bluuebunny/crossref_metadata_2025_split huggingface dataset:
Translational Control of the SigR-Directed Oxidative Stress Response in
Streptomyces
via IF3-Mediated Repression of a Noncanonical GTC Start Codon
Authors: Feeney Morgan A. , Chandra Govind , Findlay Kim C. , Paget Mark S. B. , Buttner Mark J. 
Published: June 2017

ABSTRACT

The major oxidative stress response in
Streptomyces
is controlled by the sigma factor SigR and its cognate antisigma factor RsrA, and SigR activity is tightly controlled through multiple mechanisms at both the transcriptional and posttranslational levels. Here we show that
sigR
has a highly unusual GTC start codon and that this leads to another level of SigR regulation, in which SigR translation is repressed by translation initiation factor 3 (IF3). Changing the GTC to a canonical start codon causes SigR to be overproduced relative to RsrA, resulting in unregulated and constitutive expression of the SigR regulon. Similarly, introducing IF3* mutations that impair its ability to repress SigR translation has the same effect. Thus, the noncanonical GTC
sigR
start codon and its repression by IF3 are critical for the correct and proper functioning of the oxidative stress regulatory system.
sigR
and
rsrA
are cotranscribed and translationally coupled, and it had therefore been assumed that SigR and RsrA are produced in stoichiometric amounts. Here we show that RsrA can be transcribed and translated independently of SigR, present evidence that RsrA is normally produced in excess of SigR, and describe the factors that determine SigR-RsrA stoichiometry.

IMPORTANCE
In all sigma factor-antisigma factor regulatory switches, the relative abundance of the two proteins is critical to the proper functioning of the system. Many sigma-antisigma operons are cotranscribed and translationally coupled, leading to a generic assumption that the sigma and antisigma factors are produced in a fixed 1:1 ratio. In the case of
sigR
-
rsrA
, we show instead that the antisigma factor is produced in excess over the sigma factor, providing a buffer to prevent spurious release of sigma activity. This excess arises in part because
sigR
has an extremely rare noncanonical GTC start codon, and as a result, SigR translation initiation is repressed by IF3. This finding highlights the potential significance of noncanonical start codons, very few of which have been characterized experimentally. It also emphasizes the limitations of predicting start codons using bioinformatic approaches, which rely heavily on the assumption that ATG, GTG, and TTG are the only permissible start codons.
A qualitative analysis of the Three Good Things intervention in healthcare workers
Authors: Rippstein-Leuenberger Karin , Mauthner Oliver , Bryan Sexton J , Schwendimann Rene 
Published: June 2017

BackgroundIntensive care unit (ICU) personnel have an elevated prevalence of job-related burn-out and post-traumatic stress disorder, which can ultimately impact patient care. To strengthen healthcare workers’ skills to deal with stressful events, it is important to focus not only on minimising suffering but also on increasing happiness, as this entails many more benefits than simply feeling good. Thus, the purpose of this study was to explore the content of the ‘good things’ reported by healthcare workers participating in the ‘Three Good Things’ intervention.MethodsIn a tertiary care medical centre, a sample of 89 neonatal ICU (NICU) healthcare professionals registered for the online intervention. Of these, 32 individuals eventually participated fully in the 14-day online Three Good Things intervention survey. Daily emails reminded participants to reflect on and respond to the questions: “What are the three things that went well today?” and “What was your role in bringing them about?” To analyse their responses, we applied a thematic analysis, which was guided by our theoretical understanding of resilience.ResultsInvolving more than 1300 statements, the Three Good Things responses of the 32 study participants, including registered nurses, physicians and neonatal nurse practitioners, led to the identification of three main themes: (1) having a good day at work; (2) having supportive relationships and (3) making meaningful use of self-determined time.ConclusionsThe findings show the personal and professional relevance of supportive relationships strengthened by clear communication and common activities that foster positive emotions. The Three Good Things exercise acknowledges the importance of self-care in healthcare workers and appears to promote well-being, which might ultimately strengthen resilience.
New quantitative features for the morphological differentiation of abnormal lymphoid cell images from peripheral blood
Authors: Puigví Laura , Merino Anna , Alférez Santiago , Acevedo Andrea , Rodellar José 
Published: June 2017

