bluuebunny/crossref_metadata_2025_split huggingface dataset:
A 0.1–1.4 GHz inductorless low-noise amplifier with 13 dBm IIP3 and 24 dBm IIP2 in 180 nm CMOS
Authors: Guo Benqing , Chen Jun , Chen Hongpeng , Wang Xuebing 
Published: December 2017

An inductorless noise-canceling CMOS low-noise amplifier (LNA) with wideband linearization technique is proposed. The complementary configuration by stacked NMOS/PMOS is employed to compensate second-order nonlinearity of the circuit. The third-order distortion of the auxiliary stage is also mitigated by that of the weak inversion transistors in the main path. The bias and scaling size combined by digital control words are further tuned to obtain enhanced linearity over the desired band. Implemented in a 0.18 [Formula: see text]m CMOS process, simulated results show that the proposed LNA provides a voltage gain of 16.1 dB and a NF of 2.8–3.4 dB from 0.1 GHz to 1.4 GHz. The IIP3 and IIP2 of 13–18.9 and 24–40 dBm are obtained, respectively. The circuit core consumes 19 mW from a 1.8 V supply.
Liver tissue metabolically transformed by alcohol induces immune recognition of liver self-proteins but not in vivo inflammation
Authors: Duryee Michael J. , Wiese Benjamin M. , Bowman Jordan R. , Vanlandingham Jared D. , Klassen Lynell W. , Thiele Geoffrey E. , Hunter Carlos D. , Anderson Daniel R. , Mikuls Ted R. , Thiele Geoffrey M. 
Published: December 2017

Precision-cut liver slices (PCLSs) provide a novel model for studies of alcoholic liver disease (ALD). This is relevant, as in vivo ethanol exposure does not appear to generate significant liver damage in ethanol-fed mice, except in the National Institute on Alcohol Abuse and Alcoholism binge model of ALD. Previous studies have shown that the two metabolites of ethanol consumption, malondialdhyde (MDA) and acetaldehyde (AA), combine to form MDA-AA (MAA) adducts, which have been correlated with the development and progression of ALD. In this study, murine PCLSs were incubated with ethanol and examined for the production of MAA adducts. PCLSs were homogenized, and homogenates were injected into C57BL/6 mice. PCLSs from control-, pair-, and ethanol-fed animals served as targets in in situ cytotoxic assays using primed T cells from mice hyperimmunized with control or ethanol-exposed PCLS homogenates. A CD45.1/CD45.2 passive-transfer model was used to determine whether T cells from the spleens of mice hyperimmunized with PCLS ethanol-exposed homogenates trafficked to the liver. PCLSs incubated with ethanol generated MAA-modified proteins in situ. Cytotoxic (CD8+) T cells from immunized mice killed naïve PCLSs from control- and pair-fed mice in vitro, a response that was blunted in PCLSs from ethanol-fed mice. Furthermore, CD45.1 CD8+ T cells from hyperimmunized mice trafficked to the liver but did not initiate liver damage. This study demonstrates that exposure to liver tissue damaged by ethanol mediates robust immune responses to well-characterized alcohol metabolites and native liver proteins in vitro. Moreover, although these proinflammatory T cells traffic to the liver, these responses appear to be dampened in vivo by locally acting pathways. NEW & NOTEWORTHY This study shows that the metabolites of ethanol and lipid breakdown produce malondialdehyde-acetaldehyde adducts in the precision-cut liver slice model system. Additionally, precision-cut liver slices exposed to ethanol and harboring malondialdehyde-acetaldehyde adducts generate liver-specific antibody and T cell responses in the spleens of naïve mice that could traffic to the liver.
No Association between Organochlorine Concentrations in Adipose Tissue and Survival after Non-Hodgkin Lymphoma
Authors: Roswall Nina , Sørensen Mette , Bräuner Elvira Vaclavik , Tjønneland Anne , Raaschou-Nielsen Ole 
Published: December 2017

