bluuebunny/crossref_metadata_2025 huggingface dataset:
Spatial Modeling of Drug Delivery Routes for Treatment of Disseminated Ovarian Cancer
Authors: Winner Kimberly R. Kanigel , Steinkamp Mara P. , Lee Rebecca J. , Swat Maciej , Muller Carolyn Y. , Moses Melanie E. , Jiang Yi , Wilson Bridget S.
Published: January 2016

In ovarian cancer, metastasis is typically confined to the peritoneum. Surgical removal of the primary tumor and macroscopic secondary tumors is a common practice, but more effective strategies are needed to target microscopic spheroids persisting in the peritoneal fluid after debulking surgery. To treat this residual disease, therapeutic agents can be administered by either intravenous or intraperitoneal infusion. Here, we describe the use of a cellular Potts model to compare tumor penetration of two classes of drugs (cisplatin and pertuzumab) when delivered by these two alternative routes. The model considers the primary route when the drug is administered either intravenously or intraperitoneally, as well as the subsequent exchange into the other delivery volume as a secondary route. By accounting for these dynamics, the model revealed that intraperitoneal infusion is the markedly superior route for delivery of both small-molecule and antibody therapies into microscopic, avascular tumors typical of patients with ascites. Small tumors attached to peritoneal organs, with vascularity ranging from 2% to 10%, also show enhanced drug delivery via the intraperitoneal route, even though tumor vessels can act as sinks during the dissemination of small molecules. Furthermore, we assessed the ability of the antibody to enter the tumor by in silico and in vivo methods and suggest that optimization of antibody delivery is an important criterion underlying the efficacy of these and other biologics. The use of both delivery routes may provide the best total coverage of tumors, depending on their size and vascularity. Cancer Res; 76(6); 1320–34. ©2015 AACR.
miR-892b Silencing Activates NF-κB and Promotes Aggressiveness in Breast Cancer
Authors: Jiang Lili , Yu Liang , Zhang Xin , Lei Fangyong , Wang Lan , Liu Xiangxia , Wu Shu , Zhu Jinrong , Wu Geyan , Cao Lixue , Liu Aibin , Song Libing , Li Jun
Published: January 2016

The strength and duration of NF-κB signaling is tightly controlled at multiple levels under physiologic conditions, but the mechanism underlying constitutive activation of the NF-κB pathway in cancer remains unclear. In this study, we investigated miRNA-mediated regulation of the NF-κB cascade in breast cancer. We report that miR-892b expression was significantly downregulated in human breast cancer specimens and correlated with poor patient survival. Overexpression of miR-892b in breast cancer cells significantly decreased tumor growth, metastatic capacity, and the ability to induce angiogenesis, whereas miR-892b depletion enhanced these properties, in vitro and in vivo. Furthermore, we demonstrate that miR-892b attenuated NF-κB signaling by directly targeting and suppressing multiple mediators of NF-κB, including TRAF2, TAK1, and TAB3, and thus, miR-892b silencing in breast cancer cells sustains NF-κB activity. Moreover, miR-892b downregulation was attributed to aberrant hypermethylation of its promoter. Taken together, our results provide insight into a new mechanism by which NF-κB signaling becomes constitutively activated in breast cancer and suggest a tumor-suppressive role for miR-829b, prompting further investigation into miRNA mimics for cancer therapy. Cancer Res; 76(5); 1101–11. ©2016 AACR.
SOX4 Is Essential for Prostate Tumorigenesis Initiated by PTEN Ablation
Authors: Bilir Birdal , Osunkoya Adeboye O. , Wiles W. Guy , Sannigrahi Soma , Lefebvre Veronique , Metzger Daniel , Spyropoulos Demetri D. , Martin W. David , Moreno Carlos S.
Published: January 2016

Understanding remains incomplete of the mechanisms underlying initiation and progression of prostate cancer, the most commonly diagnosed cancer in American men. The transcription factor SOX4 is overexpressed in many human cancers, including prostate cancer, suggesting it may participate in prostate tumorigenesis. In this study, we investigated this possibility by genetically deleting Sox4 in a mouse model of prostate cancer initiated by loss of the tumor suppressor Pten. We found that specific homozygous deletion of Sox4 in the adult prostate epithelium strongly inhibited tumor progression initiated by homozygous loss of Pten. Mechanistically, Sox4 ablation reduced activation of AKT and β-catenin, leading to an attenuated invasive phenotype. Furthermore, SOX4 expression was induced by Pten loss as a result of the activation of PI3K–AKT–mTOR signaling, suggesting a positive feedback loop between SOX4 and PI3K–AKT–mTOR activity. Collectively, our findings establish that SOX4 is a critical component of the PTEN/PI3K/AKT pathway in prostate cancer, with potential implications for combination-targeted therapies against both primary and advanced prostate cancers. Cancer Res; 76(5); 1112–21. ©2015 AACR.
Anticancer Effects of Mesothelin-Targeted Immunotoxin Therapy Are Regulated by Tyrosine Kinase DDR1
Authors: Ali-Rahmani Fatima , FitzGerald David J. , Martin Scott , Patel Paresma , Prunotto Marco , Ormanoglu Pinar , Thomas Craig , Pastan Ira
Published: January 2016

