bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rapid and lasting enhancement of dopaminergic modulation at the hippocampal mossy fiber synapse by electroconvulsive treatment
Authors: Kobayashi Katsunori , Imoto Yuki , Yamamoto Fumi , Kawasaki Mayu , Ueno Miyuki , Segi-Nishida Eri , Suzuki Hidenori 
Published: October 2016

Electroconvulsive therapy (ECT) is an established effective treatment for medication-resistant depression with the rapid onset of action. However, its cellular mechanism of action has not been revealed. We have previously shown that chronic antidepressant drug treatments enhance dopamine D1-like receptor-dependent synaptic potentiation at the hippocampal mossy fiber (MF)-CA3 excitatory synapse. In this study we show that ECT-like treatments in mice also have marked effects on the dopaminergic synaptic modulation. Repeated electroconvulsive stimulation (ECS), an animal model of ECT, strongly enhanced the dopamine-induced synaptic potentiation at the MF synapse in hippocampal slices. Significant enhancement was detectable after the second ECS, and further repetition of ECS up to 11 times monotonously increased the magnitude of enhancement. After repeated ECS, the dopamine-induced synaptic potentiation remained enhanced for more than 4 wk. These synaptic effects of ECS were accompanied by increased expression of the dopamine D1 receptor gene. Our results demonstrate that robust neuronal activation by ECS induces rapid and long-lasting enhancement of dopamine-induced synaptic potentiation at the MF synapse, likely via increased expression of the D1 receptor, at least in part. This rapid enhancement of dopamine-induced potentiation at the excitatory synapse may be relevant to the fast-acting antidepressant effect of ECT. NEW & NOTEWORTHY We show that electroconvulsive therapy (ECT)-like stimulation greatly enhances synaptic potentiation induced by dopamine at the excitatory synapse formed by the hippocampal mossy fiber in mice. The effect of ECT-like stimulation on the dopaminergic modulation was rapidly induced, maintained for more than 4 wk after repeated treatments, and most likely mediated by increased expression of the dopamine D1 receptor. These effects may be relevant to fast-acting strong antidepressant action of ECT.
Transglutaminase Interaction with α6/β4-Integrin Stimulates YAP1-Dependent ΔNp63α Stabilization and Leads to Enhanced Cancer Stem Cell Survival and Tumor Formation
Authors: Fisher Matthew L. , Kerr Candace , Adhikary Gautam , Grun Dan , Xu Wen , Keillor Jeffrey W. , Eckert Richard L. 
Published: October 2016

Abstract
Transglutaminase 2 (TG2) expression is required for epidermal squamous cell carcinoma cancer stem cell survival. However, the molecular signaling mechanisms triggered by TG2 that mediate this survival action are not well understood. Here we show that TG2 is constitutively expressed in ECS cells, where it interacts with α6/β4 integrin to stimulate FAK and Src signaling, leading to PI3K activation of phosphoinositide-dependent kinase 1 (PDK1). PDK1 inhibits Hippo signaling, leading to enhanced nuclear accumulation of YAP1, which interacted with and stabilized ΔNp63α to enhance epidermal squamous cell carcinoma spheroid formation, invasion, and migration. Overall, these findings suggest that constitutive TG2 expression results in stabilization of ΔNp63α, leading to maintenance of cancer stem cell properties and enhanced tumor formation. Cancer Res; 76(24); 7265–76. ©2016 AACR.
Reallocating Time to Sleep, Sedentary Time, or Physical Activity: Associations with Waist Circumference and Body Mass Index in Breast Cancer Survivors
Authors: Boyle Terry , Vallance Jeff K. , Buman Matthew P. , Lynch Brigid M. 
Published: October 2016