Abstract
Background: Non-Hodgkin lymphoma (NHL) is the most common hematologic malignancy in the world. Involvement of organochlorines has been proposed in disease etiology. No study has investigated organochlorine exposure in relation to survival after a NHL diagnosis.
Methods: In a survivor cohort consisting of 232 NHL cases from the Danish Diet, Cancer and Health cohort, we examined the association between adipose tissue organochlorine concentrations [polychlorinated biphenyls (PCBs) and pesticides] and subsequent survival, using Cox proportional hazards models.
Results: We found no statistically significant association between organochlorine concentrations and subsequent survival. If anything, there was a nonsignificant tendency toward an inverse association with PCBs, but not pesticides.
Conclusions: In conclusion, the current study does not support an increased risk of death among NHL patients with high tissue concentrations of organochlorines.
Impact: This is the first study to investigate adipose organochlorine concentrations and survival after a NHL diagnosis. Cancer Epidemiol Biomarkers Prev; 27(2); 224–6. ©2017 AACR.
PIK3CA C2 Domain Deletions Hyperactivate Phosphoinositide 3-kinase (PI3K), Generate Oncogene Dependence, and Are Exquisitely Sensitive to PI3Kα Inhibitors
Authors: Croessmann Sarah , Sheehan Jonathan H. , Lee Kyung-min , Sliwoski Gregory , He Jie , Nagy Rebecca , Riddle David , Mayer Ingrid A. , Balko Justin M. , Lanman Richard , Miller Vincent A. , Cantley Lewis C. , Meiler Jens , Arteaga Carlos L. 
Published: December 2017

Abstract
Purpose: We describe herein a novel P447_L455 deletion in the C2 domain of PIK3CA in a patient with an ER+ breast cancer with an excellent response to the PI3Kα inhibitor alpelisib. Although PIK3CA deletions are relatively rare, a significant portion of deletions cluster within amino acids 446–460 of the C2 domain, suggesting these residues are critical for p110α function.
Experimental Design: A computational structural model of PIK3CAdelP447-L455 in complex with the p85 regulatory subunit and MCF10A cells expressing PIK3CAdelP447-L455 and PIK3CAH450_P458del were used to understand the phenotype of C2 domain deletions.
Results: Computational modeling revealed specific favorable inter-residue contacts that would be lost as a result of the deletion, predicting a significant decrease in binding energy. Coimmunoprecipitation experiments showed reduced binding of the C2 deletion mutants with p85 compared with wild-type p110α. The MCF10A cells expressing PIK3CA C2 deletions exhibited growth factor–independent growth, an invasive phenotype, and higher phosphorylation of AKT, ERK, and S6 compared with parental MCF10A cells. All these changes were ablated by alpelisib treatment.
Conclusions: C2 domain deletions in PIK3CA generate PI3K dependence and should be considered biomarkers of sensitivity to PI3K inhibitors. Clin Cancer Res; 24(6); 1426–35. ©2017 AACR.
Structural Alterations of MET Trigger Response to MET Kinase Inhibition in Lung Adenocarcinoma Patients
Authors: Plenker Dennis , Bertrand Miriam , de Langen Adrianus J. , Riedel Richard , Lorenz Carina , Scheel Andreas H. , Müller Judith , Brägelmann Johannes , Daßler-Plenker Juliane , Kobe Carsten , Persigehl Thorsten , Kluge Alexander , Wurdinger Thomas , Schellen Pepijn , Hartmann Gunther , Zacherle Tobias , Menon Roopika , Thunnissen Erik , Büttner Reinhard , Griesinger Frank , Wolf Jürgen , Heukamp Lukas , Sos Martin L. , Heuckmann Johannes M. 
Published: December 2017

