bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of the localization of dendritic calcium persistent inward current on the input-output properties of spinal motoneuron pool: a computational study
Authors: Kim Hojeong 
Published: July 2017

The goal of this study is to investigate how the dendritic Ca-PIC location influences nonlinear input-output properties and depends on the type of motoneurons across the motoneuron pool. A model motoneuron pool consisting of 10 motoneurons was constructed using a recently developed two-compartment modeling approach that reflected key cell type-associated properties experimentally identified. The dendritic excitability and firing output depended systematically on both the PIC location and the motoneuron type. The PIC onset and offset in the current-voltage ( I–V) relationship tended to occur at more hyperpolarized voltages as the path length to the PIC channels from the soma increased and as the cell type shifted from high- to low-threshold motoneurons. At the same time, the firing acceleration and frequency hysteresis in the frequency-current ( F–I) relationship became faster and larger, respectively. However, the PIC onset-offset hysteresis increased as the path length and the recruitment threshold increased. Furthermore, the gain of frequency-current function before full PIC activation was larger for PIC channels located over distal dendritic regions in low- compared with high-threshold motoneurons. When compared with previously published experimental observations, the modeling concurred when Ca-PIC channels were placed closer to the soma in high- than low-threshold motoneurons in the model motoneuron pool. All of these results suggest that the negative relationship of Ca-PIC location and cell recruitment threshold may underlie the systematic variation in I–V and F–I transformation across the motoneuron pool. NEW & NOTEWORTHY How does the dendritic location of calcium persistent inward current (Ca-PIC) influence dendritic excitability and firing behavior across the spinal motoneuron pool? This issue was investigated developing a model motoneuron pool that reflected key motoneuron type-specific properties experimentally identified. The simulation results point out the negative relationship between the distance of Ca-PIC source from the soma and cell recruitment threshold as a basis underlying the systematic variation in input-output properties of motoneurons over the motoneuron pool.
Fluorocitrate-mediated depolarization of astrocytes in the retrotrapezoid nucleus stimulates breathing
Authors: Sobrinho Cleyton R. , Gonçalves Christopher M. , Takakura Ana C. , Mulkey Daniel K. , Moreira Thiago S. 
Published: July 2017

Evidence indicates that CO2/H+-evoked ATP released from retrotrapezoid nucleus (RTN) astrocytes modulates the activity of CO2-sensitive neurons. RTN astrocytes also sense H+by inhibition of Kir4.1 channels; however, the relevance of this pH-sensitive current remains unclear since ATP release appears to involve CO2-dependent gating of connexin 26 hemichannels. Considering that depolarization mediated by H+inhibition of Kir4.1 channels is expected to increase sodium bicarbonate cotransporter (NBC) conductance and favor Ca2+influx via the sodium calcium exchanger (NCX), we hypothesize that depolarization in the presence of CO2is sufficient to facilitate ATP release and enhance respiratory output. Here, we confirmed that acute exposure to fluorocitrate (FCt) reversibly depolarizes RTN astrocytes and increased activity of RTN neurons by a purinergic-dependent mechanism. We then made unilateral injections of FCt into the RTN or two other putative chemoreceptor regions (NTS and medullary raphe) to depolarize astrocytes under control conditions and during P2-recepetor blockade while measuring cardiorespiratory activities in urethane-anesthetized, vagotomized, artificially ventilated male Wistar rats. Unilateral injection of FCt into the RTN increased phrenic (PNA) amplitude and frequency without changes in arterial pressure. Unilateral injection of pyridoxal-phosphate-6-azophenyl-2′,4′-disulfonate (PPADS, a P2-receptor antagonist) into the RTN dampened both PNA amplitude and frequency responses to FCt. Injection of MRS2179 (P2Y1-receptor antagonist) into the RTN did not affect the FCt-induced respiratory responses. Fluorocitrate had no effect on breathing when injected into the NTS or raphe. These results suggest that depolarization can facilitate purinergic enhancement of respiratory drive from the RTN.NEW & NOTEWORTHY Astrocytes in the retrotrapezoid nucleus (RTN) are known to function as respiratory chemoreceptors; however, it is not clear whether changes in voltage contribute to astrocyte chemoreception. We showed that depolarization of RTN astrocytes at constant CO2levels is sufficient to modulate RTN chemoreception by a purinergic-dependent mechanism. These results support the possibility that astrocyte depolarization can facilitate purinergic enhancement of respiratory drive from the RTN.
The firing characteristics of foot sole cutaneous mechanoreceptor afferents in response to vibration stimuli
Authors: Strzalkowski Nicholas D. J. , Ali R. Ayesha , Bent Leah R. 
Published: July 2017