Abstract
Background: Moderate-to-vigorous intensity physical activity (MVPA) is inversely associated with waist circumference and body mass index (BMI) among breast cancer survivors. Limited research has focused on behaviors that account for larger portions of the day [sleep, sedentary time, and light-intensity physical activity (LPA)]. We investigated the interdependent associations of self-reported sleep, objectively assessed prolonged and short bouts of sedentary time, total LPA, and total MVPA with waist circumference and BMI.
Methods: A cross-sectional sample of breast cancer survivors (N = 256, mean age = 60 years; mean time since diagnosis = 3 years) wore an Actigraph GT3X+ accelerometer during waking hours for 7 days. Participants completed the Pittsburgh Sleep Quality Index and self-reported their waist circumference, height, and weight. An isotemporal substitution approach was used in linear regression models to explore the associations of reallocating time to sleep, sedentary and active behaviors on waist circumference, and BMI, after adjusting for potential confounders.
Results: Reallocating 30 minutes to MVPA was significantly associated with lower waist circumference when allocated from sleep (−2.50 cm), prolonged sedentary time (−2.51 cm), or LPA (−2.71 cm). Reallocating 30 minutes of prolonged sedentary time to nonprolonged sedentary time was significantly associated with lower waist circumference (−0.94 cm). Similar results were observed for BMI.
Conclusions: Reallocating 30 minutes to MVPA was associated with significantly lower waist circumference and BMI, as was reallocating 30 minutes of prolonged sedentary time to 30 minutes of nonprolonged sedentary time.
Impact: Increasing MVPA levels and decreasing time spent in prolonged, unbroken sedentary bouts may be avenues for improving body composition in this population. Cancer Epidemiol Biomarkers Prev; 26(2); 254–60. ©2016 AACR.
Impact of TP53 Mutations on Outcome in EGFR-Mutated Patients Treated with First-Line Tyrosine Kinase Inhibitors
Authors: Canale Matteo , Petracci Elisabetta , Delmonte Angelo , Chiadini Elisa , Dazzi Claudio , Papi Maximilian , Capelli Laura , Casanova Claudia , De Luigi Nicoletta , Mariotti Marita , Gamboni Alessandro , Chiari Rita , Bennati Chiara , Calistri Daniele , Ludovini Vienna , Crinò Lucio , Amadori Dino , Ulivi Paola 
Published: October 2016

Abstract
Purpose: To analyze the impact of TP53 mutations on response to first-line tyrosine kinase inhibitors (TKI) in patients with EGFR-mutated non–small cell lung cancer (NSCLC).
Experimental Design: 136 EGFR-mutated NSCLC patients receiving first-line TKIs were analyzed. TP53 mutations were evaluated in 123 patients in relation to disease control rate (DCR), objective response rate (ORR), progression-free survival (PFS), and overall survival (OS).
Results: TP53 mutations were observed in 37 (30.1%), 10 (27.0%), 6 (16.2%), 9 (24.3%), and 12 (32.4%) patients in exons 5, 6, 7, and 8, respectively. DCR was 70% in TP53-mutated patients compared with 88% in TP53-wild type (wt) patients [relative risk, RR, of disease progression: 3.17 (95% CI, 1.21–8.48), P = 0.019]. In particular, a 42% DCR was observed in patients with TP53 exon 8 mutation versus 87% in exon 8 wt patients [RR of disease progression 9.6 (2.71–36.63), P &lt; 0.001]. Shorter median PFS and OS were observed in patients with TP53 exon 8 mutations compared with others (4.2 vs. 12.5, P = 0.058, and 16.2 vs. 32.3, P = 0.114, respectively); these differences became significant in the subgroup with EGFR exon 19 deletion (4.2 vs. 16.8, P &lt; 0.001, and 7.6 vs. not reached, P = 0.006, respectively), HR 6.99 (95% CI, 2.34–20.87, P &lt; 0.001) and HR 4.75 (95% CI, 1.38–16.29, P = 0.013), respectively.
Conclusions: TP53 mutations, especially exon 8 mutations, reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions. Clin Cancer Res; 23(9); 2195–202. ©2016 AACR.
The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia
Authors: Vercruysse Thomas , De Bie Jolien , Neggers Jasper E. , Jacquemyn Maarten , Vanstreels Els , Schmid-Burgk Jonathan L. , Hornung Veit , Baloglu Erkan , Landesman Yosef , Senapedis William , Shacham Sharon , Dagklis Antonis , Cools Jan , Daelemans Dirk 
Published: October 2016

