bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioluminescence in Dinoflagellates: Evidence that the Adaptive Value of Bioluminescence in Dinoflagellates is Concentration Dependent
Authors: Hanley Karen A. , Widder Edith A. 
Published: January 2017

AbstractThree major hypotheses have been proposed to explain why dinoflagellate bioluminescence deters copepod grazing: startle response, aposematic warning, and burglar alarm. These hypotheses propose dinoflagellate bioluminescence (A) startles predatory copepods, (B) warns potential predators of toxicity, and (C) draws the attention of higher order visual predators to the copepod's location. While the burglar alarm is the most commonly accepted hypothesis, it requires a high concentration of bioluminescent dinoflagellates to be effective, meaning the bioluminescence selective advantage at lower, more commonly observed, dinoflagellate concentrations may result from another function (e.g. startle response or aposematic warning). Therefore, a series of experiments was conducted to evaluate copepod grazing (Acartia tonsa) on bioluminescent dinoflagellates (during bioluminescent and nonbioluminescent phases, corresponding to night and day, respectively) at different concentrations (10, 1000, and 3000 cells mL−1), on toxic (Pyrodinium bahamense var. bahamense) and nontoxic (Lingulodinium polyedrum) bioluminescent dinoflagellates, and in the presence of nonluminescent diatoms (Thalassiosira eccentrica). Changes in copepod ingestion rates, clearance rates, and feeding preferences as a result of these experimental factors, particularly during the mixed trails with nonluminescent diatoms, indicate there is a concentration threshold at which the burglar alarm becomes effective and below which dinoflagellate bioluminescence functions as an aposematic warning.
Strongholding the Synagogue to Stronghold the City: Urban‐Religious Configurations in an Israeli Mixed‐City
Authors: Ram Moriel , Aharon Gutman Meirav 
Published: January 2017

AbstractThis article explores the geopolitical significance of public religious institutions and the ways in which it has corresponded to changes in their urban environment. Based on a spatial analysis and ethnography of urban synagogues in the northern Israeli mixed city of Acre that were established and constructed by communities of Jewish immigrants from North African countries, we demonstrate how significant shifts in the city's demographic pattern and landscape have affected these institutions' ascribed functions and meanings. We theorise this dynamic as ‘strongholding’, or, more specifically, strongholding the synagogue as a means of strongholding the city. The formation of the synagogue as a stronghold is enacted through a dual configuration process by which the religious legitimacy, which the synagogue bestows on those who maintain it, is interwoven into a broader urban sociopolitical struggle to claim a presence in the city.
Mutation analysis and gene expression profiling of ocular melanomas in cats
Authors: Rushton J. G. , Ertl R. , Klein D. , Nell B. 
Published: January 2017

AbstractFeline ocular melanomas show a high malignant behaviour, but adjunctive therapies are non‐existent. The aim of this pilot study was to determine, whether feline ocular melanomas harbour mutations comparable to mutations in human melanomas and to evaluate the gene expression status of genes known to be involved in initiation and progression of human melanomas. Mutation hotspot regions of several genes of feline ocular melanomas were analysed by DNA sequencing and RNA expression levels of the respective genes and others were evaluated by quantitative real‐time polymerase chain reaction (RT‐qPCR). Common mutations found in human melanomas are not present in feline tumours. Gene expression analysis revealed a significant upregulation of KIT and LTA4H, as well as a downregulation of GNAQ, GNA11, BRAF and RASSF1 in feline ocular melanomas. As KIT seems to harbour a potential as target gene in human uveal melanomas, future studies should further investigate the potential of KIT as target for adjunctive therapy in feline ocular melanomas.
S100A4 (metastasin) positive mesenchymal canine mammary tumour spheroids reduce Tenascin C synthesis under DMSO exposure in vitro
Authors: Kau S. , Miller I. , Tichy A. , Gabriel C. 
Published: January 2017

