bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhanced basal late sodium current appears to underlie the age-related prolongation of action potential duration in guinea pig ventricular myocytes
Authors: Song Yejia , Belardinelli Luiz 
Published: January 2018

Aging hearts have prolonged QT interval and are vulnerable to oxidative stress. Because the QT interval indirectly reflects the action potential duration (APD), we examined the hypotheses that 1) the APD of ventricular myocytes increases with age; 2) the age-related prolongation of APD is due to an enhancement of basal late Na+ current ( INaL); and 3) inhibition of INaL may protect aging hearts from arrhythmogenic effects of hydrogen peroxide (H2O2). Experiments were performed on ventricular myocytes isolated from (young) 1-mo- and (old) 1-yr-old guinea pigs (GPs). The APD of myocytes from old GPs was significantly longer than that from young GPs and was shortened by the INaL inhibitors GS967 and tetrodotoxin. The magnitude of INaL was significantly larger in myocytes from old than from young GPs. The CaMKII inhibitors KN-93 and AIP and the NaV1.5-channel blocker methanethiosulfonate ethylammonium blocked the INaL. There were no significant differences between myocytes from young and old GPs in L-type Ca2+ current and the rapidly and slowly activating delayed rectifier K+ currents, although the inward rectifier K+ current was slightly decreased in myocytes from old GPs. H2O2 induced more early afterdepolarizations in myocytes from old than from young GPs. The effect of H2O2 was attenuated by GS967. The results suggest that 1) the APD of myocytes from old GPs is prolonged, 2) a CaMKII-mediated increase in NaV1.5-channel INaL is responsible for the prolongation of APD, and 3) inhibition of INaL may be beneficial for maintaining electrical stability under oxidative stress in myocytes of old GPs. NEW & NOTEWORTHY The action potential duration is significantly longer in ventricular myocytes from old than from young guinea pigs, which may explain, at the cellular level, the increase in QT interval with age. A CaMKII-mediated enhancement of NaV1.5-channel late current is responsible for the age-related prolongation of action potential duration. The enhanced basal late sodium current may predispose cardiac myocytes of old animals to oxidative stress and arrhythmogenesis.
Real-time particle filtering and smoothing algorithms for detecting abrupt changes in neural ensemble spike activity
Authors: Hu Sile , Zhang Qiaosheng , Wang Jing , Chen Zhe 
Published: January 2018

Sequential change-point detection from time series data is a common problem in many neuroscience applications, such as seizure detection, anomaly detection, and pain detection. In our previous work (Chen Z, Zhang Q, Tong AP, Manders TR, Wang J. J Neural Eng 14: 036023, 2017), we developed a latent state-space model, known as the Poisson linear dynamical system, for detecting abrupt changes in neuronal ensemble spike activity. In online brain-machine interface (BMI) applications, a recursive filtering algorithm is used to track the changes in the latent variable. However, previous methods have been restricted to Gaussian dynamical noise and have used Gaussian approximation for the Poisson likelihood. To improve the detection speed, we introduce non-Gaussian dynamical noise for modeling a stochastic jump process in the latent state space. To efficiently estimate the state posterior that accommodates non-Gaussian noise and non-Gaussian likelihood, we propose particle filtering and smoothing algorithms for the change-point detection problem. To speed up the computation, we implement the proposed particle filtering algorithms using advanced graphics processing unit computing technology. We validate our algorithms, using both computer simulations and experimental data for acute pain detection. Finally, we discuss several important practical issues in the context of real-time closed-loop BMI applications. NEW & NOTEWORTHY Sequential change-point detection is an important problem in closed-loop neuroscience experiments. This study proposes novel sequential Monte Carlo methods to quickly detect the onset and offset of a stochastic jump process that drives the population spike activity. This new approach is robust with respect to spike sorting noise and varying levels of signal-to-noise ratio. The GPU implementation of the computational algorithm allows for parallel processing in real time.
Location and phase effects for ocular and cervical vestibular-evoked myogenic potentials evoked by bone-conducted stimuli at midline skull sites
Authors: Govender Sendhil , Colebatch James G. 
Published: January 2018

