bluuebunny/crossref_metadata_2025_split huggingface dataset:
Intra- and interregional cortical interactions related to sharp-wave ripples and dentate spikes
Authors: Headley Drew B. , Kanta Vasiliki , Paré Denis 
Published: November 2016

The hippocampus generates population events termed sharp-wave ripples (SWRs) and dentate spikes (DSs). While little is known about DSs, SWR-related hippocampal discharges during sleep are thought to replay prior waking activity, reactivating the cortical networks that encoded the initial experience. During slow-wave sleep, such reactivations likely occur during up-states, when most cortical neurons are depolarized. However, most studies have examined the relationship between SWRs and up-states measured in single neocortical regions. As a result, it is currently unclear whether SWRs are associated with particular patterns of widely distributed cortical activity. Additionally, no such investigation has been carried out for DSs. The present study addressed these questions by recording SWRs and DSs from the dorsal hippocampus simultaneously with prefrontal, sensory (visual and auditory), perirhinal, and entorhinal cortices in naturally sleeping rats. We found that SWRs and DSs were associated with up-states in all cortical regions. Up-states coinciding with DSs and SWRs exhibited increased unit activity, power in the gamma band, and intraregional gamma coherence. Unexpectedly, interregional gamma coherence rose much more strongly in relation to DSs than to SWRs. Whereas the increase in gamma coherence was time locked to DSs, that seen in relation to SWRs was not. These observations suggest that SWRs are related to the strength of up-state activation within individual regions throughout the neocortex but not so much to gamma coherence between different regions. Perhaps more importantly, DSs coincided with stronger periods of interregional gamma coherence, suggesting that they play a more important role than previously assumed.NEW & NOTEWORTHY Off-line cortico-hippocampal interactions are thought to support memory consolidation. We surveyed the relationship between hippocampal sharp-wave ripples (SWRs) and dentate spikes (DSs) with up-states across multiple cortical regions. SWRs and DSs were associated with increased cortical gamma oscillations. Interregional gamma coherence rose much more strongly in relation to DSs than to SWRs. Moreover, it was time locked to DSs but not SWRs. These results have important implications for current theories of systems memory consolidation during sleep.
Diaphragm electromyographic activity following unilateral midcervical contusion injury in rats
Authors: Rana Sabhya , Sieck Gary C. , Mantilla Carlos B. 
Published: November 2016

Contusion-type injuries to the spinal cord are characterized by tissue loss and disruption of spinal pathways. Midcervical spinal cord injuries impair the function of respiratory muscles and may contribute to significant respiratory complications. This study systematically assessed the impact of a 100-kDy unilateral C4 contusion injury on diaphragm muscle activity across a range of motor behaviors in rats. Chronic diaphragm electromyography (EMG) was recorded before injury and at 1 and 7 days postinjury (DPI). Histological analyses assessed the extent of perineuronal net formation, white-matter sparing, and phrenic motoneuron loss. At 7 DPI, ∼45% of phrenic motoneurons were lost ipsilaterally. Relative diaphragm root mean square (RMS) EMG activity increased bilaterally across a range of motor behaviors by 7 DPI. The increase in diaphragm RMS EMG activity was associated with an increase in neural drive (RMS value at 75 ms after the onset of diaphragm activity) and was more pronounced during higher force, nonventilatory motor behaviors. Animals in the contusion group displayed a transient decrease in respiratory rate and an increase in burst duration at 1 DPI. By 7 days, following midcervical contusion, there was significant perineuronal net formation and white-matter loss that spanned 1 mm around the injury epicenter. Taken together, these findings are consistent with increased recruitment of remaining motor units, including more fatigable, high-threshold motor units, during higher force, nonventilatory behaviors. Changes in diaphragm EMG activity following midcervical contusion injury reflect complex adaptations in neuromotor control that may increase the risk of motor-unit fatigue and compromise the ability to sustain higher force diaphragm efforts.NEW & NOTEWORTHY The present study shows that unilateral contusion injury at C4 results in substantial loss of phrenic motoneurons but increased diaphragm muscle activity across a range of ventilatory and higher force, nonventilatory behaviors. Measures of neural drive indicate increased descending input to phrenic motoneurons that was more pronounced during higher force, nonventilatory behaviors. These findings reveal novel, complex adaptations in neuromotor control following injury, suggestive of increased recruitment of more fatigable, high-threshold motor units.
The Prognostic Role of Androgen Receptor in Patients with Early-Stage Breast Cancer: A Meta-analysis of Clinical and Gene Expression Data
Authors: Bozovic-Spasojevic Ivana , Zardavas Dimitrios , Brohée Sylvain , Ameye Lieveke , Fumagalli Debora , Ades Felipe , de Azambuja Evandro , Bareche Yacine , Piccart Martine , Paesmans Marianne , Sotiriou Christos 
Published: November 2016