AbstractIn breast cancer research S100A4‐positive tumour‐associated stromal cells are assumed as primary source of Tenascin C (TNC) in the metastatic environment. Aim of the present study was to isolate and characterize S100A4/TNC positive stromal canine mammary tumour (CMT) cells. Cells grown as scaffold‐free spheroids were investigated for S100A4, TNC, and proliferative activity under 1.8% DMSO stimulation by means of Western blot and immunohistochemistry. DMSO is a commonly used drug solvent despite well‐known side effects on cells including TNC expression. DMSO did not affect proliferation, but TNC was significantly reduced under DMSO exposure for 7 and 14 days, whereby for S100A4 a reducing effect was only observed after 14 days. Without DMSO, cells stably expressed TNC and S100A4 which makes them suitable to be used in experimental approaches requiring S100A4/TNC expressing CMT stromal cells. Results show that 1.8% DMSO should not be used as solvent for experiments concerning TNC/S100A4 expression.
AMPK does not play a requisite role in regulation of PPARGC1A gene expression via the alternative promoter in endurance‐trained human skeletal muscle
Authors: Popov Daniil V. , Lysenko Evgeny A. , Butkov Alexey D. , Vepkhvadze Tatiana F. , Perfilov Dmitriy V. , Vinogradova Olga L. 
Published: January 2017

New Findings
What is the central question of this study?
This study was designed to investigate the role of AMPK in the regulation of PGC‐1α gene expression via the alternative promoter through a cAMP response element‐binding protein‐1‐dependent mechanism in human skeletal muscle.

What is the main finding and its importance?
Low‐intensity exercise markedly increased the expression of PGC‐1α mRNA via the alternative promoter, without increases in ACCSer79/222 (a marker of AMPK activation) and AMPKThr172 phosphorylation. A single dose of the AMPK activator metformin indicated that AMPK was not involved in regulating PGC‐1α mRNA expression via the alternative promoter in endurance‐trained human skeletal muscle.

In human skeletal muscle, PGC‐1α is constitutively expressed via the canonical promoter. In contrast, the expression of PGC‐1α mRNA via the alternative promoter was found to be highly dependent on the intensity of exercise and to contribute largely to the postexercise increase of total PGC‐1α mRNA. This study investigated the role of AMPK in regulating PGC‐1α gene expression via the alternative promoter through a cAMP response element‐binding protein‐1‐dependent mechanism in human skeletal muscle. AMPK activation and PGC‐1α gene expression were assayed in skeletal muscle of nine endurance‐trained men before and after low‐intensity exercise (38% of maximal oxygen uptake) and with or without administration of a single dose (2 g) of the AMPK activator metformin. Low‐intensity exercise markedly and significantly increased (∼100‐fold, P < 0.05) the expression of PGC‐1α mRNA via the alternative promoter, without increasing ACCSer79/222 (a marker of AMPK activation) and AMPKThr172 phosphorylation. Moreover, in contrast to placebo, metformin increased the level of ACCSer79/222 phosphorylation immediately after exercise (2.6‐fold, P < 0.05). However postexercise expression of PGC‐1α gene via the alternative promoter was not affected. This study was unable to confirm that AMPK plays a role in regulating PGC‐1α gene expression via the alternative promoter in endurance‐trained human skeletal muscle.
Making Home Sweet and Sturdy:Toxoplasma gondiippGalNAc-Ts Glycosylate in Hierarchical Order and Confer Cyst Wall Rigidity
Authors: Tomita Tadakimi , Sugi Tatsuki , Yakubu Rama , Tu Vincent , Ma Yanfen , Weiss Louis M. 
Published: January 2017