Our object was to investigate the effect of location and phase on the properties of oVEMPs and cVEMPs evoked by two bone conducted (BC) stimuli, 500 Hz and an impulsive stimulus for midline skull sites from Nz to Iz, in normal volunteers. Compressive and rarefactive onset phases were used and the induced linear and rotational accelerations measured. We confirmed our previous finding of marked changes in the polarity of oVEMPs with location. For cVEMPs using the 500Hz stimulus there were few changes with location or phase, but the impulsive stimulus showed clear phase-related changes at several locations, with the shortest latencies occurring with compressive stimuli at AFz and Fz and the largest amplitudes at Iz. For oVEMPs, both stimuli showed clear effects of phase, with the shortest latencies with compressive stimuli at AFz and Fz and with the largest negativity at Oz or Iz. Whereas the effectiveness at Iz is consistent with a role in the linear VOR, the inversion of polarity and shorter latency around AFz and Fz is not and could not be explained by changes in acceleration of the head. The latency for BC 500Hz oVEMPs for AFz was the same as that for air-conducted (AC) stimuli. We suggest that whereas BC stimuli at most sites work through displacement of the otolith membrane, BC oVEMPs evoked at AFz and Fz may work through a direct action on utricular hair cells. Our findings have implications for clinical testing of VEMPs using midline BC stimuli. NEW & NOTEWORTHY We investigated VEMPs evoked from multiple midline skull sites. Large oVEMP responses were obtained with compressive stimuli at Iz, consistent with a role in the linear VOR, but we also showed inversion of polarity and the shortest latency for stimuli given at AFz and Fz. We propose that BC stimuli given at AFz and Fz may have a direct effect on otolith hair cells, whereas at other sites they work through displacement of the otolith membrane.
PD2/PAF1 at the Crossroads of the Cancer Network
Authors: Karmakar Saswati , Dey Parama , Vaz Arokia P. , Bhaumik Sukesh R. , Ponnusamy Moorthy P. , Batra Surinder K. 
Published: January 2018

Abstract
Pancreatic differentiation 2 (PD2)/RNA polymerase II–associated factor 1 (PAF1) is the core subunit of the human PAF1 complex (PAF1C) that regulates the promoter-proximal pausing of RNA polymerase II as well as transcription elongation and mRNA processing and coordinates events in mRNA stability and quality control. As an integral part of its transcription-regulatory function, PD2/PAF1 plays a role in posttranslational histone covalent modifications as well as regulates expression of critical genes of the cell-cycle machinery. PD2/PAF1 alone, and as a part of PAF1C, provides distinct roles in the maintenance of self-renewal of embryonic stem cells and cancer stem cells, and in lineage differentiation. Thus, PD2/PAF1 malfunction or its altered abundance is likely to affect normal cellular functions, leading to disease states. Indeed, PD2/PAF1 is found to be upregulated in poorly differentiated pancreatic cancer cells and has the capacity for neoplastic transformation when ectopically expressed in mouse fibroblast cells. Likewise, PD2/PAF1 is upregulated in pancreatic and ovarian cancer stem cells. Here, we concisely describe multifaceted roles of PD2/PAF1 associated with oncogenic transformation and implicate PD2/PAF1 as an attractive target for therapeutic development to combat malignancy. Cancer Res; 78(2); 313–9. ©2018 AACR.
O-GlcNAcylation of the Tumor Suppressor FOXO3 Triggers Aberrant Cancer Cell Growth
Authors: Shin Heon , Cha Hyun-Jeong , Na Keun , Lee Min Jung , Cho Jin-Young , Kim Chae-Yeon , Kim Eun Kyung , Kang Chang Moo , Kim Hoguen , Paik Young-Ki 
Published: January 2018

