bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeted Dual-Modality Imaging in Renal Cell Carcinoma: An Ex Vivo Kidney Perfusion Study
Authors: Hekman Marlène C.H. , Boerman Otto C. , de Weijert Mirjam , Bos Desirée L. , Oosterwijk Egbert , Langenhuijsen Hans F. , Mulders Peter F.A. , Rijpkema Mark 
Published: April 2016

Abstract
Purpose: Antibodies labeled with both a near-infrared fluorescent dye and a radionuclide can be used for tumor-targeted intraoperative dual-modality imaging. Girentuximab is a chimeric monoclonal antibody against carbonic anhydrase IX (CAIX), an antigen expressed in 95% of clear cell renal cell carcinoma (ccRCC). This study aimed to assess the feasibility of targeted dual-modality imaging with 111In-girentuximab-IRDye800CW using ex vivo perfusion of human tumorous kidneys.
Experimental Design: Seven radical nephrectomy specimens from patients with ccRCC were perfused during 11 to 15 hours with dual-labeled girentuximab and subsequently rinsed during 2.5 to 4 hours with Ringer's Lactate solution. Then, dual-modality imaging was performed on a 5- to 10-mm-thick lamella of the kidney. Fluorescence imaging was performed with a clinical fluorescence camera set-up as applied during image-guided surgery. The distribution of Indium-111 in the slice of tumor tissue was visualized by autoradiography. In two perfusions, an additional dual-labeled control antibody was added to demonstrate specific accumulation of dual-labeled girentuximab in CAIX-expressing tumor tissue.
Results: Both radionuclide and fluorescence imaging clearly visualized uptake in tumor tissue and tumor-to-normal tissue borders, as confirmed (immuno)histochemically and by gamma counting. Maximum uptake of girentuximab in tumor tissue was 0.33% of the injected dose per gram (mean, 0.12 %ID/g; range, 0.01–0.33 %ID/g), whereas maximum uptake in the normal kidney tissue was 0.04 %ID/g (mean, 0.02 %ID/g; range, 0.00–0.04 %ID/g).
Conclusions: Dual-labeled girentuximab accumulated specifically in ccRCC tissue, indicating the feasibility of dual-modality imaging to detect ccRCC. A clinical study to evaluate intraoperative dual-modality imaging in patients with ccRCC has been initiated. Clin Cancer Res; 22(18); 4634–42. ©2016 AACR.
Comprehensive Molecular Characterization of Salivary Duct Carcinoma Reveals Actionable Targets and Similarity to Apocrine Breast Cancer
Authors: Dalin Martin G. , Desrichard Alexis , Katabi Nora , Makarov Vladimir , Walsh Logan A. , Lee Ken-Wing , Wang Qingguo , Armenia Joshua , West Lyndsay , Dogan Snjezana , Wang Lu , Ramaswami Deepa , Ho Alan L. , Ganly Ian , Solit David B. , Berger Michael F. , Schultz Nikolaus D. , Reis-Filho Jorge S. , Chan Timothy A. , Morris Luc G.T. 
Published: April 2016

Abstract
Purpose: Salivary duct carcinoma (SDC) is an aggressive salivary malignancy, which is resistant to chemotherapy and has high mortality rates. We investigated the molecular landscape of SDC, focusing on genetic alterations and gene expression profiles.
Experimental Design: We performed whole-exome sequencing, RNA sequencing, and immunohistochemical analyses in 16 SDC tumors and examined selected alterations via targeted sequencing of 410 genes in a second cohort of 15 SDCs.
Results: SDCs harbored a higher mutational burden than many other salivary carcinomas (1.7 mutations/Mb). The most frequent genetic alterations were mutations in TP53 (55%), HRAS (23%), PIK3CA (23%), and amplification of ERBB2 (35%). Most (74%) tumors had alterations in either MAPK (BRAF/HRAS/NF1) genes or ERBB2. Potentially targetable alterations based on supportive clinical evidence were present in 61% of tumors. Androgen receptor (AR) was overexpressed in 75%; several potential resistance mechanisms to androgen deprivation therapy (ADT) were identified, including the AR-V7 splice variant (present in 50%, often at low ratios compared with full-length AR) and FOXA1 mutations (10%). Consensus clustering and pathway analyses in transcriptome data revealed striking similarities between SDC and molecular apocrine breast cancer.
Conclusions: This study illuminates the landscape of genetic alterations and gene expression programs in SDC, identifying numerous molecular targets and potential determinants of response to AR antagonism. This has relevance for emerging clinical studies of ADT and other targeted therapies in SDC. The similarities between SDC and apocrine breast cancer indicate that clinical data in breast cancer may generate useful hypotheses for SDC. Clin Cancer Res; 22(18); 4623–33. ©2016 AACR.
Association Between Family History, a Genetic Risk Score, and Severity of Coronary Artery Disease in Patients With Premature Acute Coronary Syndromes
Authors: Hindieh Waseem , Pilote Louise , Cheema Asim , Al-Lawati Hatim , Labos Christopher , Dufresne Line , Engert James C. , Thanassoulis George 
Published: April 2016

