bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic significance of repeated brain natriuretic peptide measurements after percutaneous transluminal septal myocardial ablation in patients with drug-refractory hypertrophic obstructive cardiomyopathy
Authors: Akita Keitaro , Tsuruta Hikaru , Yuasa Shinsuke , Murata Mitsushige , Fukuda Keiichi , Maekawa Yuichiro 
Published: May 2018

ObjectivesTo evaluate whether repeated brain natriuretic peptide (BNP) measurements after percutaneous transluminal septal myocardial ablation (PTSMA) provide prognostic information regarding the response to PTSMA in patients with drug-refractory hypertrophic obstructive cardiomyopathy (HOCM).BackgroundPlasma BNP levels are associated with clinical outcomes in patients with HOCM. However, the prognostic value of plasma BNP level changes before and after PTSMA remains unclear.MethodsWe measured the plasma BNP levels serially before and after PTSMA, and evaluated the relationship between the changes in plasma BNP levels and clinical improvement in 47 patients. The patients were assigned to two groups based on the reduction in the New York Heart Association class ≥1 (good responder) or <1 (poor responder) before and after PTSMA. The Kansas City Cardiomyopathy Questionnaire (KCCQ) was used to measure health status.ResultsThe plasma BNP levels gradually decreased after PTSMA, although the levels plateaued 3 months until 12 months after PTSMA. Although the plasma BNP levels and resting left ventricular outflow tract peak pressure gradient before PTSMA were comparable between the groups, the ratio of the BNP levels before and after PTSMA in the good responder group was significantly lower than that in the poor responder group (0.43 (range, 0.24–0.68) vs 0.78 (range, 0.62–0.93), p=0.002). The KCCQ score changes in the good responder group were significantly higher than those in the poor responder group.ConclusionsThe plasma BNP level ratio was associated with long-term clinical improvement of heart failure after PTSMA for drug-refractory HOCM.
Effective silencing of ENaC by siRNA delivered with epithelial-targeted nanocomplexes in human cystic fibrosis cells and in mouse lung
Authors: Tagalakis Aristides D , Munye Mustafa M , Ivanova Rositsa , Chen Hanpeng , Smith Claire M , Aldossary Ahmad M , Rosa Luca Z , Moulding Dale , Barnes Josephine L , Kafetzis Konstantinos N , Jones Stuart A , Baines Deborah L , Moss Guy W J , O’Callaghan Christopher , McAnulty Robin J , Hart Stephen L 
Published: May 2018

IntroductionLoss of the cystic fibrosis transmembrane conductance regulator in cystic fibrosis (CF) leads to hyperabsorption of sodium and fluid from the airway due to upregulation of the epithelial sodium channel (ENaC). Thickened mucus and depleted airway surface liquid (ASL) then lead to impaired mucociliary clearance. ENaC regulation is thus a promising target for CF therapy. Our aim was to develop siRNA nanocomplexes that mediate effective silencing of airway epithelial ENaC in vitro and in vivo with functional correction of epithelial ion and fluid transport.MethodsWe investigated translocation of nanocomplexes through mucus and their transfection efficiency in primary CF epithelial cells grown at air–liquid interface (ALI).Short interfering RNA (SiRNA)-mediated silencing was examined by quantitative RT-PCR and western analysis of ENaC. Transepithelial potential (Vt), short circuit current (Isc), ASL depth and ciliary beat frequency (CBF) were measured for functional analysis. Inflammation was analysed by histological analysis of normal mouse lung tissue sections.ResultsNanocomplexes translocated more rapidly than siRNA alone through mucus. Transfections of primary CF epithelial cells with nanocomplexes targeting αENaC siRNA, reduced αENaC and βENaC mRNA by 30%. Transfections reduced Vt, the amiloride-sensitive Isc and mucus protein concentration while increasing ASL depth and CBF to normal levels. A single dose of siRNA in mouse lung silenced ENaC by approximately 30%, which persisted for at least 7 days. Three doses of siRNA increased silencing to approximately 50%.ConclusionNanoparticle-mediated delivery of ENaCsiRNA to ALI cultures corrected aspects of the mucociliary defect in human CF cells and offers effective delivery and silencing in vivo.
Induction of gut proteasome activity in hemorrhagic shock and its recovery by treatment with diphenyldihaloketones CLEFMA and EF24
Authors: Rao Geeta , Houson Hailey , Nkepang Gregory , Yari Hooman , Teng Chengwen , Awasthi Vibhudutta 
Published: May 2018