Abstract
Purpose: Androgen receptor (AR) expression has been observed in about 70% of patients with breast cancer, but its prognostic role remains uncertain.
Experimental Design: To assess the prognostic role of AR expression in early-stage breast cancer, we performed a meta-analysis of studies that evaluated the impact of AR at the protein and gene expression level on disease-free survival (DFS) and/or overall survival (OS). Eligible studies were identified by systematic review of electronic databases using the MeSH-terms “breast neoplasm” and “androgen receptor” and were selected after a qualitative assessment based on the REMARK criteria. A pooled gene expression analysis of 35 publicly available microarray data sets was also performed from patients with early-stage breast cancer with available gene expression and clinical outcome data.
Results: Twenty-two of 33 eligible studies for the clinical meta-analysis, including 10,004 patients, were considered as evaluable for the current study after the qualitative assessment. AR positivity defined by IHC was associated with improved DFS in all patients with breast cancer [multivariate (M) analysis, HR 0.46; 95% confidence interval (CI) 0.37–0.58, P &lt; 0.001] and better OS [M-HR 0.53; 95% CI, 0.38–0.73, P &lt; 0.001]. Thirty-five datasets including 7,220 patients were eligible for the pooled gene expression analysis. High AR mRNA levels were found to confer positive prognosis overall in terms of DFS (HR 0.82; 95% CI 0.72–0.92;P = 0.0007) and OS (HR 0.84; 95% CI, 0.75–0.94; P = 0.02) only in univariate analysis.
Conclusions: Our analysis, conducted among more than 17,000 women with early-stage breast cancer included in clinical and gene expression analysis, demonstrates that AR positivity is associated with favorable clinical outcome. Clin Cancer Res; 23(11); 2702–12. ©2016 AACR.
Biomarker and Tumor Responses of Oral Cavity Squamous Cell Carcinoma to Trametinib: A Phase II Neoadjuvant Window-of-Opportunity Clinical Trial
Authors: Uppaluri Ravindra , Winkler Ashley E. , Lin Tianxiang , Law Jonathan H. , Haughey Bruce H. , Nussenbaum Brian , Paniello Randal C. , Rich Jason T. , Diaz Jason A. , Michel Loren P. , Wildes Tanya , Dunn Gavin P. , Zolkind Paul , Kallogjeri Dorina , Piccirillo Jay F. , Dehdashti Farrokh , Siegel Barry A. , Chernock Rebecca D. , Lewis James S. , Adkins Douglas R. 
Published: November 2016

Abstract
Purpose: Ras/MEK/ERK pathway activation is common in oral cavity squamous cell carcinoma (OCSCC). We performed a neoadjuvant (preoperative) trial to determine the biomarker and tumor response of OCSCC to MEK inhibition with trametinib.
Experimental Design: Patients with stage II–IV OCSCC received trametinib (2 mg/day, minimum 7 days) prior to surgery. Primary tumor specimens were obtained before and after trametinib to evaluate immunohistochemical staining for p-ERK1/2 and CD44, the primary endpoint. Secondary endpoints included changes in clinical tumor measurements and metabolic activity [maximum standardized uptake values (SUVmax) by F-18 fluorodeoxyglucose positron emission tomography/CT), and in tumor downstaging. Drug-related adverse events (AE) and surgical/wound complications were evaluated.
Results: Of 20 enrolled patients, 17 (85%) completed the study. Three patients withdrew because of either trametinib-related (n = 2: nausea, duodenal perforation) or unrelated (n = 1: constipation) AEs. The most common AE was rash (9/20 patients, 45%). Seventeen patients underwent surgery. No unexpected surgical/wound complications occurred. Evaluable matched pre- and posttrametinib specimens were available in 15 (88%) of these patients. Reduction in p-ERK1/2 and CD44 expression occurred in 5 (33%) and 2 (13%) patients, respectively. Clinical tumor response by modified World Health Organization criteria was observed in 11 of 17 (65%) evaluable patients (median 46% decrease, range 14%–74%). Partial metabolic response (≥25% reduction in SUVmax) was observed in 6 of 13 (46%) evaluable patients (median 25% decrease, range 6%–52%). Clinical-to-pathologic tumor downstaging occurred in 9 of 17 (53%) evaluable patients.
Conclusions: Trametinib resulted in significant reduction in Ras/MEK/ERK pathway activation and in clinical and metabolic tumor responses in patients with OCSCC. Clin Cancer Res; 23(9); 2186–94. ©2016 AACR.
Trifluoperazine, a Well-Known Antipsychotic, Inhibits Glioblastoma Invasion by Binding to Calmodulin and Disinhibiting Calcium Release Channel IP3R
Authors: Kang Seokmin , Hong Jinpyo , Lee Jung Moo , Moon Hyo Eun , Jeon Borami , Choi Jungil , Yoon Nal Ae , Paek Sun Ha , Roh Eun Joo , Lee C. Justin , Kang Sang Soo 
Published: November 2016

