bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mild hypothermia preserves myocardial conduction during ischemia by maintaining gap junction intracellular communication and Na+ channel function
Authors: Nassal Michelle M. J. , Wan Xiaoping , Dale Zack , Deschênes Isabelle , Wilson Lance D. , Piktel Joseph S. 
Published: March 2017

Acute cardiac ischemia induces conduction velocity (CV) slowing and conduction block, promoting reentrant arrhythmias leading to sudden cardiac arrest. Previously, we found that mild hypothermia (MH; 32°C) attenuates ischemia-induced conduction block and CV slowing in a canine model of early global ischemia. Acute ischemia impairs cellular excitability and the gap junction (GJ) protein connexin (Cx)43. We hypothesized that MH prevented ischemia-induced conduction block and CV slowing by preserving GJ expression and localization. Canine left ventricular preparations at control (36°C) or MH (32°C) were subjected to no-flow prolonged (30 min) ischemia. Optical action potentials were recorded from the transmural left ventricular wall, and CV was measured throughout ischemia. Cx43 and Na+ channel (NaCh) remodeling was assessed using both confocal immunofluorescence (IF) and/or Western blot analysis. Cellular excitability was determined by microelectrode recordings of action potential upstroke velocity (d V/d tmax) and resting membrane potential (RMP). NaCh current was measured in isolated canine myocytes at 36 and 32°C. As expected, MH prevented conduction block and mitigated ischemia-induced CV slowing during 30 min of ischemia. MH maintained Cx43 at the intercalated disk (ID) and attenuated ischemia-induced Cx43 degradation by both IF and Western blot analysis. MH also preserved d V/d tmax and NaCh function without affecting RMP. No difference in NaCh expression was seen at the ID by IF or Western blot analysis. In conclusion, MH preserves myocardial conduction during prolonged ischemia by maintaining Cx43 expression at the ID and maintaining NaCh function. Hypothermic preservation of GJ coupling and NaCh may be novel antiarrhythmic strategies during resuscitation. NEW & NOTEWORTHY Therapeutic hypothermia is now a class I recommendation for resuscitation from cardiac arrest. This study determined that hypothermia preserves gap junction coupling as well as Na+ channel function during acute cardiac ischemia, attenuating conduction slowing and preventing conduction block, suggesting that induced hypothermia may be a novel antiarrhythmic strategy in resuscitation.
Moderate and intense muscular exercises induce marked intramyocellular metabolic acidosis in sickle cell disease mice
Authors: Chatel Benjamin , Messonnier Laurent A. , Hourdé Christophe , Vilmen Christophe , Bernard Monique , Bendahan David 
Published: March 2017

Sickle cell disease (SCD) is associated with an impaired oxygen delivery to skeletal muscle that could alter ATP production processes. The present study aimed to determine the effects of sickle hemoglobin (HbS) on muscle pH homeostasis in response to exercise in homozygous (HbSS, n = 9) and heterozygous (HbAS, n = 10) SCD (Townes) mice in comparison to control (HbAA, n = 10) littermates. Magnetic resonance spectroscopy of phosphorus 31 enabled to measure intramuscular pH and phosphocreatine (PCr) concentration during rest-stimulation-recovery protocols at two different intensities. Maximal activity of some enzymes involved in muscle energetics and content of proteins involved in pH regulation were also investigated. HbSS mice presented a more pronounced exercise-induced intramuscular acidosis, whatever the intensity of exercise. Moreover, the depletion of PCr was also exacerbated in HbSS mice in response to intense exercise as compared with both HbAA and HbAS mice ( P < 0.01). While no difference was observed concerning proteins involved in muscle pH regulation, the activity of enolase (a glycolytic enzyme) was higher in both HbSS and HbAS mice as compared with controls ( P < 0.05). Interestingly, HbAS mice presented also metabolic impairments as compared with their control counterparts. This study has identified for the first time an exacerbated exercise-induced intramuscular acidosis in SCD mice.NEW & NOTEWORTHY The main finding of the present study was that the exercise-induced intramuscular acidosis was systematically more pronounced in sickle cell disease (SCD) mice as compared with their control counterparts. This result is important since it has been demonstrated in vitro that acidosis can trigger hemoglobin polymerization. From that point of view, our results tend to support the idea that high-intensity exercise may increase the risk of hemoglobin polymerization in SCD.
Pancreatic Cancer Progression Relies upon Mutant p53-Induced Oncogenic Signaling Mediated by NOP14
Authors: Du Yongxing , Liu Ziwen , You Lei , Hou Pengjiao , Ren Xiaoxia , Jiao Tao , Zhao Wenjing , Li Zongze , Shu Hong , Liu Changzheng , Zhao Yupei 
Published: March 2017

