bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immunomodulatory Effects of Pneumococcal Extracellular Vesicles on Cellular and Humoral Host Defenses
Authors: Codemo Mario , Muschiol Sandra , Iovino Federico , Nannapaneni Priyanka , Plant Laura , Wai Sun Nyunt , Henriques-Normark Birgitta 
Published: April 2018

ABSTRACT

Gram-positive bacteria, including the major respiratory pathogen
Streptococcus pneumoniae
, were recently shown to produce extracellular vesicles (EVs) that likely originate from the plasma membrane and are released into the extracellular environment. EVs may function as cargo for many bacterial proteins, however, their involvement in cellular processes and their interactions with the innate immune system are poorly understood. Here, EVs from pneumococci were characterized and their immunomodulatory effects investigated. Pneumococcal EVs were protruding from the bacterial surface and released into the medium as 25 to 250 nm lipid stained vesicles containing a large number of cytosolic, membrane, and surface-associated proteins. The cytosolic pore-forming toxin pneumolysin was significantly enriched in EVs compared to a total bacterial lysate but was not required for EV formation. Pneumococcal EVs were internalized into A549 lung epithelial cells and human monocyte-derived dendritic cells and induced proinflammatory cytokine responses irrespective of pneumolysin content. EVs from encapsulated pneumococci were recognized by serum proteins, resulting in C3b deposition and formation of C5b-9 membrane attack complexes as well as factor H recruitment, depending on the presence of the choline binding protein PspC. Addition of EVs to human serum decreased opsonophagocytic killing of encapsulated pneumococci. Our data suggest that EVs may act in an immunomodulatory manner by allowing delivery of vesicle-associated proteins and other macromolecules into host cells. In addition, EVs expose targets for complement factors in serum, promoting pneumococcal evasion of humoral host defense.

IMPORTANCE
Streptococcus pneumoniae
is a major contributor to morbidity and mortality worldwide, being the major cause of milder respiratory tract infections such as otitis and sinusitis and of severe infections such as community-acquired pneumonia, with or without septicemia, and meningitis. More knowledge is needed on how pneumococci interact with the host, deliver virulence factors, and activate immune defenses. Here we show that pneumococci form extracellular vesicles that emanate from the plasma membrane and contain virulence properties, including enrichment of pneumolysin. We found that pneumococcal vesicles can be internalized into epithelial and dendritic cells and bind complement proteins, thereby promoting pneumococcal evasion of complement-mediated opsonophagocytosis. They also induce pneumolysin-independent proinflammatory responses. We suggest that these vesicles can function as a mechanism for delivery of pneumococcal proteins and other immunomodulatory components into host cells and help pneumococci to avoid complement deposition and phagocytosis-mediated killing, thereby possibly contributing to the symptoms found in pneumococcal infections.
Management of recurrent pancreatic cancer after surgical resection: a protocol for systematic review, evidence mapping and meta-analysis
Authors: Lee Jong-chan , Ahn Soyeon , Cho In Kuk , Lee Jongchan , Kim Jaihwan , Hwang Jin-Hyeok 
Published: April 2018