Abstract
Calcium (Ca2+) signaling is an important signaling process, implicated in cancer cell proliferation and motility of the deadly glioblastomas that aggressively invade neighboring brain tissue. We have previously demonstrated that caffeine blocks glioblastoma invasion and extends survival by inhibiting Ca2+ release channel inositol 1,4,5-trisphosphate receptor (IP3R) subtype 3. Trifluoperazine (TFP) is an FDA-approved antipsychotic drug for schizophrenia. Interestingly, TFP has been recently reported to show a strong anticancer effect on lung cancer, hepatocellular carcinoma, and T-cell lymphoma. However, the possible anticancer effect of TFP on glioblastoma has not been tested. Here, we report that TFP potently suppresses proliferation, motility, and invasion of glioblastoma cells in vitro, and tumor growth in in vivo xenograft mouse model. Unlike caffeine, TFP triggers massive and irreversible release of Ca2+ from intracellular stores by IP3R subtype 1 and 2 by directly interacting at the TFP-binding site of a Ca2+-binding protein, calmodulin subtype 2 (CaM2). TFP binding to CaM2 causes a dissociation of CaM2 from IP3R and subsequent opening of IP3R. Compared with the control neural stem cells, various glioblastoma cell lines showed enhanced expression of CaM2 and thus enhanced sensitivity to TFP. On the basis of these findings, we propose TFP as a potential therapeutic drug for glioblastoma by aberrantly and irreversibly increasing Ca2+ in glioblastoma cells. Mol Cancer Ther; 16(1); 217–27. ©2016 AACR.
Establishment of the In Vivo Efficacy of Pretargeted Radioimmunotherapy Utilizing Inverse Electron Demand Diels-Alder Click Chemistry
Authors: Houghton Jacob L. , Membreno Rosemery , Abdel-Atti Dalya , Cunanan Kristen M. , Carlin Sean , Scholz Wolfgang W. , Zanzonico Pat B. , Lewis Jason S. , Zeglis Brian M. 
Published: November 2016

Abstract
The pretargeting system based on the inverse electron demand Diels-Alder reaction (IEDDA) between trans-cyclooctene (TCO) and tetrazine (Tz) combines the favorable pharmacokinetic properties of radiolabeled small molecules with the affinity and specificity of antibodies. This strategy has proven to be an efficient method for the molecularly targeted delivery of pharmaceuticals, including isotopes for radiological imaging. Despite encouraging results from in vivo PET imaging studies, this promising system has yet to be thoroughly evaluated for pretargeted radioimmunotherapy (PRIT). Toward that end, we synthesized two novel 177Lu-labeled tetrazine-bearing radioligands. Next, we compared the usefulness of our ligands for PRIT when paired with TCO-modified 5B1—a human, anti-CA19.9 mAb—in preclinical murine models of pancreatic cancer. The exemplary ligand, 177Lu-DOTA-PEG7-Tz, showed rapid (4.6 ± 0.8% ID/g at 4 hours) and persistent (16.8 ± 3.9% ID/g at 120 hours) uptake in tumors while concurrently clearing from blood and nontarget tissues. Single-dose therapy studies using 5B1-TCO and varying amounts of 177Lu-DOTA-PEG7-Tz (400, 800, and 1,200 μCi) showed that our system elicits a dose-dependent therapeutic response in mice bearing human xenografts. Furthermore, dosimetry calculations suggest that our approach is amenable to clinical applications with its excellent dosimetric profile in organs of clearance (i.e., liver and kidneys) as well as in dose-limiting tissues, such as red marrow. This study established that a pretargeted methodology utilizing the IEDDA reaction can rapidly and specifically deliver a radiotherapeutic payload to tumor tissue, thus illustrating its excellent potential for clinical translation. Mol Cancer Ther; 16(1); 124–33. ©2016 AACR.
TAS-116, a Novel Hsp90 Inhibitor, Selectively Enhances Radiosensitivity of Human Cancer Cells to X-rays and Carbon Ion Radiation
Authors: Lee Younghyun , Sunada Shigeaki , Hirakawa Hirokazu , Fujimori Akira , Nickoloff Jac A. , Okayasu Ryuichi 
Published: November 2016

