.7 mL kg
−1
min
−1
). Peak exercise C(a-v)o
2
was lower in HFpEF compared with HFrEF (11.5±0.27 versus 13.5±0.34 mL/dL, respectively,
P
<0.0001), despite no differences in age, hemoglobin level, peak respiratory exchange ratio, Ca
o
2
, or cardiac filling pressures. Peak C(a-v)o
2
and peak heart rate emerged as the leading predictors of peak V
o
2
in HFpEF. Impaired peripheral o
2
extraction was the predominant limiting factor to exercise capacity in 40% of patients with HFpEF and was closely related to elevated systemic blood pressure during exercise (
r
=0.49,
P
=0.0005).

Conclusions—

In the first study to directly measure C(a-v)o
2
throughout exercise in HFpEF, HFrEF, and normals, we found that peak C(a-v)o
2
was a major determinant of exercise capacity in HFpEF. The important functional limitation imposed by impaired o
2
extraction may reflect intrinsic abnormalities in skeletal muscle or peripheral microvascular function, and represents a potential target for therapeutic intervention.