bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization of bacterial antimicrobial peptides active against Campylobacter jejuni
Authors: Lohans Christopher T. , van Belkum Marco J. , Li Jing , Vederas John C.
Published: October 2014

Campylobacter jejuni is one of the major causes of food poisoning, often resulting from the consumption of improperly cooked poultry products. The emergence of C. jejuni strains resistant to conventional antibiotics necessitates the evaluation of other possible treatments or preventative measures to minimize the impact and prevalence of infections. Antimicrobial peptides produced by bacteria have begun to emerge as a potential means of decreasing the levels of C. jejuni in poultry, thereby limiting Campylobacter contamination in associated food products. A number of bacteriocins produced by Gram-positive bacteria have unexpectedly been described as having antimicrobial activity against the Gram-negative C. jejuni. Additionally, some nonribosomal lipopeptides produced by Bacillus and Paenibacillus spp. show efficacy against this pathogen. This review will describe the bacterial antimicrobial peptides reported to be active against C. jejuni, with an emphasis on the characterization of their primary structures. However, for many of these peptides, little is known about their amino acid sequences and structures. Furthermore, there are unusual inconsistencies associated with the reported amino acid sequences for several of the more well-studied bacteriocins. Clarifying the chemical nature of these promising antimicrobial peptides is necessary before their potential utility for livestock protection from C. jejuni can be fully explored. Once these peptides are better characterized, they may prove to be strong candidates for minimizing the impact of Campylobacter on human health.
Alba Field – how seismic technologies have influenced reservoir characterization and field development
Authors: Moore Ian
Published: October 2014

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.
Quantity of dietary protein intake, but not pattern of intake, affects net protein balance primarily through differences in protein synthesis in older adults
Authors: Kim Il-Young , Schutzler Scott , Schrader Amy , Spencer Horace , Kortebein Patrick , Deutz Nicolaas E. P. , Wolfe Robert R. , Ferrando Arny A.
Published: October 2014

To examine whole body protein turnover and muscle protein fractional synthesis rate (MPS) following ingestions of protein in mixed meals at two doses of protein and two intake patterns, 20 healthy older adult subjects (52–75 yr) participated in one of four groups in a randomized clinical trial: a level of protein intake of 0.8 g (1RDA) or 1.5 g·kg−1·day−1 (∼2RDA) with uneven (U: 15/20/65%) or even distribution (E: 33/33/33%) patterns of intake for breakfast, lunch, and dinner over the day (1RDA-U, 1RDA-E, 2RDA-U, or 2RDA-E). Subjects were studied with primed continuous infusions of l-[2H5]phenylalanine and l-[2H2]tyrosine on day 4 following 3 days of diet habituation. Whole body protein kinetics [protein synthesis (PS), breakdown, and net balance (NB)] were expressed as changes from the fasted to the fed states. Positive NB was achieved at both protein levels, but NB was greater in 2RDA vs. 1RDA (94.8 ± 6.0 vs. 58.9 ± 4.9 g protein/750 min; P = 0.0001), without effects of distribution on NB. The greater NB was due to the higher PS with 2RDA vs. 1RDA (15.4 ± 4.8 vs. −18.0 ± 8.4 g protein/750 min; P = 0.0018). Consistent with PS, MPS was greater with 2RDA vs. 1RDA, regardless of distribution patterns. In conclusion, whole body net protein balance was greater with protein intake above recommended dietary allowance (0.8 g protein·kg−1·day−1) in the context of mixed meals, without demonstrated effects of protein intake pattern, primarily through higher rates of protein synthesis at whole body and muscle levels.
Light phase-restricted feeding slows basal heart rate to exaggerate the type-3 long QT syndrome phenotype in mice
Authors: Schroder Elizabeth A. , Burgess Don E. , Manning Cody L. , Zhao Yihua , Moss Arthur J. , Patwardhan Abhijit , Elayi Claude S. , Esser Karyn A. , Delisle Brian P.
Published: October 2014

