bluuebunny/crossref_metadata_2025_split huggingface dataset:
A circuit for saccadic suppression in the primate brain
Authors: Berman Rebecca A. , Cavanaugh James , McAlonan Kerry , Wurtz Robert H. 
Published: December 2016

Saccades should cause us to see a blur as the eyes sweep across a visual scene. Specific brain mechanisms prevent this by producing suppression during saccades. Neuronal correlates of such suppression were first established in the visual superficial layers of the superior colliculus (SC) and subsequently have been observed in cortical visual areas, including the middle temporal visual area (MT). In this study, we investigated suppression in a recently identified circuit linking visual SC (SCs) to MT through the inferior pulvinar (PI). We examined responses to visual stimuli presented just before saccades to reveal a neuronal correlate of suppression driven by a copy of the saccade command, referred to as a corollary discharge. We found that visual responses were similarly suppressed in SCs, PI, and MT. Within each region, suppression of visual responses occurred with saccades into both visual hemifields, but only in the contralateral hemifield did this suppression consistently begin before the saccade (~100 ms). The consistency of the signal along the circuit led us to hypothesize that the suppression in MT was influenced by input from the SC. We tested this hypothesis in one monkey by inactivating neurons within the SC and found evidence that suppression in MT depends on corollary discharge signals from motor SC (SCi). Combining these results with recent findings in rodents, we propose a complete circuit originating with corollary discharge signals in SCi that produces suppression in visual SCs, PI, and ultimately, MT cortex. NEW & NOTEWORTHY A fundamental puzzle in visual neuroscience is that we frequently make rapid eye movements (saccades) but seldom perceive the visual blur accompanying each movement. We investigated neuronal correlates of this saccadic suppression by recording from and perturbing a recently identified circuit from brainstem to cortex. We found suppression at each stage, with evidence that it was driven by an internally generated signal. We conclude that this circuit contributes to neuronal suppression of visual signals during eye movements.
Single-neuron responses to intraoral delivery of odor solutions in primary olfactory and gustatory cortex
Authors: Maier Joost X. 
Published: December 2016

Smell plays a major role in our perception of food. Odorants released inside the mouth during consumption are combined with taste and texture qualities of a food to guide flavor preference learning and food choice behavior. Here, we built on recent physiological findings that implicated primary sensory cortex in multisensory flavor processing. Specifically, we used extracellular recordings in awake rats to characterize responses of single neurons in primary olfactory (OC) and gustatory cortex (GC) to intraoral delivery of odor solutions and compare odor responses to taste and plain water responses. The data reveal responses to olfactory, oral somatosensory, and gustatory qualities of intraoral stimuli in both OC and GC. Moreover, modality-specific responses overlap in time, indicating temporal convergence of multisensory, flavor-related inputs. The results extend previous work suggesting a role for primary OC in mediating influences of taste on smell that characterize flavor perception and point to an integral role for GC in olfactory processing. NEW & NOTEWORTHY Food perception is inherently multisensory, taking into account taste, smell, and texture qualities. However, the neural mechanisms underlying flavor perception remain unknown. Recording neural activity directly from the rat brain while animals consume multisensory flavor stimuli, we demonstrate that information about odor, taste, and mouthfeel of food converges on primary taste and smell cortex. The results suggest that processing of naturalistic, multisensory information involves an interacting network of primary sensory areas.
Years of Life and Productivity Loss from Potentially Avoidable Colorectal Cancer Deaths in U.S. Counties with Lower Educational Attainment (2008–2012)
Authors: Weir Hannah K. , Li Chunyu , Henley S. Jane , Joseph Djenaba 
Published: December 2016