Abstract
Posttranslational modifications of tumor suppressors can induce abnormal cell growth. Here, we identify site-specific O-GlcNAcylation as a critical block of FOXO3 that may abrogate a part of the p53 pathway, resulting in aberrant cancer cell growth. Of seven O-GlcNAcylation sites identified within the FOXO3 transactivation domain, we found that changes in O-GlcNAcylation at Ser284 modulated p21-mediated cancer cell growth. Overexpression of either O-GlcNAcylated FOXO3 (FOX-OV) or a Ser-to-Ala mutant (S284A) in PANC-1 cells indicated that S284 O-GlcNAc acts as a critical block of the FOXO tumor suppressor and induces proliferation in PANC-1 cancer cells by stimulating the MDM2-p53-p21 axis. Furthermore, S284A mutant cells lacking S284 O-GlcNAc and FOX-OV cells exhibited opposing MDM2-p53-p21 axis expression patterns at both the mRNA and protein levels. Thus, our study provides evidence to support a role for S284 O-GlcNAc as a critical block of FOXO3 to induce subsequent cancer cell growth via abrogation of the p53 regulatory circuit.
Significance: These findings highlight a posttranslational mechanism for indirect abrogation of the p53 pathway, one that may occur with some frequency in human cancer cells. Cancer Res; 78(5); 1214–24. ©2018 AACR.
Genomic Correlates of Response to Everolimus in Aggressive Radioiodine-refractory Thyroid Cancer: A Phase II Study
Authors: Hanna Glenn J. , Busaidy Naifa L. , Chau Nicole G. , Wirth Lori J. , Barletta Justine A. , Calles Antonio , Haddad Robert I. , Kraft Stefan , Cabanillas Maria E. , Rabinowits Guilherme , O'Neill Anne , Limaye Sewanti A. , Alexander Erik K. , Moore Francis D. , Misiwkeiwicz Krystof , Thomas Tom , Nehs Matthew , Marqusee Ellen , Lee Stephanie L. , Jänne Pasi A. , Lorch Jochen H. 
Published: January 2018

Abstract
Purpose: Targeting mutations leading to PI3K/mTOR/Akt activation are of interest in thyroid cancer. We evaluated the efficacy of everolimus in aggressive, radioactive iodine–refractory (RAIR) thyroid cancer and correlated tumor mutational profiling with response. Exploratory medullary and anaplastic thyroid cancer cohorts were included.
Experimental Design: This single-arm, multi-institutional phase II study was conducted from 2009 to 2013 in patients with incurable RAIR thyroid cancer who had radiographic progression six months prior to enrollment. The primary endpoint was progression-free survival (PFS) with a median follow-up of 31.8 months. The study is closed to enrollment but treatment and follow-up are ongoing. A targeted next-generation sequencing platform was used for mutational analysis.
Results: Thirty-three patients with differentiated thyroid cancer (DTC), 10 with medullary thyroid cancer (MTC), and 7 with anaplastic thyroid cancer (ATC) enrolled. For the DTC cohort, median PFS was 12.9 months (95% CI, 7.3–18.5) with a 2-year PFS of 23.6% (95% CI, 10.5–39.5). Median OS was not reached; 2-year OS was 73.5% (95% CI, 53.8–85.8). Among ATC patients, 1 had a partial response and was progression-free until 17.9 months after study entry and one had disease stability for 26 months, respectively. The genomically profiled cohort enriched for PI3K/mTOR/Akt alterations. PI3K/mTOR/Akt–mutated ATC subgroups appeared to benefit from everolimus. Treatment-related adverse events were as anticipated.
Conclusions: Everolimus has significant antitumor activity in thyroid cancer. While genomic profiling does not currently guide therapeutic selection in thyroid cancer patients, these data have important implications when considering the use of an mTOR inhibitor in an era of precision medicine. Clin Cancer Res; 24(7); 1546–53. ©2018 AACR.
Expanded Genomic Profiling of Circulating Tumor Cells in Metastatic Breast Cancer Patients to Assess Biomarker Status and Biology Over Time (CALGB 40502 and CALGB 40503, Alliance)
Authors: Magbanua Mark Jesus M. , Rugo Hope S. , Wolf Denise M. , Hauranieh Louai , Roy Ritu , Pendyala Praveen , Sosa Eduardo V. , Scott Janet H. , Lee Jin Sun , Pitcher Brandelyn , Hyslop Terry , Barry William T. , Isakoff Steven J. , Dickler Maura , van't Veer Laura , Park John W. 
Published: January 2018