Abstract
Mutant p53 (mutp53) proteins promote tumor invasion and metastasis in pancreatic ductal adenocarcinoma (PDAC). However, the mechanism underlying sustained activation of mutp53 oncogenic signaling is currently unclear. In this study, we report that NOP14 nucleolar protein (NOP14) expression is upregulated in PDAC tumors and metastatic tissue specimens. NOP14 overexpression promoted cell motility, whereas NOP14 inhibition decreased invasive capacity of PDAC cells. In vivo invasion assays conducted on established subcutaneously, orthotopically, and intravenously injected tumor mouse models also indicated NOP14 as a promoter of PDAC metastasis. Mechanistically, mutp53 was validated as a functional target of NOP14; NOP14 primed tumor invasion and metastasis by increasing the stability of mutp53 mRNA. The NOP14/mutp53 axis suppressed p21 expression at both the transcriptional and posttranscriptional levels via induction of miR-17-5p in PDAC cells. In vivo, high NOP14 expression in PDAC patient tumors correlated with local metastasis and lymph invasion. Overall, our findings define a novel mechanism for understanding the function of NOP14 in the metastatic cascade of PDAC. Targeting NOP14 allows for effective suppression of tumor invasion in a mutp53-dependent manner, implicating NOP14 inhibition as a potential approach for attenuating metastasis in p53-mutant tumors. Cancer Res; 77(10); 2661–73. ©2017 AACR.
Successful Transfer of Umbilical Cord Blood CD34+ Hematopoietic Stem and Progenitor-derived NK Cells in Older Acute Myeloid Leukemia Patients
Authors: Dolstra Harry , Roeven Mieke W.H. , Spanholtz Jan , Hangalapura Basav N. , Tordoir Marleen , Maas Frans , Leenders Marij , Bohme Fenna , Kok Nina , Trilsbeek Carel , Paardekooper Jos , van der Waart Anniek B. , Westerweel Peter E. , Snijders Tjeerd J.F. , Cornelissen Jan , Bos Gerard , Pruijt Hans F.M. , de Graaf Aniek O. , van der Reijden Bert A. , Jansen Joop H. , van der Meer Arnold , Huls Gerwin , Cany Jeannette , Preijers Frank , Blijlevens Nicole M.A. , Schaap Nicolaas M. 
Published: March 2017

Abstract
Purpose: Older acute myeloid leukemia (AML) patients have a poor prognosis; therefore, novel therapies are needed. Allogeneic natural killer (NK) cells have been adoptively transferred with promising clinical results. Here, we report the first-in-human study exploiting a unique scalable NK-cell product generated ex vivo from CD34+ hematopoietic stem and progenitor cells (HSPC) from partially HLA-matched umbilical cord blood units.
Experimental Design: Ten older AML patients in morphologic complete remission received an escalating HSPC-NK cell dose (between 3 and 30 × 106/kg body weight) after lymphodepleting chemotherapy without cytokine boosting.
Results: HSPC-NK cell products contained a median of 75% highly activated NK cells, with &lt;1 × 104 T cells/kg and &lt;3 × 105 B cells/kg body weight. HSPC-NK cells were well tolerated, and neither graft-versus-host disease nor toxicity was observed. Despite no cytokine boosting being given, transient HSPC-NK cell persistence was clearly found in peripheral blood up to 21% until day 8, which was accompanied by augmented IL15 plasma levels. Moreover, donor chimerism up to 3.5% was found in bone marrow. Interestingly, in vivo HSPC-NK cell maturation was observed, indicated by the rapid acquisition of CD16 and KIR expression, while expression of most activating receptors was sustained. Notably, 2 of 4 patients with minimal residual disease (MRD) in bone marrow before infusion became MRD negative (&lt;0.1%), which lasted for 6 months.
Conclusions: These findings indicate that HSPC-NK cell adoptive transfer is a promising, potential “off-the-shelf” translational immunotherapy approach in AML. Clin Cancer Res; 23(15); 4107–18. ©2017 AACR.
Pooled Clustering of High-Grade Serous Ovarian Cancer Gene Expression Leads to Novel Consensus Subtypes Associated with Survival and Surgical Outcomes
Authors: Wang Chen , Armasu Sebastian M. , Kalli Kimberly R. , Maurer Matthew J. , Heinzen Ethan P. , Keeney Gary L. , Cliby William A. , Oberg Ann L. , Kaufmann Scott H. , Goode Ellen L. 
Published: March 2017