Objective—
A genetic risk score (GRS) for coronary artery disease has recently been shown to be independent of family history (FHx) in predicting future cardiovascular events. We sought to determine whether the presence of these risk factors, either individually or together, was associated with a higher burden of angiographic coronary artery disease.

Approach and Results—

We included 763 patients with premature acute coronary syndrome (median age, 50 [46–53] years; 30.8% women) with at least 1 major epicardial vessel stenosis enrolled in the Gender and Sex Determinants of Cardiovascular Disease From Bench to Beyond in Premature Acute Coronary Syndrome (GENESIS-PRAXY) study, a multicentre prospective cohort study of premature patients with acute coronary syndrome (aged ≤55 years). The prevalence of multivessel disease (ie, ≥2 vessels with >50% stenosis) in individuals with FHx was 49.7% as compared with 37.9% in those without FHx (
P
<0.01 for comparison). In adjusted models for age, sex, traditional risk factors, and GRS, FHx was associated with a higher prevalence of 3-vessel disease (odds ratio [OR], 1.42; 95% confidence interval, 0.91–2.21;
P
=0.12 for 2-vessel disease and OR, 2.26; 95% confidence interval, 1.29–3.95;
P
=0.005 for 3-vessel disease). Individuals with a high GRS were also more likely to have multivessel disease (OR, 1.41; 95% confidence interval, 1.01–1.99;
P
=0.047) after adjustment for traditional risk factors, including FHx. Individuals with both a FHx and a high GRS as compared with those with neither had the highest ORs for multivessel disease (adjusted OR, 2.14; 95% confidence interval, 1.24–3.69;
P
=0.0064).

Conclusions—
In patients with premature acute coronary syndrome, the presence of either a high GRS or FHx is associated with greater severity of coronary artery disease at angiography. Whether preventive strategies targeted to genetically predisposed individuals will reduce the burden of early acute coronary syndrome warrants further study.
Artery Tertiary Lymphoid Organs Control Multilayered Territorialized Atherosclerosis B-Cell Responses in Aged
ApoE

−/−

Mice
Authors: Srikakulapu Prasad , Hu Desheng , Yin Changjun , Mohanta Sarajo K. , Bontha Sai Vineela , Peng Li , Beer Michael , Weber Christian , McNamara Coleen A. , Grassia Gianluca , Maffia Pasquale , Manz Rudolf A. , Habenicht Andreas J.R. 
Published: April 2016

Objective—

Explore aorta B-cell immunity in aged apolipoprotein E-deficient (
ApoE

−/−

) mice.

Approach and Results—

Transcript maps, fluorescence-activated cell sorting, immunofluorescence analyses, cell transfers, and Ig-ELISPOT (enzyme-linked immunospot) assays showed multilayered atherosclerosis B-cell responses in artery tertiary lymphoid organs (ATLOs). Aging-associated aorta B-cell–related transcriptomes were identified, and transcript atlases revealed highly territorialized B-cell responses in ATLOs versus atherosclerotic lesions: ATLOs showed upregulation of bona fide B-cell genes, including Cd19, Ms4a1 (Cd20), Cd79a/b, and Ighm although intima plaques preferentially expressed molecules involved in non–B effector responses toward B-cell–derived mediators, that is, Fcgr3 (Cd16), Fcer1g (Cd23), and the C1q family. ATLOs promoted B-cell recruitment. ATLO B-2 B cells included naive, transitional, follicular, germinal center, switched IgG1
+
, IgA
+
, and IgE
+
memory cells, plasmablasts, and long-lived plasma cells. ATLOs recruited large numbers of B-1 cells whose subtypes were skewed toward interleukin-10
+
B-1b cells versus interleukin-10
−
B-1a cells. ATLO B-1 cells and plasma cells constitutively produced IgM and IgG and a fraction of plasma cells expressed interleukin-10. Moreover,
ApoE

−/−

mice showed increased germinal center B cells in renal lymph nodes, IgM-producing plasma cells in the bone marrow, and higher IgM and anti–MDA-LDL (malondialdehyde-modified low-density lipoprotein) IgG serum titers.