AimsThis work aims to propose a set of quantitative features through digital image analysis for significant morphological qualitative features of different cells for an objective discrimination among reactive, abnormal and blast lymphoid cells.MethodsAbnormal lymphoid cells circulating in peripheral blood in chronic lymphocytic leukaemia, B-prolymphocytic leukaemia, hairy cell leukaemia, splenic marginal zone lymphoma, mantle cell lymphoma, follicular lymphoma, T-prolymphocytic leukaemia, T large granular lymphocytic leukaemia and Sézary syndrome, normal, reactive and blast lymphoid cells were included. From 325 patients, 12 574 cell images were obtained and 2676 features (27 geometric and 2649 related to colour and texture) were extracted and analysed.ResultsWe analysed the 20 most relevant features for the morphological differentiation of the 12 lymphoid cell groups under study. Most of them showed significant differences: 19 comparing follicular and mantle cells, 18 for blast and reactive cells, 17 for Sézary cells and T prolymphocytes and 16 for B and T prolymphocytes and 16 for villous lymphocytes. Moreover, a total of five quantitative features were significant for the discrimination among reactive and the set of abnormal lymphoid cells included.ConclusionsImage analysis may assist in quantifying cell morphology turning qualitative data into quantitative values. New cytological variables were established based on geometric and colour/texture features to contribute to a more accurate and objective morphological assessment of lymphoid cells and their association with flow cytometry methods may be interesting to explore in the next future.
Different roles for inhibition in the rhythm-generating respiratory network
Authors: Harris Kameron Decker , Dashevskiy Tatiana , Mendoza Joshua , Garcia Alfredo J. , Ramirez Jan-Marino , Shea-Brown Eric 
Published: June 2017

Unraveling the interplay of excitation and inhibition within rhythm-generating networks remains a fundamental issue in neuroscience. We use a biophysical model to investigate the different roles of local and long-range inhibition in the respiratory network, a key component of which is the pre-Bötzinger complex inspiratory microcircuit. Increasing inhibition within the microcircuit results in a limited number of out-of-phase neurons before rhythmicity and synchrony degenerate. Thus unstructured local inhibition is destabilizing and cannot support the generation of more than one rhythm. A two-phase rhythm requires restructuring the network into two microcircuits coupled by long-range inhibition in the manner of a half-center. In this context, inhibition leads to greater stability of the two out-of-phase rhythms. We support our computational results with in vitro recordings from mouse pre-Bötzinger complex. Partial excitation block leads to increased rhythmic variability, but this recovers after blockade of inhibition. Our results support the idea that local inhibition in the pre-Bötzinger complex is present to allow for descending control of synchrony or robustness to adverse conditions like hypoxia. We conclude that the balance of inhibition and excitation determines the stability of rhythmogenesis, but with opposite roles within and between areas. These different inhibitory roles may apply to a variety of rhythmic behaviors that emerge in widespread pattern-generating circuits of the nervous system. NEW & NOTEWORTHY The roles of inhibition within the pre-Bötzinger complex (preBötC) are a matter of debate. Using a combination of modeling and experiment, we demonstrate that inhibition affects synchrony, period variability, and overall frequency of the preBötC and coupled rhythmogenic networks. This work expands our understanding of ubiquitous motor and cognitive oscillatory networks.
Autocrine BMP-4 Signaling Is a Therapeutic Target in Colorectal Cancer
Authors: Yokoyama Yuichiro , Watanabe Toshiaki , Tamura Yusuke , Hashizume Yoshinobu , Miyazono Kohei , Ehata Shogo 
Published: June 2017

Abstract
Poor prognoses for colorectal cancer patients with metastatic lesions have driven demand for the development of novel targeted therapies. Here, we demonstrate that expression of bone morphogenetic protein 4 (BMP-4) is universally upregulated in human colorectal cancer cells and tissues, resulting in activated BMP signaling. Inhibition of endogenous BMP signaling by the BMP type I receptor inhibitor LDN-193189 elevated expression of the phosphatase DUSP5 in colorectal cancer cells, inducing apoptosis via dephosphorylation of Erk MAPK. Administering LDN-193189 to mice diminished tumor formation of colorectal cancer cells. Our findings suggest inhibition of autocrine BMP-4 as a candidate treatment strategy for colorectal cancer. Cancer Res; 77(15); 4026–38. ©2017 AACR.
Treatment of Pancreatic Cancer Patient–Derived Xenograft Panel with Metabolic Inhibitors Reveals Efficacy of Phenformin
Authors: Rajeshkumar N.V. , Yabuuchi Shinichi , Pai Shweta G. , De Oliveira Elizabeth , Kamphorst Jurre J. , Rabinowitz Joshua D. , Tejero Héctor , Al-Shahrour Fátima , Hidalgo Manuel , Maitra Anirban , Dang Chi V. 
Published: June 2017