Long QT syndrome type 3 (LQT3) is caused by mutations in the SCN5A-encoded Nav1.5 channel. LQT3 patients exhibit time of day-associated abnormal increases in their heart rate-corrected QT (QTc) intervals and risk for life-threatening episodes. This study determines the effects of uncoupling environmental time cues that entrain circadian rhythms (time of light and time of feeding) on heart rate and ventricular repolarization in wild-type (WT) or transgenic LQT3 mice ( Scn5a+/ΔKPQ). We used an established light phase-restricted feeding paradigm that disrupts the alignment among the circadian rhythms in the central pacemaker of the suprachiasmatic nucleus and peripheral tissues including heart. Circadian analysis of the RR and QT intervals showed the Scn5a+/ΔKPQ mice had QT rhythms with larger amplitudes and 24-h midline means and a more pronounced slowing of the heart rate. For both WT and Scn5a+/ΔKPQ mice, light phase-restricted feeding shifted the RR and QT rhythms ∼12 h, increased their amplitudes greater than twofold, and raised the 24-h midline mean by ∼10%. In contrast to WT mice, the QTc interval in Scn5a+/ΔKPQ mice exhibited time-of-day prolongation that was flipped after light phase-restricted feeding. The time-of-day changes in the QTc intervals of Scn5a+/ΔKPQ mice were secondary to a steeper power relation between their QT and RR intervals. We conclude that uncoupling time of feeding from normal light cues can dramatically slow heart rate to unmask genotype-specific differences in the QT intervals and aggravate the LQT3-related phenotype.
Cigarette smoke enhances proliferation and extracellular matrix deposition by human fetal airway smooth muscle
Authors: Vogel Elizabeth R. , VanOosten Sarah K. , Holman Michelle A. , Hohbein Danielle D. , Thompson Michael A. , Vassallo Robert , Pandya Hitesh C. , Prakash Y. S. , Pabelick Christina M.
Published: October 2014

Cigarette smoke is a common environmental insult associated with increased risk of developing airway diseases such as wheezing and asthma in neonates and children. In adults, asthma involves airway remodeling characterized by increased airway smooth muscle (ASM) cell proliferation and increased extracellular matrix (ECM) deposition, as well as airway hyperreactivity. The effects of cigarette smoke on remodeling and contractility in the developing airway are not well-elucidated. In this study, we used canalicular-stage (18–20 wk gestational age) human fetal airway smooth muscle (fASM) cells as an in vitro model of the immature airway. fASM cells were exposed to cigarette smoke extract (CSE; 0.5–1.5% for 24–72 h), and cell proliferation, ECM deposition, and intracellular calcium ([Ca2+]i) responses to agonist (histamine 10 μM) were used to evaluate effects on remodeling and hyperreactivity. CSE significantly increased cell proliferation and deposition of ECM molecules collagen I, collagen III, and fibronectin. In contrast, [Ca2+]i responses were not significantly affected by CSE. Analysis of key signaling pathways demonstrated significant increase in extracellular signal-related kinase (ERK) and p38 activation with CSE. Inhibition of ERK or p38 signaling prevented CSE-mediated changes in proliferation, whereas only ERK inhibition attenuated the CSE-mediated increase in ECM deposition. Overall, these results demonstrate that cigarette smoke may enhance remodeling in developing human ASM through hyperplasia and ECM production, thus contributing to development of neonatal and pediatric airway disease.
A non-BRICHOSSFTPCmutant (SP-CI73T) linked to interstitial lung disease promotes a late block in macroautophagy disrupting cellular proteostasis and mitophagy
Authors: Hawkins Arie , Guttentag Susan H. , Deterding Robin , Funkhouser William K. , Goralski Jennifer L. , Chatterjee Shampa , Mulugeta Surafel , Beers Michael F.
Published: October 2014

Mutation of threonine for isoleucine at codon 73 (I73T) in the human surfactant protein C (hSP-C) gene ( SFTPC) accounts for a significant portion of SFTPC mutations associated with interstitial lung disease (ILD). Cell lines stably expressing tagged primary translation product of SP-C isoforms were generated to test the hypothesis that deposition of hSP-CI73Twithin the endosomal system promotes disruption of a key cellular quality control pathway, macroautophagy. By fluorescence microscopy, wild-type hSP-C (hSP-CWT) colocalized with exogenously expressed human ATP binding cassette class A3 (hABCA3), an indicator of normal trafficking to lysosomal-related organelles. In contrast, hSP-CI73Twas dissociated from hABCA3 but colocalized to the plasma membrane as well as the endosomal network. Cells expressing hSP-CI73Texhibited increases in size and number of cytosolic green fluorescent protein/microtubule-associated protein 1 light-chain 3 (LC3) vesicles, some of which colabeled with red fluorescent protein from the gene dsRed/hSP-CI73T. By transmission electron microscopy, hSP-CI73Tcells contained abnormally large autophagic vacuoles containing organellar and proteinaceous debris, which phenocopied ultrastructural changes in alveolar type 2 cells in a lung biopsy from a SFTPC I73T patient. Biochemically, hSP-CI73Tcells exhibited increased expression of Atg8/LC3, SQSTM1/p62, and Rab7, consistent with a distal block in autophagic vacuole maturation, confirmed by flux studies using bafilomycin A1 and rapamycin. Functionally, hSP-CI73Tcells showed an impaired degradative capacity for an aggregation-prone huntingtin-1 reporter substrate. The disruption of autophagy-dependent proteostasis was accompanied by increases in mitochondria biomass and parkin expression coupled with a decrease in mitochondrial membrane potential. We conclude that hSP-CI73Tinduces an acquired block in macroautophagy-dependent proteostasis and mitophagy, which could contribute to the increased vulnerability of the lung epithelia to second-hit injury as seen in ILD.
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