AbstractPurpose: We profiled circulating tumor cells (CTCs) to study the biology of blood-borne metastasis and to monitor biomarker status in metastatic breast cancer (MBC).Methods: CTCs were isolated from 105 patients with MBC using EPCAM-based immunomagnetic enrichment and fluorescence-activated cells sorting (IE/FACS), 28 of whom had serial CTC analysis (74 samples, 2–5 time points). CTCs were subjected to microfluidic-based multiplex QPCR array of 64 cancer-related genes (n = 151) and genome-wide copy-number analysis by array comparative genomic hybridization (aCGH; n = 49).Results: Combined transcriptional and genomic profiling showed that CTCs were 26% ESR1−ERBB2−, 48% ESR1+ERBB2−, and 27% ERBB2+. Serial testing showed that ERBB2 status was more stable over time compared with ESR1 and proliferation (MKI67) status. While cell-to-cell heterogeneity was observed at the single-cell level, with increasingly stable expression in larger pools, patient-specific CTC expression “fingerprints” were also observed. CTC copy-number profiles clustered into three groups based on the extent of genomic aberrations and the presence of large chromosomal imbalances. Comparative analysis showed discordance in ESR1/ER (27%) and ERBB2/HER2 (23%) status between CTCs and matched primary tumors. CTCs in 65% of the patients were considered to have low proliferation potential. Patients who harbored CTCs with high proliferation (MKI67) status had significantly reduced progression-free survival (P = 0.0011) and overall survival (P = 0.0095) compared with patients with low proliferative CTCs.Conclusions: We demonstrate an approach for complete isolation of EPCAM-positive CTCs and downstream comprehensive transcriptional/genomic characterization to examine the biology and assess breast cancer biomarkers in these cells over time. Clin Cancer Res; 24(6); 1486–99. ©2018 AACR.
Keeping Tumors Out of the MAPK Fitness Zone
Authors: Stern David F. 
Published: January 2018

Abstract
Summary: Greatest fitness of tumor cell subclones in patients undergoing MAPK-targeting therapies requires just-right levels of MAPK pathway signaling. New therapeutic approaches induce tumor cell death by intensifying MAPK signaling induced by inhibitor withdrawal in combination with DNA damage, or prevent selection of resistant clones with a steep fitness barrier imposed by triple combination of BRAF, MEK, and ERK inhibitors. Cancer Discov; 8(1); 20–3. ©2018 AACR.
See related article by Hong et al., p. 74.
Serotonin Transporter Gene (SLC6A4) Polymorphism May Be Associated with Chinese Globus Pharyngeus and Its Antidepressant Effects
Authors: Liu Yao , Jia Lin , Jiang Shu-man , Chen Dong-yun , Song Jiang-shun , Xu Jian 
Published: January 2018