Abstract
Purpose: To identify effective metabolic inhibitors to suppress the aggressive growth of pancreatic ductal adenocarcinoma (PDAC), we explored the in vivo antitumor efficacy of metabolic inhibitors, as single agents, in a panel of patient-derived PDAC xenograft models (PDX) and investigated whether genomic alterations of tumors correlate with the sensitivity to metabolic inhibitors.
Experimental Design: Mice with established PDAC tumors from 6 to 13 individual PDXs were randomized and treated, once daily for 4 weeks, with either sterile PBS (vehicle) or the glutaminase inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl)ethyl sulfide (BPTES), transaminase inhibitor aminooxyacetate (AOA), pyruvate dehydrogenase kinase inhibitor dichloroacetate (DCA), autophagy inhibitor chloroquine (CQ), and mitochondrial complex I inhibitor phenformin/metformin.
Results: Among the agents tested, phenformin showed significant tumor growth inhibition (&gt;30% compared with vehicle) in 5 of 12 individual PDXs. Metformin, at a fivefold higher dose, displayed significant tumor growth inhibition in 3 of 12 PDXs similar to BPTES (2/8 PDXs) and DCA (2/6 PDXs). AOA and CQ had the lowest response rates. Gene set enrichment analysis conducted using the baseline gene expression profile of pancreatic tumors identified a gene expression signature that inversely correlated with phenformin sensitivity, which is in agreement with the phenformin gene expression signature of NIH Library of Integrated Network-based Cellular Signatures (LINCS). The PDXs that were more sensitive to phenformin showed a baseline reduction in amino acids and elevation in oxidized glutathione. There was no correlation between phenformin response and genetic alterations in KRAS, TP53, SMAD4, or PTEN.
Conclusions: Phenformin treatment showed relatively higher antitumor efficacy against established PDAC tumors, compared with the efficacy of other metabolic inhibitors and metformin. Phenformin treatment significantly diminished PDAC tumor progression and prolonged tumor doubling time. Overall, our results serve as a foundation for further evaluation of phenformin as a therapeutic agent in pancreatic cancer. Clin Cancer Res; 23(18); 5639–47. ©2017 AACR.
Wnt/β-catenin Signaling Contributes to Tumor Malignancy and Is Targetable in Gastrointestinal Stromal Tumor
Authors: Zeng Shan , Seifert Adrian M. , Zhang Jennifer Q. , Cavnar Michael J. , Kim Teresa S. , Balachandran Vinod P. , Santamaria-Barria Juan A. , Cohen Noah A. , Beckman Michael J. , Medina Benjamin D. , Rossi Ferdinand , Crawley Megan H. , Loo Jennifer K. , Maltbaek Joanna H. , Besmer Peter , Antonescu Cristina R. , DeMatteo Ronald P. 
Published: June 2017

Abstract
Gastrointestinal stromal tumor (GIST) is the most common type of sarcoma and usually harbors either a KIT or PDGFRA mutation. However, the molecular basis for tumor malignancy is not well defined. Although the Wnt/β-catenin signaling pathway is important in a variety of cancers, its role in GIST is uncertain. Through analysis of nearly 150 human GIST specimens, we found that some human GISTs expressed β-catenin and contained active, dephosphorylated nuclear β-catenin. Furthermore, advanced human GISTs expressed reduced levels of the Wnt antagonist DKK4. Accordingly, in human GIST T1 cells, Wnt stimulation increased β-catenin–mediated transcriptional activity in a reporter assay as well as transcription of the downstream target genes Axin2 and CCND1. In contrast, DKK4 overexpression in GIST T1 cells reduced Wnt/β-catenin signaling. In addition, we showed that nuclear β-catenin stability was partially regulated by the E3 ligase COP1, as demonstrated with coimmunoprecipitation and COP1 knockdown. Three molecular inhibitors of the Wnt/β-catenin pathway demonstrated antitumor efficacy in various GIST models, both in vitro and in vivo. Notably, the tankyrase inhibitor G007-LK alone had substantial activity against tumors of genetically engineered KitV558Δ/+ mice, and the effect was increased by the addition of the Kit inhibitor imatinib mesylate. Collectively, our findings demonstrate that Wnt/β-catenin signaling is a novel therapeutic target for selected untreated or imatinib-resistant GISTs. Mol Cancer Ther; 16(9); 1954–66. ©2017 AACR.
Cisplatin Increases Sensitivity to FGFR Inhibition in Patient-Derived Xenograft Models of Lung Squamous Cell Carcinoma
Authors: Weeden Clare E. , Holik Aliaksei Z. , Young Richard J. , Ma Stephen B. , Garnier Jean-Marc , Fox Stephen B. , Antippa Phillip , Irving Louis B. , Steinfort Daniel P. , Wright Gavin M. , Russell Prudence A. , Ritchie Matthew E. , Burns Christopher J. , Solomon Benjamin , Asselin-Labat Marie-Liesse 
Published: June 2017