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

Chronic 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

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 < 0.0001 and P < 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

Advanced 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

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

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

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

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.
Successful Treatment of Disabling Paroxysmal Nonkinesigenic Dyskinesia with Deep Brain Stimulation of the Globus Pallidus Internus
Authors: van Coller Riaan , Slabbert Pieter , Vaidyanathan Janardan , Schutte Clara
Published: October 2014

Paroxysmal nonkinesigenic dyskinesia (PNKD) causes episodes of treatment-resistant involuntary movements. Previous case reports showed effective treatment of PNKD with deep brain stimulation (DBS). We report 2 patients in whom DBS was highly successful when other treatment modalities had failed. Methods: Two patients aged 34 and 24 years with a longstanding history of PNKD were treated with globus pallidus internus (GPi) DBS. Motor effects were monitored and followed up postoperatively and again at 6 months after surgery. Results: Both patients responded very well to GPi DBS with complete suppression of dyskinesia after surgery in 1 patient and in the second after an additional adjustment of stimulation. Conclusion: GPi DBS might be an effective alternative treatment modality for PNKD.
Increasing Infection Rate in Multiple Implanted Pulse Generator Changes in Movement Disorder Patients Treated with Deep Brain Stimulation
Authors: Thrane Jens F. , Sunde Niels A. , Bergholt Bo , Rosendal Frederikke
Published: October 2014

Background: Deep brain stimulation has been performed at the Department of Neurosurgery, Aarhus University Hospital (AUH), for 16 years. The risk of infection related to implantable pulse generator (IPG) replacement constitutes a weakness in the long-term DBS treatment. Object: The aim of this study is to investigate the association between risk of infection and number of IPG replacements. Methods: All patients who underwent IPG replacement at the AUH from June 1996 until September 2012 were included in the study, and their medical records were systematically reviewed. The data was analyzed using Fisher's exact test on contingency tables. Results: 220 procedures of IPG replacement were completed on 105 patients who suffered from various movement disorders. Up to 5 IPG changes were registered in a single patient. Thirteen patients incurred infection requiring surgical intervention. Testing for risk of infection associated with number of IPG changes, this study found significantly different infection rates (p = 0.0052). In the groups with 3 and 4 IPG changes, infection rates reached over 20%. Conclusion: This study found significantly different rates of infection related to the number of IPG changes. Further investigation and resources should be directed towards improving the lifespan of IPGs.
Anaphylaxis Induced by a Drug Containing Lysozyme and Papain: Influence of Papain on the IgE Response
Authors: Benedé Sara , Pérez-Rangel Inmaculada , Lozano-Ojalvo Daniel , Molina Elena , Ibañez María Dolores , López-Fandiño Rosina , López-Expósito Iván
Published: October 2014

