bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sympathetic modulation of electrical activation in normal and infarcted myocardium: implications for arrhythmogenesis
Authors: Ajijola Olujimi A. , Lux Robert L. , Khahera Anadjeet , Kwon OhJin , Aliotta Eric , Ennis Daniel B. , Fishbein Michael C. , Ardell Jeffrey L. , Shivkumar Kalyanam 
Published: January 2017

The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n = 12) or anterior myocardial infarction (MI, n = 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CVL) was increased by RSGS (0.98 ± 0.11 vs. 1.2 ± 0.14m/s, P < 0.001) but not transverse CV (CVT). This increase was abrogated by β-adrenergic receptor and gap junction (GJ) blockade. Neither CVL nor CVT was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 ± 37 vs. 322 ± 30 ms, P < 0.001, and 423 ± 36 vs. 398 ± 36 ms, P = 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 ± 1.2 vs. 17.3 ± 1.6 ms, P = 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals ( P < 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic peri-infarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis. NEW & NOTEWORTHY This study demonstrates regional control of conduction velocity in normal hearts by sympathetic nerves. In infarcted hearts, however, not only is modulation of propagation heterogeneous, some regions showed paradoxical conduction slowing. Sympathoexcitation altered propagation in all infarcted hearts studied, and we describe the temporal arrhythmogenic potential of these findings. Listen to this article’s corresponding podcast at http://ajpheart.podbean.com/e/sympathetic-nerves-and-cardiac-propagation/ .
A Multifunctional Role for Adjuvant Anti-4-1BB Therapy in Augmenting Antitumor Response by Chimeric Antigen Receptor T Cells
Authors: Mardiana Sherly , John Liza B. , Henderson Melissa A. , Slaney Clare Y. , von Scheidt Bianca , Giuffrida Lauren , Davenport Alexander J. , Trapani Joseph A. , Neeson Paul J. , Loi Sherene , Haynes Nicole M. , Kershaw Michael H. , Beavis Paul A. , Darcy Phillip K. 
Published: January 2017

Abstract
Adoptive immunotherapy utilizing chimeric antigen receptor (CAR) T cells has demonstrated high success rates in hematologic cancers, but results against solid malignancies have been limited to date, due in part to the immunosuppressive tumor microenvironment. Activation of the 4-1BB (CD137) pathway using an agonistic α-4-1BB antibody is known to provide strong costimulatory signals for augmenting and diversifying T-cell responses. We therefore hypothesized that a combination of α-4-1BB and CAR T-cell therapy would result in improved antitumor responses. Using a human-Her2 self-antigen mouse model, we report here that α-4-1BB significantly enhanced CAR T-cell efficacy directed against the Her2 antigen in two different established solid tumor settings. Treatment also increased the expression of IFNγ and the proliferation marker Ki67 in tumor-infiltrating CAR T cells when combined with α-4-1BB. Strikingly, α-4-1BB significantly reduced host immunosuppressive cells at the tumor site, including regulatory T cells and myeloid-derived suppressor cells, correlating with an increased therapeutic response. We conclude that α-4-1BB has a multifunctional role for enhancing CAR T-cell responses and that this combination therapy has high translational potential, given current phase I/II clinical trials with α-4-1BB against various types of cancer. Cancer Res; 77(6); 1296–309. ©2017 AACR.
SRSF2 Regulates Alternative Splicing to Drive Hepatocellular Carcinoma Development
Authors: Luo Chunling , Cheng Yuanming , Liu Yuguo , Chen Linlin , Liu Lina , Wei Ning , Xie Zhiqin , Wu Wenwu , Feng Ying 
Published: January 2017