Conclusions—
ATLOs orchestrate dichotomic, territorialized, and multilayered B-cell responses in the diseased aorta; germinal center reactions indicate generation of autoimmune B cells within the diseased arterial wall during aging.
Cardiovascular Risk Factors and Ischemic Heart Disease
Authors: Elosua Roberto , Lluís-Ganella Carla , Subirana Isaac , Havulinna Aki , Läll Kristi , Lucas Gavin , Sayols-Baixeras Sergi , Pietilä Arto , Alver Maris , Cabrera de León Antonio , Sentí Mariano , Siscovick David , Mellander Olle , Fischer Krista , Salomaa Veikko , Marrugat Jaume 
Published: April 2016

Background—
Cardiovascular risk factors tend to aggregate. The biological and predictive value of this aggregation is questioned and genetics could shed light on this debate. Our aims were to reappraise the impact of risk factor confluence on ischemic heart disease (IHD) risk by testing whether genetic risk scores (GRSs) associated with these factors interact on an additive or multiplicative scale, and to determine whether these interactions provide additional value for predicting IHD risk.

Methods and Results—

We selected genetic variants associated with blood pressure, body mass index, waist circumference, triglycerides, type-2 diabetes mellitus, high-density lipoprotein and low-density lipoprotein cholesterol, and IHD to create GRSs for each factor. We tested and meta-analyzed the impact of additive (synergy index) and multiplicative (β
interaction
) interactions between each GRS pair in 1 case–control (n=6042) and 4 cohort studies (n=17 794) and evaluated the predictive value of these interactions. We observed 2 multiplicative interactions: GRS
LDL
·GRS
Triglycerides
(β
interaction
=–0.096; SE=0.028) and nonpleiotropic GRS
IHD
·GRS
LDL
(β
interaction
=0.091; SE=0.028). Inclusion of these interaction terms did not improve predictive capacity.

Conclusions—
The confluence of low-density lipoprotein cholesterol and triglycerides genetic risk load has an additive effect on IHD risk. The interaction between low-density lipoprotein cholesterol and IHD genetic load is more than multiplicative, supporting the hazardous impact on atherosclerosis progression of the combination of inflammation and increased lipid levels. The capacity of risk factor confluence to improve IHD risk prediction is questionable. Further studies in larger samples are warranted to confirm and expand our results.
Decade Long Trends (2001–2011) in Duration of Pre‐Hospital Delay Among Elderly Patients Hospitalized for an Acute Myocardial Infarction
Authors: Makam Raghavendra P. , Erskine Nathaniel , Yarzebski Jorge , Lessard Darleen , Lau Jason , Allison Jeroan , Gore Joel M. , Gurwitz Jerry , McManus David D. , Goldberg Robert J. 
Published: April 2016

Background

Early intervention with medical and/or coronary revascularization treatment approaches remains the cornerstone of the management of patients hospitalized with acute myocardial infarction (
AMI
). However, several patient groups, especially the elderly, are known to delay seeking prompt medical care after onset of
AMI
‐associated symptoms. Current trends, and factors associated with prolonged prehospital delay among elderly patients hospitalized with
AMI
, are incompletely understood.

Methods and Results

Data from a population‐based study of patients hospitalized at all 11 medical centers in central Massachusetts with a confirmed
AMI
on a biennial basis between 2001 and 2011 were analyzed. Information about duration of prehospital delay after onset of acute coronary symptoms was abstracted from hospital medical records. In patients 65 years and older, the overall median duration of prehospital delay was 2.0 hours, with corresponding median delays of 2.0, 2.1, and 2.0 hours in those aged 65 to 74 years, 75 to 84 years, and in patients 85 years and older, respectively. There were no significant changes over time in median delay times in each of the age strata examined in both crude and multivariable adjusted analyses. A limited number of patient characteristics were associated with prolonged delay in this patient population.