Recombinant immunotoxins (RIT) have been highly successful in cancer therapy due, in part, to the high cancer-specific expression of cell surface antigens such as mesothelin, which is overexpressed in mesothelioma, ovarian, lung, breast, and pancreatic cancers, but is limited in normal cells. RG7787 is a clinically optimized RIT consisting of a humanized anti-mesothelin Fab fused to domain III of Pseudomonas exotoxin A, in which immunogenic B-cell epitopes are silenced. To enhance the therapeutic efficacy of RITs, we conducted a kinome RNAi sensitization screen, which identified discoidin domain receptor 1 (DDR1), a collagen-activated tyrosine kinase, as a potential target. The collagen/DDR1 axis is implicated in tumor–stromal interactions and potentially affects tumor response to therapy. Therefore, we investigated the effects of DDR1 on RIT. Knockdown of DDR1 by siRNA or treatment with inhibitor, 7rh, greatly enhanced the cytotoxic activity of RG7787 in several cancer cell lines. Investigation into the mechanism of action showed DDR1 silencing was associated with decreased expression of several ribosomal proteins and enhanced inhibition of protein synthesis. Conversely, induction of DDR1 expression or collagen-stimulated DDR1 activity protected cancer cells from RG7787 killing. Moreover, the combination of RG7787 and DDR1 inhibitor caused greater shrinkage of tumor xenografts than either agent alone. These data demonstrate that DDR1 is a key modulator of RIT activity and represents a novel therapeutic strategy to improve targeting of mesothelin-expressing cancers. Cancer Res; 76(6); 1560–8. ©2015 AACR.
Serum Endotoxins and Flagellin and Risk of Colorectal Cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) Cohort
Authors: Kong So Yeon , Tran Hao Quang , Gewirtz Andrew T. , McKeown-Eyssen Gail , Fedirko Veronika , Romieu Isabelle , Tjønneland Anne , Olsen Anja , Overvad Kim , Boutron-Ruault Marie-Christine , Bastide Nadia , Affret Aurélie , Kühn Tilman , Kaaks Rudolf , Boeing Heiner , Aleksandrova Krasimira , Trichopoulou Antonia , Kritikou Maria , Vasilopoulou Effie , Palli Domenico , Krogh Vittorio , Mattiello Amalia , Tumino Rosario , Naccarati Alessio , Bueno-de-Mesquita H.B. , Peeters Petra H. , Weiderpass Elisabete , Quirós J. Ramón , Sala Núria , Sánchez María-José , Castaño José María Huerta , Barricarte Aurelio , Dorronsoro Miren , Werner Mårten , Wareham Nicholas J. , Khaw Kay-Tee , Bradbury Kathryn E. , Freisling Heinz , Stavropoulou Faidra , Ferrari Pietro , Gunter Marc J. , Cross Amanda J. , Riboli Elio , Bruce W. Robert , Jenab Mazda
Published: January 2016

Background: Chronic inflammation and oxidative stress are thought to be involved in colorectal cancer development. These processes may contribute to leakage of bacterial products, such as lipopolysaccharide (LPS) and flagellin, across the gut barrier. The objective of this study, nested within a prospective cohort, was to examine associations between circulating LPS and flagellin serum antibody levels and colorectal cancer risk.

Methods: A total of 1,065 incident colorectal cancer cases (colon, n = 667; rectal, n = 398) were matched (1:1) to control subjects. Serum flagellin- and LPS-specific IgA and IgG levels were quantitated by ELISA. Multivariable conditional logistic regression models were used to calculate ORs and 95% confidence intervals (CI), adjusting for multiple relevant confouding factors.

Results: Overall, elevated anti-LPS and anti-flagellin biomarker levels were not associated with colorectal cancer risk. After testing potential interactions by various factors relevant for colorectal cancer risk and anti-LPS and anti-flagellin, sex was identified as a statistically significant interaction factor (Pinteraction < 0.05 for all the biomarkers). Analyses stratified by sex showed a statistically significant positive colorectal cancer risk association for men (fully-adjusted OR for highest vs. lowest quartile for total anti-LPS + flagellin, 1.66; 95% CI, 1.10–2.51; Ptrend, 0.049), whereas a borderline statistically significant inverse association was observed for women (fully-adjusted OR, 0.70; 95% CI, 0.47–1.02; Ptrend, 0.18).

Conclusion: In this prospective study on European populations, we found bacterial exposure levels to be positively associated to colorectal cancer risk among men, whereas in women, a possible inverse association may exist.

Impact: Further studies are warranted to better clarify these preliminary observations. Cancer Epidemiol Biomarkers Prev; 25(2); 291–301. ©2016 AACR.
Immunotherapy against Metastatic Melanoma with Human iPS Cell–Derived Myeloid Cell Lines Producing Type I Interferons
Authors: Miyashita Azusa , Fukushima Satoshi , Nakahara Satoshi , Kubo Yosuke , Tokuzumi Aki , Yamashita Junji , Aoi Jun , Haruta Miwa , Senju Satoru , Nishimura Yasuharu , Jinnin Masatoshi , Ihn Hironobu
Published: January 2016

In recent years, immunotherapy for advanced melanoma has been gaining increased attention. The efficacy of anti-cytotoxic T-lymphocyte antigen 4 antibodies, anti-programmed cell death 1 antibodies, and the BRAFV600E kinase inhibitor has been proven in metastatic melanoma. At the same time, adoptive cell transfer has significant effects against metastatic melanoma; however, it is difficult to apply on a broad scale because of the problems related to cell preparation. To overcome these problems, we developed immune cell therapy using induced pluripotent stem (iPS) cells. The benefit of our method is that a large number of cells can be readily obtained. We focused on macrophages for immune cell therapy because macrophage infiltration is frequently observed in solid cancers. In this study, the efficacy of human iPS cell–derived myeloid cell lines (iPS-ML) genetically modified to express type I IFNs against human melanoma cells was examined. The morphology, phagocytic ability, and surface markers of iPS-ML were similar to those of macrophages. The iPS-ML that express type I IFNs (iPS-ML-IFN) showed significant effects in inhibiting the growth of disseminated human melanoma cells in SCID mice. The infiltration of iPS-ML into the tumor nests was confirmed immunohistologically. The iPS-ML-IFNs increased the expression of CD169, a marker of M1 macrophages that can activate antitumor immunity. The iPS-ML-IFNs could infiltrate into tumor tissue and exert anticancer effects in the local tumor tissue. In conclusion, this method will provide a new therapeutic modality for metastatic melanoma. Cancer Immunol Res; 4(3); 248–58. ©2015 AACR.
Melanoma Brain Metastasis Pseudoprogression after Pembrolizumab Treatment
Authors: Cohen Justine V. , Alomari Ahmed K. , Vortmeyer Alexander O. , Jilaveanu Lucia B. , Goldberg Sarah B. , Mahajan Amit , Chiang Veronica L. , Kluger Harriet M.
Published: January 2016