Background: This paper reports the case of an egg-allergic pediatric patient who, once desensitized to egg following a successful rush oral immunotherapy protocol, could also tolerate Lizipaina®, a drug containing lysozyme (LYS) and papain, which had previously caused him a severe allergic reaction. Because the LYS amount that elicited the anaphylactic reaction (5 mg) was much lower than that tolerated during a double-blind placebo-controlled food challenge (corresponding to approximately 60 mg of LYS), the possibility that the presence of papain could increase the allergenic potential of LYS was investigated. Methods: Lizipaina, LYS and LYS hydrolyzed with papain were analyzed by SDS-PAGE under reducing and nonreducing conditions, and Western blotting of sera from egg-allergic patients was performed in order to detect IgE-binding fragments. Finally, sequence identification of the IgE-reactive bands was carried out by MALDI-TOF/TOF. Results: The SDS-PAGE pattern of LYS treated with papain under nonreducing conditions showed the presence of intact LYS that partially disappeared following reduction with β-mercaptoethanol, releasing IgE-reactive fragments as determined by Western blotting. MALDI-TOF/TOF revealed that papain degraded LYS, giving rise to three IgE-binding fragments: LYS (22-129), LYS (34-96) and LYS (62-128) that likely remained linked through the disulfide bonds present in the LYS molecule. Conclusion: The combined administration of LYS with proteolytic enzymes such as papain may have developed a severe allergic reaction in the patient studied, underlining the importance of considering all the components and their interactions when drugs are to be consumed by allergic persons.
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.
Identification of Therapeutic Covariant MicroRNA Clusters in Hypoxia-Treated Cardiac Progenitor Cell Exosomes Using Systems Biology
Authors: Gray Warren D. , French Kristin M. , Ghosh-Choudhary Shohini , Maxwell Joshua T. , Brown Milton E. , Platt Manu O. , Searles Charles D. , Davis Michael E.
Published: October 2014

Rationale:

Myocardial infarction is a leading cause of death in developed nations, and there remains a need for cardiac therapeutic systems that mitigate tissue damage. Cardiac progenitor cells (CPCs) and other stem cell types are attractive candidates for treatment of myocardial infarction; however, the benefit of these cells may be as a result of paracrine effects.

Objective:

We tested the hypothesis that CPCs secrete proregenerative exosomes in response to hypoxic conditions.

Methods and Results:

The angiogenic and antifibrotic potential of secreted exosomes on cardiac endothelial cells and cardiac fibroblasts were assessed. We found that CPC exosomes secreted in response to hypoxia enhanced tube formation of endothelial cells and decreased profibrotic gene expression in TGF-β–stimulated fibroblasts, indicating that these exosomes possess therapeutic potential. Microarray analysis of exosomes secreted by hypoxic CPCs identified 11 miRNAs that were upregulated compared with exosomes secreted by CPCs grown under normoxic conditions. Principle component analysis was performed to identify miRNAs that were coregulated in response to distinct exosome-generating conditions. To investigate the cue–signal–response relationships of these miRNA clusters with a physiological outcome of tube formation or fibrotic gene expression, partial least squares regression analysis was applied. The importance of each up- or downregulated miRNA on physiological outcomes was determined. Finally, to validate the model, we delivered exosomes after ischemia–reperfusion injury. Exosomes from hypoxic CPCs improved cardiac function and reduced fibrosis.

Conclusions:

These data provide a foundation for subsequent research of the use of exosomal miRNA and systems biology as therapeutic strategies for the damaged heart.
Protest on the Fly
Authors: Snow David A. , Moss Dana M.
Published: October 2014

This article reexamines spontaneity as an important, albeit neglected, mechanism in collective action dynamics, and elaborates on its operation and effects in protest events and social movements. We do not presume that spontaneity is routinely at play in all collective actions. Rather, based on our grounded analysis of historical and ethnographic data, we contend that spontaneity is triggered by certain conditions: nonhierarchical organization; uncertain/ambiguous moments and events; behavioral/emotional priming; and certain ecological/spatial factors. We conclude by elaborating why the activation of spontaneous actions matters in shaping the course and character of protest events and movements, and we suggest that spontaneity be resuscitated in the study of collective action and everyday life more generally.
One-Year Outcomes of Emergency Department Patients With Atrial Fibrillation
Authors: Yang Yan-Min , Shao Xing-Hui , Zhu Jun , Zhang Han , Liu Yao , Gao Xin , Yu Li-Tian , Liu Li-Sheng , Zhao Li , Yu Peng-Fei , Zhang Hua , He Qing , Gu Xiao-Dan
Published: October 2014