Abstract
Purpose: We sought to investigate the clinical response to MET inhibition in patients diagnosed with structural MET alterations and to characterize their functional relevance in cellular models.
Experimental Design: Patients were selected for treatment with crizotinib upon results of hybrid capture–based next-generation sequencing. To confirm the clinical observations, we analyzed cellular models that express these MET kinase alterations.
Results: Three individual patients were identified to harbor alterations within the MET receptor. Two patients showed genomic rearrangements, leading to a gene fusion of KIF5B or STARD3NL and MET. One patient diagnosed with an EML4-ALK rearrangement developed a MET kinase domain duplication as a resistance mechanism to ceritinib. All 3 patients showed a partial response to crizotinib that effectively inhibits MET and ALK among other kinases. The results were further confirmed using orthogonal cellular models.
Conclusions: Crizotinib leads to a clinical response in patients with MET rearrangements. Our functional analyses together with the clinical data suggest that these structural alterations may represent actionable targets in lung cancer patients. Clin Cancer Res; 24(6); 1337–43. ©2017 AACR.
β-Catenin mRNA Silencing and MEK Inhibition Display Synergistic Efficacy in Preclinical Tumor Models
Authors: Ganesh Shanthi , Shui Xue , Craig Kevin P. , Koser Martin L. , Chopda Girish R. , Cyr Wendy A. , Lai Chengjung , Dudek Henryk , Wang Weimin , Brown Bob D. , Abrams Marc T. 
Published: December 2017

Abstract
Colorectal carcinomas harbor well-defined genetic abnormalities, including aberrant activation of Wnt/β-catenin and MAPK pathways, often simultaneously. Although the MAPK pathway can be targeted using potent small-molecule drugs, including BRAF and MEK inhibitors, β-catenin inhibition has been historically challenging. RNAi approaches have advanced to the stage of clinical viability and are especially well suited for transcriptional modulators, such as β-catenin. In this study, we report therapeutic effects of combined targeting of these pathways with pharmacologic agents. Using a recently described tumor-selective nanoparticle containing a β-catenin–targeting RNAi trigger, in combination with the FDA-approved MEK inhibitor (MEKi) trametinib, we demonstrate synergistic tumor growth inhibition in in vivo models of colorectal cancer, melanoma, and hepatocellular carcinoma. At dose levels that were insufficient to significantly impact tumor growth as monotherapies, combination regimens resulted in synergistic efficacy and complete tumor growth inhibition. Importantly, dual MEKi/RNAi therapy dramatically improved survival of mice bearing colorectal cancer liver metastases. In addition, pharmacologic silencing of β-catenin mRNA was effective against tumors that are inherently resistant or that acquire drug-induced resistance to trametinib. These results provide a strong rationale for clinical evaluation of this dual-targeting approach for cancers harboring Wnt/β-catenin and MAPK pathway mutations. Mol Cancer Ther; 17(2); 544–53. ©2017 AACR.
DKK3 (Dickkopf 3) Alters Atherosclerotic Plaque Phenotype Involving Vascular Progenitor and Fibroblast Differentiation Into Smooth Muscle Cells
Authors: Karamariti Eirini , Zhai Chungang , Yu Baoqi , Qiao Lei , Wang Zhihong , Potter Claire M.F. , Wong Mei Mei , Simpson Russell M.L. , Zhang Zhongyi , Wang Xiaocong , del Barco Barrantes Ivan , Niehrs Christof , Kong Deling , Zhao Qiang , Zhang Yun , Hu Yanhua , Zhang Cheng , Xu Qingbo 
Published: December 2017

Objective—
DKK3 (dickkopf 3), a 36-kD secreted glycoprotein, has been shown to be involved in the differentiation of partially reprogrammed cells and embryonic stem cells to smooth muscle cells (SMCs), but little is known about its involvement in vascular disease. This study aims to assess the effects of DKK3 on atherosclerotic plaque composition.

Approach and Results—

In the present study, we used a murine model of atherosclerosis (
ApoE
−/−
) in conjunction with
DKK3
−/−
and performed tandem stenosis of the carotid artery to evaluate atherosclerotic plaque development. We found that the absence of DKK3 leads to vulnerable atherosclerotic plaques, because of a reduced number of SMCs and reduced matrix protein deposition, as well as increased hemorrhage and macrophage infiltration. Further in vitro studies revealed that DKK3 can induce differentiation of Sca1
+
(stem cells antigen 1) vascular progenitors and fibroblasts into SMCs via activation of the TGF-β (transforming growth factor-β)/ATF6 (activating transcription factor 6) and Wnt signaling pathways. Finally, we assessed the therapeutic potential of DKK3 in mouse and rabbit models and found that DKK3 altered the atherosclerotic plaque content via increasing SMC numbers and reducing vascular inflammation.