IntroductionAlthough recurrence rate among cases of resected pancreatic cancer are as high as 85%, an optimal treatment for recurrent pancreatic cancer (RePC) has not been established. Previous evidence regarding RePC is scarce, and randomised controlled trials (RCTs) are particularly lacking. The evidence mapping (EM) method has been introduced as a tool intended to complement the conventional systematic review (SR) and meta-analysis (MA) and is suitable for this issue. This review aims to investigate the optimal treatment options for RePC, using a newly developed automatic EM tool.Method and analysisAll study types, including RCTs, non-randomised studies and other forms of observational studies will be included in the SR-EM. The Medline, Embase, Cochrane library and Scopus databases will be searched for reports of five treatment options for local and metastatic recurrences, including re-resection, chemotherapy, radiotherapy, best supportive care and other novel treatments, published from database inception to 30 April 2017. References from relevant studies will be searched manually. If meta-analysis is feasible, the primary outcome measure will be median overall survival. Two independent authors will select the studies and assess the risk of bias, and a third author will resolve discrepancies in consensus meeting. To visualise EM, we will use a novel web-based and open-access mapping programme, Plotting E-Map (PLOEM) (http://plotting-e-map.com). If eligible combinations of interventions for quantitative comparison are identified, we will conduct subgroup MAs using random-effect models and I2statistics. Publication bias will be visualised using funnel plots.Ethics and disseminationThis study will not use primary data, and therefore formal ethical approval is not required. The findings will be disseminated through peer-reviewed journals and committee conferences.PROSPEROregistration numberCRD42016049178.
Local isometric immersions of pseudo-spherical surfaces and kth order evolution equations
Authors: Kahouadji Nabil , Kamran Niky , Tenenblat Keti 
Published: April 2018

We consider the class of evolution equations of the form [Formula: see text], [Formula: see text], that describe pseudo-spherical surfaces. These were classified by Chern and Tenenblat in [Pseudospherical surfaces and evolution equations, Stud. Appl. Math 74 (1986) 55–83.]. This class of equations is characterized by the property that to each solution of such an equation, there corresponds a 2-dimensional Riemannian metric of constant curvature [Formula: see text]. Motivated by the special properties of the sine-Gordon equation, we investigate the following problem: given such a metric, is there a local isometric immersion in [Formula: see text] such that the coefficients of the second fundamental form of the immersed surface depend on a jet of finite order of [Formula: see text]? We extend our earlier results for second-order evolution equations [N. Kahouadji, N. Kamran and K. Tenenblat, Local isometric immersions of pseudo-spherical surfaces and evolution equations, Fields Inst. Commun. 75 (2015) 369–381; N. Kahouadji, N. Kamran and K. Tenenblat, Second-order equations and local isometric immersions of pseudo-spherical surfaces, Comm. Anal. Geom. 24(3) (2016) 605–643.] to [Formula: see text]th order equations by proving that there is only one type of equation that admit such an isometric immersion. More precisely, we prove under the condition of finite jet dependency that the coefficients of the second fundamental forms of the local isometric immersion determined by the solutions [Formula: see text] are universal, i.e. they are independent of [Formula: see text]. Moreover, we show that there exists a foliation of the domain of the parameters of the surface by straight lines with the property that the mean curvature of the surface is constant along the images of these straight lines under the isometric immersion.
Enhanced Lymphodepletion Is Insufficient to Replace Exogenous IL2 or IL15 Therapy in Augmenting the Efficacy of Adoptively Transferred Effector CD8+ T Cells
Authors: Johnson C. Bryce , May Bennett R. , Riesenberg Brian P. , Suriano Samantha , Mehrotra Shikhar , Garrett-Mayer Elizabeth , Salem Mohamed L. , Jeng Emily K. , Wong Hing C. , Paulos Chrystal M. , Wrangle John M. , Cole David J. , Rubinstein Mark P. 
Published: April 2018

