bluuebunny/crossref_metadata_2025_split huggingface dataset:
Contribution of the Ade Resistance-Nodulation-Cell Division-Type Efflux Pumps to Fitness and Pathogenesis of Acinetobacter baumannii
Authors: Yoon Eun-Jeong , Balloy Viviane , Fiette Laurence , Chignard Michel , Courvalin Patrice , Grillot-Courvalin Catherine 
Published: June 2016

ABSTRACT

Overexpression of chromosomal resistance-nodulation-cell division (RND)-type efflux systems with broad substrate specificity contributes to multidrug resistance (MDR) in
Acinetobacter baumannii
. We have shown that modulation of expression of the structural genes for the efflux systems AdeABC and AdeIJK confers MDR and results in numerous alterations of membrane-associated cellular functions, in particular biofilm formation. However, the contribution of these RND pumps to cell fitness and virulence has not yet been studied. The biological cost of an antibiotic resistance mechanism is a key parameter in determining its stability and dissemination. From an entirely sequenced susceptible clinical isolate, we have generated a set of isogenic derivatives having single point mutations resulting in overexpression of each efflux system or with every pump deleted by allelic replacement. We found that overproduction of the pumps results in a significant decrease in fitness of the bacterial host when measured by competition experiments
in vitro
. Fitness and virulence were also evaluated
in vivo
both in systemic and pulmonary infection models in immunocompetent mice. A diminished competitiveness of the AdeABC-overexpressing mutant was observed only after intraperitoneal inoculation, but not after intranasal inoculation, the latter mimicking the most frequent type of human
A. baumannii
infection. However, in mice infected intranasally, this mutant was more virulent and stimulated an enhanced neutrophil activation in the lungs. Altogether, these data account for the observation that
adeABC
overexpression is common in MDR
A. baumannii
frequently found in ventilator-associated pneumonia.

IMPORTANCE
Overproduction of the RND AdeABC efflux system is observed with a high incidence in multidrug-resistant
Acinetobacter baumannii
and results in increased resistance to several antibiotics of choice for the treatment of infections caused by this nosocomial pathogen. It was therefore important to study the biological cost of the overexpression of the
adeABC
structural operon which is normally tightly regulated. Fitness diminution of an overexpressing mutant detected
in vitro
and
in vivo
in a model that mimics sepsis was not observed in a pulmonary infection model in which the mutant was more virulent. This points out that increased virulence can occur independently from prolonged persistence in the infected organ and can account for the elevated incidence of this resistance mechanism in clinical isolates. The study also indicates that transposon libraries will identify only virulence genes that are expressed under physiological conditions but not those that are tightly regulated.
Targeting Mycobacterium tuberculosis Tumor Necrosis Factor Alpha-Downregulating Genes for the Development of Antituberculous Vaccines
Authors: Olsen Aaron , Chen Yong , Ji Qingzhou , Zhu Guofeng , De Silva Aruna Dharshan , Vilchèze Catherine , Weisbrod Torin , Li Weimin , Xu Jiayong , Larsen Michelle , Zhang Jinghang , Porcelli Steven A. , Jacobs William R. , Chan John 
Published: June 2016