ABSTRACTThe protozoan intracellular parasiteToxoplasma gondiiforms latent cysts in the central nervous system (CNS) and persists for the lifetime of the host. This cyst is cloaked with a glycosylated structure called the cyst wall. Previously, we demonstrated that a mucin-like glycoprotein, CST1, localizes to the cyst wall and confers structural rigidity on brain cysts in a mucin-like domain-dependent manner. The mucin-like domain of CST1 is composed of 20 units of threonine-rich tandem repeats that areO-GalNAc glycosylated. A family of enzymes termed polypeptideN-acetylgalactosaminyltransferases (ppGalNAc-Ts) initiatesO-GalNAc glycosylation. To identify which isoforms of ppGalNAc-Ts are responsible for the glycosylation of the CST1 mucin-like domain and to evaluate the function of each ppGalNAc-T in the overall glycosylation of the cyst wall, all five ppGalNAc-T isoforms were deleted individually from theT. gondiigenome. The ppGalNAc-T2 and -T3 deletion mutants produced various glycosylation defects on the cyst wall, implying that many cyst wall glycoproteins are glycosylated by T2 and T3. Both T2 and T3 glycosylate the CST1 mucin-like domain, and this glycosylation is necessary for CST1 to confer structural rigidity on the cyst wall. We established that T2 is required for the initial glycosylation of the mucin-like domain and that T3 is responsible for the sequential glycosylation on neighboring acceptor sites, demonstrating hierarchical glycosylation by two distinct initiating and filling-in ppGalNAc-Ts in an intact organism.IMPORTANCEToxoplasma gondiiis an obligate intracellular parasite that infects a third of the world’s population. It can cause severe congenital disease and devastating encephalitis in immunocompromised individuals. We identified two glycosyltransferases, ppGalNAc-T2 and -T3, which are responsible for glycosylating cyst wall proteins in a hierarchical fashion. This glycosylation confers structural rigidity on the brain cyst. Our studies provide new insights into the mechanisms ofO-GalNAc glycosylation inT. gondii.
Delayed enhancing lesions after coil embolization of aneurysms: clinical experience and benchtop analyses
Authors: Oh Se Won , Shin Na Young , Lee Ho-Joon , Kim Byung Moon , Kim Dong Joon 
Published: January 2017

BackgroundForeign body emboli during endovascular treatment (EVT) may cause delayed enhancing lesions (DELs).ObjectiveTo report our experiences of this complication in patients treated for cerebral aneurysms and to investigate the cause of the lesions by benchtop analyses.MethodsThree patients with DELs on MRI after EVT were retrospectively investigated. Unusual friction had occurred in the midst of coil delivery in two patients. The imaging findings, cause of the lesions due to the devices used for the procedure, treatment, and follow-up results were assessed. Two benchtop analyses were performed. First, a microcatheter that showed similar unusual friction during coiling was retrieved and dissected at the point of friction. Second, the EVT procedure was simulated with multiple coil advancement and withdrawal maneuvers within an acutely angulated microcatheter to identify downstream foreign body material emboli.ResultsThe DELs were identified 27–37 days (mean 32.7) after the procedure. The patients presented with left arm weakness, headache, and no other symptoms. The lesions were located in the hemisphere corresponding to the treatment. The symptoms subsided after conservative therapy. The dissected microcatheter showed whitish semitransparent material adherent to the inner lumen. Similar material was sieved after multiple coil advancement and withdrawal maneuvers.ConclusionsDELs may be caused by fragmentation and emboli of the inner coating wall of the microcatheter. Development of unusual friction during coil delivery may be a sign of damage of the microcatheter inner wall and the device should be discarded.
Perineural Invasion and Risk of Lethal Prostate Cancer
Authors: Zareba Piotr , Flavin Richard , Isikbay Masis , Rider Jennifer R. , Gerke Travis A. , Finn Stephen , Pettersson Andreas , Giunchi Francesca , Unger Robert H. , Tinianow Alex M. , Andersson Swen-Olof , Andrén Ove , Fall Katja , Fiorentino Michelangelo , Mucci Lorelei A. 
Published: January 2017

