bluuebunny/crossref_metadata_2025_split huggingface dataset:
The frequency of urinary tract infection and subclinical bacteriuria in dogs with allergic dermatitis treated with oclacitinib: a prospective study
Authors: Simpson Andrew C. , Schissler Jennifer R. , Rosychuk Rod A.W. , Moore A Russell 
Published: May 2017

BackgroundOclacitinib is a selective Janus kinase inhibitor for the treatment of canine allergic pruritus and atopic dermatitis in dogs. Glucocorticoids and ciclosporin increase urinary tract infection (UTI) frequency in dogs with inflammatory skin disease.ObjectiveProspective study to evaluate the frequency ofUTIand subclinical bacteriuria in dogs with allergic dermatitis receiving oclacitinib.MethodsClient‐owned dogs ≥2 years of age with a history of allergic dermatitis without apparent history of urinary tract disease or predisposition toUTIwere included. Prior to enrolment, urinalysis and quantitative urine culture were performed after a washout period of at least 14 days from systemic antimicrobial drugs and 28 days for ciclosporin and systemic glucocorticoids. Dogs received oclacitinib at labelled dosing for an intended period of 180–230 days with a follow‐up urinalysis and urine culture performed regardless of urinary tract signs. Systemic antimicrobial and immune‐modulating drugs were not administered during the study.ResultsNone of the 55 dogs in this study developedUTIwhile receiving oclacitinib based on follow‐up urinalysis and urine culture performed during a range of 58–280 days (mean 195 days). Two dogs developed self‐limiting abnormal urinary tract signs without urine culture or urinalysis findings consistent withUTI.Conclusions and clinical importanceThese findings indicate that bacteriuria is not an expected adverse effect in dogs treated with oclacitinib without a prior history ofUTIor predisposing condition during this treatment period. Therefore, routine urine culture is not indicated for such dogs in the absence of abnormal urinalysis or clinical signs of urinary tract disease.
Engagement in Physical Activity During Recess: Gender and Grade Level Differences in the Elementary Grades
Authors: Shervey Sarah Wollersheim , DiPerna James C. 
Published: May 2017

Background:There are many purported benefits to recess including engaging in physical activity, forming positive peer relationships, and taking a break from the classroom. Current research, however, is inconclusive regarding the presence of gender and developmental differences in physical activity that takes place during recess. The purpose of this study was to examine differences in the amount of physical activity that occurs during recess across gender and grade level.Methods:Students from first- and sixth-grade classrooms participated in the study, and physical activity was measured using accelerometers to record the number of steps taken during recess.Results:A 2 × 2 factorial ANOVA indicated sixth grade males engaged in more physical activity than sixth grade females, first grade males, and first grade females.Conclusions:Because they are not engaging in as much physical activity as their sixth grade male counterparts, ways to help female and younger students take more steps during recess should be explored.
Physiological and Performance Measures for Baseline Concussion Assessment
Authors: Dobney Danielle M. , Thomas Scott G. , Taha Tim , Keightley Michelle 
Published: May 2017

Context: Baseline testing is a common strategy for concussion assessment and management. Research continues to evaluate novel measures for potential to improve baseline testing methods. Objectives: The primary objective was to (1) determine the feasibility of including physiological, neuromuscular, and mood measures as part of baseline concussion testing protocol, (2) describe typical values in a varsity athlete sample, and (3) estimate the influence of concussion history on these baseline measures. Design: Prospective observational study. Setting: Ryerson University Athletic Therapy Clinic. Participants: One hundred varsity athletes. Main Outcome Measures: Frequency and domain measures of heart rate variability, blood pressure, grip strength, profile of mood states—short form, and the Sport Concussion Assessment Tool-2. Results: Physiological, neuromuscular performance, and mood measures were feasible at baseline. Participants with a history of 2 or more previous concussions displayed significantly higher diastolic blood pressure. Females reported higher total mood disturbance compared with males. Conclusions: Physiological and neuromuscular performance measures are safe and feasible as baseline concussion assessment outcomes. History of concussion may have an influence on diastolic blood pressure.
Quantitative Kinetic Analyses of Shutting Off a Two-Component System
Authors: Gao Rong , Stock Ann M. 
Published: May 2017