ABSTRACTTumor necrosis factor alpha (TNF) plays a critical role in the control ofMycobacterium tuberculosis, in part by augmenting T cell responses through promoting macrophage phagolysosomal fusion (thereby optimizing CD4+T cell immunity by enhancing antigen presentation) and apoptosis (a process that can lead to cross-priming of CD8+T cells).M. tuberculosiscan evade antituberculosis (anti-TB) immunity by inhibiting host cell TNF production via expression of specific mycobacterial components. We hypothesized thatM. tuberculosismutants with an increased capacity to induce host cell TNF production (TNF-enhancing mutants) and thus with enhanced immunogenicity can be useful for vaccine development. To identify mycobacterial genes that regulate host cell TNF production, we used a TNF reporter macrophage clone to screen an H37RvM. tuberculosiscosmid library constructed inM. smegmatis. The screen has identified a set of TNF-downregulating mycobacterial genes that, when deleted in H37Rv, generate TNF-enhancing mutants. Analysis of mutants disrupted for a subset of TNF-downregulating genes, annotated to code for triacylglycerol synthases and fatty acyl-coenzyme A (acyl-CoA) synthetase, enzymes that concern lipid biosynthesis and metabolism, has revealed that these strains can promote macrophage phagolysosomal fusion and apoptosis better than wild-type (WT) bacilli. Immunization of mice with the TNF-enhancingM. tuberculosismutants elicits CD4+and CD8+T cell responses that are superior to those engendered by WT H37Rv. The results suggest that TNF-upregulatingM. tuberculosisgenes can be targeted to enhance the immunogenicity of mycobacterial strains that can serve as the substrates for the development of novel anti-TB vaccines.IMPORTANCEOne way to control tuberculosis (TB), which remains a major global public health burden, is by immunization with an effective vaccine. The efficacy ofMycobacterium bovisBCG, the only currently approved TB vaccine, is inconsistent. Tumor necrosis factor alpha (TNF) is a cytokine that plays an important role in controlling TB.M. tuberculosis, the causative agent of TB, can counter this TNF-based defense by decreasing host cell TNF production. This study identifiedM. tuberculosisgenes that can mediate inhibition of TNF production by macrophage (an immune cell critical to the control of TB). We have knocked out a number of these genes to generateM. tuberculosismutants that can enhance macrophage TNF production. Immunization with these mutants in mice triggered a T cell response stronger than that elicited by the parental bacillus. Since T cell immunity is pivotal in controllingM. tuberculosis, the TNF-enhancing mutants can be used to develop novel TB vaccines.
Aspergillus
Cell Wall Chitin Induces Anti- and Proinflammatory Cytokines in Human PBMCs via the Fc-γ Receptor/Syk/PI3K Pathway
Authors: Becker K. L. , Aimanianda V. , Wang X. , Gresnigt M. S. , Ammerdorffer A. , Jacobs C. W. , Gazendam R. P. , Joosten L. A. B. , Netea M. G. , Latgé J. P. , van de Veerdonk F. L. 
Published: June 2016

ABSTRACT

Chitin is an important cell wall component of
Aspergillus fumigatus
conidia, of which hundreds are inhaled on a daily basis. Previous studies have shown that chitin has both anti- and proinflammatory properties; however the exact mechanisms determining the inflammatory signature of chitin are poorly understood, especially in human immune cells. Human peripheral blood mononuclear cells were isolated from healthy volunteers and stimulated with chitin from
Aspergillus fumigatus
. Transcription and production of the proinflammatory cytokine interleukin-1β (IL-1β) and the anti-inflammatory cytokine IL-1 receptor antagonist (IL-1Ra) were measured from the cell culture supernatant by quantitative PCR (qPCR) or enzyme-linked immunosorbent assay (ELISA), respectively. Chitin induced an anti-inflammatory signature characterized by the production of IL-1Ra in the presence of human serum, which was abrogated in immunoglobulin-depleted serum. Fc-γ-receptor-dependent recognition and phagocytosis of IgG-opsonized chitin was identified as a novel IL-1Ra-inducing mechanism by chitin. IL-1Ra production induced by chitin was dependent on Syk kinase and phosphatidylinositol 3-kinase (PI3K) activation. In contrast, costimulation of chitin with the pattern recognition receptor (PRR) ligands lipopolysaccharide, Pam3Cys, or muramyl dipeptide, but not β-glucan, had synergistic effects on the induction of proinflammatory cytokines by human peripheral blood mononuclear cells (PBMCs). In conclusion, chitin can have both pro- and anti-inflammatory properties, depending on the presence of pathogen-associated molecular patterns and immunoglobulins, thus explaining the various inflammatory signatures reported for chitin.

IMPORTANCE
Invasive aspergillosis and allergic aspergillosis are increasing health care problems. Patients get infected by inhalation of the airborne spores of
Aspergillus fumigatus
. A profound knowledge of how
Aspergillus
and its cell wall components are recognized by the host cell and which type of immune response it induces is necessary to develop target-specific treatment options with less severe side effects than the treatment options to date. There is controversy in the literature about the receptor for chitin in human cells. We identified the Fc-γ receptor and Syk/PI3K pathway via which chitin can induce anti-inflammatory immune responses by inducing IL-1 receptor antagonist in the presence of human immunoglobulins but also proinflammatory responses in the presence of bacterial components. This explains why
Aspergillus
does not induce strong inflammation just by inhalation and rather fulfills an immune-dampening function. While in a lung coinfected with bacteria,
Aspergillus
augments immune responses by shifting toward a proinflammatory reaction.
Does revision ACL reconstruction measure up to primary surgery? A meta-analysis comparing patient-reported and clinician-reported outcomes, and radiographic results
Authors: Grassi Alberto , Ardern Clare L , Marcheggiani Muccioli Giulio Maria , Neri Maria Pia , Marcacci Maurilio , Zaffagnini Stefano 
Published: June 2016