Conclusions

The results of this community‐wide study demonstrate that delay in seeking prompt medical care continues to be a significant problem among elderly patients hospitalized with
AMI
. The lack of improvement in the timeliness of patients’ care‐seeking behavior during the years under study remains of considerable clinical and public health concern.
Leukocyte Count and Intracerebral Hemorrhage Expansion
Authors: Morotti Andrea , Phuah Chia-Ling , Anderson Christopher D. , Jessel Michael J. , Schwab Kristin , Ayres Alison M. , Pezzini Alessandro , Padovani Alessandro , Gurol M. Edip , Viswanathan Anand , Greenberg Steven M. , Goldstein Joshua N. , Rosand Jonathan 
Published: April 2016

Background and Purpose—
Acute leukocytosis is a well-established response to intracerebral hemorrhage (ICH). Leukocytes, because of their interaction with platelets and coagulation factors, may in turn play a role in hemostasis. We investigated whether admission leukocytosis was associated with reduced bleeding after acute ICH.

Methods—
Consecutive patients with primary ICH were prospectively collected from 1994 to 2015 and retrospectively analyzed. We included subjects with a follow-up computed tomographic scan available and automated complete white blood cell count performed within 48 hours from onset. Baseline and follow-up hematoma volumes were calculated with semiautomated software, and hematoma expansion was defined as volume increase >30% or 6 mL. The association between white blood cell count and ICH expansion was investigated with multivariate logistic regression.

Results—

A total of 1302 subjects met eligibility criteria (median age, 75 years; 55.8% men), of whom 207 (15.9%) experienced hematoma expansion. Higher leukocyte count on admission was associated with reduced risk of hematoma expansion (odds ratio for 1000 cells increase, 0.91; 95% confidence interval, 0.86–0.96;
P
=0.001). The risk of hematoma expansion was inversely associated with neutrophil count (odds ratio, 0.90; 95% confidence interval, 0.85–0.96;
P
=0.001) and directly associated with monocyte count (odds ratio, 2.71; 95% confidence interval, 1.08–6.83;
P
=0.034). There was no association between lymphocyte count and ICH expansion (odds ratio, 0.96; 95% confidence interval, 0.79–1.17;
P
=0.718).

Conclusions—
Higher admission white blood cell count is associated with lower risk of hematoma expansion. This highlights a potential role of the inflammatory response in modulating the coagulation cascade after acute ICH.
Resource Allocation for Lagrangian Tracking
Authors: Jones Benjamin T. , Solow Andrew , Ji Rubao 
Published: April 2016

AbstractAccurate estimation of the transport probabilities among regions in the ocean provides valuable information for understanding plankton transport, the spread of pollutants, and the movement of water masses. Individual-based particle-tracking models simulate a large ensemble of Lagrangian particles and are a common method to estimate these transport probabilities. Simulating a large ensemble of Lagrangian particles is computationally expensive, and appropriately allocating resources can reduce the cost of this method. Two universal questions in the design of studies that use Lagrangian particle tracking are how many particles to release and how to distribute particle releases. A method is presented for tailoring the number and the release location of particles to most effectively achieve the objectives of a study. The method detailed here is a sequential analysis procedure that seeks to minimize the number of particles that are required to satisfy a predefined metric of result quality. The study assesses the result quality as the precision of the estimates for the elements of a transport matrix and also describes how the method may be extended for use with other metrics. Applying this methodology to both a theoretical system and a particle transport model of the Gulf of Maine results in more precise estimates of the transport probabilities with fewer particles than from uniformly or randomly distributing particle releases. The application of this method can help reduce the cost of and increase the robustness of results from studies that use Lagrangian particles.
Owner-reported lower urinary tract signs in a cohort of young cats
Authors: Longstaff Louise , Gruffydd-Jones Timothy J , Buffington CA Tony , Casey Rachel A , Murray Jane K 
Published: April 2016