ABSTRACT

Cells rely on accurate control of signaling systems to adapt to environmental perturbations. System deactivation upon stimulus removal is as important as activation of signaling pathways. The two-component system (TCS) is one of the major bacterial signaling schemes. In many TCSs, phosphatase activity of the histidine kinase (HK) is believed to play an essential role in shutting off the pathway and resetting the system to the prestimulus state. Two basic challenges are to understand the dynamic behavior of system deactivation and to quantitatively evaluate the role of phosphatase activity under natural cellular conditions. Here we report a kinetic analysis of the response to shutting off the archetype
Escherichia coli
PhoR-PhoB TCS pathway using both transcription reporter assays and
in vivo
phosphorylation analyses. Upon removal of the stimulus, the pathway is shut off by rapid dephosphorylation of the PhoB response regulator (RR) while PhoB-regulated gene products gradually reset to prestimulus levels through growth dilution. We developed an approach combining experimentation and modeling to assess
in vivo
kinetic parameters of the phosphatase activity with kinetic data from multiple phosphatase-diminished mutants. This enabled an estimation of the PhoR phosphatase activity
in vivo
, which is much stronger than the phosphatase activity of PhoR cytoplasmic domains analyzed
in vitro
. We quantitatively modeled how strong the phosphatase activity needs to be to suppress nonspecific phosphorylation in TCSs and discovered that strong phosphatase activity of PhoR is required for cross-phosphorylation suppression.

IMPORTANCE
Activation of TCSs has been extensively studied; however, the kinetics of shutting off TCS pathways is not well characterized. We present comprehensive analyses of the shutoff response for the PhoR-PhoB system that reveal the impact of phosphatase activity on shutoff kinetics. This allows development of a quantitative framework not only to characterize the phosphatase activity in the natural cellular environment but also to understand the requirement for specific strengths of phosphatase activity to suppress nonspecific phosphorylation. Our model suggests that the ratio of the phosphatase rate to the nonspecific phosphorylation rate correlates with TCS expression levels and the ratio of the RR to HK, which may contribute to the great diversity of enzyme levels and activities observed in different TCSs.
Characteristics of Ni–Cr–Fe laser clad layers on EA4T steel
Authors: Chen Wenjing , Chen Hui , Wang Yongjing , Li Congchen , Wang Xiaoli 
Published: May 2017

The Ni–Cr–Fe metal powder was deposited on EA4T steel by laser cladding technology. The microstructure and chemical composition of the cladding layer were analyzed by optical microscopy (OM), scanning electron microscopy (SEM) and X-ray diffraction (XRD). The bonding ability between the cladding layer and the matrix was measured. The results showed that the bonding between the cladding layer and the EA4T steel was metallurgical bonding. The microstructure of cladding layer was composed of planar crystals, columnar crystals and dendrite, which consisted of Cr2Ni3, [Formula: see text] phase, M[Formula: see text]C6 and Ni3B phases. When the powder feeding speed reached 4 g/min, the upper bainite occurred in the heat affected zone (HAZ). Moreover, the tensile strength of the joint increased, while the yield strength and the ductility decreased.
Molecular sieving polymer for DNA/RNA separation in capillary electrophoresis
Authors: Liu Chenchen , Yamaguchi Yoshinori , Dou Xiaoming 
Published: May 2017

In capillary polymer electrophoresis, the property of polymer sieving matrix dominates the migration behavior of DNA/RNA. We investigated the capillary electrophoresis of RNA ranging from 100 nt to 10,000 nt in polyacrylamide (PA) solutions with different molecular weights (Mw) and different concentrations. We observed that the resolution length (RSL) of RNA fragments was improved and the migration time was prolonged, when polymer concentration was increased. The resolution for small RNA fragments ([Formula: see text]1000 nt) was improved with the increase of polymer concentration, whereas the large ones ([Formula: see text]3000 nt) became inseparable. In addition, we estimated the smallest resolvable nucleotide length (Ls) by the plot of RSL against RNA size.
Effect of chromium substitution on crystal and lattice structure of soft manganese zinc ferrites
Authors: Yadav Anand , Varshney Dinesh 
Published: May 2017