Abstract
Background: Educational attainment (EA) is inversely associated with colorectal cancer risk. Colorectal cancer screening can save lives if precancerous polyps or early cancers are found and successfully treated. This study aims to estimate the potential productivity loss (PPL) and associated avoidable colorectal cancer–related deaths among screen-eligible adults residing in lower EA counties in the United States.
Methods: Mortality and population data were used to examine colorectal cancer deaths (2008–2012) among adults aged 50 to 74 years in lower EA counties, and to estimate the expected number of deaths using the mortality experience from high EA counties. Excess deaths (observed−expected) were used to estimate potential years life lost, and the human capital method was used to estimate PPL in 2012 U.S. dollars.
Results: County-level colorectal cancer death rates were inversely associated with county-level EA. Of the 100,857 colorectal cancer deaths in lower EA counties, we estimated that more than 21,000 (1 in 5) was potentially avoidable and resulted in nearly $2 billion annual productivity loss.
Conclusions: County-level EA disparities contribute to a large number of potentially avoidable colorectal cancer–related deaths. Increased prevention and improved screening potentially could decrease deaths and help reduce the associated economic burden in lower EA communities. Increased screening could further reduce deaths in all EA groups.
Impact: These results estimate the large economic impact of potentially avoidable colorectal cancer–related deaths in economically disadvantaged communities, as measured by lower EA. Cancer Epidemiol Biomarkers Prev; 26(5); 736–42. ©2016 AACR.
microRNA-221 Enhances MYCN via Targeting Nemo-like Kinase and Functions as an Oncogene Related to Poor Prognosis in Neuroblastoma
Authors: He Xiao-yan , Tan Zheng-lan , Mou Qin , Liu Fang-jie , Liu Shan , Yu Chao-wen , Zhu Jin , Lv Lin-ya , Zhang Jun , Wang Shan , Bao Li-ming , Peng Bin , Zhao Hui , Zou Lin 
Published: December 2016

Abstract
Purpose: MYCN is one of the most well-characterized genetic markers of neuroblastoma. However, the mechanisms as to how MYCN mediate neuroblastoma tumorigenesis are not fully clear. Increasing evidence has confirmed that the dysregulation of miRNAs is involved in MYCN-mediated neuroblastoma tumorigenesis, supporting their potential as therapeutic targets for neuroblastoma. Although miR-221 has been reported as one of the upregulated miRNAs, the interplay between miR-221 and MYCN-mediated neuroblastoma progression remains largely elusive.
Experimental Design: The expression of miR-221 in the formalin-fixed, paraffin-embedded tissues from 31 confirmed patients with neuroblastoma was detected by locked nucleic acid-in situ hybridization and qRT-PCR. The correlation between miR-221 expression and clinical features in patients with neuroblastoma was assessed. The mechanisms as to how miR-221 regulate MYCN in neuroblastoma were addressed. The effect of miR-221 on cellular proliferation in neuroblastoma was determined both in vitro and in vivo.
Results: miR-221 was significantly upregulated in neuroblastoma tumor cells and tissues that overexpress MYCN, and high expression of miR-221 was positively associated with poor survival in patients with neuroblastoma. Nemo-like kinase (NLK) as a direct target of miR-221 in neuroblastoma was verified. In addition, overexpression of miR-221 decreased LEF1 phosphorylation but increased the expression of MYCN via targeting of NLK and further regulated cell cycle, particularly in S-phase, promoting the growth of neuroblastoma cells.
Conclusions: This study provides a novel insight for miR-221 in the control of neuroblastoma cell proliferation and tumorigenesis, suggesting potentials of miR-221 as a prognosis marker and therapeutic target for patients with MYCN overexpressing neuroblastoma. Clin Cancer Res; 23(11); 2905–18. ©2016 AACR.
Nanoparticle-Based Celecoxib and Plumbagin for the Synergistic Treatment of Melanoma
Authors: Gowda Raghavendra , Kardos Gregory , Sharma Arati , Singh Sanjay , Robertson Gavin P. 
Published: December 2016

Abstract
Using multiple drugs to kill cancer cells can decrease drug resistance development. However, this approach is frequently limited by the bioavailability and toxicity of the combined agents and delivery at ratios to specific locations that synergistically kill cancer cells. Loading the individual agents into a nanoparticle that releases the drugs at synergizing ratios at a single location is one approach to resolve this concern. Celecoxib and plumbagin are two drugs that were identified from a screen to synergistically kill melanoma cells compared with normal cells. Combined use of these agents by traditional approaches was not possible due to poor bioavailability and toxicologic concerns. This study details the development of a nanoliposomal-based agent containing celecoxib and plumbagin, called CelePlum-777, which is stable and releases these drugs at an optimal ratio for maximal synergistic killing efficacy. CelePlum-777 was more effective at killing melanoma than normal cells and inhibited xenograft melanoma tumor growth by up to 72% without apparent toxicity. Mechanistically, the drug combination in CelePlum-777 led to enhanced inhibition of melanoma cell proliferation mediated by decreasing levels of key cyclins important for cancer cell proliferation and survival, which was not observed with the individual agents. Thus, a novel nanoparticle-based drug has been developed containing celecoxib and plumbagin that lacks toxicity and delivers the agents at a synergistically killing drug ratio to kill cancer cells. Mol Cancer Ther; 16(3); 440–52. ©2016 AACR.
Angiopoietin-2 as a Biomarker and Target for Immune Checkpoint Therapy
Authors: Wu Xinqi , Giobbie-Hurder Anita , Liao Xiaoyun , Connelly Courtney , Connolly Erin M. , Li Jingjing , Manos Michael P. , Lawrence Donald , McDermott David , Severgnini Mariano , Zhou Jun , Gjini Evisa , Lako Ana , Lipschitz Mikel , Pak Christine J. , Abdelrahman Sara , Rodig Scott , Hodi F. Stephen 
Published: December 2016