Abstract
Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb clinical trials when dosed 1 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily. Here, we investigate and validate the drug–target interaction of KPT-8602 and explore its activity against acute lymphoblastic leukemia (ALL).
Experimental Design: We examined the effect of KPT-8602 on XPO1 function and XPO1-cargo as well as on a panel of leukemia cell lines. Mutant XPO1 leukemia cells were designed to validate KPT-8602′s drug-target interaction. In vivo, anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models.
Results: KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines in vitro. Using CRISPR/Cas9 genome editing, we demonstrated the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validated the drug target interaction. In vivo, KPT-8602 showed potent anti-leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis.
Conclusions: KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. Clin Cancer Res; 23(10); 2528–41. ©2016 AACR.
5T4-Targeted Therapy Ablates Cancer Stem Cells and Prevents Recurrence of Head and Neck Squamous Cell Carcinoma
Authors: Kerk Samuel A. , Finkel Kelsey A. , Pearson Alexander T. , Warner Kristy A. , Zhang Zhaocheng , Nör Felipe , Wagner Vivian P. , Vargas Pablo A. , Wicha Max S. , Hurt Elaine M. , Hollingsworth Robert E. , Tice David A. , Nör Jacques E. 
Published: October 2016

AbstractPurpose: Locoregional recurrence is a frequent treatment outcome for patients with advanced head and neck squamous cell carcinoma (HNSCC). Emerging evidence suggests that tumor recurrence is mediated by a small subpopulation of uniquely tumorigenic cells, that is, cancer stem cells (CSC), that are resistant to conventional chemotherapy, endowed with self-renewal and multipotency.Experimental Design: Here, we evaluated the efficacy of MEDI0641, a novel antibody–drug conjugate targeted to 5T4 and carrying a DNA-damaging “payload” (pyrrolobenzodiazepine) in preclinical models of HNSCC.Results: Analysis of a tissue microarray containing 77 HNSCC with follow-up of up to 12 years revealed that patients with 5T4high tumors displayed lower overall survival than those with 5T4low tumors (P = 0.038). 5T4 is more highly expressed in head and neck CSC (ALDHhighCD44high) than in control cells (non-CSC). Treatment with MEDI0641 caused a significant reduction in the CSC fraction in HNSCC cells (UM-SCC-11B, UM-SCC-22B) in vitro. Notably, a single intravenous dose of 1 mg/kg MEDI0641 caused long-lasting tumor regression in three patient-derived xenograft (PDX) models of HNSCC. MEDI0641 ablated CSC in the PDX-SCC-M0 model, reduced it by five-fold in the PDX-SCC-M1, and two-fold in the PDX-SCC-M11 model. Importantly, mice (n = 12) treated with neoadjuvant, single administration of MEDI0641 prior to surgical tumor removal showed no recurrence for more than 200 days, whereas the control group had 7 recurrences (in 12 mice; P = 0.0047).Conclusions: Collectively, these findings demonstrate that an anti-5T4 antibody–drug conjugate reduces the fraction of CSCs and prevents local recurrence and suggest a novel therapeutic approach for patients with HNSCC. Clin Cancer Res; 23(10); 2516–27. ©2016 AACR.
Heterogeneity of Acquired Resistance to Anti-EGFR Monoclonal Antibodies in Patients with Metastatic Colorectal Cancer
Authors: Pietrantonio Filippo , Vernieri Claudio , Siravegna Giulia , Mennitto Alessia , Berenato Rosa , Perrone Federica , Gloghini Annunziata , Tamborini Elena , Lonardi Sara , Morano Federica , Picciani Benedetta , Busico Adele , Volpi Chiara Costanza , Martinetti Antonia , Battaglin Francesca , Bossi Ilaria , Pellegrinelli Alessio , Milione Massimo , Cremolini Chiara , Di Bartolomeo Maria , Bardelli Alberto , de Braud Filippo 
Published: October 2016