AbstractEffector CD8+ T cells conditioned with IL12 during activation mediate enhanced antitumor efficacy after adoptive transfer into lymphodepleted hosts; this is due in part to improved IL7 responsiveness. Therefore, we hypothesized that increasing the intensity or type of lymphodepletion would deplete more IL7-consuming host cells and improve the persistence and antitumor activity of IL12-conditioned CD8+ T cells. Using cyclophosphamide, fludarabine, and total body irradiation (TBI, 6 Gy) either individually or in combination, we found that combined lymphodepletion best enhanced T-cell engraftment in mice. This improvement was strongly related to the extent of leukopenia, as posttransfer levels of donor T cells inversely correlated to host cell counts after lymphodepletion. Despite the improvement in engraftment seen with combination lymphodepletion, dual-agent lymphodepletion did not augment the antitumor efficacy of donor T cells compared with TBI alone. Similarly, IL7 supplementation after TBI and transfer of tumor-reactive T cells failed to improve persistence or antitumor immunity. However, IL15 or IL2 supplementation greatly augmented the persistence and antitumor efficacy of donor tumor-reactive T cells. Our results indicate that the amount of host IL7 induced after single agent lymphodepletion is sufficient to potentiate the expansion and antitumor activity of donor T cells, and that the efficacy of future regimens may be improved by providing posttransfer support with IL2 or IL15.Significance: The relationship between lymphodepletion and cytokine support plays a critical role in determining donor T-cell engraftment and antitumor efficacy. Cancer Res; 78(11); 3067–74. ©2018 AACR.
Complete and Durable Responses in Primary Central Nervous System Posttransplant Lymphoproliferative Disorder with Zidovudine, Ganciclovir, Rituximab, and Dexamethasone
Authors: Dugan James P. , Haverkos Bradley M. , Villagomez Lynda , Martin Ludmila K. , Lustberg Mark , Patton John , Martin Marisa , Huang Ying , Nuovo Gerard , Yan Fengting , Cavaliere Robert , Fingeroth Joyce , Kenney Shannon C. , Ambinder Richard F. , Lozanski Gerard , Porcu Pierluigi , Caligiuri Michael A. , Baiocchi Robert A. 
Published: April 2018

Abstract
Purpose: Primary central nervous system posttransplant lymphoproliferative disorder (PCNS-PTLD) is a complication of solid organ transplantation with a poor prognosis and typically associated with Epstein–Barr virus (EBV). We hypothesized EBV lytic-phase protein expression would allow successful treatment with antiviral therapy.
Patients and Methods: Thirteen patients were treated with zidovudine (AZT), ganciclovir (GCV), dexamethasone, and rituximab in EBV+ PCNS-PTLD. Twice-daily, intravenous AZT 1,500 mg, GCV 5 mg/kg, and dexamethasone 10 mg were given for 14 days. Weekly rituximab 375 mg/m2 was delivered for the first 4 weeks. Twice-daily valganciclovir 450 mg and AZT 300 mg started day 15. Lytic and latent protein expression was assessed using in situ hybridization and immunohistochemistry. Immunoblot assay assessed lytic gene activation. Cells transfected with lytic kinase vectors were assessed for sensitivity to our therapy using MTS tetrazolium and flow cytometry.
Results: The median time to response was 2 months. Median therapy duration was 26.5 months. Median follow-up was 52 months. The estimated 2-year overall survival (OS) was 76.9% (95% CI, 44.2%–91.9%). Overall response rate (ORR) was 92% (95% CI, 64%–100%). BXLF1/vTK and BGLF4 expression was found in the seven tumor biopsies evaluated. Lytic gene expression was induced in vitro using the four-drug regimen. Transfection with viral kinase cDNA increased cellular sensitivity to antiviral therapy.
Conclusions: EBV+ PCNS-PTLD expressed lytic kinases and therapy with AZT, GCV, rituximab and dexamethasone provided durable responses. Induction of the lytic protein expression and increased cellular sensitivity to antiviral therapy after transfection with viral kinase cDNA provides a mechanistic rationale for our approach. Clin Cancer Res; 24(14); 3273–81. ©2018 AACR.
Discovery of a Glucocorticoid Receptor (GR) Activity Signature Using Selective GR Antagonism in ER-Negative Breast Cancer
Authors: West Diana C. , Kocherginsky Masha , Tonsing-Carter Eva Y. , Dolcen D. Nesli , Hosfield David J. , Lastra Ricardo R. , Sinnwell Jason P. , Thompson Kevin J. , Bowie Kathleen R. , Harkless Ryan V. , Skor Maxwell N. , Pierce Charles F. , Styke Sarah C. , Kim Caroline R. , de Wet Larischa , Greene Geoffrey L. , Boughey Judy C. , Goetz Matthew P. , Kalari Krishna R. , Wang Liewei , Fleming Gini F. , Györffy Balázs , Conzen Suzanne D. 
Published: April 2018