Single unit microneurography was used to record the firing characteristics of the four classes of foot sole cutaneous afferents [fast and slowly adapting type I and II (FAI, FAII, SAI, and SAII)] in response to sinusoidal vibratory stimuli. Frequency (3–250 Hz) and amplitude (0.001–2 mm) combinations were applied to afferent receptive fields through a 6-mm diameter probe. The impulses per cycle, defined as the number of action potentials evoked per vibration sine wave, were measured over 1 s of vibration at each frequency-amplitude combination tested. Afferent entrainment threshold (lowest amplitude at which an afferent could entrain 1:1 to the vibration frequency) and afferent firing threshold (minimum amplitude for which impulses per cycle was greater than zero) were then obtained for each frequency. Increases in vibration frequency are generally associated with decreases in expected impulses per cycle ( P < 0.001), but each foot sole afferent class appears uniquely tuned to vibration stimuli. FAII afferents tended to have the lowest entrainment and firing thresholds ( P < 0.001 for both); however, these afferents seem to be sensitive across frequency. In contrast to FAII afferents, SAI and SAII afferents tended to demonstrate optimal entrainment to frequencies below 20 Hz and FAI afferents faithfully encoded frequencies between 8 and 60 Hz. Contrary to the selective activation of distinct afferent classes in the hand, application of class-specific frequencies in the foot sole is confounded due to the high sensitivity of FAII afferents. These findings may aid in the development of sensorimotor control models or the design of balance enhancement interventions. NEW & NOTEWORTHY Our work provides a mechanistic look at the capacity of foot sole cutaneous afferents to respond to vibration of varying frequency and amplitude. We found that foot sole afferent classes are uniquely tuned to vibration stimuli; however, unlike in the hand, they cannot be independently activated by class-specific frequencies. Viewing the foot sole as a sensory structure, the present findings may aid in the refinement of sensorimotor control models and design of balance enhancement interventions.
SYD985, a Novel Duocarmycin-Based HER2-Targeting Antibody–Drug Conjugate, Shows Antitumor Activity in Uterine and Ovarian Carcinosarcoma with HER2/Neu Expression
Authors: Menderes Gulden , Bonazzoli Elena , Bellone Stefania , Black Jonathan , Predolini Federica , Pettinella Francesca , Masserdotti Alice , Zammataro Luca , Altwerger Gary , Buza Natalia , Hui Pei , Wong Serena , Litkouhi Babak , Ratner Elena , Silasi Dan-Arin , Azodi Masoud , Schwartz Peter E. , Santin Alessandro D. 
Published: July 2017

Abstract
Purpose: Carcinosarcomas (CS) are highly aggressive gynecologic malignancies containing both carcinomatous and sarcomatous elements with heterogeneous HER2/neu expression. We compared the efficacy of SYD985 (Synthon Biopharmaceuticals BV), a novel HER2-targeting antibody–drug conjugate (ADC), to trastuzumab emtansine (T-DM1, Genentech-Roche) against primary uterine and ovarian CS.
Experimental Design: Eight primary CS cell lines were evaluated for HER2/neu surface expression by IHC and gene amplification by FISH assays. The in vitro experiments included cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), proliferation, viability, and bystander killing. In vivo activity was studied in mouse xenograft and patient-derived xenograft (PDX) models.
Results: SYD985 and T-DM1 induced similar levels of ADCC against CS cell lines with low and high HER2/neu expression when challanged in the presence of effector cells. In contrast, SYD985 was 7- to 54-fold more potent than T-DM1 in the absence of effector cells. SYD985, unlike T-DM1, was active against CS demonstrating low or heterogeneous HER2/neu expression. Specifically, the mean IC50 values were 0.060 μg/mL and 3.221 μg/mL (P &lt; 0.0001) against HER2/neu 0/1+ cell lines and 0.013 μg/mL and 0.096 μg/mL (P &lt; 0.0001) against HER2/neu 3+ cell lines for SYD985 versus T-DM1, respectively. Importantly, unlike T-DM1, SYD985 induced efficient bystander killing of HER2/neu 0/1+ tumor cells admixed with HER2/neu 3+ cells. In vivo studies confirmed that SYD985 is more active than T-DM1 in CS and highly effective against HER2/neu expressing xenografts and PDX.
Conclusions: SYD985 may represent a novel and highly effective ADC against HER2-expressing CS. Clinical studies with SYD985 in patients harboring chemotherapy-resistant CS with low/moderate and high HER2 expression are warranted. Clin Cancer Res; 23(19); 5836–45. ©2017 AACR.
Sym015: A Highly Efficacious Antibody Mixture against MET-Amplified Tumors
Authors: Poulsen Thomas Tuxen , Grandal Michael Monrad , Skartved Niels Jørgen Østergaard , Hald Rikke , Alifrangis Lene , Koefoed Klaus , Lindsted Trine , Fröhlich Camilla , Pollmann Sofie Ellebæk , Eriksen Karsten Wessel , Dahlman Anna , Jacobsen Helle Jane , Bouquin Thomas , Pedersen Mikkel Wandahl , Horak Ivan David , Lantto Johan , Kragh Michael 
Published: July 2017