Abstract
Aberrant RNA splicing is recognized to contribute to cancer pathogenesis, but the underlying mechanisms remain mainly obscure. Here, we report that the splicing factor SRSF2 is upregulated frequently in human hepatocellular carcinoma (HCC), where this event is associated with poor prognosis in patients. RNA-seq and other molecular analyses were used to identify SRSF2-regulated alternative splicing events. SRSF2 binding within an alternative exon was associated with its inclusion in the RNA, whereas SRSF2 binding in a flanking constitutive exon was associated with exclusion of the alternative exon. Notably, cancer-associated splice variants upregulated by SRSF2 in clinical specimens of HCC were found to be crucial for pathogenesis and progression in hepatoma cells, where SRSF2 expression increased cell proliferation and tumorigenic potential by controlling expression of these variants. Our findings identify SRSF2 as a key regulator of RNA splicing dysregulation in cancer, with possible clinical implications as a candidate prognostic factor in patients with HCC. Cancer Res; 77(5); 1168–78. ©2017 AACR.
Superior Efficacy and Selectivity of Novel Small-Molecule Kinase Inhibitors of T790M-Mutant EGFR in Preclinical Models of Lung Cancer
Authors: Rho Jin Kyung , Lee In Yong , Choi Yun Jung , Choi Chang-Min , Hur Jae-Young , Koh Jong Sung , Lee Jaekyoo , Suh Byung-Chul , Song Ho-Juhn , Salgaonkar Paresh , Lee Jungmi , Lee Jaesang , Jung Dong Sik , Kim Sang-Yeob , Woo Dong-Cheol , Baek In-Jeoung , Lee Joo-Yong , Ha Chang Hoon , Sung Young Hoon , Kim Jeong Kon , Kim Woo Sung , Song Joon Seon , Kim Cheol Hyeon , Bivona Trever G. , Lee Jae Cheol 
Published: January 2017

Abstract
The clinical utility of approved EGFR small-molecule kinase inhibitors is plagued both by toxicity against wild-type EGFR and by metastatic progression in the central nervous system, a disease sanctuary site. Here, we report the discovery and preclinical efficacy of GNS-1486 and GNS-1481, two novel small-molecule EGFR kinase inhibitors that are selective for T790M-mutant isoforms of EGFR. Both agents were effective in multiple mouse xenograft models of human lung adenocarcinoma (T790M-positive or -negative), exhibiting less activity against wild-type EGFR than existing approved EGFR kinase inhibitors (including osimertinib). In addition, GNS-1486 showed superior potency against intracranial metastasis of EGFR-mutant lung adenocarcinoma. Our results offer a preclinical proof of concept for new EGFR kinase inhibitors with the potential to improve therapeutic index and efficacy against brain metastases in patients. Cancer Res; 77(5); 1200–11. ©2017 AACR.
ARF Confers a Context-Dependent Response to Chemotherapy in Muscle-Invasive Bladder Cancer
Authors: Owczarek Tomasz B. , Kobayashi Takashi , Ramirez Ricardo , Rong Lijie , Puzio-Kuter Anna M. , Iyer Gopa , Teo Min Yuen , Sánchez-Vega Francisco , Wang Jingqiang , Schultz Nikolaus , Zheng Tian , Solit David B. , Al-Ahmadie Hikmat A. , Abate-Shen Cory 
Published: January 2017

AbstractMuscle-invasive bladder cancer (MIBC) generally responds poorly to treatment and tends to exhibit significant mortality. Here we show that expression of the tumor suppressor p14ARF (ARF) is upregulated in aggressive subtypes of MIBC. Accumulation of ARF in the nucleolus is associated with poor outcome and attenuated response to chemotherapy. In both genetically engineered mouse models and murine xenograft models of human MIBC, we demonstrate that tumors expressing ARF failed to respond to treatment with the platinum-based chemotherapy agent cisplatin. Resistance was mediated in part by the integrin-binding protein ITGB3BP (CENPR) and reflected ARF-dependent impairment of protein translation, which was exaggerated by drug treatment. Overall, our results highlight a context-dependent role for ARF in modulating the drug response of bladder cancer. Cancer Res; 77(4); 1035–46. ©2017 AACR.
Serum Metabolomic Profiles Identify ER-Positive Early Breast Cancer Patients at Increased Risk of Disease Recurrence in a Multicenter Population
Authors: Hart Christopher D. , Vignoli Alessia , Tenori Leonardo , Uy Gemma Leonora , Van To Ta , Adebamowo Clement , Hossain Syed Mozammel , Biganzoli Laura , Risi Emanuela , Love Richard R. , Luchinat Claudio , Di Leo Angelo 
Published: January 2017