AbstractImmune checkpoint therapies targeting CTLA-4 and PD-1 have proven effective in cancer treatment. However, the identification of biomarkers for predicting clinical outcomes and mechanisms to overcome resistance remain as critical needs. Angiogenesis is increasingly appreciated as an immune modulator with potential for combinatorial use with checkpoint blockade. Angiopoietin-2 (ANGPT2) is an immune target in patients and is involved in resistance to anti-VEGF treatment with the monoclonal antibody bevacizumab. We investigated the predictive and prognostic value of circulating ANGPT2 in metastatic melanoma patients receiving immune checkpoint therapy. High pretreatment serum ANGPT2 was associated with reduced overall survival in CTLA-4 and PD-1 blockade–treated patients. These treatments also increased serum ANGPT2 in many patients early after treatment initiation, whereas ipilimumab plus bevacizumab treatment decreased serum concentrations. ANGPT2 increases were associated with reduced response and/or overall survival. Ipilimumab increased, and ipilimumab plus bevacizumab decreased, tumor vascular ANGPT2 expression in a subset of patients, which was associated with increased and decreased tumor infiltration by CD68+ and CD163+ macrophages, respectively. In vitro, bevacizumab blocked VEGF-induced ANGPT2 expression in tumor-associated endothelial cells, whereas ANGPT2 increased PD-L1 expression on M2-polarized macrophages. Treatments elicited long-lasting and functional antibody responses to ANGPT2 in a subset of patients receiving clinical benefit. Our findings suggest that serum ANGPT2 may be considered as a predictive and prognostic biomarker for immune checkpoint therapy and may contribute to treatment resistance via increasing proangiogenic and immunosuppressive activities in the tumor microenvironment. Targeting ANGPT2 provides a rational combinatorial approach to improve the efficacy of immune therapy. Cancer Immunol Res; 5(1); 17–28. ©2016 AACR.
Thrombocytopathy leading to impaired in vivo haemostasis and thrombosis in platelet type von Willebrand disease
Authors: Kaur Harmanpreet , Corscadden Kathryn , Ware Jerry , Othman Maha 
Published: December 2016

SummaryPlatelet defects due to hyper-responsive GPIbα causing enhanced VWF interaction, counter-intuitively result in bleeding rather than thrombosis. The historical explanation of platelet/VWF clearance fails to explain mechanisms of impaired haemostasis particularly in light of reported poor platelet binding to fibrinogen. This study aimed to evaluate the defects of platelets with hyper-responsive GPIbα and their contribution to impaired in vivo thrombosis. Using the PT-VWD mouse model, platelets from the hTgG233V were compared to control hTgWT mice. Platelets’ pro-coagulant capacity was evaluated using flowcytometry assessment of P-selectin and annexin V. Whole blood platelet aggregation in response to ADP, collagen and thrombin was tested. Clot kinetics using laser injury thrombosis model and the effect of GPIbα inhibition in vivo using 6B4; a monoclonal antibody, were evaluated. Thrombin-induced platelet P-selectin and PS exposure were significantly reduced in hTgG233V compared to hTgWT and not signifi-cantly different when compared to unstimulated platelets. The hTgG233V platelets aggregated normally in response to collagen, and had a delayed response to ADP and thrombin, when compared to hTgWT platelets. Laser injury showed significant impairment of in vivo thrombus formation in hTgG233V compared to hTgWT mice. There was a significant lag in in vitro clot formation in turbidity assay but no impairment in thrombin generation was observed using thromboelastography. The in vivo inhibition of GPIbα facilitated new – unstable – clot formation but did not improve the lag. We conclude platelets with hyper-responsive GPIbα have complex intrinsic defects beyond the previously described mechanisms. Abnormal signalling through GPIbα and potential therapy using inhibitors require further investigations.Supplementary Material to this article is available online at www.thrombosis-online.com.
Optimal timing of vitamin K antagonist resumption after upper gastrointestinal bleeding
Authors: Wallvik Niklas , Eriksson Joakim , Höijer Jonas , Bottai Matteo , Holmström Margareta , Schulman Sam , Majeed Ammar 
Published: December 2016