The role of immunotherapy in treatment of brain metastases is unknown because most trials exclude patients with active brain lesions. As new immunomodulating agents gain approval for many malignancies, it is important to know if they have unique effects in the central nervous system (CNS). Here, we present a case of a patient with progressing brain metastases treated with a single cycle of pembrolizumab, who presented with mental status changes 11 days thereafter. MRI of the brain showed enlargement of CNS lesions with intense central enhancement and diffuse perilesional edema. Histologic evaluation of a resected lesion revealed isolated clusters of tumor cells surrounded by reactive astrocytosis, scattered inflammatory cells, and an abundance of microglial cells. Given the increasing use of immune checkpoint inhibitors in patients with brain metastases from melanoma and other diseases, recognition of pseudoprogression and management with immune suppression are essential. Cancer Immunol Res; 4(3); 179–82. ©2015 AACR.
Identification of T-cell Receptors Targeting KRAS-Mutated Human Tumors
Authors: Wang Qiong J. , Yu Zhiya , Griffith Kayla , Hanada Ken-ichi , Restifo Nicholas P. , Yang James C.
Published: January 2016

KRAS is one of the most frequently mutated proto-oncogenes in human cancers. The dominant oncogenic mutations of KRAS are single amino acid substitutions at codon 12, in particular G12D and G12V present in 60% to 70% of pancreatic cancers and 20% to 30% of colorectal cancers. The consistency, frequency, and tumor specificity of these “neoantigens” make them attractive therapeutic targets. Recent data associate T cells that target mutated antigens with clinical immunotherapy responses in patients with metastatic melanoma, lung cancer, or cholangiocarcinoma. Using HLA-peptide prediction algorithms, we noted that HLA-A*11:01 could potentially present mutated KRAS variants. By immunizing HLA-A*11:01 transgenic mice, we generated murine T cells and subsequently isolated T-cell receptors (TCR) highly reactive to the mutated KRAS variants G12V and G12D. Peripheral blood lymphocytes (PBL) transduced with these TCRs could recognize multiple HLA-A*11:01+ tumor lines bearing the appropriate KRAS mutations. In a xenograft model of large established tumor, adoptive transfer of these transduced PBLs reactive with an HLA-A*11:01, G12D-mutated pancreatic cell line could significantly reduce its growth in NSG mice (P = 0.002). The success of adoptive transfer of TCR-engineered T cells against melanoma and other cancers supports clinical trials with these T cells that recognize mutated KRAS in patients with a variety of common cancer types. Cancer Immunol Res; 4(3); 204–14. ©2015 AACR.
Temporal Trends and Variation in Early Scheduled Follow-Up After a Hospitalization for Heart Failure
Authors: DeVore Adam D. , Cox Margueritte , Eapen Zubin J. , Yancy Clyde W. , Bhatt Deepak L. , Heidenreich Paul A. , Peterson Eric D. , Fonarow Gregg C. , Hernandez Adrian F.
Published: January 2016

Background—

Previous data demonstrate early follow-up (ie, within 7 days of discharge) after a hospitalization for heart failure is associated with a lower risk of readmission, yet is uncommon and varies widely across hospitals. Limited data exist on whether the use of early follow-up after discharge has improved over time.

Methods and Results—

We used data from Get With The Guidelines-Heart Failure (GWTG-HF) linked to Medicare claims to examine temporal trends in early follow-up and to assess for patient and hospital characteristics associated with early scheduled follow-up. In the overall GWTG-HF cohort, we studied 52 438 patients discharged from 239 hospitals from 2009 to 2012. Scheduled early follow-up at the time of hospital discharge rose from 51% to 65% over time (
P
<0.001). After multivariable adjustment, patients with older age (odds ratio, 1.04; 95% confidence interval, 1.01–1.07), certain comorbidities (anemia, diabetes mellitus, and chronic kidney disease), and the use of anticoagulation at discharge (odds ratio, 1.16; 95% confidence interval, 1.11–1.22) were associated with greater likelihood for early scheduled follow-up. Patients treated in hospitals located in the Midwest (odds ratio, 0.67; 95% confidence interval, 0.50–0.91) were less likely to have early scheduled follow-up. In a subset of patients with linked Medicare claims, we observed smaller improvements in actual early follow-up visits over time from 26% to 30% (
P
=0.005).

Conclusions—

From 2009 to 2012, there was improvement in early scheduled outpatient follow-up and, in the subset analyzed, improvement in actual early follow-up visits for hospitalized patients with heart failure. However, substantial opportunities remain for improving heart failure transitional care.
Efficacy and Safety of Available Protocols for Aspirin Hypersensitivity for Patients Undergoing Percutaneous Coronary Intervention
Authors: Bianco Matteo , Bernardi Alessandro , D’Ascenzo Fabrizio , Cerrato Enrico , Omedè Pierluigi , Montefusco Antonio , DiNicolantonio James J. , Zoccai Giuseppe Biondi , Varbella Ferdinando , Carini Giovanni , Moretti Claudio , Pozzi Roberto , Gaita Fiorenzo
Published: January 2016

Background—

The most suitable approach for patients with aspirin hypersensitivity undergoing percutaneous coronary intervention remains to be assessed.