AbstractPurpose: Detecting signals of micrometastatic disease in patients with early breast cancer (EBC) could improve risk stratification and allow better tailoring of adjuvant therapies. We previously showed that postoperative serum metabolomic profiles were predictive of relapse in a single-center cohort of estrogen receptor (ER)–negative EBC patients. Here, we investigated this further using preoperative serum samples from ER-positive, premenopausal women with EBC who were enrolled in an international phase III trial.Experimental Design: Proton nuclear magnetic resonance (NMR) spectroscopy of 590 EBC samples (319 with relapse or ≥6 years clinical follow-up) and 109 metastatic breast cancer (MBC) samples was performed. A Random Forest (RF) classification model was built using a training set of 85 EBC and all MBC samples. The model was then applied to a test set of 234 EBC samples, and a risk of recurrence score was generated on the basis of the likelihood of the sample being misclassified as metastatic.Results: In the training set, the RF model separated EBC from MBC with a discrimination accuracy of 84.9%. In the test set, the RF recurrence risk score correlated with relapse, with an AUC of 0.747 in ROC analysis. Accuracy was maximized at 71.3% (sensitivity, 70.8%; specificity, 71.4%). The model performed independently of age, tumor size, grade, HER2 status and nodal status, and also of Adjuvant! Online risk of relapse score.Conclusions: In a multicenter group of EBC patients, we developed a model based on preoperative serum metabolomic profiles that was prognostic for disease recurrence, independent of traditional clinicopathologic risk factors. Clin Cancer Res; 23(6); 1422–31. ©2017 AACR.
Association of Rapid Care Process Implementation on Reperfusion Times Across Multiple ST-Segment–Elevation Myocardial Infarction Networks
Authors: Fordyce Christopher B. , Al-Khalidi Hussein R. , Jollis James G. , Roettig Mayme L. , Gu Joan , Bagai Akshay , Berger Peter B. , Corbett Claire C. , Dauerman Harold L. , Fox Kathleen , Garvey J. Lee , Henry Timothy D. , Rokos Ivan C. , Sherwood Matthew W. , Wilson B. Hadley , Granger Christopher B. 
Published: January 2017

Background—
The Mission: Lifeline STEMI Systems Accelerator program, implemented in 16 US metropolitan regions, resulted in more patients receiving timely reperfusion. We assessed whether implementing key care processes was associated with system performance improvement.

Methods and Results—

Hospitals (n=167 with 23 498 ST-segment–elevation myocardial infarction patients) were surveyed before (March 2012) and after (July 2014) program intervention. Data were merged with patient-level clinical data over the same period. For reperfusion, hospitals were grouped by whether a specific process of care was implemented, preexisting, or never implemented. Uptake of 4 key care processes increased after intervention: prehospital catheterization laboratory activation (62%–91%;
P
<0.001), single call transfer protocol from an outside facility (45%–70%;
P
<0.001), and emergency department bypass for emergency medical services direct presenters (48%–59%;
P
=0.002) and transfers (56%–79%;
P
=0.001). There were significant differences in median first medical contact-to-device times among groups implementing prehospital activation (88 minutes implementers versus 89 minutes preexisting versus 98 minutes nonimplementers;
P
<0.001 for comparisons). Similarly, patients treated at hospitals implementing single call transfer protocols had shorter median first medical contact-to-device times (112 versus 128 versus 152 minutes;
P
<0.001). Emergency department bypass was also associated with shorter median first medical contact-to-device times for emergency medical services direct presenters (84 versus 88 versus 94 minutes;
P
<0.001) and transfers (123 versus 127 versus 167 minutes;
P
<0.001).

Conclusions—
The Accelerator program increased uptake of key care processes, which were associated with improved system performance. These findings support efforts to implement regional ST-segment–elevation myocardial infarction networks focused on prehospital catheterization laboratory activation, single call transfer protocols, and emergency department bypass.
Zaimek wskazujący w zdaniach z orzeczeniem imiennym: funkcja predykatywna czy anaforyczna?
Authors: Kiklewicz Aleksander 
Published: January 2017