PurposeTo compare patient-reported and clinician-reported outcomes, and radiographic results between patients who had had revision ACL reconstruction and those who had had primary ACL reconstruction.DesignSystematic review and meta-analysisData sourcesThe MEDLINE, CINAHL, EMBASE and SPORTDiscus electronic databases were searched on 6 August 2015, using 3 main concepts: (1) revision ACL reconstruction, (2) primary ACL reconstruction and (3) treatment outcomes.Eligibility criteria for selecting studiesArticles that compared patient-reported or clinician-reported outcomes or radiographic results between patients who had had revision ACL reconstruction and those who had had primary surgery with a minimum of 2 years follow-up were included. The outcomes evaluated were the Lysholm Knee Scoring Scale, objective International Knee Documentation Committee (IKDC) classification, Tegner Activity Scale, side-to-side difference in anterior tibial translation measured with KT-1000/2000 arthrometer, pivot shift test, tibiofemoral osteoarthritis grading on plain radiographs and subsequent knee surgeries.Results8 studies (300 revision ACL reconstructions and 413 primary ACL reconstructions) were included in the meta-analysis. Patients who had had revision surgery reported inferior Lysholm Knee Scoring Scale scores (mean difference: 7.8 points), had inferior clinician-reported knee function as assessed with the objective IKDC classification (IKDC category A: 27% vs 57%; IKDC category C or D: 22% vs 8%) and pivot shift test (grade II or III: 7% vs 2%), and more radiographic evidence of tibiofemoral osteoarthritis (50% vs 25%) compared with patients who had had primary surgery.ConclusionsRevision ACL reconstruction restored similar anterior-posterior knee laxity compared with primary ACL reconstruction. Patients who had had revision surgery reported inferior Lysholm Knee Scoring Scale scores, had inferior clinician-reported knee function and more radiographic signs of tibiofemoral osteoarthritis compared with patients with primary ACL reconstruction.
Symptoms and risk factors of depression during and after the football career of elite female players
Authors: Prinz Birgit , Dvořák Jiří , Junge Astrid 
Published: June 2016

BackgroundThe mental health of elite athletes has received increasing attention in recent years, but no study has evaluated the career–time prevalence of depression, and very few have analysed risk factors of mental health problems during or after the career.Methods157 (response rate 64.1%) female players who played in the German First League answered an anonymous online survey on details of their football career, stressful and helpful conditions, depression and need of psychotherapeutic support during and after the football career.ResultsThe career–time prevalence of depression symptoms was 32.3%. Significant differences in the average depression score were observed for playing positions (F=2.75; p<0.05) and levels of play (F=3.53; p<0.01). About half of the players (49.7%) stated ‘conflicts with coach/management’ as an important reason for their low in moods, followed by ‘low in performance/injury’ (48.4%) and ‘too little support/acknowledgement by the coach’ (40.0%). ‘Psychological strain/stress’ (46.5%) was (after injury) the second most important reason for lows in performance. During their career, almost 40% of players wanted or needed psychological support, but only 10% received it. After their career, the percentage of players wanting or needing psychological support decreased to 24%, of whom 90% received it.ConclusionsThe high prevalence of depression symptoms in combination with low use of psychotherapy during the career shows the need for de-stigmatisation of mental health issues in elite football. Furthermore, it seems very important to educate coaches, physicians, physiotherapists and club managers to recognise and prevent mental health problems of their players.
miR-182-5p Induced by STAT3 Activation Promotes Glioma Tumorigenesis
Authors: Xue Jianfei , Zhou Aidong , Wu Yamei , Morris Saint-Aaron , Lin Kangyu , Amin Samirkumar , Verhaak Roeland , Fuller Gregory , Xie Keping , Heimberger Amy B. , Huang Suyun 
Published: June 2016