Abstract
Purpose: Activation of the receptor tyrosine kinase MET is associated with poor clinical outcome in certain cancers. To target MET more effectively, we developed an antagonistic antibody mixture, Sym015, consisting of two humanized mAbs directed against nonoverlapping epitopes of MET.
Experimental Design/Results: We screened a large panel of well-annotated human cancer cell lines and identified a subset with highly elevated MET expression. In particular, cell lines of lung cancer and gastric cancer origin demonstrated high MET expression and activation, and Sym015 triggered degradation of MET and significantly inhibited growth of these cell lines. Next, we tested Sym015 in patient- and cell line–derived xenograft models with high MET expression and/or MET exon 14 skipping alterations, and in models harboring MET amplification as a mechanism of resistance to EGFR-targeting agents. Sym015 effectively inhibited tumor growth in all these models and was superior to an analogue of emibetuzumab, a monoclonal IgG4 antibody against MET currently in clinical development. Sym015 also induced antibody-dependent cellular cytotoxicity (ADCC) in vitro, suggesting that secondary effector functions contribute to the efficacy of Sym015.
Retrospectively, all responsive, high MET-expressing models were scored as highly MET-amplified by in situ hybridization, pointing to MET amplification as a predictive biomarker for efficacy. Preclinical toxicology studies in monkeys showed that Sym015 was well tolerated, with a pharmacokinetic profile supporting administration of Sym015 every second or third week in humans.
Conclusions: The preclinical efficacy and safety data provide a clear rationale for the ongoing clinical studies of Sym015 in patients with MET-amplified tumors. Clin Cancer Res; 23(19); 5923–35. ©2017 AACR.
Therapy of Small Cell Lung Cancer (SCLC) with a Topoisomerase-I–inhibiting Antibody–Drug Conjugate (ADC) Targeting Trop-2, Sacituzumab Govitecan
Authors: Gray Jhanelle E. , Heist Rebecca S. , Starodub Alexander N. , Camidge D. Ross , Kio Ebenezer A. , Masters Gregory A. , Purcell W. Thomas , Guarino Michael J. , Misleh Jamal , Schneider Charles J. , Schneider Bryan J. , Ocean Allyson , Johnson Tirrell , Gandhi Leena , Kalinsky Kevin , Scheff Ronald , Messersmith Wells A. , Govindan Serengulam V. , Maliakal Pius P. , Mudenda Boyd , Wegener William A. , Sharkey Robert M. , Goldenberg David M. 
Published: July 2017