Methods and Results—

Pubmed, Google Scholar, and Cochrane were systematically searched for papers describing protocols about aspirin hypersensitivity in the percutaneous coronary intervention setting. Discharge from hospital with aspirin was the primary end point, whereas rates of adverse reactions being a secondary outcome. An online international survey was performed to critically analyze rates of aspirin hypersensitivity and its medical and interventional management. Eleven studies with 283 patients were included. An endovenous desensitization protocol was performed on one of them, with high efficacy rate (98%) and a low adverse reaction rate when compared with oral administration. No significant differences were reported among the oral protocols in terms of efficacy (less versus more fractionated [95.8% {95.4%–96.2%} versus 95.9% {95.2–96.5%}]), whereas higher incidence of rash and angioedema were reported for protocols with <6 doses escalation (2.6% [1.1%–4.1%] versus 2.6% [1.9%–3.2%]). In the survey, we collected answer from 86 physician of the 100 interviewed. Fifty-six percent of them managed aspirin hypersensitivity changing the therapeutic regimen (eg, clopidogrel monotherapy and indobufen). Despite the previous safety data, desensitization protocols were adopted by only 42% of surveyed cardiologist.

Conclusions—

Available protocols for aspirin hypersensitivity are effective and safe, representing a feasible approach for patients needing dual antiplatelet therapy.
Cardiovascular Effects of Unilateral Nephrectomy in Living Kidney Donors
Authors: Moody William E. , Ferro Charles J. , Edwards Nicola C. , Chue Colin D. , Lin Erica Lai Sze , Taylor Robin J. , Cockwell Paul , Steeds Richard P. , Townend Jonathan N.
Published: January 2016

Abstract—

There is a robust inverse graded association between glomerular filtration rate (GFR) and cardiovascular risk, but proof of causality is lacking. Emerging data suggest living kidney donation may be associated with increased cardiovascular mortality although the mechanisms are unclear. We hypothesized that the reduction in GFR in living kidney donors is associated with increased left ventricular mass, impaired left ventricular function, and increased aortic stiffness. This was a multicenter, parallel group, blinded end point study of living kidney donors and healthy controls (n=124), conducted from March 2011 to August 2014. The primary outcome was a change in left ventricular mass assessed by magnetic resonance imaging (baseline to 12 months). At 12 months, the decrease in isotopic GFR in donors was −30±12 mL/min/1.73m
2
. In donors compared with controls, there were significant increases in left ventricular mass (+7±10 versus −3±8 g;
P
<0.001) and mass:volume ratio (+0.06±0.12 versus −0.01±0.09 g/mL;
P
<0.01), whereas aortic distensibility (−0.29±1.38 versus +0.28±0.79×10
−3
mm Hg
−1
;
P
=0.03) and global circumferential strain decreased (−1.1±3.8 versus +0.4±2.4%;
P
=0.04). Donors had greater risks of developing detectable highly sensitive troponin T (odds ratio, 16.2 [95% confidence interval, 2.6–100.1];
P
<0.01) and microalbuminuria (odds ratio, 3.8 [95% confidence interval, 1.1–12.8];
P
=0.04). Serum uric acid, parathyroid hormone, fibroblast growth factor-23, and high-sensitivity C-reactive protein all increased significantly. There were no changes in ambulatory blood pressure. Change in GFR was independently associated with change in left ventricular mass (
R
2
=0.28;
P
=0.01). These findings suggest that reduced GFR should be regarded as an independent causative cardiovascular risk factor.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01028703.
Digoxin Use Is Associated With Reduced Interstage Mortality in Patients With No History of Arrhythmia After Stage I Palliation for Single Ventricle Heart Disease
Authors: Brown David W. , Mangeot Colleen , Anderson Jeffrey B. , Peterson Laura E. , King Eileen C. , Lihn Stacey L. , Neish Steven R. , Fleishman Craig , Phelps Christina , Hanke Samuel , Beekman Robert H. , Lannon Carole M. ,   the National Pediatric Cardiology Quality Improvement Collaborative
Published: January 2016

Background

Interstage mortality (
IM
) remains significant after stage 1 palliation (S1P) for single‐ventricle heart disease (
SVD
), with many deaths sudden and unexpected. We sought to determine whether digoxin use post‐S1P is associated with reduced
IM
, utilizing the multicenter database of the National Pediatric Cardiology Quality Improvement Collaborative (
NPCQIC
).

Methods and Results

From June 2008 to July 2013, 816 infants discharged after S1P from 50 surgical sites completed the interstage to stage
II
palliation, transplant, or
IM
. Arrhythmia during S1P hospitalization or discharge on antiarrhythmic medications were exclusions (n=270); 2 patients were lost to follow‐up. Two analyses were performed: (1) propensity‐score adjusted logistic regression with
IM
as outcome and (2) retrospective cohort analysis for patients discharged on digoxin versus not, matched for surgical site and other established
IM
risk factors. Of 544 study patients, 119 (21.9%) were discharged on digoxin. Logistic regression analysis with propensity score, site‐size group, and digoxin use as predictor variables showed an increased risk of
IM
in those not discharged on digoxin (odds ratio, 8.6; lower confidence limit, 1.9; upper confidence limit, 38.3;
P
<0.01). The retrospective cohort analysis for 60 patients on digoxin (matched for site of care, type of S1P, post‐S1P
ECMO
use, genetic syndrome, discharge feeding route, ventricular function, tricuspid regurgitation, and aortic arch gradient) showed 0%
IM
in the digoxin at discharge group and an estimated
IM
difference between the 2 groups of 9% (
P
=0.04).