Abstract
Hsp90 inhibitors have been investigated as cancer therapeutics in monotherapy and to augment radiotherapy; however, serious adverse effects of early-generation Hsp90 inhibitors limited their development. TAS-116 is a novel Hsp90 inhibitor with lower adverse effects than other Hsp90 inhibitors, and here, we investigated the radiosensitizing effects of TAS-116 in low linear energy transfer (LET) X-ray and high LET carbon ion–irradiated human cancer cells and mouse tumor xenografts. TAS-116 decreased cell survival of both X-ray and carbon ion–irradiated human cancer cell lines (HeLa and H1299 cells), and similar to other Hsp90 inhibitors, it did not affect radiosensitivity of noncancerous human fibroblasts. TAS-116 increased the number of radiation-induced γ-H2AX foci and delayed the repair of DNA double-strand breaks (DSB). TAS-116 reduced the expression of proteins that mediate repair of DSBs by homologous recombination (RAD51) and nonhomologous end joining (Ku, DNA-PKcs), and suppressed formation of RAD51 foci and phosphorylation/activation of DNA-PKcs. TAS-116 also decreased expression of the cdc25 cell-cycle progression marker, markedly increasing G2–M arrest. Combined treatment of mouse tumor xenografts with carbon ions and TAS-116 showed promising delay in tumor growth compared with either individual treatment. These results demonstrate that TAS-116 radiosensitizes human cancer cells to both X-rays and carbon ions by inhibiting the two major DSB repair pathways, and these effects were accompanied by marked cell-cycle arrest. The promising results of combination TAS-116 + carbon ion radiotherapy of tumor xenografts justify further exploration of TAS-116 as an adjunct to radiotherapy using low or high LET radiation. Mol Cancer Ther; 16(1); 16–24. ©2016 AACR.
Comparing Standard to Feature-Based Meteorological Model Evaluation Techniques in Bogotá, Colombia
Authors: Nedbor-Gross Robert , Henderson Barron H. , Davis Justin R. , Pachón Jorge E. , Rincón Alexander , Guerrero Oscar J. , Grajales Freddy 
Published: November 2016

AbstractStandard meteorological model performance evaluation (sMPE) can be insufficient in determining “fitness” for air quality modeling. An sMPE compares predictions of meteorological variables with community-based thresholds. Conceptually, these thresholds measure the model’s capability to represent mesoscale features that cause variability in air pollution. A method that instead examines features could provide a better estimate of fitness. This work compares measures of fitness from sMPE analysis with a feature-based MPE (fMPE). Meteorological simulations for Bogotá, Colombia, using the Weather Research and Forecasting (WRF) Model provide an ideal case study that highlights the importance of fMPE. Bogotá is particularly interesting because the complex topography presents challenges for WRF in sMPE. A cluster analysis identified four dominant meteorological features associated with air quality driven by wind patterns. The model predictions are able to pass several sMPE thresholds but show poor performance for wind direction. The base simulation can be improved with alternative surface characterization datasets for terrain, soil classification, and land use. Despite doubling the number of days with acceptable specific humidity, overall acceptability was never more than 10%. By comparison, an fMPE showed that predictions were able to reproduce the air-quality-relevant features on 38.4% of the days. The fMPE is based on features derived from an observational cluster analysis that have clear relationships with air quality, which suggests that reproducing those features will indicate better air quality model performance. An fMPE may be particularly useful for high-resolution modeling (1 km or less) when finescale variability can cause poor sMPE performance even when the general pattern that drives air pollution is well reproduced.
On the Discrepancies in Tropical Belt Expansion between Reanalyses and Climate Models and among Tropical Belt Width Metrics
Authors: Davis Nicholas , Birner Thomas 
Published: November 2016