Background: Although globus pharyngeus is not rare in clinical practice, little is known about its associated gene polymorphism. We investigated the association between the SLC6A4 polymorphism and globus pharyngeus and its response to treatment with antidepressants. Methods: A total of 84 patients were diagnosed with globus pharyngeus according to Rome III, and 160 healthy controls were genotyped for the SLC6A4 polymorphism using polymerase chain reaction amplification and agarose gel electrophoresis. All patients with globus were studied using high-resolution manometry pre-therapy. Globus patients were randomized into paroxetine or amitriptyline groups for a 6-week treatment and asked to complete the following pre- and post-therapy questionnaires: the Glasgow Edinburgh Throat Scale (GETS), the Pittsburgh Sleep Quality Index, and the Hamilton Rating Scale Anxiety/Depression. Treatment response was defined as a >50% reduction in the GETS scores. Results: A significant difference was observed in the globus S/S genotype with anxiety compared to that without anxiety (χ2 = 14.579, p = 0.006). The L/S genotype showed a significant difference between high upper esophageal sphincter pressure (>104 mm Hg) and non-high upper esophageal sphincter pressure patients (χ2 = 14.433, p = 0.006). A significant association between the S/S genotype and the response to antidepressant treatment was also observed, while patients with sleep disorders or depression showed no association. Conclusion: A significant association was observed between the S/S genotype of the SLC6A4 polymorphism and globus pharyngeus, suggesting that SLC6A4 is a potential candidate gene involved in the pathogenesis of globus pharyngeus.
Efficacy of Reduced Dosage of Amoxicillin in an Eradication Therapy for Helicobacter pylori Infection in Patients on Hemodialysis: A Randomized Controlled Trial
Authors: Sahara Shu , Sugimoto Mitsushige , Ichikawa Hitomi , Kagami Takuma , Sakao Yukitoshi , Ohashi Naro , Horio Yoshiaki , Sugimoto Ken , Kato Akihiko , Furuta Takahisa , Yasuda Hideo 
Published: January 2018

Background: An optimum Helicobacter pylori-eradication regimen for hemodialysis patients is yet to be established because of different pharmacokinetics of amoxicillin involved between hemodialysis patients and healthy subjects. We investigated to establish appropriate doses of amoxicillin for H. pylori infection eradication in hemodialysis patients. Methods: Of 409 hemodialysis patients screened for H. pylori infection, 37 H. pylori-positive patients were randomized to different 1-week eradication regimens: esomeprazole 20 mg twice a day (b.i.d.) and clarithromycin 200 mg b.i.d., plus amoxicillin at either 750 mg b.i.d. (group A; conventional) or 250 mg b.i.d. (group B; experimental). Sixty-three patients with normal renal function received the conventional regimen (group C). Successful eradication was confirmed by urea breath testing. Results: Eradication rates of group B (reduced amoxicillin-regimen) were 84.2% in intention-to-treat analysis and 88.9% in per-protocol analysis, which were similar with group A (77.8 and 77.8%) and group C (74.6 and 81.0%). However, the incidence of adverse events in group A was significantly higher than that in group C (22.2 vs. 5.1%, p = 0.027). Conclusions: In H. pylori-positive hemodialysis patients, amoxicillin at 250 mg b.i.d. may be an appropriate scheme for eradication with equivalent effects to the conventional therapy and safety effects for adverse events.
Vonoprazan is Superior to Rabeprazole for Healing Endoscopic Submucosal Dissection: Induced Ulcers
Authors: Yamasaki Akira , Yoshio Toshiyuki , Muramatsu Yusuke , Horiuchi Yusuke , Ishiyama Akiyoshi , Hirasawa Toshiaki , Tsuchida Tomohiro , Sasaki Yutaka , Fujisaki Junko 
Published: January 2018