There is lack of data about patient characteristics, practice patterns, and long-term adverse outcomes in patients with atrial fibrillation (AF) attending emergency departments (EDs) in China. A total of 2016 patients from 20 representative EDs were included. During 1 year, all-cause mortality was 291 (14.6%) cases, stroke/noncentral nervous system systemic embolism rate was 159 (8.0%) cases, and major bleeding was 26 (1.3%) cases. Heart failure, the major cause of mortality, accounted for 43.0% of deaths. Of 375 (18.6%) patients who used warfarin at baseline, only 217 (57.9%) patients were still on anticoagulation therapy during 1-year follow-up. Compared with the patients who continued on warfarin, the mortality rate was higher in those who did not continue (15.9% vs 5.5%, P < .001). Patients seen in ED with AF appear to have a high incidence rate of long-term all-cause mortality and inadequate anticoagulation rate.
Comparison of Serum Cystatin C and Creatinine Level Changes for Prognosis of Patients After Peripheral Arterial Angiography
Authors: Yang Yanjiao , Zhao Xiaojiao , Tang Xiao , Lu Jianxin , Zhou Minjie , Wang Wenji , Wang Lixin , Guo Daqiao , Ding Feng
Published: October 2014

We compared changes in serum cystatin C (Cys C) and creatinine (sCr) levels for detecting contrast-induced acute kidney injury; 350 consecutive patients who underwent peripheral arterial angiography were prospectively enrolled. Serum Cys C and sCr levels were assayed at predefined time points after contrast-media exposure. During 1-year follow-up, major adverse events (MAEs) including all-cause mortality and dialysis were assessed. A sCr increase ≥25% was not associated with MAEs, whereas a serum Cys C increase ≥5% at 24 hours was associated with higher probability of MAEs ( P = .010). The independent predictors of 1-year MAEs were older age ( P = .004), lower prealbumin levels ( P = .022), and serum Cys C increase ≥5%. In patients who underwent peripheral angiography, a serum Cys C increase ≥5% was an independent predictor of 1-year MAEs.
Serum lipoprotein(a) concentrations do not change significantly in the immediate seven-day period post myocardial infarction
Authors: Patel Prashanth , Davies Timothy , Madira Webster , Gupta Pankaj
Published: October 2014

Background

Lipoprotein(a) is an independent predictor of cardiovascular disease and its variability after myocardial infarction was assessed in this study.

Methods

Lipoprotein(a) was analysed by a size insensitive latex immunoturbidimetric end point assay in samples from days 0 to 7 in 31 patients admitted with myocardial infarction.

Results

Median lipoprotein(a) changed by −0.9%, −0.1% and 9.6% on days 1, 2–3 and 4–7, respectively, and was not statistically significant. Median total cholesterol reduced by 8.7%, 9.1%, 14.5% and C-reactive protein increased by 68.4%, 510%, 502% over days 1, 2–3, 4–7, respectively.

Conclusions

Unlike total cholesterol and C-reactive protein, lipoprotein(a) does not demonstrate significant variability for up to seven days after myocardial infarction and measurements made during this period after myocardial infarction are physiologically meaningful.
Homicidal arsenic poisoning
Authors: Duncan Andrew , Taylor Andrew , Leese Elizabeth , Allen Sam , Morton Jackie , McAdam Julie
Published: October 2014

The case of a 50-year-old man who died mysteriously after being admitted to hospital is reported. He had raised the possibility of being poisoned prior to his death. A Coroner’s post-mortem did not reveal the cause of death but this was subsequently established by post-mortem trace element analysis of liver, urine, blood and hair all of which revealed very high arsenic concentrations.
Evaluating Differential Effects Using Regression Interactions and Regression Mixture Models
Authors: Van Horn M. Lee , Jaki Thomas , Masyn Katherine , Howe George , Feaster Daniel J. , Lamont Andrea E. , George Melissa R. W. , Kim Minjung
Published: October 2014

Research increasingly emphasizes understanding differential effects. This article focuses on understanding regression mixture models, which are relatively new statistical methods for assessing differential effects by comparing results to using an interactive term in linear regression. The research questions which each model answers, their formulation, and their assumptions are compared using Monte Carlo simulations and real data analysis. The capabilities of regression mixture models are described and specific issues to be addressed when conducting regression mixtures are proposed. The article aims to clarify the role that regression mixtures can take in the estimation of differential effects and increase awareness of the benefits and potential pitfalls of this approach. Regression mixture models are shown to be a potentially effective exploratory method for finding differential effects when these effects can be defined by a small number of classes of respondents who share a typical relationship between a predictor and an outcome. It is also shown that the comparison between regression mixture models and interactions becomes substantially more complex as the number of classes increases. It is argued that regression interactions are well suited for direct tests of specific hypotheses about differential effects and regression mixtures provide a useful approach for exploring effect heterogeneity given adequate samples and study design.
Enhanced M1/M2 Macrophage Ratio Promotes Orthodontic Root Resorption
Authors: He D. , Kou X. , Luo Q. , Yang R. , Liu D. , Wang X. , Song Y. , Cao H. , Zeng M. , Gan Y. , Zhou Y.
Published: October 2014