Multiorgan failure in hemorrhagic shock is triggered by gut barrier dysfunction and consequent systemic infiltration of proinflammatory factors. Our previous study has shown that diphenyldihaloketone drugs 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid (CLEFMA) and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone (EF24) restore gut barrier dysfunction and reduce systemic inflammatory response in hemorrhagic shock. We investigated the effect of hemorrhagic shock on proteasome activity of intestinal epithelium and how CLEFMA and EF24 treatments modulate proteasome function in hemorrhagic shock. CLEFMA or EF24 (0.4 mg/kg) were given 1 h after withdrawing 50% of blood from Sprague-Dawley rats; no other resuscitation was provided. After another 5 h of compensation, small gut was collected to process tissue for proteasome activity, immunoblotting, and mRNA levels of genes responsible for unfolded-protein response (XBP1, ATF4, glucose-regulated protein of 78/95 kDa, and growth arrest and DNA damage inducible genes 153/34), polyubiquitin B and C, and immunoproteasome subunits β type-8 and -10 and proteasome activator subunit 1. We found that hemorrhagic shock induced proteasome activity in gut tissue and reduced the amounts of ubiquitinated proteins displayed on antiubiquitin immunoblots. However, simultaneous induction of unfolded-protein response or immunoproteasome genes was not observed. CLEFMA and EF24 treatments abolished the hemorrhagic shock-induced increase in proteasome activity. Further investigations revealed that the induction of proteasome in hemorrhagic shock is associated with disassembly of 26S proteasome; CLEFMA and EF24 prevented this disassembly. Consistent with these data, CLEFMA and EF24 reduced hemorrhagic shock-induced degradation of 20S substrate ornithine decarboxylase in gut tissue. These results suggest that activated proteasome plays an important role in ischemic gut pathophysiology, and it can be a druggable target in shock-induced gut dysfunction. NEW & NOTEWORTHY Ischemic injury to the gut is a trigger for the systemic inflammatory response and multiple organ failure in trauma and hemorrhagic shock. We show for the first time that hemorrhagic shock induces the gut proteasome activity by engendering 26S proteasome disassembly. Diphenyldihaloketones 4-[3,5-bis[(2-chlorophenyl)methylene]-4-oxo-1-piperidinyl]-4-oxo-2-butenoic acid and 3,5-bis[(2-fluorophenyl)methylene]-4-piperidinone treatment prevented the 26S disassembly. Understanding the role of proteasome in shock-associated gut injury will assist in the development of therapeutic means to address it.
Increased TASK channel-mediated currents underlie high-fat diet induced vagal afferent dysfunction
Authors: Park Sung Jin , Yu Yang , Wagner Brittany , Valinsky William C. , Lomax Alan E. , Beyak Michael J. 
Published: May 2018