Abstract
Purpose: We evaluated a Trop-2–targeting antibody conjugated with SN-38 in metastatic small cell lung cancer (mSCLC) patients.
Experimental Design: Sacituzumab govitecan was studied in patients with pretreated (median, 2; range, 1–7) mSCLC who received either 8 or 10 mg/kg i.v. on days 1 and 8 of 21-day cycles. The primary endpoints were safety and objective response rate (ORR); duration of response, progression-free survival (PFS), and overall survival (OS) were secondary endpoints.
Results: Sixty percent of patients showed tumor shrinkage from baseline CTs. On an intention-to-treat basis (N = 50), the ORR was 14% (17% for the 10-mg/kg group); the median response duration, 5.7 months; the clinical benefit rate (CBR ≥4 months), 34%; median PFS, 3.7 months; and median OS, 7.5 months. There was a suggested improvement in PR, CBR, and PFS with sacituzumab govitecan in second-line patients who were sensitive to first-line therapy, but no difference between first-line chemosensitive versus chemoresistant patients in the overall population. There was a statistically significant higher OS in those patients who received prior topotecan versus no topotecan therapy in a small subgroup. Grade ≥3 adverse events included neutropenia (34%), fatigue (13%), diarrhea (9%), and anemia (6%). Trop-2 tumor staining was not required for patient selection. No antibodies to the drug conjugate or its components were detected on serial blood collections.
Conclusions: Sacituzumab govitecan appears to have a safe and effective therapeutic profile in heavily pretreated mSCLC patients, including those who are chemosensitive or chemoresistant to first-line chemotherapy. Additional studies as a monotherapy or combination therapy are warranted. Clin Cancer Res; 23(19); 5711–9. ©2017 AACR.
Relationship Between Serum Inflammatory Marker Levels and the Dynamic Changes in Coronary Plaque Characteristics After Statin Therapy
Authors: Kwon Osung , Kang Soo-Jin , Kang Se Hun , Lee Pil Hyung , Yun Sung-Cheol , Ahn Jung-Min , Park Duk-Woo , Lee Seung-Whan , Kim Young-Hak , Lee Cheol Whan , Han Ki Hoon , Park Seong-Wook , Park Seung-Jung 
Published: July 2017

Background—
The mechanism of statin for atheroma stabilization remains unclear. We aimed to assess the relationship between on-treatment changes in serum inflammatory biomarker levels and plaque composition in differed nonculprit coronary lesions.

Methods and Results—

The changes in serum biochemical values, and intravascular ultrasound data were evaluated in 218 patients with virtual histology (VH)-intravascular ultrasound—defined fibroatheroma-containing segments after 12-month rosuvastatin treatment. When stratifying patients into quartiles according to the change in high-sensitivity C-reactive protein (hsCRP), there was a significant positive linear relationship for the changes in %necrotic core (coefficient, 1.31; standard error, 0.54) and %dense calcium volumes (coefficient, 0.80; standard error, 0.27), but a negative linear relationship for the changes in %fibrous (coefficient, −0.94; standard error, 0.45) and %fibrofatty volumes (coefficient, −1.17; standard error, 0.56; all
P
<0.05). The decrease in hsCRP (−1.2±3.9 versus 0.5±3.4 mg/L;
P
=0.02) was greater in those without VH-defined thin-cap fibroatheroma (TCFA, defined as >30° of necrotic core abutting the lumen in 3 consecutive slices) than those with VH-TCFA at follow-up. Diabetes mellitus, a larger normalized total atheroma volume, and the presence of VH-TCFA at baseline predicted the presence of VH-TCFA at follow-up (odds ratio, 4.01, 1.18, and 9.21, respectively; all
P
<0.05), whereas the change in hsCRP showed a trend (odds ratio, 1.19;
P
=0.07). The change in low-density lipoprotein-cholesterol had no relationship with the changes in hsCRP or plaque compositions.

Conclusions—
With 12-month rosuvastatin therapy, a greater hsCRP reduction (not low-density lipoprotein-cholesterol) was associated with a greater decrease in %necrotic core volume and the absence of VH-TCFA, indicating a link between the anti-inflammatory action of statin and plaque stabilization by reducing NC and reinforcing fibrous cap.

Clinical Trial Registration—

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT00997880.
Acute Occlusions of Dual-Layer Carotid Stents After Endovascular Emergency Treatment of Tandem Lesions
Authors: Yilmaz Umut , Körner Heiko , Mühl-Benninghaus Ruben , Simgen Andreas , Kraus Catherine , Walter Silke , Behnke Stefanie , Faßbender Klaus , Reith Wolfgang , Unger Marcus M. 
Published: July 2017

Background and Purpose—
A new generation of carotid artery stents that uses a second micromesh layer to reduce embolic events during carotid artery stenting has recently been introduced. The purpose of this study was to compare acute occlusion rates of these new dual-layer stents with those of single-layer stents in the setting of emergency carotid artery stenting with intracranial mechanical thrombectomy in acute ischemic stroke.

Methods—
Consecutive patients with acute tandem (intra- and extracranial) lesions of the anterior circulation who were endovascularly treated at our institution were identified from our registry of neuroendovascular interventions. Clinical, angiographic, and neuroimaging data were analyzed. End points included acute occlusions of the carotid stents (within 72 hours after stenting) and symptomatic intracerebral hemorrhage.