Abstract
Purpose: Here we assess whether molecular subtyping identifies biological features of tumors that correlate with survival and surgical outcomes of high-grade serous ovarian cancer (HGSOC).
Experimental Design: Consensus clustering of pooled mRNA expression data from over 2,000 HGSOC cases was used to define molecular subtypes of HGSOCs. This de novo classification scheme was then applied to 381 Mayo Clinic HGSOC patients with detailed survival and surgical outcome information.
Results: Five molecular subtypes of HGSOC were identified. In the pooled dataset, three subtypes were largely concordant with prior studies describing proliferative, mesenchymal, and immunoreactive tumors (concordance &gt; 70%), and the group of tumors previously described as differentiated type was segregated into two new types, one of which (anti-mesenchymal) had downregulation of genes that were typically upregulated in the mesenchymal subtype. Molecular subtypes were significantly associated with overall survival (P &lt; 0.001) and with rate of optimal surgical debulking (≤1 cm, P = 1.9E−4) in the pooled dataset. Among stage III-C or IV Mayo Clinic patients, molecular subtypes were also significantly associated with overall survival (P = 0.001), as well as rate of complete surgical debulking (no residual disease; 16% in mesenchymal tumors compared with &gt;28% in other subtypes; P = 0.02).
Conclusions: HGSOC tumors may be categorized into five molecular subtypes that associate with overall survival and the extent of residual disease following debulking surgery. Because mesenchymal tumors may have features that were associated with less favorable surgical outcome, molecular subtyping may have future utility in guiding neoadjuvant treatment decisions for women with HGSOC. Clin Cancer Res; 23(15); 4077–85. ©2017 AACR.
Plasmin Cleaves Von Willebrand Factor at K1491-R1492 in the A1–A2 Linker Region in a Shear- and Glycan-Dependent Manner In Vitro
Authors: Brophy Teresa M. , Ward Soracha E. , McGimsey Thomas R. , Schneppenheim Sonja , Drakeford Clive , O’Sullivan Jamie M. , Chion Alain , Budde Ulrich , O’Donnell James S. 
Published: March 2017

Objective—
Previous studies have demonstrated a role for plasmin in regulating plasma von Willebrand factor (VWF) multimer composition. Moreover, emerging data have shown that plasmin-induced cleavage of VWF is of particular importance in specific pathological states. Interestingly, plasmin has been successfully used as an alternative to ADAMTS13 (a disintegrin and metalloproteinase with thrombospondin type 1 motif) in a mouse model of thrombotic thrombocytopenic purpura. Consequently, elucidating the molecular mechanisms through which plasmin binds and cleaves VWF is not only of basic scientific interest but also of direct clinical importance. Our aim was to investigate factors that modulate the susceptibility of human VWF to proteolysis by plasmin.

Approach and Results—
We have adapted the VWF vortex proteolysis assay to allow for time-dependent shear exposure studies. We show that globular VWF is resistant to plasmin cleavage under static conditions, but is readily cleaved by plasmin under shear. Although both plasmin and ADAMTS13 cleave VWF in a shear-dependent manner, plasmin does not cleave at the Tyr1605-Met1606 ADAMTS13 proteolytic site in the A2 domain. Rather under shear stress conditions, or in the presence of denaturants, such as urea or ristocetin, plasmin cleaves the K1491-R1492 peptide bond within the VWF A1–A2 linker region. Finally, we demonstrate that VWF susceptibility to plasmin proteolysis at K1491-R1492 is modulated by local N-linked glycan expression within A1A2A3, and specifically inhibited by heparin binding to the A1 domain.