We have previously demonstrated that satiety sensing vagal afferent neurons are less responsive to meal-related stimuli in obesity because of reduced electrical excitability. As leak K+ currents are key determinants of membrane excitability, we hypothesized that leak K+ currents are increased in vagal afferents during obesity. Diet-induced obesity was induced by feeding C57Bl/6J mice a high-fat diet (HFF) (60% energy from fat) for 8–10 wk. In vitro extracellular recordings were performed on jejunal afferent nerves. Whole cell patch-clamp recordings were performed on mouse nodose ganglion neurons. Leak K+ currents were isolated using ion substitution and pharmacological blockers. mRNA for TWIK-related acid-sensitive K+ (TASK) subunits was measured using quantitative real-time PCR. Intestinal afferent responses to nutrient (oleate) and non-nutrient (ATP) stimuli were significantly decreased in HFF mice. Voltage clamp experiments revealed the presence of a voltage-insensitive resting potassium conductance that was increased by external alkaline pH and halothane, known properties of TASK currents. In HFF neurons, leak K+ current was approximately doubled and was reduced by TASK1 and TASK3 inhibitors. The halothane sensitive current was similarly increased. Quantitative PCR revealed the presence of mRNA encoding TASK1 (KCNK3) and TASK3 (KCNK9) channels in nodose neurons. TASK3 transcript was significantly increased in HFF mice. The reduction in vagal afferent excitability in obesity is due in part to an increase of resting (leak) K+ conductance. TASK channels may account for the impairment of satiety signaling in diet-induced obesity and thus is a therapeutic target for obesity treatment. NEW & NOTEWORTHY This study characterized the electrophysiological properties and gene expression of the TWIK-related acid-sensitive K+ (TASK) channel in vagal afferent neurons. TASK conductance was increased and contributed to decreased excitability in diet-induced obesity. TASK channels may account for the impairment of satiety signaling in diet-induced obesity and thus is a promising therapeutic target.
slan+ Monocytes and Macrophages Mediate CD20-Dependent B-cell Lymphoma Elimination via ADCC and ADCP
Authors: Vermi William , Micheletti Alessandra , Finotti Giulia , Tecchio Cristina , Calzetti Federica , Costa Sara , Bugatti Mattia , Calza Stefano , Agostinelli Claudio , Pileri Stefano , Balzarini Piera , Tucci Alessandra , Rossi Giuseppe , Furlani Lara , Todeschini Giuseppe , Zamò Alberto , Facchetti Fabio , Lorenzi Luisa , Lonardi Silvia , Cassatella Marco A. 
Published: May 2018

Abstract
Terminal tissue differentiation and function of slan+ monocytes in cancer is largely unexplored. Our recent studies demonstrated that slan+ monocytes differentiate into a distinct subset of dendritic cells (DC) in human tonsils and that slan+ cells colonize metastatic carcinoma-draining lymph nodes. Herein, we report by retrospective analysis of multi-institutional cohorts that slan+ cells infiltrate various types of non-Hodgkin lymphomas (NHL), particularly the diffuse large B-cell lymphoma (DLBCL) group, including the most aggressive, nodal and extranodal, forms. Nodal slan+ cells displayed features of either immature DC or macrophages, in the latter case ingesting tumor cells and apoptotic bodies. We also found in patients with DLBCL that peripheral blood slan+ monocytes, but not CD14+ monocytes, increased in number and displayed highly efficient rituximab-mediated antibody-dependent cellular cytotoxicity, almost equivalent to that exerted by NK cells. Notably, slan+ monocytes cultured in conditioned medium from nodal DLBCL (DCM) acquired a macrophage-like phenotype, retained CD16 expression, and became very efficient in rituximab-mediated antibody-dependent cellular phagocytosis (ADCP). Macrophages derived from DCM-treated CD14+ monocytes performed very efficient rituximab-mediated ADCP, however, using different FcγRs from those used by slan+ macrophages. Our observations shed new light on the complexity of the immune microenvironment of DLBCL and demonstrate plasticity of slan+ monocytes homing to cancer tissues. Altogether, data identify slan+ monocytes and macrophages as prominent effectors of antibody-mediated tumor cell targeting in patients with DLBCL.
Significance: slan+ monocytes differentiate into macrophages that function as prominent effectors of antibody-mediated tumor cell targeting in lymphoma.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/13/3544/F1.large.jpg. Cancer Res; 78(13); 3544–59. ©2018 AACR.
The miR-371∼373 Cluster Represses Colon Cancer Initiation and Metastatic Colonization by Inhibiting the TGFBR2/ID1 Signaling Axis
Authors: Ullmann Pit , Rodriguez Fabien , Schmitz Martine , Meurer Steffen K. , Qureshi-Baig Komal , Felten Paul , Ginolhac Aurélien , Antunes Laurent , Frasquilho Sonia , Zügel Nikolaus , Weiskirchen Ralf , Haan Serge , Letellier Elisabeth 
Published: May 2018