Conclusions—
Cumulatively, we provide the first evidence that DKK3 is a potent SMC differentiation factor, which might have a therapeutic effect in reducing intraplaque hemorrhage related to atherosclerotic plaque phenotype.
Filamin A Modulates Store-Operated Ca
2+
Entry by Regulating STIM1 (Stromal Interaction Molecule 1)–Orai1 Association in Human Platelets
Authors: Lopez Jose J. , Albarrán Letizia , Jardín Isaac , Sanchez-Collado Jose , Redondo Pedro C. , Bermejo Nuria , Bobe Regis , Smani Tarik , Rosado Juan A. 
Published: December 2017

Objective—
Here, we provide evidence for the role of FLNA (filamin A) in the modulation of store-operated calcium entry (SOCE).

Approach and Results—

SOCE is a major mechanism for calcium influx controlled by the intracellular Ca
2+
stores. On store depletion, the endoplasmic reticulum calcium sensor STIM1 (stromal interaction molecule 1) redistributes into puncta at endoplasmic reticulum/plasma membrane junctions, a process supported by the cytoskeleton, where it interacts with the calcium channels; however, the mechanism for fine-tuning SOCE is not completely understood. Our results demonstrate that STIM1 interacts with FLNA on calcium store depletion in human platelets. The interaction is dependent on the phosphorylation of FLNA at Ser
2152
by the cAMP-dependent protein kinase. Impairment of FLNA phosphorylation and knockdown of FLNA expression using siRNA increased SOCE in platelets. Similarly, SOCE was significantly greater in FLNA-deficient melanoma M2 cells than in the FLNA-expressing M2 subclone A7. Expression of FLNA in M2 cells attenuated SOCE, an effect prevented when the cells were transfected with the nonphosphorylatable FLNA S2152A mutant. Transfection of M2 cells with the STIM1(K684,685E) mutant reduced the STIM1–FLNA interaction. In platelets, attenuation of FLNA expression using siRNA resulted in enhanced association of STIM1 with the cytoskeleton, greater STIM1–Orai1 interaction, and SOCE. Introduction of an anti-FLNA (2597–2647) antibody attenuated the STIM1–FLNA interaction and enhanced thrombin-induced platelet aggregation.

Conclusions—
Our results indicate that FLNA modulates SOCE and then the correct platelet function, by fine-tuning the distribution of STIM1 in the cytoskeleton and the interaction with Orai1 channels.
Melanocortin 1 Receptor Deficiency Promotes Atherosclerosis in Apolipoprotein E
−/−
Mice
Authors: Rinne Petteri , Kadiri James J. , Velasco-Delgado Mauricio , Nuutinen Salla , Viitala Miro , Hollmén Maija , Rami Martina , Savontaus Eriika , Steffens Sabine 
Published: December 2017

Objective—
The MC1-R (melanocortin 1 receptor) is expressed by monocytes and macrophages where it mediates anti-inflammatory actions. MC1-R also protects against macrophage foam cell formation primarily by promoting cholesterol efflux through the ABCA1 (ATP-binding cassette transporter subfamily A member 1) and ABCG1 (ATP-binding cassette transporter subfamily G member 1). In this study, we aimed to investigate whether global deficiency in MC1-R signaling affects the development of atherosclerosis.

Approach and Results—

Apoe
−/−
(apolipoprotein E deficient) mice were crossed with recessive yellow (Mc1r
e/e
) mice carrying dysfunctional MC1-R and fed a high-fat diet to induce atherosclerosis. Apoe
−/−
Mc1r
e/e
mice developed significantly larger atherosclerotic lesions in the aortic sinus and in the whole aorta compared with Apoe
−/−
controls. In terms of plaque composition, MC1-R deficiency was associated with less collagen and smooth muscle cells and increased necrotic core, indicative of more vulnerable lesions. These changes were accompanied by reduced
Abca1
and
Abcg1
expression in the aorta. Furthermore, Apoe
−/−
Mc1r
e/e
mice showed a defect in bile acid metabolism that aggravated high-fat diet–induced hypercholesterolemia and hepatic lipid accumulation. Flow cytometric analysis of leukocyte profile revealed that dysfunctional MC1-R enhanced arterial accumulation of classical Ly6C
high
monocytes and macrophages, effects that were evident in mice fed a normal chow diet but not under high-fat diet conditions. In support of enhanced arterial recruitment of Ly6C
high
monocytes, these cells had increased expression of L-selectin and P-selectin glycoprotein ligand 1.