Abstract
Malignant glioma is an often fatal type of cancer. Aberrant activation of STAT3 leads to glioma tumorigenesis. STAT3-induced transcription of protein-coding genes has been extensively studied; however, little is known about STAT3-regulated miRNA gene transcription in glioma tumorigenesis. In this study, we found that abnormal activation or decreased expression of STAT3 promotes or inhibits the expression of miR-182-5p, respectively. Bioinformatics analyses determined that tumor suppressor protocadherin-8 (PCDH8) is a candidate target gene of miR-182-5p. miR-182-5p negatively regulated PCDH8 expression by directly targeting its 3′-untranslated region. PCDH8 knockdown induced the proliferative and invasive capacities of glioma cells. Silencing of PCDH8 or miR-182-5p mimics could reverse the inhibitory effect of WP1066, a STAT3 inhibitor, or STAT3 knockdown in vitro and in vivo on glioma progression. Clinically, expression levels of PCDH8 were inversely correlated with those of p-STAT3 or miR-182-5p in glioblastoma tissues. These findings reveal that the STAT3/miR-182-5p/PCDH8 axis has a critical role in glioma tumorigenesis and that targeting the axis may provide a new therapeutic approach for human glioma. Cancer Res; 76(14); 4293–304. ©2016 AACR.
Molecular Pathways: Targeting the PI3K Pathway in Cancer—BET Inhibitors to the Rescue
Authors: Stratikopoulos Elias E. , Parsons Ramon E. 
Published: June 2016

AbstractThe PI3K signaling pathway is a complex and tightly regulated network that is critical for many physiologic processes, such as cell growth, proliferation, metabolism, and survival. Aberrant activation of this pathway can occur through mutation of almost any of its major nodes and has been implicated in a number of human diseases, including cancer. The high frequency of mutations in this pathway in multiple types of cancer has led to the development of small-molecule inhibitors of PI3K, several of which are currently in clinical trials. However, several feedback mechanisms either within the PI3K pathway or in compensatory pathways can render tumor cells resistant to therapy. Recently, targeting proteins of the bromodomain and extraterminal (BET) family of epigenetic readers of histone acetylation has been shown to effectively block adaptive signaling response of cancer cells to inhibitors of the PI3K pathway, which at least in some cases can restore sensitivity. BET inhibitors also enforce blockade of the MAPK, JAK/STAT, and ER pathways, suggesting they may be a rational combinatorial partner for divergent oncogenic signals that are subject to homeostatic regulation. Here, we review the PI3K pathway as a target for cancer therapy and discuss the potential use of BET inhibition to enhance the clinical efficacy of PI3K inhibitors. Clin Cancer Res; 22(11); 2605–10. ©2016 AACR.
Voxel Level Radiologic–Pathologic Validation of Restriction Spectrum Imaging Cellularity Index with Gleason Grade in Prostate Cancer
Authors: Yamin Ghiam , Schenker-Ahmed Natalie M. , Shabaik Ahmed , Adams Dennis , Bartsch Hauke , Kuperman Joshua , White Nathan S. , Rakow-Penner Rebecca A. , McCammack Kevin , Parsons J. Kellogg , Kane Christopher J. , Dale Anders M. , Karow David S. 
Published: June 2016

Abstract
Purpose: Restriction spectrum imaging (RSI-MRI), an advanced diffusion imaging technique, can potentially circumvent current limitations in tumor conspicuity, in vivo characterization, and location demonstrated by multiparametric magnetic resonance imaging (MP-MRI) techniques in prostate cancer detection. Prior reports show that the quantitative signal derived from RSI-MRI, the cellularity index, is associated with aggressive prostate cancer as measured by Gleason grade (GG). We evaluated the reliability of RSI-MRI to predict variance with GG at the voxel-level within clinically demarcated prostate cancer regions.
Experimental Design: Ten cases were processed using whole mount sectioning after radical prostatectomy. Regions of tumor were identified by an uropathologist. Stained prostate sections were scanned at high resolution (75 μm/pixel). A grid of tiles corresponding to voxel dimensions was graded using the GG system. RSI-MRI cellularity index was calculated from presurgical prostate MR scans and presented as normalized z-score maps. In total, 2,795 tiles were analyzed and compared with RSI-MRI cellularity.
Results: RSI-MRI cellularity index was found to distinguish between prostate cancer and benign tumor (t = 25.48, P &lt; 0.00001). Significant differences were also found between benign tissue and prostate cancer classified as low-grade (GG = 3; t = 11.56, P &lt; 0.001) or high-grade (GG ≥ 4; t = 24.03, P &lt; 0.001). Furthermore, RSI-MRI differentiated between low and high-grade prostate cancer (t = 3.23; P = 0.003).
Conclusions: Building on our previous findings of correlation between GG and the RSI-MRI among whole tumors, our current study reveals a similar correlation at voxel resolution within tumors. Because it can detect variations in tumor grade with voxel-level precision, RSI-MRI may become an option for planning targeted procedures where identifying the area with the most aggressive disease is important. Clin Cancer Res; 22(11); 2668–74. ©2016 AACR.
Dose Finding of Small-Molecule Oncology Drugs: Optimization throughout the Development Life Cycle
Authors: Jänne Pasi A. , Kim Geoffrey , Shaw Alice T. , Sridhara Rajeshwari , Pazdur Richard , McKee Amy E. 
Published: June 2016