Conclusions—
Improved understanding of the plasmin–VWF interaction offers exciting opportunities to develop novel adjunctive therapies for the treatment of refractory thrombotic thrombocytopenic purpura.
Identification of Cadherin 2 (
CDH2
) Mutations in Arrhythmogenic Right Ventricular Cardiomyopathy
Authors: Mayosi Bongani M. , Fish Maryam , Shaboodien Gasnat , Mastantuono Elisa , Kraus Sarah , Wieland Thomas , Kotta Maria-Christina , Chin Ashley , Laing Nakita , Ntusi Ntobeko B.A. , Chong Michael , Horsfall Christopher , Pimstone Simon N. , Gentilini Davide , Parati Gianfranco , Strom Tim-Matthias , Meitinger Thomas , Pare Guillaume , Schwartz Peter J. , Crotti Lia 
Published: March 2017

Background—
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetically heterogeneous condition caused by mutations in genes encoding desmosomal proteins in up to 60% of cases. The 40% of genotype-negative cases point to the need of identifying novel genetic substrates by studying genotype-negative ARVC families.

Methods and Results—

Whole exome sequencing was performed on 2 cousins with ARVC. Validation of 13 heterozygous variants that survived internal quality and frequency filters was performed by Sanger sequencing. These variants were also genotyped in all family members to establish genotype–phenotype cosegregation. High-resolution melting analysis followed by Sanger sequencing was used to screen for mutations in cadherin 2 (
CDH2
) gene in unrelated genotype-negative patients with ARVC. In a 3-generation family, we identified by whole exome sequencing a novel mutation in
CDH2
(c.686A>C, p.Gln229Pro) that cosegregated with ARVC in affected family members. The
CDH2
c.686A>C variant was not present in >200 000 chromosomes available through public databases, which changes a conserved amino acid of cadherin 2 protein and is supported as the causal mutation by parametric linkage analysis. We subsequently screened 73 genotype-negative ARVC probands tested previously for mutations in known ARVC genes and found an additional likely pathogenic variant in
CDH2
(c.1219G>A, p.Asp407Asn).
CDH2
encodes cadherin 2 (also known as N-cadherin), a protein that plays a vital role in cell adhesion, making it a biologically plausible candidate gene in ARVC pathogenesis.

Conclusions—

These data implicate
CDH2
mutations as novel genetic causes of ARVC and contribute to a more complete identification of disease genes involved in cardiomyopathy.
Pathway-Specific Aggregate Biomarker Risk Score Is Associated With Burden of Coronary Artery Disease and Predicts Near-Term Risk of Myocardial Infarction and Death
Authors: Ghasemzadeh Nima , Hayek Salim S. , Ko Yi-An , Eapen Danny J. , Patel Riyaz S. , Manocha Pankaj , Al Kassem Hatem , Khayata Mohamed , Veledar Emir , Kremastinos Dimitrios , Thorball Christian W. , Pielak Tomasz , Sikora Sergey , Zafari A. Maziar , Lerakis Stamatios , Sperling Laurence , Vaccarino Viola , Epstein Stephen E. , Quyyumi Arshed A. 
Published: March 2017

Background—
Inflammation, coagulation, and cell stress contribute to atherosclerosis and its adverse events. A biomarker risk score (BRS) based on the circulating levels of biomarkers C-reactive protein, fibrin degradation products, and heat shock protein-70 representing these 3 pathways was a strong predictor of future outcomes. We investigated whether soluble urokinase plasminogen activator receptor (suPAR), a marker of immune activation, is predictive of outcomes independent of the aforementioned markers and whether its addition to a 3-BRS improves risk reclassification.

Methods and Results—
C-reactive protein, fibrin degradation product, heat shock protein-70, and suPAR were measured in 3278 patients undergoing coronary angiography. The BRS was calculated by counting the number of biomarkers above a cutoff determined using the Youden’s index. Survival analyses were performed using models adjusted for traditional risk factors. A high suPAR level ≥3.5 ng/mL was associated with all-cause death and myocardial infarction (hazard ratio, 1.83; 95% confidence interval, 1.43–2.35) after adjustment for risk factors, C-reactive protein, fibrin degradation product, and heat shock protein-70. Addition of suPAR to the 3-BRS significantly improved the C statistic, integrated discrimination improvement, and net reclassification index for the primary outcome. A BRS of 1, 2, 3, or 4 was associated with a 1.81-, 2.59-, 6.17-, and 8.80-fold increase, respectively, in the risk of death and myocardial infarction. The 4-BRS was also associated with severity of coronary artery disease and composite end points.