Results—

Forty-seven patients were included. Dual-layer stents (n=20) had a significantly higher rate of acute occlusions than single-layer stents (n=27; 45% versus 3.7%;
P
=0.001; odds ratio, 21.3; 95% confidence interval, 2.4–188.4). There were no significant differences in the rates of patients who had any antiplatelet or dual antiplatelet medication before admission, in the rates of postinterventional symptomatic intracerebral hemorrhage, the mean National Institutes of Health Stroke Scale scores at admission, or the modified Rankin Scale scores at discharge.

Conclusions—
The recently introduced dual-layer stents have a higher risk of acute occlusion compared with single-layer stents in the treatment of acute stroke.
Challenges in the Medical Management of Symptomatic Intracranial Stenosis in an Urban Setting
Authors: Sangha Rajbeer S. , Naidech Andrew M. , Corado Carlos , Ansari Sameer A. , Prabhakaran Shyam 
Published: July 2017

Background and Purpose—
Since the SAMMPRIS trial (Stenting and Aggressive Medical Management for Preventing Recurrent Stroke in Intracranial Stenosis), aggressive medical management (AMM), which includes dual antiplatelet therapy (DAPT) and high-dose statin (HDS) therapy, is recommended for patients with symptomatic intracranial atherosclerotic disease. However, limited data on the real-world application of this regimen exist. We hypothesized that recurrent stroke risk among patients treated with AMM is similar to the medical arm of the SAMMPRIS cohort.

Methods—
Using a prospective registry, we identified all patients admitted between August 2012 and March 2015 with (1) confirmed ischemic stroke or transient ischemic attack; (2) independently adjudicated symptomatic intracranial atherosclerotic disease; and (3) follow-up at 30 days. We analyzed 30-day risk of recurrent ischemic stroke stratified by treatment: (1) AMM: DAPT plus HDS therapy, (2) HDS alone, and (3) DAPT alone. We also assessed 30-day risk among patients who met prespecified SAMMPRIS eligibility criteria.

Results—

Among 99 patients who met study criteria (51.5% male, 54.5% black, mean age 68.2±11.2 years), 49 (48.5%) patients were treated with AMM, 69 (69.7%) with DAPT, and 73 (73.7%) with HDS therapy. At 30 days, 20 (20.2%) patients had recurrent strokes in the territory of stenosis. Compared with the risk in the medical arm of SAMMPRIS (4.4%), the 30-day risk of recurrent stroke was 20.4% in AMM patients, 21.5% in HDS patients, 22.4% in DAPT patients, and 23.2% in SAMMPRIS-eligible patients (all
P
<0.001).

Conclusions—
Recurrent stroke risk within 30 days in patients with symptomatic intracranial atherosclerotic disease was higher than that observed in the medical arm of SAMMPRIS even in the subgroup receiving AMM. Replication of the SAMMPRIS findings requires further prospective study.
Seasonal Analysis of Cloud Objects in the High-Resolution Rapid Refresh (HRRR) Model Using Object-Based Verification
Authors: Griffin Sarah M. , Otkin Jason A. , Rozoff Christopher M. , Sieglaff Justin M. , Cronce Lee M. , Alexander Curtis R. , Jensen Tara L. , Wolff Jamie K. 
Published: July 2017

AbstractIn this study, object-based verification using the method for object-based diagnostic evaluation (MODE) is used to assess the accuracy of cloud-cover forecasts from the experimental High-Resolution Rapid Refresh (HRRRx) model during the warm and cool seasons. This is accomplished by comparing cloud objects identified by MODE in observed and simulated Geostationary Operational Environmental Satellite 10.7-μm brightness temperatures for August 2015 and January 2016. The analysis revealed that more cloud objects and a more pronounced diurnal cycle occurred during August, with larger object sizes observed in January because of the prevalence of synoptic-scale cloud features. With the exception of the 0-h analyses, the forecasts contained fewer cloud objects than were observed. HRRRx forecast accuracy is assessed using two methods: traditional verification, which compares the locations of grid points identified as observation and forecast objects, and the MODE composite score, an area-weighted calculation using the object-pair interest values computed by MODE. The 1-h forecasts for both August and January were the most accurate for their respective months. Inspection of the individual MODE attribute interest scores showed that, even though displacement errors between the forecast and observation objects increased between the 0-h analyses and 1-h forecasts, the forecasts were more accurate than the analyses because the sizes of the largest cloud objects more closely matched the observations. The 1-h forecasts from August were found to be more accurate than those during January because the spatial displacement between the cloud objects was smaller and the forecast objects better represented the size of the observation objects.