Mechanical force–induced orthodontic root resorption is a major clinical challenge in orthodontic treatment. Macrophages play an important role in orthodontic root resorption, but the underlying mechanism remains unclear. In this study, we examined the mechanism by which the ratio of M1 to M2 macrophage polarization affects root resorption during orthodontic tooth movement. Root resorption occurred when nickel–titanium coil springs were applied on the upper first molars of rats for 3 to 14 d. Positively stained odontoclasts or osteoclasts with tartrate-resistant acid phosphatase were found in resorption areas. Meanwhile, M1-like macrophages positive for CD68 and inducible nitric oxide synthase (iNOS) persistently accumulated on the compression side of periodontal tissues. In addition, the expressions of the M1 activator interferon-γ and the M1-associated pro-inflammatory cytokine tumor necrosis factor (TNF)-α were upregulated on the compression side of periodontal tissues. When the coil springs were removed at the 14th day after orthodontic force application, root resorption was partially rescued. The number of CD68+CD163+ M2-like macrophages gradually increased on the compression side of periodontal tissues. The levels of M2 activator interleukin (IL)-4 and the M2-associated anti-inflammatory cytokine IL-10 also increased. Systemic injection of the TNF-α inhibitor etanercept or IL-4 attenuated the severity of root resorption and decreased the ratio of M1 to M2 macrophages. These data imply that the balance between M1 and M2 macrophages affects orthodontic root resorption. Root resorption was aggravated by an enhanced M1/M2 ratio but was partially rescued by a reduced M1/M2 ratio.
Resin-composite Blocks for Dental CAD/CAM Applications
Authors: Ruse N.D. , Sadoun M.J.
Published: October 2014

Advances in digital impression technology and manufacturing processes have led to a dramatic paradigm shift in dentistry and to the widespread use of computer-aided design/computer-aided manufacturing (CAD/CAM) in the fabrication of indirect dental restorations. Research and development in materials suitable for CAD/CAM applications are currently the most active field in dental materials. Two classes of materials are used in the production of CAD/CAM restorations: glass-ceramics/ceramics and resin composites. While glass-ceramics/ceramics have overall superior mechanical and esthetic properties, resin-composite materials may offer significant advantages related to their machinability and intra-oral reparability. This review summarizes recent developments in resin-composite materials for CAD/CAM applications, focusing on both commercial and experimental materials.
The Interplay between Socioeconomic Inequalities and Clinical Oral Health
Authors: Steele J. , Shen J. , Tsakos G. , Fuller E. , Morris S. , Watt R. , Guarnizo-Herreño C. , Wildman J.
Published: October 2014

Oral health inequalities associated with socioeconomic status are widely observed but may depend on the way that both oral health and socioeconomic status are measured. Our aim was to investigate inequalities using diverse indicators of oral health and 4 socioeconomic determinants, in the context of age and cohort. Multiple linear or logistic regressions were estimated for 7 oral health measures representing very different outcomes (2 caries prevalence measures, decayed/missing/filled teeth, 6-mm pockets, number of teeth, anterior spaces, and excellent oral health) against 4 socioeconomic measures (income, education, Index of Multiple Deprivation, and occupational social class) for adults aged ≥21 y in the 2009 UK Adult Dental Health Survey data set. Confounders were adjusted and marginal effects calculated. The results showed highly variable relationships for the different combinations of variables and that age group was critical, with different relationships at different ages. There were significant income inequalities in caries prevalence in the youngest age group, marginal effects of 0.10 to 0.18, representing a 10- to 18-percentage point increase in the probability of caries between the wealthiest and every other quintile, but there was not a clear gradient across the quintiles. With number of teeth as an outcome, there were significant income gradients after adjustment in older groups, up to 4.5 teeth (95% confidence interval, 2.2-6.8) between richest and poorest but none for the younger groups. For periodontal disease, income inequalities were mediated by other socioeconomic variables and smoking, while for anterior spaces, the relationships were age dependent and complex. In conclusion, oral health inequalities manifest in different ways in different age groups, representing age and cohort effects. Income sometimes has an independent relationship, but education and area of residence are also contributory. Appropriate choices of measures in relation to age are fundamental if we are to understand and address inequalities.