Abstract
Purpose: Even if RAS-BRAF wild-type and HER2/MET–negative metastatic colorectal cancer (mCRC) patients frequently respond to anti-EGFR mAbs, acquired resistance almost invariably occurs. Mechanisms of resistance to EGFR blockade include the emergence of KRAS, NRAS, and EGFR extracellular domain mutations as well as HER2/MET alterations. However, these findings derive from retrospective studies that analyzed one single resistance mechanism at a time; moreover, it is still unclear how molecular heterogeneity affects clonal evolution in patients. In this work, we aimed at extensively characterizing and correlating the molecular characteristics of tissue- and blood-based data in a prospective cohort of patients with mCRC who received anti-EGFR antibodies.
Experimental design: Twenty-two RAS-BRAF wild-type, HER2/MET–negative mCRC patients progressing on anti-EGFR therapy after initial response underwent rebiopsy. Next-generation sequencing and silver in situ hybridization (SISH)/IHC analyses were performed both on archival tumors and postprogression samples. Circulating tumor (ctDNA) molecular profiles were obtained in matched tissue–plasma samples.
Results: RAS mutations and HER2/MET amplification were the most frequently detected resistance mechanisms in both tissue and blood sample analysis. On the other hand, BRAF and EGFR ectodomain mutations were much rarer. Patients with acquired MET amplification showed worse PFS on anti-EGFRs. We detected both intralesion heterogeneity, as suggested by co-occurrence of different resistance mechanisms in the same sample, and interlesion heterogeneity. The combined analysis of tissue and blood (ctDNA) results highlights the complexity of clonal evolution triggered by EGFR blockade.
Conclusions: Our results indicate that it may be extremely challenging to target the complex landscape of molecular heterogeneity associated with emergence of resistance to targeted therapies in patients with mCRC. Clin Cancer Res; 23(10); 2414–22. ©2016 AACR.
Diversity and seasonality of polypore fungi in the moist deciduous forests of Peechi-Vazhani Wildlife Sanctuary, Kerala, India
Authors: Iqbal A. Muhammed , Vidyasagaran Kattany , Ganesh P. Narayan 
Published: October 2016

The objective of present study was to understand the diversity, distribution and seasonality of polypore fungi in the moist deciduous forests of Peechi-Vazhani Wildlife Sanctuary in three different seasons. Results obtained showed that density and frequency of occurrence have been varied significantly during different seasons and the community structure and species composition during monsoon and post monsoon seasons were distinct from pre-monsoon season. Fomitopsis feei with higher abundance values dominated the moist deciduous forests during monsoon season (17.72) and post-monsoon season (13.79). During pre-monsoon season, Daedalea flavida was the dominant species with abundance value of 10.93. The above fungi were predominant during all the seasons due to their high ecological amplitude. Fungal diversity analysis showed that species richness was higher during monsoon season and revealed the influence of seasonal variation on fungal diversity. The high species similarity was observed between monsoon and post monsoon season compared to pre-monsoon and monsoon.
Sucrose Nonfermenting-Related Kinase Enzyme–Mediated Rho-Associated Kinase Signaling is Responsible for Cardiac Function
Authors: Cossette Stephanie M. , Bhute Vijesh J. , Bao Xiaoping , Harmann Leanne M. , Horswill Mark A. , Sinha Indranil , Gastonguay Adam , Pooya Shabnam , Bordas Michelle , Kumar Suresh N. , Mirza Shama P. , Palecek Sean P. , Strande Jennifer L. , Ramchandran Ramani 
Published: October 2016

Background—

Cardiac metabolism is critical for the functioning of the heart, and disturbance in this homeostasis is likely to influence cardiac disorders or cardiomyopathy. Our laboratory has previously shown that SNRK (sucrose nonfermenting related kinase) enzyme, which belongs to the AMPK (adenosine monophosphate–activated kinase) family, was essential for cardiac metabolism in mammals.
Snrk
global homozygous knockout (KO) mice die at postnatal day 0, and conditional deletion of
Snrk
in cardiomyocytes (
Snrk
cmcKO) leads to cardiac failure and death by 8 to 10 months.

Methods and Results—

We performed additional cardiac functional studies using echocardiography and identified further cardiac functional deficits in
Snrk
cmcKO mice. Nuclear magnetic resonance-based metabolomics analysis identified key metabolic pathway deficits in
SNRK
knockdown cardiomyocytes in vitro. Specifically, metabolites involved in lipid metabolism and oxidative phosphorylation are altered, and perturbations in these pathways can result in cardiac function deficits and heart failure. A phosphopeptide-based proteomic screen identified ROCK (Rho-associated kinase) as a putative substrate for SNRK, and mass spec-based fragment analysis confirmed key amino acid residues on ROCK that are phosphorylated by SNRK. Western blot analysis on heart lysates from
Snrk
cmcKO adult mice and
SNRK
knockdown cardiomyocytes showed increased ROCK activity. In addition, in vivo inhibition of ROCK partially rescued the in vivo
Snrk
cmcKO cardiac function deficits.