Abstract
In the current era of rapid marketing approval for promising new products in oncology, dose finding and optimization for small-molecule oncology drugs occurs throughout the development cycle and into the postmarketing setting. Many trials that support a regulatory application have high rates of dose reductions and discontinuations, which may result in postmarketing requirements (PMR) to study alternate doses or dosing schedules. Kinase inhibitors particularly have been susceptible to this problem, and among the 31 approved drugs of this class, the approvals of eight have included such PMRs and/or commitments. Thus, the current paradigm for dose finding and optimization could be improved. Newer strategies for dose finding rather than traditional 3 + 3 designs should be considered where feasible, and dose optimization should be continued after phase I and throughout development. Such strategies will increase the likelihood of a right dose for the right drug at the time of regulatory approval. Clin Cancer Res; 22(11); 2613–7. ©2016 AACR.
See all articles in this CCR Focus section, “New Approaches for Optimizing Dosing of Anticancer Agents.”
Lessons Learned: Dose Selection of Small Molecule–Targeted Oncology Drugs
Authors: Bullock Julie M. , Rahman Atiqur , Liu Qi 
Published: June 2016

Abstract
Evaluation of dose plays a critical role in a successful oncology development program. Typically for oncology agents, the first-in-man phase I dose-escalation trials are conducted to determine a maximum tolerated dose (MTD). This MTD is taken forward into subsequent trials to establish the safety and efficacy of the drug product. Although this approach was appropriate historically for cytotoxics, the application of MTD as the recommend phase II dose has been problematic for the newer small molecule–targeted oncology agents. Promising alternative approaches using dose and exposure exploration, including lessons learned from recent targeted oncology agent development and approvals, are summarized and discussed. Clin Cancer Res; 22(11); 2630–8. ©2016 AACR.
See all articles in this CCR Focus section, “New Approaches for Optimizing Dosing of Anticancer Agents.”
Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy
Authors: Incio Joao , Liu Hao , Suboj Priya , Chin Shan M. , Chen Ivy X. , Pinter Matthias , Ng Mei R. , Nia Hadi T. , Grahovac Jelena , Kao Shannon , Babykutty Suboj , Huang Yuhui , Jung Keehoon , Rahbari Nuh N. , Han Xiaoxing , Chauhan Vikash P. , Martin John D. , Kahn Julia , Huang Peigen , Desphande Vikram , Michaelson James , Michelakos Theodoros P. , Ferrone Cristina R. , Soares Raquel , Boucher Yves , Fukumura Dai , Jain Rakesh K. 
Published: June 2016

AbstractIt remains unclear how obesity worsens treatment outcomes in patients with pancreatic ductal adenocarcinoma (PDAC). In normal pancreas, obesity promotes inflammation and fibrosis. We found in mouse models of PDAC that obesity also promotes desmoplasia associated with accelerated tumor growth and impaired delivery/efficacy of chemotherapeutics through reduced perfusion. Genetic and pharmacologic inhibition of angiotensin-II type-1 receptor reverses obesity-augmented desmoplasia and tumor growth and improves response to chemotherapy. Augmented activation of pancreatic stellate cells (PSC) in obesity is induced by tumor-associated neutrophils (TAN) recruited by adipocyte-secreted IL1β. PSCs further secrete IL1β, and inactivation of PSCs reduces IL1β expression and TAN recruitment. Furthermore, depletion of TANs, IL1β inhibition, or inactivation of PSCs prevents obesity-accelerated tumor growth. In patients with pancreatic cancer, we confirmed that obesity is associated with increased desmoplasia and reduced response to chemotherapy. We conclude that cross-talk between adipocytes, TANs, and PSCs exacerbates desmoplasia and promotes tumor progression in obesity.Significance: Considering the current obesity pandemic, unraveling the mechanisms underlying obesity-induced cancer progression is an urgent need. We found that the aggravation of desmoplasia is a key mechanism of obesity-promoted PDAC progression. Importantly, we discovered that clinically available antifibrotic/inflammatory agents can improve the treatment response of PDAC in obese hosts. Cancer Discov; 6(8); 852–69. ©2016 AACR.See related commentary by Bronte and Tortora, p. 821.This article is highlighted in the In This Issue feature, p. 803