Conclusions—
The present study highlights the importance of MC1-R in the development of atherosclerosis. Deficiency in MC1-R signaling exacerbates atherosclerosis by disturbing cholesterol handling and by increasing arterial monocyte accumulation.
Comparison of Risk Factor Control in the Year After Discharge for Ischemic Stroke Versus Acute Myocardial Infarction
Authors: Bravata Dawn M. , Daggy Joanne , Brosch Jared , Sico Jason J. , Baye Fitsum , Myers Laura J. , Roumie Christianne L. , Cheng Eric , Coffing Jessica , Arling Greg 
Published: December 2017

Background and Purpose—
The Veterans Health Administration has engaged in quality improvement to improve vascular risk factor control. We sought to examine blood pressure (<140/90 mm Hg), lipid (LDL [low-density lipoprotein] cholesterol <100 mg/dL), and glycemic control (hemoglobin A1c <9%), in the year post-hospitalization for acute ischemic stroke or acute myocardial infarction (AMI).

Methods—
We identified patients who were hospitalized (fiscal year 2011) with ischemic stroke, AMI, congestive heart failure, transient ischemic attack, or pneumonia/chronic obstructive pulmonary disease. The primary analysis compared risk factor control after incident ischemic stroke versus AMI. Facilities were included if they cared for ≥25 ischemic stroke and ≥25 AMI patients. A generalized linear mixed model including patient- and facility-level covariates compared risk factor control across diagnoses.

Results—

Forty thousand two hundred thirty patients were hospitalized (n=75 facilities): 2127 with incident ischemic stroke and 4169 with incident AMI. Fewer stroke patients achieved blood pressure control than AMI patients (64%; 95% confidence interval, 0.62–0.67 versus 77%; 95% confidence interval, 0.75–0.78;
P
<0.0001). After adjusting for patient and facility covariates, the odds of blood pressure control were still higher for AMI than ischemic stroke patients (odds ratio, 1.39; 95% confidence interval, 1.21–1.51). There were no statistical differences for AMI versus stroke patients in hyperlipidemia (
P
=0.534). Among patients with diabetes mellitus, the odds of glycemic control were lower for AMI than ischemic stroke patients (odds ratio, 0.72; 95% confidence interval, 0.54–0.96).

Conclusions—
Given that hypertension control is a cornerstone of stroke prevention, interventions to improve poststroke hypertension management are needed.
Carotid Intima-Media Thickness Is Associated With White Matter Hyperintensities
Authors: Della-Morte David , Dong Chuanhui , Markert Matthew S. , Elkind Mitchell S.V. , Sacco Ralph L. , Wright Clinton B. , Rundek Tatjana 
Published: December 2017

Background and Purpose—
Brain white matter hyperintensities (WMH) have been associated with increased risk of stroke, cognitive decline, and dementia. WMH can be a manifestation of small vessel disease, although the total microvascular contribution to multifactorial WMH pathophysiology remains unknown. We hypothesized a possible relationship between carotid intima-media thickness (cIMT), an ultrasound imaging marker of subclinical vascular disease, and brain WMH in a multiethnic, elderly stroke-free community-based cohort.

Methods—
We evaluated the relationship between cIMT and WMH in the population-based Northern Manhattan Study, among individuals free of stroke. We used linear regression to examine the association of continuous measures of cIMT with quantitatively derived WMH volume, as a proportion of cranial volume, measured from fluid-attenuaded inversion recovery magnetic resonance imaging while adjusting for sociodemographics, lifestyle, and vascular risk factors.