Abstract
The vast majority of colorectal cancer–related deaths can be attributed to metastatic spreading of the disease. Therefore, deciphering molecular mechanisms of metastatic dissemination is a key prerequisite to improve future treatment options. With this aim, we took advantage of different colorectal cancer cell lines and recently established primary cultures enriched in colon cancer stem cells, also known as tumor-initiating cells (TIC), to identify genes and miRNAs with regulatory functions in colorectal cancer progression. We show here that metastasis-derived TICs display increased capacity for self-renewal, TGFβ signaling activity, and reduced expression of the miR-371∼373 cluster compared with nonmetastatic cultures. TGFβ receptor 2 (TGFBR2) and aldehyde dehydrogenase A1 (ALDH1A1) were identified as important target genes of the miR-371∼373 cluster. In addition, TGFBR2 repression, either by direct knockdown or indirectly via overexpression of the entire miR-371∼373 cluster, decreased tumor-initiating potential of TICs. We observed significantly reduced in vitro self-renewal activity as well as lowered tumor initiation and metastatic outgrowth capacity in vivo following stable overexpression of the miR-371∼373 cluster in different colon TIC cultures. Inhibitor of DNA binding 1 (ID1) was affected by both TGFBR2 and miR-371∼373 cluster alterations. Functional sphere and tumor formation as well as metastatic dissemination assays validated the link between miR-371∼373 and ID1. Altogether, our results establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel regulatory mechanism of TIC self-renewal and metastatic colonization.
Significance: These findings establish the miR-371∼373/TGFBR2/ID1 signaling axis as a novel mechanism regulating self-renewal of tumor-initiating cell and metastatic colonization, potentially opening new concepts for therapeutic targeting of cancer metastasis.
Graphical Abstract: http://cancerres.aacrjournals.org/content/canres/78/14/3793/F1.large.jpg. Cancer Res; 78(14); 3793–808. ©2018 AACR.
TRAF1 Is Critical for Regulating the BRAF/MEK/ERK Pathway in Non–Small Cell Lung Carcinogenesis
Authors: Wang Qiushi , Gao Ge , Zhang Tianshun , Yao Ke , Chen Hanyong , Park Mi Hee , Yamamoto Hiroyuki , Wang Keke , Ma Weiya , Malakhova Margarita , Bode Ann M. , Dong Zigang 
Published: May 2018

Abstract
Tumor necrosis factor receptor (TNFR)–associated factor 1 (TRAF1) is a unique TRAF protein that can interact directly or indirectly with multiple TNFR family members, regulatory proteins, kinases, and adaptors that contribute to its diverse functions in specific tissues. However, the role of TRAF1 in non–small cell lung cancer (NSCLC) remains unknown. In this study, we report that TRAF1 is overexpressed in human lung cancer cells and tissues. TRAF1 expression level inversely correlated with patient survival probability. Loss of TRAF1 decelerated tumor invasion in a urethane-induced lung carcinogenesis mouse model. Furthermore, TRAF1 expression affected TRAF2-mediated BRAF Lys48–linked ubiquitination, which was followed by the inhibition of growth and differentiation, and the induction of death in lung cancer cells. Overall, our work suggests that TRAF1 plays a novel role in the regulation of the BRAF/MEK/ERK signaling pathway in NSCLC and offers a candidate molecular target for lung cancer prevention and therapy.
Significance: These findings identify TRAF1 as a new therapeutic target for NSCLC. Cancer Res; 78(14); 3982–94. ©2018 AACR.
Dual Suppressive Effect of miR-34a on the FOXM1/eEF2-Kinase Axis Regulates Triple-Negative Breast Cancer Growth and Invasion
Authors: Bayraktar Recep , Ivan Cristina , Bayraktar Emine , Kanlikilicer Pinar , Kabil Nashwa N. , Kahraman Nermin , Mokhlis Hamada A. , Karakas Didem , Rodriguez-Aguayo Cristian , Arslan Ahmet , Sheng Jianting , Wong Stephen , Lopez-Berestein Gabriel , Calin George A. , Ozpolat Bulent 
Published: May 2018