Demonstrative pronoun in sentences with nominal predicate: predicative or anaphor function?This article deals with a particular type of simple sentences with a complex predicate which includes the demonstrative pronoun Pol. to / Russ. это ‘this.’ The author presents the view, prevailing in the linguistic literature, that in terms of syntactic structure, such units perform the role of the so-called copula. The analysis of linguistic material of modern Russian and Polish (taking into account the category of functional syntax) leads to the conclusion that such instances are in fact cases of subject duplication, which is used to emphasise the subject in spoken language. Zaimek wskazujący w zdaniach z orzeczeniem imiennym: funkcja predykatywna czy anaforyczna?Przedmiotem artykułu jest szczególny typ zdań prostych z orzeczeniem złożonym zawierającym zaimek wskazujący to/это. Autor przedstawia panujący w literaturze lingwistycznej pogląd, że jednostka ta zajmuje w strukturze zdania pozycję tzw. łącznika (copuli). Z analizy materiału językowego współczesnego języka polskiego (przy uwzględnieniu kategorii składni funkcjonalnej) wynika, że w rzeczywistości mamy tu do czynienia z duplikacją podmiotu, która służy do emfatycznego wyodrębnienia tego członu zdania w mowie.
Isolating the Atmospheric Circulation Response to Arctic Sea Ice Loss in the Coupled Climate System
Authors: Blackport Russell , Kushner Paul J. 
Published: January 2017

Abstract
In this study, coupled ocean–atmosphere–land–sea ice Earth system model (ESM) simulations driven separately by sea ice albedo reduction and by projected greenhouse-dominated radiative forcing are combined to cleanly isolate the sea ice loss response of the atmospheric circulation. A pattern scaling approach is proposed in which the local multidecadal mean atmospheric response is assumed to be separately proportional to the total sea ice loss and to the total low-latitude ocean surface warming. The proposed approach estimates the response to Arctic sea ice loss with low-latitude ocean temperatures fixed and vice versa. The sea ice response includes a high northern latitude easterly zonal wind response, an equatorward shift of the eddy-driven jet, a weakening of the stratospheric polar vortex, an anticyclonic sea level pressure anomaly over coastal Eurasia, a cyclonic sea level pressure anomaly over the North Pacific, and increased wintertime precipitation over the west coast of North America. Many of these responses are opposed by the response to low-latitude surface warming with sea ice fixed. However, both sea ice loss and low-latitude surface warming act in concert to reduce subseasonal temperature variability throughout the middle and high latitudes. The responses are similar in two related versions of the National Center for Atmospheric Research Earth system models, apart from the stratospheric polar vortex response. Evidence is presented that internal variability can easily contaminate the estimates if not enough independent climate states are used to construct them.
Evaluation and Error Analysis of Official Forecasts of Tropical Cyclones during 2005–14 over the Western North Pacific. Part I: Storm Tracks
Authors: Peng Xudong , Fei Jianfang , Huang Xiaogang , Cheng Xiaoping 
Published: January 2017

Abstract
Official forecasts of tropical cyclone (TC) tracks issued by the China Meteorological Administration (CMA); the Regional Specialized Meteorological Centre in Tokyo, Japan; and the Joint Typhoon Warning Center (JTWC) were used to evaluate the accuracies, biases, and trends of TC track forecasts during 2005–14 over the western North Pacific. Overall, the JTWC demonstrated the best forecasting performance. However, the CMA showed the most significant rate of improvement. Two main zones were discovered in the regional distribution of forecast errors: a low-latitude zone that comprises the South China Sea and the sea region east of the Philippines, and a midlatitude zone comprising the southern Sea of Japan and the sea region east of Japan. When TCs moved into the former zone, there were both translational speed and direction biases in the forecast tracks, whereas slow biases were predominated in the latter zone. Twelve synoptic flow patterns of TCs with the largest error have been identified based on the steering flow theory. Among them, the most two common pattern are the pattern with the combination of cyclonic circulations, subtropical ridges, and midlatitude troughs (CRT, 26 TCs), and the pattern of the TCs’ track that cannot be explained by steering flow (NSF, 6 TCs). In the CRT pattern, TCs move northwestward forced by the cyclonic circulations and the subtropical ridges and then turn poleward and eastward under the influence of the midlatitude troughs. In the NSF pattern, storms embedded in the southwest flow by the cyclonic circulation and the steering flow suggest TCs should turn to the right and move northeastward but instead TCs persisted in moving northwestward.
Some Thoughts on the Psychoanalytic Situation
Authors: Chasseguet-Smirgel Janine 
Published: January 2017