Abstract
Background: Prostate cancer has a propensity to invade and grow along nerves, a phenomenon called perineural invasion (PNI). Recent studies suggest that the presence of PNI in prostate cancer has been associated with cancer aggressiveness.
Methods: We investigated the association between PNI and lethal prostate cancer in untreated and treated prostate cancer cohorts: the Swedish Watchful Waiting Cohort of 615 men who underwent watchful waiting, and the U.S. Health Professionals Follow-Up Study of 849 men treated with radical prostatectomy. One pathologist performed a standardized histopathologic review assessing PNI and Gleason grade. Patients were followed from diagnosis until metastasis or death.
Results: The prevalence of PNI was 7% and 44% in the untreated and treated cohorts, respectively. PNI was more common in high Gleason grade tumors in both cohorts. PNI was associated with enhanced tumor angiogenesis, but not tumor proliferation or apoptosis. In the Swedish study, PNI was associated with lethal prostate cancer [OR 7.4; 95% confidence interval (CI), 3.6–16.6; P &lt; 0.001]. A positive, although not statistically significant, association persisted after adjustment for age, Gleason grade, and tumor volume (OR 1.9; 95% CI, 0.8–5.1; P = 0.17). In the U.S. study, PNI predicted lethal prostate cancer independent of clinical factors (HR 1.8; 95% CI, 1.0, 3.3; P =0.04).
Conclusions: These data support the hypothesis that perineural invasion creates a microenvironment that promotes cancer aggressiveness.
Impact: Our findings suggest that PNI should be a standardized component of histopathologic review, and highlights a mechanism underlying prostate cancer metastasis. Cancer Epidemiol Biomarkers Prev; 26(5); 719–26. ©2017 AACR.
FDA Approval of Nivolumab for the First-Line Treatment of Patients with BRAFV600 Wild-Type Unresectable or Metastatic Melanoma
Authors: Beaver Julia A. , Theoret Marc R. , Mushti Sirisha , He Kun , Libeg Meredith , Goldberg Kirsten , Sridhara Rajeshwari , McKee Amy E. , Keegan Patricia , Pazdur Richard 
Published: January 2017

Abstract
On November 23, 2015, the FDA approved nivolumab (OPDIVO; Bristol-Myers Squibb) as a single agent for the first-line treatment of patients with BRAFV600 wild-type, unresectable or metastatic melanoma. An international, double-blind, randomized (1:1) trial conducted outside of the United States allocated 418 patients to receive nivolumab 3 mg/kg intravenously every 2 weeks (n = 210) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 208). Patients with disease progression who met protocol-specified criteria (∼25% of each trial arm) were permitted to continue with the assigned treatment in a blinded fashion until further disease progression is documented. Overall survival was statistically significantly improved in the nivolumab arm compared with the dacarbazine arm [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.30–0.60; P &lt; 0.0001]. Progression-free survival was also statistically significantly improved in the nivolumab arm (HR, 0.43; 95% CI, 0.34–0.56; P &lt; 0.0001). The most common adverse reactions (≥20%) of nivolumab were fatigue, diarrhea, constipation, nausea, musculoskeletal pain, rash, and pruritus. Nivolumab demonstrated a favorable benefit–risk profile compared with dacarbazine, supporting regular approval; however, it remains unclear whether treatment beyond disease progression contributes to the overall clinical benefit of nivolumab. Clin Cancer Res; 23(14); 3479–83. ©2017 AACR.
Extended Treatment with Single-Agent Ibrutinib at the 420 mg Dose Leads to Durable Responses in Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
Authors: Coutré Steven E. , Furman Richard R. , Flinn Ian W. , Burger Jan A. , Blum Kristie , Sharman Jeff , Jones Jeffrey , Wierda William , Zhao Weiqiang , Heerema Nyla A. , Johnson Amy J. , Tran Anh , Zhou Cathy , Bilotti Elizabeth , James Danelle F. , Byrd John C. , O'Brien Susan 
Published: January 2017