Conclusions

Among
SVD
infants in the
NPCQIC
database discharged post‐S1P with no history of arrhythmia, use of digoxin at discharge was associated with reduced
IM
.
Mitochondrial Reactive Oxygen Species Mediate Cardiac Structural, Functional, and Mitochondrial Consequences of Diet‐Induced Metabolic Heart Disease
Authors: Sverdlov Aaron L. , Elezaby Aly , Qin Fuzhong , Behring Jessica B. , Luptak Ivan , Calamaras Timothy D. , Siwik Deborah A. , Miller Edward J. , Liesa Marc , Shirihai Orian S. , Pimentel David R. , Cohen Richard A. , Bachschmid Markus M. , Colucci Wilson S.
Published: January 2016

Background

Mitochondrial reactive oxygen species (
ROS
) are associated with metabolic heart disease (
MHD
). However, the mechanism by which
ROS
cause
MHD
is unknown. We tested the hypothesis that mitochondrial
ROS
are a key mediator of
MHD
.

Methods and Results

Mice fed a high‐fat high‐sucrose (
HFHS
) diet develop
MHD
with cardiac diastolic and mitochondrial dysfunction that is associated with oxidative posttranslational modifications of cardiac mitochondrial proteins. Transgenic mice that express catalase in mitochondria and wild‐type mice were fed an
HFHS
or control diet for 4 months. Cardiac mitochondria from
HFHS
‐fed wild‐type mice had a 3‐fold greater rate of H
2
O
2
production (
P
=0.001 versus control diet fed), a 30% decrease in complex
II
substrate–driven oxygen consumption (
P
=0.006), 21% to 23% decreases in complex I and
II
substrate–driven
ATP
synthesis (
P
=0.01), and a 62% decrease in complex
II
activity (
P
=0.002). In transgenic mice that express catalase in mitochondria, all
HFHS
diet–induced mitochondrial abnormalities were ameliorated, as were left ventricular hypertrophy and diastolic dysfunction. In
HFHS
‐fed wild‐type mice complex
II
substrate–driven
ATP
synthesis and activity were restored ex vivo by dithiothreitol (5 mmol/L), suggesting a role for reversible cysteine oxidative posttranslational modifications. In vitro site‐directed mutation of complex
II
subunit B Cys100 or Cys103 to redox‐insensitive serines prevented complex
II
dysfunction induced by
ROS
or high glucose/high palmitate in the medium.

Conclusion

Mitochondrial
ROS
are pathogenic in
MHD
and contribute to mitochondrial dysfunction, at least in part, by causing oxidative posttranslational modifications of complex I and
II
proteins including reversible oxidative posttranslational modifications of complex
II
subunit B Cys100 and Cys103.
Intravenous Lipid Infusion Induces Endoplasmic Reticulum Stress in Endothelial Cells and Blood Mononuclear Cells of Healthy Adults
Authors: Tampakakis Emmanouil , Tabit Corey E. , Holbrook Monika , Linder Erika A. , Berk Brittany D. , Frame Alissa A. , Bretón‐Romero Rosa , Fetterman Jessica L. , Gokce Noyan , Vita Joseph A. , Hamburg Naomi M.
Published: January 2016

Background

Endoplasmic reticulum (
ER
) stress and the subsequent unfolded protein response may initially be protective, but when prolonged, have been implicated in atherogenesis in diabetic conditions. Triglycerides and free fatty acids (
FFAs
) are elevated in patients with diabetes and may contribute to
ER
stress. We sought to evaluate the effect of acute
FFA
elevation on
ER
stress in endothelial and circulating white cells.

Methods and Results

Twenty‐one healthy subjects were treated with intralipid (20%; 45 mL/h) plus heparin (12 U/kg/h) infusion for 5 hours. Along with increased triglyceride and
FFA
levels, intralipid/heparin infusion reduced the calf reactive hyperemic response without a change in conduit artery flow‐mediated dilation consistent with microvascular dysfunction. To investigate the short‐term effects of elevated triglycerides and
FFA
, we measured markers of
ER
stress in peripheral blood mononuclear cells (
PBMC
s) and vascular endothelial cells (
VEC
s). In
VEC
s, activating transcription factor 6 (
ATF
6) and phospho‐inositol requiring kinase 1 (
pIRE
1) proteins were elevated after infusion (both
P
<0.05). In
PBMC
s,
ATF
6 and spliced X‐box‐binding protein 1 (
XBP
‐1) gene expression increased by 2.0‐ and 2.5‐fold, respectively (both
P
<0.05), whereas
CHOP
and
GADD
34 decreased by ≈67% and 74%, respectively (both
P
<0.01).
ATF
6 and
pIRE
1 protein levels also increased (both
P
<0.05), and confocal microscopy revealed the nuclear localization of
ATF
6 after infusion, suggesting activation.

Conclusions

Along with microvascular dysfunction, intralipid infusion induced an early protective
ER
stress response evidenced by activation of
ATF
6 and
IRE
1 in both leukocytes and endothelial cells. Our results suggest a potential link between metabolic disturbances and
ER
stress that may be relevant to vascular disease.
Galectin‐3 Is Elevated and Associated With Adverse Outcomes in Patients With Single‐Ventricle Fontan Circulation
Authors: Opotowsky Alexander R. , Baraona Fernando , Owumi Justin , Loukas Brittani , Singh Michael N. , Valente Anne Marie , Wu Fred , Cheng Susan , Veldtman Gruschen , Rimm Eric B. , Landzberg Michael J.
Published: January 2016

Background

Galectin‐3 may play a role in cardiac and noncardiac fibrosis, and elevated circulating levels of this protein predict adverse outcomes in patients with heart failure who do not have congenital heart disease. We investigated galectin‐3 in adults with single‐ventricle Fontan circulation, patients who are prone to premature clinical deterioration in the context of extensive multiorgan fibrosis.