Abstract
Lung squamous cell carcinoma (SqCC) is a molecularly complex and genomically unstable disease. No targeted therapy is currently approved for lung SqCC, although potential oncogenic drivers of SqCC have been identified, including amplification of the fibroblast growth factor receptor 1 (FGFR1). Reports from a recently completed clinical trial indicate low response rates in patients treated with FGFR tyrosine kinase inhibitors, suggesting inadequacy of FGFR1 amplification as a biomarker of response, or the need for combination treatment. We aimed to develop accurate models of lung SqCC and determine improved targeted therapies for these tumors. We show that detection of FGFR1 mRNA by RNA in situ hybridization is a better predictor of response to FGFR inhibition than FGFR1 gene amplification using clinically relevant patient-derived xenograft (PDX) models of lung SqCC. FGFR1-overexpressing tumors were observed in all histologic subtypes of non–small cell lung cancers (NSCLC) as assessed on a tissue microarray, indicating a broader range of tumors that may respond to FGFR inhibitors. In FGFR1-overexpressing PDX tumors, we observed increased differentiation and reduced proliferation following FGFR inhibition. Combination therapy with cisplatin was able to increase tumor cell death, and dramatically prolonged animal survival compared to single-agent treatment. Our data suggest that FGFR tyrosine kinase inhibitors can benefit NSCLC patients with FGFR1-overexpressing tumors and provides a rationale for clinical trials combining cisplatin with FGFR inhibitors. Mol Cancer Ther; 16(8); 1610–22. ©2017 AACR.
Intermittent Dosing with Sulindac Provides Effective Colorectal Cancer Chemoprevention in the Azoxymethane-Treated Mouse Model
Authors: Chandra Swati , Nymeyer Ariel C. , Rice Photini Faith , Gerner Eugene W. , Barton Jennifer K. 
Published: June 2017

Abstract
Sulindac is an NSAID that can provide effective chemoprevention for colorectal cancer. In this study, alternative dosing regimens of sulindac were evaluated for their chemoprevention effectiveness in the azoxymethane-treated A/J mouse model of colorectal cancer. High-resolution endoscopic optical coherence tomography was utilized to time-serially measure tumor number and tumor burden in the distal colon as the biological endpoints. Four treatment groups were studied: (i) daily for 20 weeks (sulindac-daily); (ii) for 2 weeks, then no sulindac for 2 weeks, cycle repeated 5 times (sulindac-2); (iii) for 10 weeks (“on”), then no sulindac for 10 weeks (“off”; sulindac-10); and (iv) no sulindac (sulindac-none). Sulindac-2 and sulindac-daily had statistically significantly lower final tumor counts and slopes (change in number of tumors per week) when compared with sulindac-none (P &lt; 0.0001). All of the treatment groups had statistically significantly lower final tumor burdens and slopes when compared with sulindac-none (P &lt; 0.001). There was a prolonged latency period in the sulindac-10 group, with no significant difference between the “off” portion of this treatment and sulindac-none. These results suggest that, although daily doses of sulindac provide the most optimal effects, intermittent doses of sulindac in a 50% duty cycle with an overall 4-week period (sulindac-2 model) can provide highly effective chemoprevention of colorectal cancer in this model. After cessation of sulindac treatment (sulindac-10 “off”), there is no evidence of either a persistent chemopreventive effect or a rebound effect. Cancer Prev Res; 10(8); 459–66. ©2017 AACR.
Patient-Reported Health-Related Quality of Life Is a Predictor of Outcomes in Ambulatory Heart Failure Patients Treated With Left Ventricular Assist Device Compared With Medical Management
Authors: Stehlik Josef , Estep Jerry D. , Selzman Craig H. , Rogers Joseph G. , Spertus John A. , Shah Keyur B. , Chuang Joyce , Farrar David J. , Starling Randall C. 
Published: June 2017

Background—
The prospective observational ROADMAP study (Risk Assessment and Comparative Effectiveness of Left Ventricular Assist Device and Medical Management) demonstrated that ambulatory advanced heart failure patients selected for left ventricular assist device (LVAD) were more likely to be alive at 1 year on original therapy with ≥75-m improvement in 6-minute walk distance compared with patients assigned to optimal medical management. Whether baseline health-related quality of life (hrQoL) resulted in a heterogeneity of this treatment benefit is unknown.