Conclusions—
Collectively, our data suggest that SNRK in cardiomyocytes is responsible for maintaining cardiac metabolic homeostasis, which is mediated in part by ROCK, and alteration of this homeostasis influences cardiac function in the adult heart.
Guideline-Appropriate Care and In-Hospital Outcomes in Patients With Heart Failure in Teaching and Nonteaching Hospitals
Authors: Patel Dhavalkumar B. , Shah Rachit M. , Bhatt Deepak L. , Liang Li , Schulte Phillip J. , DeVore Adam D. , Hernandez Adrian F. , Heidenreich Paul A. , Yancy Clyde W. , Fonarow Gregg C. 
Published: October 2016

Background—
Despite increasing awareness regarding evidence-based guidelines, considerable gaps exist for heart failure (HF) quality of care at teaching hospitals (TH) and nonteaching hospitals (NTH). We analyzed data from Get With The Guidelines (GWTG)-HF to compare the rates and trends of guideline-recommended care at TH and NTH for patients with HF.

Method and Results—

Baseline patient characteristics, performance measures, and in-hospital outcomes were compared between 197 187 HF patients admitted to TH and 106 924 patients admitted to NTH between 2005 and 2014. Patients treated in TH were younger and were more likely to be black and uninsured. Defect-free care (defined as 100% compliance with performance measures) was similar in both group of hospitals (crude rates: 88% at TH versus 86% at NTH, adjusted odds ratio 0.99, 95% confidence interval 0.73–1.34) as were individual performance measures: discharge instruction, documentation of ejection fraction, use of angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists, use of β-blocker, and smoking cessation counseling. During the study period, there was improvement in adherence with performance measures over time, with no significant difference at TH (adjusted odds ratio 1.20, 95% confidence interval 1.11–1.30;
P
<0.01) and NTH (adjusted odds ratio 1.09, 95% confidence interval 1.02–1.17;
P
=0.01; interaction
P
value 0.07).

Conclusions—
Data from the GWTG-HF program suggest that there was improving and comparable adherence with HF performance measures and use of guideline-recommended therapies irrespective of hospital teaching status.
Children’s Rights in the European Court of Human Rights – An Emerging Power Structure
Authors: Jacobsen Anette Faye 
Published: October 2016

Legal research has shown mixed results regarding the application of a child-centred approach in judgments from the European Court of Human Rights. With an interdisciplinary perspective, however, a number of remarkable features become visible.This article explores case law from the European system with a blended methodology. First, a quantitative assessment of the Court’s judgments over the last decade reveals, surprisingly, that the child’s best interests doctrine has become widely used only recently, despite the principle being invoked as early as 1988. Secondly, an in-depth discourse analysis of selected landmark cases shows how the child-centred approach, in certain types of case, has gained status as the paramount consideration to the extent that it may sideline competing principles in the balancing exercise of adjudication. In the conclusion, the two types of enquiries, the statistical and the qualitative scrutiny of judgments, are combined to offer an assessment of the power of children’s rights alongside other interests in the European human rights machinery.
Typification of the Linnaean name Coreopsis alba, basionym of Bidens alba (Asteraceae)
Authors: FERRER-GALLEGO P. PABLO 
Published: October 2016

An illustration from Hermann’s Paradisus batavus (1698) is designated as the lectotype of the Linnaean name Coreopsis alba, basionym of the current name Bidens alba (L.) DC. (Asteraceae). An epitype is designated to make the taxonomic identity of the lectotype unambiguous.
Contributions of Moist Convection and Internal Gravity Waves to Building the Atmospheric −5/3 Kinetic Energy Spectra
Authors: Sun Y. Qiang , Rotunno Richard , Zhang Fuqing 
Published: October 2016

Abstract
With high-resolution mesoscale model simulations, the authors have confirmed a recent study demonstrating that convective systems, triggered in a horizontally homogeneous environment, are able to generate a background mesoscale kinetic energy spectrum with a slope close to −5/3, which is the observed value for the kinetic energy spectrum at mesoscales. This shallow slope can be identified at almost all height levels from the lower troposphere to the lower stratosphere in the simulations, implying a strong connection between different vertical levels. The present study also computes the spectral kinetic energy budget for these simulations to further analyze the processes associated with the creation of the spectrum. The buoyancy production generated by moist convection, while mainly injecting energy in the upper troposphere at small scales, could also contribute at larger scales, possibly as a result of the organization of convective cells into mesoscale convective systems. This latter injected energy is then transported by energy fluxes (due to gravity waves and/or convection) both upward and downward. Nonlinear interactions, associated with the velocity advection term, finally help build the approximate −5/3 slope through upscale and/or downscale propagation at all levels.