Abstract
Purpose: Recent studies indicated that dysregulation of noncoding RNAs (ncRNA) such as miRNAs is involved in pathogenesis of various human cancers. However, the molecular mechanisms underlying miR-34a are not fully understood in triple-negative breast cancer (TNBC).
Experimental Design: We performed in vitro functional assays on TNBC cell lines to investigate the role of miR-34a in FOXM1/eEF2K signaling axis. TNBC tumor xenograft models were used for in vivo therapeutic delivery of miR-34a.
Results: In this study, we investigated the role of p53-driven ncRNA miR-34a and found that miR-34a is associated with significantly longer patient survival in TNBC and inversely correlated with levels of proto-oncogenic eEF2K, which was associated with significantly shorter overall patient survival. We showed that miR-34a directly binds to the 3′-untranslated region of eEF2K and FOXM1 mRNAs and suppresses their expression, leading to inhibition of TNBC cell proliferation, motility, and invasion. Notably, restoring miR-34a expression recapitulated the effects of inhibition of eEF2K and FOXM1, the transcription factor for eEF2K and the direct target of p53, in TNBC cell lines, whereas overexpression of eEF2K and FOXM1 rescued the effects and signaling pathways mediated by miR-34a. Moreover, in vivo therapeutic delivery of miR-34a nanoparticles by systemic intravenous administration delayed tumor growth of two different orthotopic TNBC tumor xenograft models by inhibiting eEF2K and FOXM1, intratumoral proliferation and angiogenesis, and inducing apoptosis.
Conclusions: Overall, our findings provide new insights into the tumor suppressor role of miR-34a by dual-targeting of FOXM1/eEF2K signaling axis and suggest that miR-34a–based gene therapy may be a potential therapeutic strategy in TNBC. Clin Cancer Res; 24(17); 4225–41. ©2018 AACR.
Satellite RNA Increases DNA Damage and Accelerates Tumor Formation in Mouse Models of Pancreatic Cancer
Authors: Kishikawa Takahiro , Otsuka Motoyuki , Suzuki Tatsunori , Seimiya Takahiro , Sekiba Kazuma , Ishibashi Rei , Tanaka Eri , Ohno Motoko , Yamagami Mari , Koike Kazuhiko 
Published: May 2018

Abstract
Highly repetitive tandem arrays such as satellite sequences in the centromeric and pericentromeric regions of chromosomes, which were previously considered to be silent, are actively transcribed in various biological processes, including cancers. In the pancreas, this aberrant expression occurs even in Kras-mutated pancreatic intraepithelial neoplasia (PanIN) tissues, which are precancerous lesions. To determine the biological role of satellite RNAs in carcinogenesis in vivo, we constructed mouse major satellite (MajSAT) RNA-expressing transgenic mice. However, these transgenic mice did not show spontaneous malignant tumor formation under normal breeding. Importantly, however, DNA damage was increased in pancreatic tissues induced by caerulein treatment or high-fat diet, which may be due to impaired nuclear localization of Y-Box Binding Protein 1 (YBX1), a component of the DNA damage repair machinery. In addition, when crossed with pancreas-specific Kras-mutant mice, MajSAT RNA expression resulted in an earlier increase in PanIN formation. These results suggest that aberrant MajSAT RNA expression accelerates oncogenesis by increasing the probability of a second driver mutation, thus accelerating cells to exit from the breakthrough phase to the expansion phase.
Implications: Aberrant expression of satellite RNAs accelerates oncogenesis through a mechanism involving increased DNA damage. Mol Cancer Res; 16(8); 1255–62. ©2018 AACR.
Noninvasive Assessment of Preload Reserve Enhances Risk Stratification of Patients With Heart Failure With Reduced Ejection Fraction
Authors: Matsumoto Kensuke , Onishi Akira , Yamada Hirotsugu , Kusunose Kenya , Suto Makiko , Hatani Yutaka , Matsuzoe Hiroki , Tatsumi Kazuhiro , Tanaka Hidekazu , Hirata Ken-Ichi 
Published: May 2018