This article develops ideas set out in a previous study on the “archaic matrix of the Oedipus complex” versus the fully developed Oedipus complex (their similarities and their differences), applying these to a study of the psychoanalytic situation. The central hypothesis is that there is a correspondence between the psychoanalytic situation and the structure of the mental apparatus. The author supposes that our perception of the world is intimately linked to the primary maternal relationship, to our wish to fuse with the mother once more, and to the accompanying fear such a wish inspires. To deal with this we create enclaves where the regressive wish can be satisfied without fear of ego dissolution. The author suggests that the psychoanalytic situation is one such enclave. She examines its specific features in the light of the structure of the mental apparatus as she defines it.
Model Scenes: Implications for Psychoanalytic Treatment
Authors: Lachmann Frank M. , Lichtenberg Joseph 
Published: January 2017

Model scenes are constructed by analyst and patient to organize puzzling information, integrate previous understanding, and initiate further exploration of experience. They are derived from a variety of sources: literature (oedipal myth); transference; ordinary or traumatic childhood events that occupy a pivotal position. Model scenes may conceptualize experiences of any age and motivational system, and are contrasted with screen memories and “telescoping” of events. Two clinical examples are used to illustrate the relation between the model scene and the transference. Model scenes provide a valuable clinical tool for moving from general to specific experience. They afford empathic entry into the transference experience and the opportunity through which the experience of motivations representative of past and present can be conceptualized and integrated into a cohesive self organization.
Use of Ultrasonic Shears in the Harvest of the Free Osteocutaneous Fibula Flap
Authors: Burton Jon N. , El-Deiry Mark W. 
Published: January 2017

Objective: Traditionally, the fibula free flap has been raised by electrocautery and sharp dissection with clipping and tying of vessels. Use of the ultrasonic scalpel has been proposed to be a faster, more hemostatic, and less traumatic method of harvest. Methods: We performed a retrospective chart review of 58 patients who underwent fibula free flap reconstruction between 2007 and 2010. The main outcome measures were blood loss, operative time, and flap harvest time. Results: Use of the ultrasonic shears was not associated with a statistically significant reduction in intraoperative blood loss, operative time, or flap harvest time. However, the flap harvest time did trend toward statistical significance (p = 0.073). Use of distribution-based effect sizes demonstrated a moderate clinically important difference in favor of the ultrasonic shears for both operative time and flap harvest time. Conclusions: The use of ultrasonic shears is comparable to traditional methods of fibula free flap harvest and can be considered an alternative method of harvest.
Nasal Resonance in Middle-Aged Women: A Multiparameter Approach
Authors: D'haeseleer Evelien , Depypere Herman , Claeys Sofie , Lierde Kristiane M. Van 
Published: January 2017

Objectives: Aging influences several speech characteristics in middle-aged women. However, the effect of aging on nasal resonance has not been widely investigated, and findings are contradictory. The purpose of this study was to investigate the effect of aging on nasal resonance by comparing young women (between 20 and 28 years of age) with middle-aged women (between 45 and 55 years of age). Methods: Thirty-one middle-aged women with a mean age of 48 years participated in the subject group. The control group consisted of 22 young women with a mean age of 23 years. To investigate nasal resonance, we used a multiparameter approach by means of the Nasal Severity Index (NSI). Objective acoustic (nasal resonance scores of sounds and connected speech measured with the Nasometer) and aerodynamic measurements (maximum duration time of /s/, vital capacity, and mirror fogging test), as well as perceptual evaluations (Gutzmann /a/-/i/ test), were performed. Results: The results of this study showed no differences in aerodynamic measurements and nasal resonance scores of connected speech and the sounds /i/, /u/, and /m/. Only the mean nasal resonance score of /a/ and the Gutzmann /a/ test were significantly different between the young and middle-aged women. The mean (±SD) NSI scores of the young women (12.93 ± 17.9) and the middle-aged women (-1.49 ± 14.4) both corresponded to normal nasal resonance. Conclusions: The results of this study indicate that both young and middle-aged women show a normal nasal resonance. Differences in objective and subjective measurements of nasal resonance were only found in isolated vowels, and not in connected speech.