Abstract
Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone.
Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig).
Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n = 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR = 1.9; P = 0.012).
Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients. Clin Cancer Res; 24(14); 3433–46. ©2018 AACR.
Coverage in Fuzzy Set Qualitative Comparative Analysis (fsQCA): A New Fuzzy Proposition for Describing Empirical Relevance
Authors: Veri Francesco 
Published: April 2018

Abstract
The parameter of fits in fuzzy set Qualitative Comparative Analysis (fsQCA), which includes consistency and coverage, evaluate the strength of the empirical support for theoretical arguments describing set relations. Social scientist Charles Ragin proposed a formula for coverage intended to calculate how much of the variation in an outcome can be explained by causal conditions. However, this formula fails to determine empirical relevance from the analysis of sufficiency because it does not consider the set-theoretic information contained in each fuzzy value. The inaccuracies are primarily due to the inability of the coverage formula to fully grasp the quantifiable and qualitative dimensions of the concept of coverage. In this article, the author proposes a new calculation of coverage able to aggregate the quantifiable and qualitative analytical dimension of coverage in fuzzy terms.
Preconditioning of Arctic Stratospheric Polar Vortex Shift Events
Authors: Huang Jinlong , Tian Wenshou , Gray Lesley J. , Zhang Jiankai , Li Yan , Luo Jiali , Tian Hongying 
Published: April 2018

Abstract
This study examines the preconditioning of events in which the Arctic stratospheric polar vortex shifts toward Eurasia (EUR events), North America (NA events), and the Atlantic (ATL events) using composite analysis. An increase in blocking days over northern Europe and a decrease in blocking days over the Bering Strait favor the movement of the vortex toward Eurasia, while the opposite changes in blocking days over those regions favor the movement of the vortex toward North America. An increase in blocking days over the eastern North Atlantic and a decrease in blocking days over the Bering Strait are conducive to movement of the stratospheric polar vortex toward the Atlantic. These anomalous precursor blocking patterns are interpreted in terms of the anomalous zonal wave-1 or wave-2 planetary wave fluxes into the stratosphere that are known to influence the vortex position and strength. In addition, the polar vortex shift events are further classified into events with small and large polar vortex deformation, since the two types of events are likely to have a different impact at the surface. A significant difference in the zonal wave-2 heat flux into the lower stratosphere exists prior to the two types of events and this is linked to anomalous blocking patterns. This study further defines three types of tropospheric blocking events in which the spatial patterns of blocking frequency anomalies are similar to the blocking patterns prior to EUR, NA, and ATL events, respectively, and our reanalysis reveals that the polar vortex is indeed more likely to shift toward Eurasia, North America, and the Atlantic in the presence of the above three defined tropospheric blocking events. These shifts of the polar vortex toward Eurasia, North America, and the Atlantic lead to statistically significant negative height anomalies near the tropopause and corresponding surface cooling anomalies over these three regions.
PDGFR-β restores blood-brain barrier functions in a mouse model of focal cerebral ischemia
Authors: Shen Jie , Xu Guihua , Zhu Runxiu , Yuan Jun , Ishii Yoko , Hamashima Takeru , Matsushima Takako , Yamamoto Seiji , Takatsuru Yusuke , Nabekura Junichi , Sasahara Masakiyo 
Published: April 2018