Background:
The leg-positive pressure maneuver can safely and noninvasively apply preload stress without increase in total body fluid volume. The purpose of this study was to determine whether preload stress could be useful for risk stratification of patients with heart failure with reduced ejection fraction.

Methods and Results:

For this study, 120 consecutive patients with heart failure with reduced ejection fraction were prospectively recruited. The stroke work index was estimated as product of stroke volume index and mean blood pressure, and the E/e′ ratio was calculated to estimate ventricular filling pressure. The echocardiographic parameters were obtained both at rest and during leg-positive pressure stress. During the median follow-up period of 20 months, 30 patients developed adverse cardiovascular events. During preload stress, stroke work index increased significantly (from 3280±1371 to 3857±1581 mm Hg·mL/m
2
;
P
<0.001) along with minimal changes in ventricular filling pressure (E/e′, from 16±10 to 17±9;
P
<0.05) in patients without cardiovascular events. However, patients with cardiovascular events showed impairment of Frank–Starling mechanism (stroke work index, from 2863±969 to 2903±1084 mm Hg·mL/m
2
;
P
=0.70) and a serious increase in E/e′ ratio (from 19±11 to 25±14;
P
<0.001). Both the patients without contractile reserve and those without diastolic reserve exhibited worse event-free survival than the others (
P
<0.001). In a Cox proportional-hazards analysis, the changes in stroke work index (hazard ratio: 0.44 per 500 mm Hg·mL/m
2
increase;
P
=0.001) and in E/e′ (hazard ratio: 2.58 per 5-U increase;
P
<0.001) were predictors of cardiovascular events.

Conclusion:
Contractile reserve and diastolic reserve during leg-positive pressure stress are important determinants of cardiovascular outcomes for patients with heart failure with reduced ejection fraction.
Abrupt Transitions in Submesoscale Structure in Southern Drake Passage: Glider Observations and Model Results
Authors: Viglione Giuliana A. , Thompson Andrew F. , Flexas M. Mar , Sprintall Janet , Swart Sebastiaan 
Published: May 2018

AbstractEnhanced vertical velocities associated with submesoscale motions may rapidly modify mixed layer depths and increase exchange between the mixed layer and the ocean interior. These dynamics are of particular importance in the Southern Ocean, where the ventilation of many density classes occurs. Here we present results from an observational field program in southern Drake Passage, a region preconditioned for submesoscale instability owing to its strong mesoscale eddy field, persistent fronts, strong down-front winds, and weak vertical stratification. Two gliders sampled from December 2014 through March 2015 upstream and downstream of the Shackleton Fracture Zone (SFZ). The acquired time series of mixed layer depths and buoyancy gradients enabled calculations of potential vorticity and classifications of submesoscale instabilities. The regions flanking the SFZ displayed remarkably different characteristics despite similar surface forcing. Mixed layer depths were nearly twice as deep, and horizontal buoyancy gradients were larger downstream of the SFZ. Upstream of the SFZ, submesoscale variability was confined to the edges of topographically steered fronts, whereas downstream these motions were more broadly distributed. Comparisons to a one-dimensional (1D) mixing model demonstrate the role of submesoscale instabilities in generating mixed layer variance. Numerical output from a submesoscale-resolving simulation indicates that submesoscale instabilities are crucial for correctly reproducing upper-ocean stratification. These results show that bathymetry can play a key role in generating dynamically distinct submesoscale characteristics over short spatial scales and that submesoscale motions can be locally active during summer months.