Chromium-doped manganese–zinc ferrite samples were prepared by solid-state reaction route to probe the effect of chromium ion on the crystal and lattice structure of mixed manganese–zinc ferrite. X-ray diffraction patterns reveal that Mn[Formula: see text]Zn[Formula: see text]Cr[Formula: see text]Fe[Formula: see text]O[Formula: see text] ([Formula: see text] = 0.0, 0.1, 0.2, 0.3, 0.4 and 0.5) ferrite has polycrystalline cubic spinel structure with some secondary phase of [Formula: see text]–Fe[Formula: see text]O[Formula: see text]. The Raman spectra reveal four Raman active phonon modes in the measurement range of 200–750 cm[Formula: see text] with small shift in Raman modes towards higher wave number. The average particle size for Mn[Formula: see text]Zn[Formula: see text]Fe[Formula: see text]O[Formula: see text] is found to be 37.28 nm which reduces to 33.64 nm for Mn[Formula: see text]Cr[Formula: see text]Fe[Formula: see text]O[Formula: see text]. As the ion doping of chromium increases, the modes of vibration are found to shift towards higher wavelength and blueshift is attributed to the higher ionic radii of Cr[Formula: see text] as compared to Zn[Formula: see text].
Targetable T-type Calcium Channels Drive Glioblastoma
Authors: Zhang Ying , Cruickshanks Nichola , Yuan Fang , Wang Baomin , Pahuski Mary , Wulfkuhle Julia , Gallagher Isela , Koeppel Alexander F. , Hatef Sarah , Papanicolas Christopher , Lee Jeongwu , Bar Eli E. , Schiff David , Turner Stephen D. , Petricoin Emanuel F. , Gray Lloyd S. , Abounader Roger 
Published: May 2017

Abstract
Glioblastoma (GBM) stem-like cells (GSC) promote tumor initiation, progression, and therapeutic resistance. Here, we show how GSCs can be targeted by the FDA-approved drug mibefradil, which inhibits the T-type calcium channel Cav3.2. This calcium channel was highly expressed in human GBM specimens and enriched in GSCs. Analyses of the The Cancer Genome Atlas and REMBRANDT databases confirmed upregulation of Cav3.2 in a subset of tumors and showed that overexpression associated with worse prognosis. Mibefradil treatment or RNAi-mediated attenuation of Cav3.2 was sufficient to inhibit the growth, survival, and stemness of GSCs and also sensitized them to temozolomide chemotherapy. Proteomic and transcriptomic analyses revealed that Cav3.2 inhibition altered cancer signaling pathways and gene transcription. Cav3.2 inhibition suppressed GSC growth in part by inhibiting prosurvival AKT/mTOR pathways and stimulating proapoptotic survivin and BAX pathways. Furthermore, Cav3.2 inhibition decreased expression of oncogenes (PDGFA, PDGFB, and TGFB1) and increased expression of tumor suppressor genes (TNFRSF14 and HSD17B14). Oral administration of mibefradil inhibited growth of GSC-derived GBM murine xenografts, prolonged host survival, and sensitized tumors to temozolomide treatment. Our results offer a comprehensive characterization of Cav3.2 in GBM tumors and GSCs and provide a preclinical proof of concept for repurposing mibefradil as a mechanism-based treatment strategy for GBM. Cancer Res; 77(13); 3479–90. ©2017 AACR.
Tumor-Associated Macrophages Promote Malignant Progression of Breast Phyllodes Tumors by Inducing Myofibroblast Differentiation
Authors: Nie Yan , Chen Jianing , Huang Di , Yao Yandan , Chen Jiewen , Ding Lin , Zeng Jiayi , Su Shicheng , Chao Xue , Su Fengxi , Yao Herui , Hu Hai , Song Erwei 
Published: May 2017

Abstract
Myofibroblast differentiation plays an important role in the malignant progression of phyllodes tumor, a fast-growing neoplasm derived from periductal stromal cells of the breast. Macrophages are frequently found in close proximity with myofibroblasts, but it is uncertain whether they are involved in the myofibroblast differentiation during phyllodes tumor progression. Here we show that increased density of tumor-associated macrophage (TAM) correlates with malignant progression of phyllodes tumor. We found that TAMs stimulated myofibroblast differentiation and promoted the proliferation and invasion of phyllodes tumor cells. Furthermore, we found that levels of the chemokine CCL18 in TAM was an independent prognostic factor of phyllodes tumor. Mechanistic investigations showed that CCL18 promoted expression of α-smooth muscle actin, a hallmark of myofibroblast, along with the proliferation and invasion of phyllodes tumor cells, and that CCL18-driven myofibroblast differentiation was mediated by an NF-κB/miR-21/PTEN/AKT signaling axis. In murine xenograft models of human phyllodes tumor, CCL18 accelerated tumor growth, induced myofibroblast differentiation, and promoted metastasis. Taken together, our findings indicated that TAM drives myofibroblast differentiation and malignant progression of phyllodes tumor through a CCL18-driven signaling cascade amenable to antibody disruption. Cancer Res; 77(13); 3605–18. ©2017 AACR.
STING Activation Reverses Lymphoma-Mediated Resistance to Antibody Immunotherapy
Authors: Dahal Lekh N. , Dou Lang , Hussain Khiyam , Liu Rena , Earley Alexander , Cox Kerry L. , Murinello Salome , Tracy Ian , Forconi Francesco , Steele Andrew J. , Duriez Patrick J. , Gomez-Nicola Diego , Teeling Jessica L. , Glennie Martin J. , Cragg Mark S. , Beers Stephen A. 
Published: May 2017