SummaryThe optimal timing of vitamin K antagonists (VKAs) resumption after an upper gastrointestinal (GI) bleeding, in patients with continued indication for oral anticoagulation, is uncertain. We included consecutive cases of VKA-associated upper GI bleeding from three hospitals retrospectively. Data on the bleeding location, timing of VKA resumption, recurrent GI bleeding and thromboembolic events were collected. A model was constructed to evaluate the ‘total risk’, based on the sum of the cumulative rates of recurrent GI bleeding and thromboembolic events, depending on the timing of VKA resumption. A total of 121 (58 %) of 207 patients with VKA-associated upper GI bleeding were restarted on anticoagulation after a median (interquartile range) of one (0.2–3.4) week after the index bleeding. Restarting VKAs was associated with a reduced risk of thromboembolism (HR 0.19; 95 % CI, 0.07–0.55) and death (HR 0.61; 95 % CI, 0.39–0.94), but with an increased risk of recurrent GI bleeding (HR 2.5; 95 % CI, 1.4–4.5). The composite risk obtained from the combined statistical model of recurrent GI bleeding, and thromboembolism decreased if VKAs were resumed after three weeks and reached a nadir at six weeks after the index GI bleeding. On this background we will discuss how the disutility of the outcomes may influence the decision regarding timing of resumption. In conclusion, the optimal timing of VKA resumption after VKA-associated upper GI bleeding appears to be between 3–6 weeks after the index bleeding event but has to take into account the degree of thromboembolic risk, patient values and preferences.
Normal Reference Values and
z
Scores of the Pulmonary Artery Acceleration Time in Children and Its Importance for the Assessment of Pulmonary Hypertension
Authors: Koestenberger Martin , Grangl Gernot , Avian Alexander , Gamillscheg Andreas , Grillitsch Marlene , Cvirn Gerhard , Burmas Ante , Hansmann Georg 
Published: December 2016

Background—
Pulsed-wave Doppler determination of the pulmonary artery acceleration time (PAAT) as a surrogate for pulmonary artery pressure was found to be of clinical value for assessment of pulmonary hypertension (PH) with studies to date exclusively performed in adults. This study aims to provide representative, normal reference values for PAAT in children of all ages. Moreover, we validated abnormal PAAT values in 54 children with PH.

Methods and Results—

We conducted a prospective echocardiographic study in 756 healthy children (aged 1 day to 18 years) and in 54 children with PH. Possible associations of age, body length, body weight, body surface area, and heart rate on PAAT were investigated. The PAAT correlated positively with age (
r
=0.848), body length (
r
=0.871), body surface area (
r
=0.856), and body weight (
r
=0.825) and negatively with heart rate (
r
=−0.906). PAAT increased with age (neonates: median: 81 ms, range: 53–104; 18th year of life: median: 151 ms, range: 107–187). Receiver operating characteristic analysis for detecting PH patients using age-specific
z
scores showed an excellent performance of PAAT (
P
<0.001; area under the curve, 0.98; 95% confidence interval, 0.97–0.99) with a best cutoff score according to Youden index of –1.565 (sensitivity: 92%, specificity: 96%). PAAT values of PH patients negatively correlated (ρ=−0.497) with pulmonary vascular resistance.

Conclusions—

The PAAT normal reference values and
z
scores we provide here will be useful to identify children with a shortened PAAT. Abnormal PAAT values with scores <−2 were predictive of PH.
Effect of Arteriovenous Anastomosis on Blood Pressure Reduction in Patients With Isolated Systolic Hypertension Compared With Combined Hypertension
Authors: Ott Christian , Lobo Melvin D. , Sobotka Paul A. , Mahfoud Felix , Stanton Alice , Cockcroft John , Sulke Neil , Dolan Eamon , van der Giet Markus , Hoyer Joachim , Furniss Stephen S. , Foran John P. , Witkowski Adam , Januszewicz Andrzej , Schoors Danny , Tsioufis Konstantinos , Rensing Benno J. , Saxena Manish , Scott Benjamin , Ng G. André , Achenbach Stephan , Schmieder Roland E. ,   the ROX CONTROL HTN Investigators, Schmid Michael , Jain Ajay , Knight Charles , Mathur Anthony , Balmforth Peter , Luitjens Sandra F. , Smits Gerard , Mungur Dhanraj , Prejbisz Aleksander , Kadziela Jacek , Florczak Elżbieta , Galvin Joseph , Dimitriadis Kyriakos 
Published: December 2016