Results—

In a cohort of 1229 participants (mean age, 71±9 years; 60% women, 15% White; 18% Black; 65% Hispanics), the mean cIMT was 0.71±0.08 mm and the median log-transformed WMH volume was 0.36 (interquartile range, 0.21–0.76). In a multivariable model, larger cIMT was significantly associated with greater WMH volume (β=0.046 per SD cIMT;
P
=0.04). Age and race/ethnicity were significant modifiers (
P
for age, 0.02; and
P
for race/ethnicity, 0.04). cIMT was associated with WMH volume in participants 70 years or older (β=0.088 per SD cIMT;
P
=0.01) and among Hispanics (β=0.084 per SD cIMT;
P
=0.003).

Conclusions—
Larger cIMT was associated with greater burden of cerebral WM lesions independently of demographics and traditional vascular risk factors, particularly among elderly and Hispanic participants, who are at high risk for stroke and cognitive decline.
Association Between Heart Rate and Subclinical Cerebrovascular Disease in the Elderly
Authors: Nakanishi Koki , Jin Zhezhen , Homma Shunichi , Elkind Mitchell S.V. , Rundek Tatjana , Lee Seitetz C. , Tugcu Aylin , Yoshita Mitsuhiro , DeCarli Charles , Wright Clinton B. , Sacco Ralph L. , Di Tullio Marco R. 
Published: December 2017

Background and Purpose—
Although increased heart rate (HR) is a predictor of cardiovascular events and mortality, its possible association with subclinical cerebrovascular disease, which is prevalent in the elderly, has not been evaluated. This study aimed to investigate the association of daytime, nighttime, 24-hour HR, and HR variability with subclinical cerebrovascular disease in an elderly cohort without history of stroke.

Methods—
The study cohort consisted of 680 participants (mean age, 73±7 years; 42% men) in sinus rhythm who underwent 24-hour ambulatory blood pressure and HR monitoring, 2-dimensional echocardiography, and brain magnetic resonance imaging as part of the CABL study (Cardiac Abnormalities and Brain Lesion). Subclinical cerebrovascular disease was defined as silent brain infarcts and white matter hyperintensity volume (WMHV). The relationship of HR measures with the presence of silent brain infarct and upper quartile of log WMHV (log WMHV4) was analyzed.

Results—

Presence of silent brain infarct was detected in 93 participants (13.7%); mean log WMHV was −0.92±0.93 (median, −1.05; min, −5.88; max, 1.74). Multivariate analysis showed that only nighttime HR (adjusted odds ratio, 1.29 per 10 bpm; 95% confidence interval, 1.03–1.61;
P
=0.026) was significantly associated with log WMHV4, independent of traditional cardiovascular risk factors, ambulatory systolic blood pressure, and echocardiographic parameters. No similar association was observed for daytime HR and HR variability. There was no significant association between all HR measures and silent brain infarct.

Conclusions—
In a predominantly elderly cohort, elevated nighttime HR was associated with WMHV, suggesting an independent role of HR in subclinical cerebrovascular disease.
Evolution of Turbulence in the Diurnal Warm Layer
Authors: Moulin Aurélie J. , Moum James N. , Shroyer Emily L. 
Published: December 2017

AbstractThe daily evolution of temperature, stratification, and turbulence in the diurnal warm layer is described from time series measurements at low to moderate winds and strong insolation in the equatorial Indian Ocean. At 2.0-m depth, turbulence dissipation rates (ε) decreased by two orders of magnitude over 1–2 h immediately after sunrise, initiated by stratification caused by penetrating solar radiation prior to the change in sign of net surface heat flux from cooling to warming. Decaying turbulence preceded a period of rapid growth, in which ε increased by two orders of magnitude over a few hours, and following which ε approached a daytime period of near-steady state. Decay and growth rates predicted by a simplified turbulence model are consistent with those observed. During the daytime period of near-steady state, asymmetric temperature ramps were associated with enhanced ε, supporting the interpretation that this period represents a balance between buoyancy and shear production associated with a shear-driven response to trapping of momentum within the diurnal warm layer.