Abstract
Tumors routinely attract and co-opt macrophages to promote their growth, angiogenesis, and metastasis. Macrophages are also the key effector cell for mAb therapies. Here we report that the tumor microenvironment creates an immunosuppressive signature on tumor-associated macrophages (TAM), which favors expression of inhibitory rather than activating Fcγ receptors (FcγR), thereby limiting the efficacy of mAb immunotherapy. We assessed a panel of TLR and STING agonists (a) for their ability to reprogram macrophages to a state optimal for mAb immunotherapy. Both STINGa and TLRa induced cytokine release, modulated FcγR expression, and augmented mAb-mediated tumor cell phagocytosis in vitro. However, only STINGa reversed the suppressive FcγR profile in vivo, providing strong adjuvant effects to anti-CD20 mAb in murine models of lymphoma. Potent adjuvants like STINGa, which can improve FcγR activatory:inhibitory (A:I) ratios on TAM, are appealing candidates to reprogram TAM and curb tumor-mediated immunosuppression, thereby empowering mAb efficacy. Cancer Res; 77(13); 3619–31. ©2017 AACR.
Merkel Cell Polyomavirus Small T Antigen Initiates Merkel Cell Carcinoma-like Tumor Development in Mice
Authors: Verhaegen Monique E. , Mangelberger Doris , Harms Paul W. , Eberl Markus , Wilbert Dawn M. , Meireles Julia , Bichakjian Christopher K. , Saunders Thomas L. , Wong Sunny Y. , Dlugosz Andrzej A. 
Published: May 2017

Abstract
Merkel cell carcinoma (MCC) tumor cells express several markers detected in normal Merkel cells, a nonproliferative population of neuroendocrine cells that arise from epidermis. MCCs frequently contain Merkel cell polyomavirus (MCPyV) DNA and express viral transforming antigens, sT and tLT, but the role of these putative oncogenes in MCC development, and this tumor's cell of origin, are unknown. Using a panel of preterm transgenic mice, we show that epidermis-targeted coexpression of sT and the cell fate-determinant atonal bHLH transcription factor 1 (ATOH1) leads to development of widespread cellular aggregates, with histology and marker expression mimicking that of human intraepidermal MCC. The MCC-like tumor phenotype was dependent on the FBXW7-binding domain of sT, but not the sT-PP2A binding domain. Coexpression of MCPyV tLT did not appreciably alter the phenotype driven by either sT or sT combined with ATOH1. MCPyV sT, when coexpressed with ATOH1, is thus sufficient to initiate development of epidermis-derived MCC-like tumors in mice. Cancer Res; 77(12); 3151–7. ©2017 AACR.
Dynamic Changes in PD-L1 Expression and Immune Infiltrates Early During Treatment Predict Response to PD-1 Blockade in Melanoma
Authors: Vilain Ricardo E. , Menzies Alexander M. , Wilmott James S. , Kakavand Hojabr , Madore Jason , Guminski Alexander , Liniker Elizabeth , Kong Benjamin Y. , Cooper Adam J. , Howle Julie R. , Saw Robyn P.M. , Jakrot Valerie , Lo Serigne , Thompson John F. , Carlino Matteo S. , Kefford Richard F. , Long Georgina V. , Scolyer Richard A. 
Published: May 2017