Background and Aims: Endoscopic submucosal dissection (ESD) is a well-established minimally invasive treatment for early gastric cancer. To heal ESD-induced ulcers, we commonly prescribe proton pump inhibitors (PPIs). Vonoprazan is our new choice, which is reported to have a stronger and longer acid inhibitory effect than existing PPIs. Here, we aimed to evaluate the efficacy of vonoprazan for healing ESD-induced ulcers compared with rabeprazole. Methods: We reviewed 190 patients who underwent ESD before and after we switched the acid secretion inhibitor from rabeprazole to vonoprazan. We evaluated scarring and reduction rates at 4 weeks after ESD. Results: Scarring rates were not different between vonoprazan and rabeprazole (31.7 vs. 18.9%; p = 0.07). However, for ulcers ≤35 mm, vonoprazan was superior to rabeprazole (42.2 vs. 19.2%; p < 0.05). Reduction rates were superior for vonoprazan compared with rabeprazole (93.0 vs. 90.4%; p < 0.05). In multivariate analysis, vonoprazan was superior to rabeprazole for ulcer scarring (OR 2.21; p < 0.05), and ulcer location in the lower-third of the stomach had higher risk of incomplete scarring (OR 0.37; p < 0.05). Conclusion: Vonoprazan was superior to rabeprazole for healing ESD-induced ulcers.
Cardiac Endothelial Cell Transcriptome
Authors: Lother Achim , Bergemann Stella , Deng Lisa , Moser Martin , Bode Christoph , Hein Lutz 
Published: January 2018

Objective—
Endothelial cells (ECs) are a highly specialized cell type with marked diversity between different organs or vascular beds. Cardiac ECs are an important player in cardiac physiology and pathophysiology but are not sufficiently characterized yet. Thus, the aim of the present study was to analyze the cardiac EC transcriptome.

Approach and Results—

We applied fluorescence-assisted cell sorting to isolate pure ECs from adult mouse hearts. RNAseq revealed 1288 genes predominantly expressed in cardiac ECs versus heart tissue including several transcription factors. We found an overrepresentation of corresponding transcription factor binding motifs within the promotor region of EC-enriched genes, suggesting that they control the EC transcriptome. Cardiac ECs exhibit a distinct gene expression profile when compared with renal, cerebral, or pulmonary ECs. For example, we found the
Meox2
/
Tcf15, Fabp4
, and
Cd36
signaling cascade higher expressed in cardiac ECs which is a key regulator of fatty acid uptake and involved in the development of atherosclerosis.

Conclusions—
The results from this study provide a comprehensive resource of gene expression and transcriptional control in cardiac ECs. The cardiac EC transcriptome exhibits distinct differences in gene expression compared with other cardiac cell types and ECs from other organs. We identified new candidate genes that have not been investigated in ECs yet as promising targets for future evaluation.
Endogenous LINE-1 (Long Interspersed Nuclear Element-1) Reverse Transcriptase Activity in Platelets Controls Translational Events Through RNA–DNA Hybrids
Authors: Schwertz Hansjörg , Rowley Jesse W. , Schumann Gerald G. , Thorack Ulrike , Campbell Robert A. , Manne Bhanu Kanth , Zimmerman Guy A. , Weyrich Andrew S. , Rondina Matthew T. 
Published: January 2018

Objective—
One source of endogenous reverse transcriptase (eRT) activity in nucleated cells is the LINE-1/L1 (long interspersed nuclear element-1), a non-LTR retrotransposon that is implicated in the regulation of gene expression. Nevertheless, the presence and function of eRT activity and LINE-1 in human platelets, an anucleate cell, has not previously been determined.

Approach and Results—
We demonstrate that human and murine platelets possess robust eRT activity and identify the source as being LINE-1 ribonucleoprotein particles. Inhibition of eRT in vitro in isolated platelets from healthy individuals or in people with HIV treated with RT inhibitors enhanced global protein synthesis and platelet activation. If HIV patients were treated with reverse transcriptase inhibitor, we found that platelets from these patients had increased basal activation. We next discovered that eRT activity in platelets controlled the generation of RNA–DNA hybrids, which serve as translational repressors. Inhibition of platelet eRT lifted this RNA–DNA hybrid-induced translational block and was sufficient to increase protein expression of target RNAs identified by RNA–DNA hybrid immunoprecipitation.

Conclusions—
Thus, we provide the first evidence that platelets possess L1-encoded eRT activity. We also demonstrate that platelet eRT activity regulates platelet hyperreactivity and thrombosis and controls RNA–DNA hybrid formation and identify that RNA–DNA hybrids function as a novel translational control mechanism in human platelets.