Background

Options for interventional therapy to lower blood pressure (
BP
) in patients with treatment‐resistant hypertension include renal denervation and the creation of an arteriovenous anastomosis using the
ROX
coupler. It has been shown that
BP
response after
renal denervation
is greater in patients with combined hypertension (
CH
) than in patients with isolated systolic hypertension (
ISH
). We analyzed the effect of
ROX
coupler implantation in patients with
CH
as compared with
ISH
.

Methods and Results

The randomized, controlled, prospective ROX Control Hypertension Study included patients with true
treatment‐resistant hypertension
(office systolic
BP
≥140 mm Hg, average daytime ambulatory
BP
≥135/85 mm Hg, and treatment with ≥3 antihypertensive drugs including a diuretic). In a post hoc analysis, we stratified patients with
CH
(n=31) and
ISH
(n=11). Baseline office systolic
BP
(177±18 mm Hg versus 169±17 mm Hg,
P
=0.163) and 24‐hour ambulatory systolic
BP
(159±16 mm Hg versus 154±11 mm Hg,
P
=0.463) did not differ between
patients with CH
and
those with ISH
.
ROX
coupler implementation resulted in a significant reduction in office systolic
BP
(
CH
: −29±21 mm Hg versus
ISH
: −22±31 mm Hg,
P
=0.445) and 24‐hour ambulatory systolic
BP
(
CH
: −14±20 mm Hg versus
ISH
: −13±15 mm Hg,
P
=0.672), without significant differences between the two groups. The responder rate (office systolic
BP
reduction ≥10 mm Hg) after 6 months was not different (
CH
: 81% versus
ISH
: 82%,
P
=0.932).

Conclusions

Our data suggest that creation of an
arteriovenous
anastomosis using the
ROX
coupler system leads to a similar reduction of office and 24‐hour ambulatory systolic
BP
in patients with combined and isolated systolic hypertension.

Clinical Trial Registration

URL
:
http://www.clinicaltrials.gov
. Unique identifier:
NCT
01642498.
Association of Family History With Cardiovascular Disease in Hypertensive Individuals in a Multiethnic Population
Authors: Valerio Luca , Peters Ron J. , Zwinderman Aeilko H. , Pinto‐Sietsma Sara‐Joan 
Published: December 2016

Background
Hypertension alone is a poor predictor of the individual risk of cardiovascular disease. Hereditary factors of which hypertension is merely a marker may explain why some hypertensive individuals appear more susceptible to cardiovascular disease, and why some ethnicities have more often seemingly hypertension‐related cardiovascular disease than others. We hypothesize that, in hypertensive individuals, a positive family history of cardiovascular disease identifies a high‐risk subpopulation.

Methods and Results

Healthy Life in Urban Settings (HELIUS) is a cohort study among participants of Dutch, South‐Asian Surinamese, African Surinamese, Ghanaian, Turkish, and Moroccan origin aged 70 years and younger. In participants with hypertension (n=6467), we used logistic regression to assess the association of family history of cardiovascular disease with prevalent stroke and nonstroke cardiovascular disease, adjusting for sex, age, education, and smoking. To detect ethnic differences, we tested for interaction between family history and ethnicity and stratified the analysis by ethnicity. A positive family history was associated with a higher prevalence of nonstroke cardiovascular disease (odds ratio [OR], 2.05; 95%
CI
, 1.65–2.54) and stroke (OR, 1.62; 95%
CI
, 1.19–2.20). The strongest association of family history with nonstroke cardiovascular disease was found among the Dutch (OR, 2.47; 95% CI, 1.37–4.44) and with stroke among the African Surinamese (OR, 2.17; 95% CI, 1.32–3.57). The interaction between family history and African Surinamese origin for stroke was statistically significant.

Conclusions
In multiethnic populations of hypertensive patients, a positive family history of cardiovascular disease may be used clinically to identify individuals at high risk for nonstroke cardiovascular disease regardless of ethnic origin and African Surinamese individuals at high risk for stroke.