Methods and Results

We measured plasma galectin‐3 concentrations in 70 ambulatory adult Fontan patients and 21 age‐ and sex‐matched control participants. Galectin‐3 level was significantly higher in the Fontan group (11.85 ng/mL, interquartile range 9.9 to 15.0 ng/mL) versus the control group (9.4 ng/mL, interquartile range 8.2 to 10.8 ng/mL;
P
<0.001). Among Fontan patients, galectin‐3 was positively correlated with age, uric acid, and high‐sensitivity C‐reactive protein and negatively correlated with estimated glomerular filtration rate. There was no significant relationship between galectin‐3 and oxygen saturation, Fontan type, or ventricular morphology. Over a median follow‐up of 461 days, 15 events occurred among the Fontan patients: 12 nonelective hospitalizations (with 2 subsequent deaths) and 3 deaths without prior hospitalization. Patients with elevated galectin‐3 (n=19, defined as >2
SD
above the control group mean value) had a higher risk of nonelective hospitalization or death (hazard ratio 6.0, 95%
CI
2.1 to 16.8,
P
<0.001). This relationship persisted after individual adjustment for covariates including age, New York Heart Association functional class, C‐reactive protein, and estimated glomerular filtration rate and after multivariable adjustment for independently predictive covariates (hazard ratio 9.2, 95%
CI
2.4 to 35.2,
P
=0.001).

Conclusions

Galectin‐3 concentrations are elevated among adults with a Fontan circulation, and elevated galectin‐3 is associated with an increased risk of nonelective cardiovascular hospitalization or death.
Implementation of Pit Crew Approach and Cardiopulmonary Resuscitation Metrics for Out‐of‐Hospital Cardiac Arrest Improves Patient Survival and Neurological Outcome
Authors: Hopkins Christy L. , Burk Chris , Moser Shane , Meersman Jack , Baldwin Clair , Youngquist Scott T.
Published: January 2016

Introduction

Survival from out‐of‐hospital cardiac arrest (
OHCA
) varies by community and emergency medical services (
EMS
) system. We hypothesized that the adoption of multiple best practices to focus
EMS
crews on high‐quality, minimally interrupted cardiopulmonary resuscitation (CPR) would improve survival of
OHCA
patients in Salt Lake City.

Methods and Results

In September 2011, Salt Lake City Fire Department
EMS
providers underwent a systemwide restructuring of care for
OHCA
patients that focused on the adoption of high‐quality
CPR
with minimal interruptions and offline medical review of defibrillator data and feedback on
CPR
metrics. Victims were directed to
ST
‐elevation myocardial infarction receiving centers. Prospectively collected data on patient survival and neurological outcome for all
OHCA
s were compared. In the postintervention period, there were 407 cardiac arrests with 65 neurologically intact survivors (16%), compared with 330 cardiac arrests with 25 neurologically intact survivors (8%) in the preintervention period. Among patients who survived to hospital admission, a higher proportion in the postintervention period survived to hospital discharge (71/141 [50%] versus 36/98 [37%],
P
=0.037) and had a favorable neurological outcome (65 [46%] versus 25 [26%],
P
=0.0005) compared with patients treated before the protocol changes. The univariate odds ratio or the association between neurologically intact survival (cerebral performance category 1 and 2) and protocol implementation was 2.3 (95%
CI
1.4 to 3.7,
P
=0.001). Among discharged patients, the distribution of cerebral performance category scores was more favorable in the postintervention period (
P
<0.0001).

Conclusions

A multifaceted protocol, including several American Heart Assocation best practices for the resuscitation of patients with
OHCA
, was associated with improved survival and neurological outcome.
Hidden biodiversity revealed by collections-based research—Laboulbeniales in millipedes: genus Rickia
Authors: Santamaria Sergi , Enghoff Henrik , Reboleira Ana Sofia
Published: January 2016

Nine new species of the genus Rickia parasitizing Diplopoda are described: R. appendicifera from Iran on Chiraziulus, R. candelabriformis from Australia and New Zealand on several Spirostreptida, R. galatheae from New Zealand on Eumastigonus, R. gigas from Tanzania on ‘Spirostreptus’ and Archispirostreptus, R. lophophora from Tanzania on some genera of Spirostreptidae, R. obelostrepti from Tanzania on Obelostreptus, R. odontopygiidarum from Tanzania on Odontopygidae, R. platessa from Singapore and Thailand on Pachybolidae, and R. rhynchophora from Australia on Trigoniulus.  This nearly triples the previously known number of species of Rickia species on millipedes; all 14 species are treated in this study with photomicrographs, additional observations on previously described taxa and comments. A key to these species is also provided. The Laboulbeniales species were found on millipede specimens preserved mostly at the Natural History Museum of Denmark, from samples collected between 1916 to the present.
Falcula hyalina (Fragilariaceae, Bacillariophyta) from a coastal lagoon, Southern Brazil: an additional approach on its morphology

Authors: Donadel Letícia , Torgan Lezilda Carvalho
Published: January 2016

Falcula hyalina Takano (1983: 24) is an epizoic diatom commonly associated with coastal copepods in many parts of the world (Takano 1983, Mahoney & Gibson 1983, Hiromi et al. 1985, Prasad et al. 1989, Souza-Mosimann et al. 1989, Fernandes & Calixto-Feres 2012, Li et al. 2014). The species was described and illustrated using the transmission electron microscope by Takano (1983) who differentiated it from other taxa of the genus—F. rogallii Voigt (1960: 86), F. media Voigt (1960: 87), F. semiundulata Voigt (1960: 87), F. paracelsiana Voigt (1961: 54) and F. media var. subsalina Proshkina-Lavrenko (1963: 36)—by the morphometric features of the valve (length, width, and stria and areolae density). Some years later, Prasad et al. (1989) improved the morphological features of F. hyalina using the scanning electron microscope and discussed the relation of the species with similar taxa. Round et al. (1990), in the diacritic description of the genus, raised the question that F. hyalina had some features that could not match with Falcula, such as the wider sternum and poroidal apical pore field (ocellulimbus), as opposed to a series of slits at the apices. Therefore, the taxonomic position of F. hyalina still remains uncertain.
Two new syncephalous species of Eremanthus (Asteraceae: Vernonieae) from southeastern Brazil
Authors: Loeuille Benoit , Pirani José Rubens
Published: January 2016