Objectives The most common cause of lower urinary tract signs (LUTS) in cats under the age of 10 years is feline idiopathic cystitis (FIC). The prevalence of LUTS in the UK pet cat population is difficult to assess. This study used data collected prospectively to investigate the prevalence of, and risk factors for, owner-reported LUTS in a cohort of young pet cats. Methods Cat owners were recruited into a long-term longitudinal study and asked to complete questionnaires at specified age points for their cats. All cats were at least 18 months of age at the time of analysis. The prevalence of owner-reported LUTS at 18, 30 and 48 months of age was calculated, based on whether the owner had seen the cat urinating, and whether the cat had displayed one or more of the following clinical signs: dysuria, haematuria or vocalising during urination. A case-control study to investigate the risk factors for owner-reported LUTS in study cats at age 18 months was also conducted, using a multivariable logistic regression model. Results The prevalence of owner-reported LUTS in cats seen urinating by the owner was 4.3%, 3.8% and 6.0%, with 95% confidence intervals of 3.2–5.7%, 2.5–5.7% and 3.4–10.5% at ages 18, 30 and 48 months, respectively. An indoor-only lifestyle at the age of 18 months and a change in diet between the ages of 12 and 18 months were identified as risk factors for owner-reported LUTS at the age of 18 months from the multivariable model. No clear type of change in diet was identified in our sample of cats with LUTS. Conclusions and relevance The prevalence of owner-reported LUTS in a cohort of young pet cats was higher than the previously reported prevalence of LUTS in cats presenting to veterinary hospitals for LUTS or other reasons. A novel risk factor of change in diet between 12 and 18 months of age warrants further investigation.
Risk stratification for 25-year cardiovascular disease incidence in type 1 diabetes: Tree-structured survival analysis of the Pittsburgh Epidemiology of Diabetes Complications study
Authors: Miller Rachel G , Anderson Stewart J , Costacou Tina , Sekikawa Akira , Orchard Trevor J 
Published: April 2016

Background: The formal identification of subgroups with varying levels of risk is uncommon in observational studies of cardiovascular disease, although such insight might be useful for clinical management. Methods: Tree-structured survival analysis was utilized to determine whether there are meaningful subgroups at varying levels of cardiovascular disease risk in the Pittsburgh Epidemiology of Diabetes Complications study, a prospective cohort study of childhood-onset (<17 years old) type 1 diabetes. Results: Of the 561 participants free of cardiovascular disease (coronary artery disease, stroke or lower extremity arterial disease) at baseline, 263 (46.9%) had an incident cardiovascular disease event over the 25-year follow-up. Tree-structured survival analysis revealed a range of risk groups, from 24% to 85%, which demonstrate that those with short diabetes duration and elevated non–high-density lipoprotein cholesterol have similar cardiovascular disease risk to those with long diabetes duration and that renal disease is a better discriminator of risk in men than in women. Conclusion: Our findings suggest that subgroups with major cardiovascular disease risk differences exist in this type 1 diabetes cohort. Using tree-structured survival analysis may help to identify these groups and the interrelationships between their associated risk factors. This approach may improve our understanding of various clinical pathways to cardiovascular disease and help target intervention strategies.
Considerably decreased risk of cardiovascular disease with combined reductions in HbA1c, blood pressure and blood lipids in type 2 diabetes: Report from the Swedish National Diabetes Register
Authors: Eeg-Olofsson Katarina , Zethelius Björn , Gudbjörnsdottir Soffia , Eliasson Björn , Svensson Ann-Marie , Cederholm Jan 
Published: April 2016

Objectives: Assess the effect of risk factors changes on risk for cardiovascular disease and mortality in patients with type 2 diabetes selected from the Swedish National Diabetes Register. Methods: Observational study of 13,477 females and males aged 30–75 years, with baseline HbA1c 41–67 mmol/mol, systolic blood pressure 122–154 mmHg and ratio non-HDL:HDL 1.7–4.1, followed for mean 6.5 years until 2012. Four groups were created: a reference group ( n = 6757) with increasing final versus baseline HbA1c, systolic blood pressure and non-HDL:HDL cholesterol during the study period, and three groups with decreasing HbA1c ( n = 1925), HbA1c and systolic blood pressure ( n = 2050) or HbA1c and systolic blood pressure and non-HDL:HDL ( n = 2745). Results: Relative risk reduction for fatal/nonfatal cardiovascular disease was 35% with decrease in HbA1c only (mean 6 to final 49 mmol/mol), 56% with decrease in HbA1c and systolic blood pressure (mean 12 to final 128 mmHg) and 75% with combined decreases in HbA1c, systolic blood pressure and non-HDL:HDL (mean 0.8 to final 2.1), all p < 0.001 adjusting for clinical characteristics, other risk factors, treatments and previous cardiovascular disease. Similar risk reductions were found for fatal/nonfatal coronary heart disease, fatal cardiovascular disease, all-cause mortality and also in a subgroup of 3038 patients with albuminuria. Conclusion: Considerable risk reductions for cardiovascular disease and mortality were seen with combined long-term risk factor improvement.