Methods and Results—

Patient-reported hrQoL was assessed with EuroQol questionnaire and visual analogue scale (VAS). We aimed to identify predictors of event-free survival and survival with acceptable hrQoL (VAS≥60). LVAD patients had significant improvement in 3 of 5 EuroQol dimensions (
P
<0.05), but no significant changes were observed with optimal medical management. Among patients with baseline VAS<55, survival on original treatment was lower for optimal medical management patients compared with those assigned to LVAD (58±7% versus 82±5%;
P
=0.004). No such difference was seen if baseline VAS was ≥55 (70±7% versus 75±9%;
P
=0.79). Survival on original therapy with acceptable quality of life was also more likely with LVAD versus optimal medical management if baseline VAS was <55, whereas outcomes in patients with higher baseline VAS scores were similar regardless of treatment assignment (
P
=0.046 for treatment arm and baseline VAS interaction).

Conclusions—
LVAD therapy resulted in improvement of patient health status in heart failure patients with low self-reported hrQoL, but not in patients with acceptable quality of life at the time of LVAD implantation. Patient-reported hrQoL should be integrated into decision making concerning the use and timing of LVAD therapy in heart failure patients who are symptom limited but remain ambulatory.

Clinical Trial Registration—

URL:
http://www.ClinicalTrials.gov
. Unique identifier: NCT01452802.
Inhibition of MicroRNA-146a and Overexpression of Its Target Dihydrolipoyl Succinyltransferase Protect Against Pressure Overload-Induced Cardiac Hypertrophy and Dysfunction
Authors: Heggermont Ward A. , Papageorgiou Anna-Pia , Quaegebeur Annelies , Deckx Sophie , Carai Paolo , Verhesen Wouter , Eelen Guy , Schoors Sandra , van Leeuwen Rick , Alekseev Sergey , Elzenaar Ies , Vinckier Stefan , Pokreisz Peter , Walravens Ann-Sophie , Gijsbers Rik , Van Den Haute Chris , Nickel Alexander , Schroen Blanche , van Bilsen Marc , Janssens Stefan , Maack Christoph , Pinto Yigal , Carmeliet Peter , Heymans Stephane 
Published: June 2017

Background:
Cardiovascular diseases remain the predominant cause of death worldwide, with the prevalence of heart failure continuing to increase. Despite increased knowledge of the metabolic alterations that occur in heart failure, novel therapies to treat the observed metabolic disturbances are still lacking.

Methods:
Mice were subjected to pressure overload by means of angiotensin-II infusion or transversal aortic constriction. MicroRNA-146a was either genetically or pharmacologically knocked out or genetically overexpressed in cardiomyocytes. Furthermore, overexpression of dihydrolipoyl succinyltransferase (DLST) in the murine heart was performed by means of an adeno-associated virus.

Results:
MicroRNA-146a was upregulated in whole heart tissue in multiple murine pressure overload models. Also, microRNA-146a levels were moderately increased in left ventricular biopsies of patients with aortic stenosis. Overexpression of microRNA-146a in cardiomyocytes provoked cardiac hypertrophy and left ventricular dysfunction in vivo, whereas genetic knockdown or pharmacological blockade of microRNA-146a blunted the hypertrophic response and attenuated cardiac dysfunction in vivo. Mechanistically, microRNA-146a reduced its target DLST—the E2 subcomponent of the α-ketoglutarate dehydrogenase complex, a rate-controlling tricarboxylic acid cycle enzyme. DLST protein levels significantly decreased on pressure overload in wild-type mice, paralleling a decreased oxidative metabolism, whereas DLST protein levels and hence oxidative metabolism were partially maintained in microRNA-146a knockout mice. Moreover, overexpression of DLST in wild-type mice protected against cardiac hypertrophy and dysfunction in vivo.

Conclusions:
Altogether we show that the microRNA-146a and its target DLST are important metabolic players in left ventricular dysfunction.