Eremanthus praetermissus and E. ovatifolius, two new species from Brazil, are here described and illustrated. Eremanthus praetermissus is endemic to Serra do Mar, in the northeastern part of São Paulo state and the southern part of Rio de Janeiro state; it is characterized by hemispherical, brown syncephalia, heads connate for 1/3 to 2/5 of their length, with 3–4 florets per head and brown phyllaries with purple apices. Eremanthus ovatifolius is endemic to campos rupestres of Pico da Aliança, in the eastern part of Minas Gerais state, and is characterized by ovate leaves, hemispherical syncephalia, heads connate for 1/4 to 1/2 of their length and 3–4 florets per head. The affinities of these species are discussed. A key to all species of Eremanthus is provided.
Influence of Canopy Seasonal Changes on Turbulence Parameterization within the Roughness Sublayer over an Orchard Canopy
Authors: Shapkalijevski M. , Moene A. F. , Ouwersloot H. G. , Patton E. G. , Vilà-Guerau de Arellano J.
Published: January 2016

In this observational study, the role of tree phenology on the atmospheric turbulence parameterization over 10-m-tall and relatively sparse deciduous vegetation is quantified. Observations from the Canopy Horizontal Array Turbulence Study (CHATS) field experiment are analyzed to establish the dependence of the turbulent exchange of momentum, heat, and moisture, as well as kinetic energy on canopy phenological evolution through widely used parameterization models based on 1) dimensionless gradients or 2) turbulent kinetic energy (TKE) in the roughness sublayer. Observed vertical turbulent fluxes and gradients of mean wind, temperature, and humidity, as well as velocity variances, are used in combination with empirical dimensionless functions to calculate the turbulent exchange coefficient. The analysis shows that changes in canopy phenology influence the turbulent exchange of all quantities analyzed in this study. The turbulent exchange coefficients of those quantities are twice as large near the canopy top for a leafless canopy than for a full-leaf canopy under unstable and near-neutral conditions. This turbulent exchange coefficient difference is related to the differing penetration depths of the turbulent eddies organized at the canopy top, which increase for a canopy without leaves. The TKE and dissipation analysis under near-neutral atmospheric conditions additionally shows that TKE exchange increases for a leafless canopy because of reduced TKE dissipation efficiency relative to that when the canopy is in full-leaf stage. The study closes with discussion surrounding the implications of these findings for parameterizations used in large-scale models.
Mechanisms Contributing to Suppressed Precipitation in Mt. Hua of Central China. Part I: Mountain Valley Circulation
Authors: Yang Yan , Fan Jiwen , Leung L. Ruby , Zhao Chun , Li Zhanqing , Rosenfeld Daniel
Published: January 2016

A significant reduction in precipitation in the past decades has been documented over many mountain ranges such as those in central and eastern China. Consistent with the increase of air pollution in these regions, it has been argued that the precipitation trend is linked to the aerosol microphysical effect on suppressing warm rain. Rigorous quantitative investigations on the reasons responsible for the precipitation reduction are lacking. In this study, an improved Weather Research and Forecasting (WRF) Model with online coupled chemistry (WRF-Chem) is applied and simulations are conducted at the convection-permitting scale to explore the major mechanisms governing changes in precipitation from orographic clouds in the Mt. Hua area in central China. It is found that anthropogenic pollution contributes to a ~40% reduction of precipitation over Mt. Hua during the 1-month summertime period. The reduction is mainly associated with precipitation events associated with valley–mountain circulation and a mesoscale cold-front event. In this paper (Part I), the mechanism leading to a significant reduction for the cases associated with valley–mountain circulation is scrutinized. It is found that the valley breeze is weakened by aerosols as a result of absorbing aerosol-induced warming aloft and cooling near the surface as a result of aerosol–radiation interaction (ARI). The weakened valley breeze and the reduced water vapor in the valley due to reduced evapotranspiration as a result of surface cooling significantly reduce the transport of water vapor from the valley to mountain and the relative humidity over the mountain, thus suppressing convection and precipitation in the mountain.
Use of Rheumatology Laboratory Studies Among Primary Pediatricians
Authors: Correll Colleen K. , Spector Logan G. , Zhang Lei , Binstadt Bryce A. , Vehe Richard K.
Published: January 2016

Rheumatology laboratory tests are often inappropriately ordered in situations for which they are of low diagnostic utility. We surveyed pediatricians to investigate reasons for ordering these tests. The response rate was 15.3% (93/609). The most commonly ordered tests were antinuclear antibody (ANA), anti-double-stranded DNA (dsDNA) antibody, and rheumatoid factor (RF). Of the 89% (83/93) who ordered an ANA, 86% ordered it for correct/possibly correct reasons; of the 73% (68/93) who ordered RF, 80% did so for correct/possibly correct reasons; and among the 59% (54/92) who had ordered anti-dsDNA antibody, 34% ordered it for correct reasons. A positive relationship was seen between years since residency completion and correct use of ANA. However, positive associations were not seen between measures of pediatric rheumatology experience and correct use of other tests. Interventions are needed to improve pediatricians’ utilization of rheumatology tests.
Changing the (Magisterial) Subject: Women Teaching-with-Authority—from Vatican II to Tomorrow
Authors: Mannion Gerard
Published: January 2016