Although platelet-derived growth factor receptor beta (PDGFR-β) mediates the recruitment of vascular pericytes into ischemic lesion to restore the blood-brain barrier (BBB) dysfunction, its mechanisms still remain elusive . Compared with control PDGFR-βfloxed/floxed mice (Floxed), postnatally induced systemic PDGFR-β knockout mice (Esr-KO) not only showed severe brain edema, neurologic functional deficits, decreased expression of tight junction (TJ) proteins, abundant endothelial transcytosis, and deformed TJs in the BBB, but also showed reduced expression of transforming growth factor-β (TGF-β) protein after photothrombotic middle cerebral artery occlusion (MCAO). In endothelial-pericyte co-culture, an in vitro model of BBB, the increment in the barrier function of endothelial monolayer induced by pericyte co-culture was completely cancelled by silencing PDGFR-β gene expression in pericytes, and was additively improved by PDGFR-β and TGF-β receptor signals under hypoxia condition. Exogenous PDGF-BB increased the expression of p-Smad2/3, while anti-TGF-β1 antibody at least partially inhibited the phosphorylation of Smad2/3 after PDGF-BB treatment in vitro. Furthermore, pre-administration of TGF-β1 partially alleviated edema formation, neurologic dysfunction, and TJs reduction in Esr-KO mice after MCAO. Accordingly, PDGFR-β signalling, via TGF-β signalling, may be crucial for restoration of BBB integrity after cerebral ischemia and therefore represents a novel potential therapeutic target.
Minimization of the perianal infection rate of hematological malignancies with agranulocytosis by quality control circle activity and patient–hospital–student win–win concept
Authors: Jiang Qianli , Zhang Dan , Majaw Jerry , Zhao Chenjing , Chai Yanyan , Xu Zehua , Wang Ruiting , Li Xiaoli , Zou Chun , Huang Liting , Wu Hansen , Hu Pingling , Xiang Ping , Chen Qiufan , Ma Weimei , Zheng Zhihao , Sun Jing , Liu Tingfang , Li Wenyuan 
Published: April 2018

Objective The agranulocytosis-associated perianal infection (PI) rate ranges from 60% to 100% among patients with hematopoietic malignancies. In this study, we assessed the efficacy of a quality control circle (QCC) to minimize the PI rate. Methods Among 274 patients with severe immunodeficiency (agranulocytosis of ≥2 weeks) in our bone marrow transplantation center, the PI rate was 17.20%. A QCC was established following the 10 steps of the plan-do-check-act (PDCA) model; this was scientifically supported by culturing the bacterial colony from patients’ perianal skin to determine the sanitization effect and interval time. Because a warm aqueous solution of potassium permanganate is recommended for sanitization, the bacterial colony culture was also used to determine the proper drug concentration, water temperature, and soaking time. All procedures were standardized. Patients, hospital staff, and medical students were enrolled into the QCC team based on the patient–hospital–student (PHS) win–win concept. Results After establishment of the PDCA model, the PI rate among 253 patients decreased from 17.20% to 5.93% and remained at 5.25% during the following year. The medical expenses and length of hospital stay consequently decreased. Conclusion The QCC and PHS win–win concept can reduce the PI rate and promote medical quality.
An evaluation of the fall prevention practice of community-based occupational therapists working in primary care
Authors: Mackenzie Lynette , Lovarini Meryl , Price Thomas , Clemson Lindy , Tan Amy , O’Connor Claire 
Published: April 2018

Introduction Occupational therapy in primary care settings in Australia is developing. This study aimed to examine current practice in preventing falls among older people living in the community prior to attending a home safety workshop; explore the outcomes of the workshop on fall prevention practice; and investigate self-reported changes in practice 3 months after the workshop. Method The 3-hour workshop was focused on evidence-based home safety interventions and was offered to occupational therapists providing community-based services in the Sydney North Primary Health Network area. Knowledge surveys were used immediately pre and post workshop, and practice surveys were collected data at baseline and at 3-month follow-up. Results Three workshops were run in 2015–2016, with a total of 40 occupational therapists. At follow-up, a positive impact on confidence and knowledge was reported. Less impact was observed on identifying and reducing an older person’s fall risk, and on fall prevention services provided and referrals received. Changes in practice were reported by 48% ( n = 16) of the 33 participants who returned surveys at 3 months. Conclusion These findings provide support for the benefit of professional development workshops to improve confidence and knowledge, but challenges remain in facilitating change in fall prevention service delivery. Further study on screening for fall risk and collaboration between community service providers in the primary care context is recommended.