Abstract
Purpose: Ibrutinib, a first-in-class, once-daily, oral inhibitor of Bruton tyrosine kinase, promotes apoptosis, and inhibits B-cell proliferation, adhesion, and migration. Ibrutinib has demonstrated single-agent efficacy and acceptable tolerability at doses of 420 and 840 mg in patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who were treatment-naïve (TN) or had relapsed/refractory (R/R) CLL after ≥1 prior therapy in a phase Ib/II study (PCYC-1102). Subsequently, the ibrutinib 420 mg dose was approved in CLL.
Experimental Design: We report data with 44 months of follow-up on 94 patients with TN and R/R CLL/SLL receiving ibrutinib 420 mg once-daily in PCYC-1102 and the long-term extension study PCYC-1103.
Results: Ninety-four CLL/SLL patients (27 TN, 67 R/R) were treated with ibrutinib (420 mg/day). Patients with R/R disease had received a median of four prior therapies (range, 1–12). Responses were rapid and durable and median duration of response was not reached. Best overall response was 91% [85% TN (complete response, CR 26%) and 94% R/R (9% CR)]. Median progression-free survival (PFS) was not reached in either group. The 30-month PFS rate was 96% and 76% for TN and R/R patients, respectively. Ibrutinib was well tolerated with extended follow-up; rates of grade ≥3 cytopenias and fatigue, as well as discontinuations due to toxicities decreased over time.
Conclusions: Single-agent ibrutinib at 420 mg once-daily resulted in durable responses and was well tolerated with up to 44 months follow-up in patients with TN and R/R CLL/SLL. Currently, 66% of patients continue on ibrutinib. Clin Cancer Res; 23(5); 1149–55. ©2017 AACR.
Active Estrogen Receptor-alpha Signaling in Ovarian Cancer Models and Clinical Specimens
Authors: Andersen Courtney L. , Sikora Matthew J. , Boisen Michelle M. , Ma Tianzhou , Christie Alec , Tseng George , Park Yongseok , Luthra Soumya , Chandran Uma , Haluska Paul , Mantia-Smaldone Gina M. , Odunsi Kunle , McLean Karen , Lee Adrian V. , Elishaev Esther , Edwards Robert P. , Oesterreich Steffi 
Published: January 2017

Abstract
Purpose: High-grade serous ovarian cancer (HGSOC) is an aggressive disease with few available targeted therapies. Despite high expression of estrogen receptor-alpha (ERα) in approximately 80% of HGSOC and some small but promising clinical trials of endocrine therapy, ERα has been understudied as a target in this disease. We sought to identify hormone-responsive, ERα-dependent HGSOC.
Experimental Design: We characterized endocrine response in HGSOC cells across culture conditions [ two-dimensional (2D), three-dimensional (3D), forced suspension] and in patient-derived xenograft (PDX) explants, assessing proliferation and gene expression. Estrogen-regulated transcriptome data were overlapped with public datasets to develop a comprehensive panel of ERα target genes. Expression of this panel and ERα H-score were assessed in HGSOC samples from patients who received endocrine therapy. Time on endocrine therapy was used as a surrogate for clinical response.
Results: Proliferation is ERα-regulated in HGSOC cells in vitro and in vivo, and is partly dependent on 3D context. Transcriptomic studies identified genes shared by cell lines and PDX explants as ERα targets. The selective ERα downregulator (SERD) fulvestrant is more effective than tamoxifen in blocking ERα action. ERα H-score is predictive of efficacy of endocrine therapy, and this prediction is further improved by inclusion of target gene expression, particularly IGFBP3.
Conclusions: Laboratory models corroborate intertumor heterogeneity of endocrine response in HGSOC but identify features associated with functional ERα and endocrine responsiveness. Assessing ERα function (e.g., IGFBP3 expression) in conjunction with H-score may help select patients who would benefit from endocrine therapy. Preclinical data suggest that SERDs might be more effective than tamoxifen. Clin Cancer Res; 23(14); 3802–12. ©2017 AACR.
Long-term Survival and Clinical Benefit from Adoptive T-cell Transfer in Stage IV Melanoma Patients Is Determined by a Four-Parameter Tumor Immune Signature
Authors: Melief Sara M. , Visconti Valeria V. , Visser Marten , van Diepen Merel , Kapiteijn Ellen H.W. , van den Berg Joost H. , Haanen John B.A.G. , Smit Vincent T.H.B.M. , Oosting Jan , van der Burg Sjoerd H. , Verdegaal Els M.E. 
Published: January 2017