Abstract
The arid subtropics are situated at the edges of the tropical belt, where subsidence in the Hadley cells suppresses precipitation. Any meridional shift in these edge latitudes could have significant impacts on surface climate. Recent studies have investigated past and future changes in the tropical belt width and have found discrepancies in the rates of expansion estimated with different metrics and between climate models and reanalyses. Here, CMIP5 simulations and four modern reanalyses are analyzed using an ensemble of objective tropical belt width metrics to reexamine if such inconsistencies exist. The authors do not find sufficient evidence to demonstrate this discrepancy between models and reanalyses, as reanalysis trends in the tropical belt width fall within the range of model trends for any given metric. Furthermore, only metrics based on the Hadley cells are found to exhibit robust historical and future expansion. Metrics based on the subtropical jet and the tropopause show no robust response. This differentiation may be due to the strong correlation, on all time scales, between the Hadley cell edge latitudes and the latitudes of the eddy-driven jets, which consistently shift poleward in response to radiative forcings. In contrast, the subtropical jet and tropopause metrics appear to be decoupled from the Hadley cells and the eddy-driven jets and essentially measure a different tropical belt. The tropical belt width metrics are inconsistently correlated with surface climate indices based on precipitation and surface evaporation. This may make assessing the surface impacts of observed and future tropical expansion challenging.
The Sensitivity of the Terrestrial Surface Energy and Water Balance Estimates in the WRF Model to Lower Surface Boundary Representations: A South Norway Case Study
Authors: Erlandsen Helene B. , Haddeland Ingjerd , Tallaksen Lena M. , Kristiansen Jørn 
Published: November 2016

Abstract
A seasonal snow cover, expansive forests, a long coast line, and a mountainous terrain are features of Norway’s geography. Forests, ground snow, and sea surface temperature (SST) vary on time scales relevant for weather forecasting and climate projections. The mapping and model parameterization of these features vary in novelty, accuracy, and complexity. This paper investigates how increasing the influence of each of these features affects southern Norway’s surface energy and water balance in a regional climate model (WRF). High-resolution (3.7 km) experimental runs have been conducted over two consecutive hydrological years, including 1) heightening the boreal forest line (the Veg experiment), 2) increasing ground snow by altering the snow/rain criterion (the Snow experiment), or 3) increasing the SST (the SST experiment). The Veg experiment led to an increase in annual net radiation in the study area (by 3 W m−2), largely balanced out by an increase in latent heat flux. Moisture recycling increased, leaving only a negligible decrease in annual runoff. Surface temperature increased by 0.1°C, and its seasonal variability was dampened. Significant changes were also found outside the area of vegetation change. Snow decreased by 1.5 W m−2, despite slight increases in downward shortwave and longwave radiation. Both sensible heat flux and surface temperature decreased (by 1.3 W m−2 and 0.2°C, respectively), but the annual water balance remained mostly unchanged. The SST experiment led to increased downward and upward longwave radiation. Surface temperature was raised by 0.2°C. Advected oceanic moisture and thus both precipitation and runoff increased (by 2.5% and 2.8%, respectively).
Added Value of Alternative Information in Interpolated Precipitation Datasets for Hydrology
Authors: Bajamgnigni Gbambie Abdas Salam , Poulin Annie , Boucher Marie-Amélie , Arsenault Richard 
Published: November 2016

Abstract
Gridded climate datasets are produced in many parts of the world by applying various interpolation methods to weather observations, to which are sometimes added secondary information (in addition to geographic location) such as topography and radar or atmospheric model outputs. For a region of interest, the choice of a dataset for a given study can be a significant challenge given the lack of information on the similarities and differences that exist between datasets, or about the benefits that one dataset may present relative to another. This study aims to provide information on the spatial and temporal differences between gridded precipitation datasets and their implication for hydrological modeling. Three gridded datasets for the province of Quebec are considered: the Natural Resources Canada (NRCan) dataset, the Canadian Precipitation Analysis (CaPA) dataset, and the dataset from the Ministère du Développement Durable, de l’Environnement et de la Lutte contre les Changements Climatiques du Québec (MDDELCC). Using statistical metrics and diagrams, these precipitation datasets are compared with each other. Hydrological responses of 181 Quebec watersheds with respect to each gridded precipitation dataset are also analyzed using the hydrological model HSAMI. The results indicate strong similarities in the southern parts and disparities in the central and northern parts of the province of Quebec. Analysis of hydrological simulations indicates that the CaPA dataset offers the best results, particularly for watersheds located in the central and northern parts of the province. MDDELCC shows the best performance in watersheds located on the south shore of the St. Lawrence River and comes out as the overall second-best option.