Abstract
Purpose: Disruption of PD-L1/cytotoxic T-cell PD-1 signaling by immune checkpoint inhibitors improves survival in cancer patients. This study sought to identify changes in tumoral PD-L1 expression and tumor-associated immune cell flux with anti-PD-1 therapies in patients with melanoma, particularly early during treatment, and correlate them with treatment response.
Experimental Design: Forty-six tumor biopsies from 23 patients with unresectable AJCC stage III/IV melanoma receiving pembrolizumab/nivolumab were analyzed. Biopsies were collected prior to (PRE, n = 21), within 2 months of commencing treatment (EDT, n = 20) and on disease progression after previous response (PROG, n = 5). Thirteen patients responded (defined as CR, PR, or durable SD by RECIST/irRC criteria), and 10 did not respond.
Results: PRE intratumoral and peritumoral PD-1+ T-cell densities were sevenfold (P = 0.006) and fivefold higher (P = 0.011), respectively, in responders compared with nonresponders and correlated with degree of radiologic tumor response (r = −0.729, P = 0.001 and r = −0.725, P = 0.001, respectively). PRE PD-L1 expression on tumor and macrophages was not significantly different between the patient groups, but tumoral PD-L1 and macrophage PD-L1 expression was higher in the EDT of responders versus nonresponders (P = 0.025 and P = 0.033). Responder EDT biopsies (compared with PRE) also showed significant increases in intratumoral CD8+ lymphocytes (P = 0.046) and intratumoral CD68+ macrophages (P = 0.046).
Conclusions: Higher PRE PD-1+ T cells in responders suggest active suppression of an engaged immune system that is disinhibited by anti-PD-1 therapies. Furthermore, immunoprofiling of EDT biopsies for increased PD-L1 expression and immune cell infiltration showed greater predictive utility than PRE biopsies and may allow better selection of patients most likely to benefit from anti-PD-1 therapies and warrants further evaluation. Clin Cancer Res; 23(17); 5024–33. ©2017 AACR.
Epigenetic Regulation of ZBTB18 Promotes Glioblastoma Progression
Authors: Fedele Vita , Dai Fangping , Masilamani Anie P. , Heiland Dieter H. , Kling Eva , Gätjens-Sanchez Ana M. , Ferrarese Roberto , Platania Leonardo , Doostkam Soroush , Kim Hyunsoo , Nelander Sven , Weyerbrock Astrid , Prinz Marco , Califano Andrea , Iavarone Antonio , Bredel Markus , Carro Maria S. 
Published: May 2017

Abstract
Glioblastoma (GBM) comprises distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis–associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties.
Implications: This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass. Mol Cancer Res; 15(8); 998–1011. ©2017 AACR.
Infiltrating Myeloid Cells Exert Protumorigenic Actions via Neutrophil Elastase
Authors: Lerman Irina , Garcia-Hernandez Maria de la Luz , Rangel-Moreno Javier , Chiriboga Luis , Pan Chunliu , Nastiuk Kent L. , Krolewski John J. , Sen Aritro , Hammes Stephen R. 
Published: May 2017

Abstract
Tissue infiltration and elevated peripheral circulation of granulocytic myeloid-derived cells is associated with poor outcomes in prostate cancer and other malignancies. Although myeloid-derived cells have the ability to suppress T-cell function, little is known about the direct impact of these innate cells on prostate tumor growth. Here, it is reported that granulocytic myeloid-derived suppressor cells (MDSC) are the predominant tumor-infiltrating cells in prostate cancer xenografts established in athymic nude mice. MDSCs significantly increased in number in the peripheral circulation as a function of xenograft growth and were successfully depleted in vivo by Gr-1 antibody treatment. Importantly, MDSC depletion significantly decreased xenograft growth. We hypothesized that granulocytic MDSCs might exert their protumorigenic actions in part through neutrophil elastase (ELANE), a serine protease released upon granulocyte activation. Indeed, it was determined that NE is expressed by infiltrating immune cells and is enzymatically active in prostate cancer xenografts and in prostate tumors of prostate-specific Pten-null mice. Importantly, treatment with sivelestat, a small-molecule inhibitor specific for NE, significantly decreased xenograft growth, recapitulating the phenotype of Gr-1 MDSC depletion. Mechanistically, NE activated MAPK signaling and induced MAPK-dependent transcription of the proliferative gene cFOS in prostate cancer cells. Functionally, NE stimulated proliferation, migration, and invasion of prostate cancer cells in vitro. IHC on human prostate cancer clinical biopsies revealed coexpression of NE and infiltrating CD33+ MDSCs.
Implications: This report suggests that MDSCs and NE are physiologically important mediators of prostate cancer progression and may serve as potential biomarkers and therapeutic targets. Mol Cancer Res; 15(9); 1138–52. ©2017 AACR.