Conclusions—
SuPAR is independently predictive of adverse outcomes, and its addition to a 3-BRS comprising C-reactive protein, fibrin degradation product, and heat shock protein-70 improved risk reclassification. The clinical utility of using a 4-BRS for risk prediction and management of patients with coronary artery disease warrants further study.
Mania induced by adalimumab in a patient with ankylosing spondylitis
Authors: Ghossoub Elias , Habli Mohamad , Uthman Imad , Maalouf Fadi T 
Published: March 2017

Objectives Monoclonal antibodies such as antagonists of tumor necrosis factor-alpha have been shown to have beneficial effects on the well-being of patients with inflammatory illnesses. However, mood episodes triggered by such agents have been reported. We herein report the case of mania induced by adalimumab treatment in an adult with ankylosing spondylitis, which later resolved once adalimumab was discontinued and mood stabilizers were initiated. Methods A 25-year-old man, with prior history of dysthymia, was diagnosed with ankylosing spondylitis and started on adalimumab. He gradually developed manic symptoms over seven to eight months, while maintained on adalimumab. As his condition did not improve with outpatient management, the patient was admitted to the Psychiatry inpatient unit. Results Valproate and aripiprazole were initiated, and adalimumab was substituted with non-steroidal anti-inflammatory agents. Mood symptoms resolved within days, and the patient was discharged. Upon follow-up, the patient was euthymic and compliant to his psychotropic medications. He was started on certolizumab, a different immunomodulatory, for his ankylosing spondylitis. Conclusions Immunological modulation might be a key factor in triggering, maintaining, or treating mood symptoms. Further research in this field is warranted to better understand the pathophysiology of mania. To our knowledge, manic symptoms induced by adalimumab have not been previously reported in the literature, which is why our case report can have an impact in recognizing this important clinical adverse effect.
A new route to exposed thermal mass: Sound-absorbing poured concrete
Authors: Lombardo S , Orr JJ , Coley DA , Wood MJ 
Published: March 2017

This paper investigates the novel possibility of utilising the structural concrete floor slab as a means of providing additional mid- to low-frequency sound absorption through the addition of cavities on the ceiling side, formed using flexible formwork, acting as Helmholtz resonators. Mid- to low-frequency sound absorption in rooms is typically achieved through the use of perforated plasterboard or a suspended tile-in-grid system. Such an approach can separate the room from the thermal mass of the ceiling above, leading to higher peak temperatures or increased cooling load. Suspended ceilings can also increase the embodied energy of the building and limit the potential for stack effect ventilation by reducing room height. In this work, frequency-dependent absorption coefficients of perforated concrete samples were measured using an impedance tube test. The results were found to agree with a theoretical analysis, suggesting that it would be relatively easy to predict the performance of perforations of other depths and diameters including those targeted at absorbing higher frequencies. Practical application: The measurements indicate that such a slab could be used as a practical replacement for perforated plasterboard or a tile-in-grid system. This would allow the slab to be tuned to the building’s acoustic performance and structural requirements. The approach has the potential to: (1) reduce the embodied and operational energy of buildings; (2) improve thermal comfort and (3) create a better acoustic environment in situations where surface robustness or longevity is important, for example public stairwells, pathways under roads and metro stations.
Extracorporeal membrane oxygenation for acute respiratory distress syndrome in adults: an analysis of differences between survivors and non-survivors
Authors: Panholzer Bernd , Meckelburg Katrin , Huenges Katharina , Hoffmann Grischa , von der Brelie Michael , Haake Nils , Pilarczyk Kevin , Cremer Jochen , Haneya Assad 
Published: March 2017

Objectives: Over the last decade, extracorporeal membrane oxygenation (ECMO) has become a promising option for patients with severe acute respiratory distress syndrome (ARDS). In this single-center observational cohort study, data from a patient group with severe ARDS treated with ECMO was analyzed. Methods: Data from 46 patients [median age 54 years (18 to 72), male: 65.2%] were evaluated retrospectively between January 2009 and September 2015. Results: Diagnosis leading to ARDS was pneumonia in 63.1% of the patients. The median SOFA Score was 13 (10 to 19) and the median LIS was 3.5 (2.67 to 4). The median duration of ECMO support was 12 days (1 to 86). Twenty-eight patients (60.9%) were successfully weaned from ECMO and 22 patients survived (47.8%). Non-survivors needed significantly more frequent renal replacement therapy (37.5% vs. 18.2%; p<0.01) and transfusion of red blood cell concentrates [0.4 units (0.3 to 1.2) vs. 0.9 units (0.5 to 1.6); p<0.01] during ECMO support compared to patients who survived. Conclusion: This report suggests that ECMO currently allows treatment of severe ARDS with presumed improved survival. The incidence rate of acute kidney injury and transfusion are associated with adverse outcomes.