AbstractThe presence of tumor-infiltrating immune cells is associated with longer survival and a better response to immunotherapy in early-stage melanoma, but a comprehensive study of the in situ immune microenvironment in stage IV melanoma has not been performed. We investigated the combined influence of a series of immune factors on survival and response to adoptive cell transfer (ACT) in stage IV melanoma patients. Metastases of 73 stage IV melanoma patients, 17 of which were treated with ACT, were studied with respect to the number and functional phenotype of lymphocytes and myeloid cells as well as for expression of galectins-1, -3, and -9. Single factors associated with better survival were identified using Kaplan–Meier curves and multivariate Cox regression analyses, and those factors were used for interaction analyses. The results were validated using The Cancer Genome Atlas database. We identified four parameters that were associated with a better survival: CD8+ T cells, galectin-9+ dendritic cells (DC)/DC-like macrophages, a high M1/M2 macrophage ratio, and the expression of galectin-3 by tumor cells. The presence of at least three of these parameters formed an independent positive prognostic factor for long-term survival. Patients displaying this four-parameter signature were found exclusively among patients responding to ACT and were the ones with sustained clinical benefit. Cancer Immunol Res; 5(2); 170–9. ©2017 AACR.
Intracardiac Pressures Measured Using an Implantable Hemodynamic Monitor
Authors: Zile Michael R. , Bennett Tom D. , El Hajj Stephanie , Kueffer Fred J. , Baicu Catalin F. , Abraham William T. , Bourge Robert C. , Warner Stevenson Lynne 
Published: January 2017

Background—
The purpose of this analysis was to examine whether implantable hemodynamic monitor–derived baseline estimated pulmonary artery diastolic pressure (ePAD) and change from baseline ePAD were independent predictors of all-cause mortality in patients with chronic heart failure.

Methods and Results—

Retrospective analysis used data from 3 studies (n=790 patients; 216 deaths). Baseline ePAD was related to mortality using a multivariable model including baseline and demographic data. Changes in ePAD defined as change from baseline to 6 months and from baseline to 14 days before death or exit from study were related to subsequent mortality, and analysis was adjusted for baseline ePAD. Area under the pressure versus time curve during 180 days before death or exit from study was related to mortality. Baseline ePAD, independent of other covariates, was a significant predictor of mortality (hazard ratio=1.07; 95% confidence interval=1.05–1.09;
P
<0.0001). Change in ePAD was an independent predictor of mortality (hazard ratio=1.07; 95% confidence interval=1.05–1.100;
P
=0.0008). Increased ePAD of 3, 4, or 5 mm Hg from baseline to 6 months was associated with increased mortality risk of 23.8%, 32.9%, or 42.8%. Change in ePAD from baseline to 14 days before death or exit from study was higher in patients who died (3.0±8 versus 1.7±10 mm Hg;
P
=0.003). Area under the pressure versus time curve in the final 180 days before death or exit from study was higher in patients who died versus those alive at end of study (185±668 versus 17±482 mm Hg.days;
P
=0.006).

Conclusions—
Implantable hemodynamic monitor–derived baseline ePAD and change from baseline ePAD were independent predictors of mortality in chronic heart failure patients.