Pope Francis has stated that ‘The challenge [for the church] today is this: to think about the specific place of women also in those places where the authority of the church is exercised for various areas of the church.’ Here we have a pope inviting discussion on the role and authority of women in the church. This is a statement with wide-reaching moral and ecclesiological implications. To explore some of these, this paper focuses on ‘changing the (magisterial) subject’ in a twofold sense. It focuses upon transformations in the understanding of teaching authority and also upon the subjects who exercise such during and since Vatican II. In particular, it explores both topics vis-à-vis the role of women in the church, especially their contributions to the church’s exercise of magisterium. It seeks to do so in the main by reflecting upon the women present in an active capacity at Vatican II, who effectively serve as a case study for our considerations of the most pressing questions pertaining to women and magisterium, questions which Pope Francis has clearly brought center-stage once more and seems determined to engage.
Atonement, Liturgy and Metaphor: Finding Meaning in Duality
Authors: Love Cyprian
Published: January 2016

Although human understanding is generally characterized as a process which seeks to unify diverse components into a synthesis, it may equally find satisfying closure in duality and paradox. This entails that our knowledge of reality has a primordially dual aspect, and this in turn has implications for theology. It will be suggested that duality, pairing, paradox and metaphor are in various ways keys to understanding the work of Christ: thus the inner dynamic of the work of the Cross is structured like a metaphor, and our personal experience of salvation also resembles a metaphor because of its underlying dynamic of communion or koinonia with Christ. There is, in short, a general twofoldness of things, which has an outcome both in the nature of the atonement and the way Scripture presents it. Understanding of the atonement is enriched by the insight that ‘two’ is as important as ‘one.’
A ‘Chalcedonian’ Spirit Christology
Authors: Liston Greg
Published: January 2016

Two Spirit Christological propositions that are intentionally compatible with Chalcedon are defined and defended. These propositions explore the hypostatic union not merely through examining Christ’s divine and human natures, but also through examining the Spirit’s Christological mission. The first affirms that an orthodox Christology requires both the Son and Spirit’s missions to be fully recognized. The second states that both missions must relate without priority, without confusion, and without separation. Defending the propositions not only provides a succinct summary of key Spirit Christological insights, it explicitly identifies and rejects six Spirit-Christological errors existing within ancient and contemporary Christologies.
Institutionalizing the African Reach: Reviewing China’s and India’s Multilateral Drives
Authors: Panda Jagannath P.
Published: January 2016

China and India have for quite some time been participants in African politics and have employed persuasive strategies to make their presence felt in that continent. The main objective of their current participation and presence in Africa is to exploit energy resources and establish greater political connections there. The Chinese strategy is to be generous with loans and financial aid; the Indian strategy has been to employ populist and democratic measures, highlighting its historical and cultural connections with Africa. Pursuing stronger bilateral relations with African countries has been the principal medium of their continental reach. But bilateral bonding has been taking a backseat recently in their approach vis-à-vis multilateral relations, for which institutional and organisational bonding is being used as the prime medium. South Africa is a conspicuous illustration of this approach. Both China and India share strong bilateral ties with South Africa, which is the frontier state for their outreach to Africa. Their engagements with that country through multilateral forums like the AU, BRICS, BASIC and IBSA exhibit how multilateralism is becoming for them a leading approach relative to bilateralism. Their objective, besides enriching and influencing their bilateral understanding with that country, is to achieve their global ambitions and objectives in tandem with the African continent on a whole. This paper examines the instrumental approach that the two countries employ towards Africa where multilateralism is becoming a prime channel of contact over bilateralism. To what extent this approach has advanced their strategic interests in Africa commercially and politically also needs analysis.
Attitudes Toward Marriage, Partner Availability, and Interracial Dating Among Black College Students From Historically Black and Predominantly White Institutions
Authors: Stackman Valerie R. , Reviere Rebecca , Medley Barbara C.
Published: January 2016

This study examined attitudes toward marriage, perceptions of partner availability, and attitudes toward interracial dating among Black male and female college students at two historically Black colleges/universities (HBCUs) and one predominately White institution (PWI). Most students had positive attitudes toward marriage, with women significantly more favorable than men. While both men and women reported insufficient romantic partner options, female students at PWIs were significantly more likely to report insufficient partner options than male students and those at HBCUs. Most students (72.6%) were favorable toward interracial dating, but males at HBCUs had more positive attitudes. However, students at HBCUs were more unsupportive of interracial dating than those at PWIs, and females at both types of institutions reported more unfavorable attitudes toward interracial dating than males. Findings reveal gender and contextual differences in attitudes and suggest a need for more nuanced studies of Black college student attitudes.
An Oasis in Europe: Hollywood Depictions of Portugal during the Second World War
Authors: Lopes Rui
Published: January 2016

In the early 1940s, the wave of North American fiction films dealing with the Second World War devoted unprecedented attention to Portugal, then a neutral nation under a fascist-inspired dictatorship led by António de Oliveira Salazar. This article analyses the underlying discourse about Portugal in the stories filmed by Hollywood during this period. It focuses on three key motifs, namely the portrayal of the country as an escape point for refugees, as a gathering ground for spies and as a safe haven from European war and oppression. Besides identifying common patterns in the narratives, the article seeks to contextualize them by taking into account the evolution of the scripts, as well as the feedback from the Production Code Administration and the Office of War Information. It also briefly contrasts the portrayal of Portugal with that of Spain, where a similar political regime was in place. It concludes that the combination of Hollywood’s formulaic narratives and Washington’s propaganda strategy resulted in a depiction of Portugal that was patronizing yet mostly benevolent, romanticizing local living conditions and dissociating the Salazar dictatorship from its fascist origins and practices.