bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of a Theranostic Convergence Bioradiopharmaceutical for Immuno-PET Based Radioimmunotherapy of L1CAM in Cholangiocarcinoma Model
Authors: Song In Ho , Jeong Mun Sik , Hong Hyo Jeong , Shin Jong Il , Park Yong Serk , Woo Sang-Keun , Moon Byung Seok , Kim Kwang Il , Lee Yong Jin , Kang Joo Hyun , Lee Tae Sup 
Published: July 2019

AbstractPurpose:Cholangiocarcinoma is a malignancy of bile duct with a poor prognosis. Conventional chemotherapy and radiotherapy are generally ineffective, and surgical resection is the only curative treatment for cholangiocarcinoma. L1-cell adhesion molecule (L1CAM) has been known as a novel prognostic marker and therapeutic target for cholangiocarcinoma. This study aimed to evaluate the feasibility of immuno-PET imaging–based radioimmunotherapy using radiolabeled anti-L1CAM antibody in cholangiocarcinoma xenograft model.Experimental Design:We prepared a theranostic convergence bioradiopharmaceutical using chimeric anti-L1CAM antibody (cA10-A3) conjugated with 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA) chelator and labeled with 64Cu or 177Lu and evaluated the immuno-PET or SPECT/CT imaging and biodistribution with 64Cu-/177Lu-cA10-A3 in various cholangiocarcinoma xenograft models. Therapeutic efficacy and response monitoring were performed by 177Lu-cA10-A3 and 18F-FDG-PET, respectively, and immunohistochemistry was done by TUNEL and Ki-67.Results:Radiolabeled cA10-A3 antibodies specifically recognized L1CAM in vitro, clearly visualized cholangiocarcinoma tumors in immuno-PET and SPECT/CT imaging, and differentiated the L1CAM expression level in cholangiocarcinoma xenograft models. 177Lu-cA10-A3 (12.95 MBq/100 μg) showed statistically significant reduction in tumor volumes (P &lt; 0.05) and decreased glucose metabolism (P &lt; 0.01). IHC analysis revealed 177Lu-cA10-A3 treatment increased TUNEL-positive and decreased Ki-67-positive cells, compared with saline, cA10-A3, or 177Lu-isotype.Conclusions:Anti-L1CAM immuno-PET imaging using 64Cu-cA10-A3 could be translated into the clinic for characterizing the pharmacokinetics and selecting appropriate patients for radioimmunotherapy. Radioimmunotherapy using 177Lu-cA10-A3 may provide survival benefit in L1CAM-expressing cholangiocarcinoma tumor. Theranostic convergence bioradiopharmaceutical strategy would be applied as imaging biomarker-based personalized medicine in L1CAM-expressing patients with cholangiocarcinoma.
DNA Methylation as a Robust Classifier of Epithelial Ovarian Cancer
Authors: Ishak Charles A. , Lheureux Stephanie , De Carvalho Daniel D. 
Published: July 2019

Abstract
Epithelial ovarian cancers (EOC) can be defined across different histologic subtypes by specific DNA methylation profiles which correlate with outcome. Identification of distinct EOC methylation subgroups emphasizes the role of epigenetic remodeling to establish unique EOC etiology during transformation, and harbors the potential to direct personalized medicine and patient care.
See related article by Bodelon et al., p. 5937
Pharmacologic Ascorbate Primes Pancreatic Cancer Cells for Death by Rewiring Cellular Energetics and Inducing DNA Damage
Authors: Buranasudja Visarut , Doskey Claire M. , Gibson Adrienne R. , Wagner Brett A. , Du Juan , Gordon David J. , Koppenhafer Stacia L. , Cullen Joseph J. , Buettner Garry R. 
Published: July 2019

Abstract

The clinical potential of pharmacologic ascorbate (P-AscH−; intravenous delivery achieving mmol/L concentrations in blood) as an adjuvant in cancer therapy is being reevaluated. At mmol/L concentrations, P-AscH− is thought to exhibit anticancer activity via generation of a flux of H2O2 in tumors, which leads to oxidative distress. Here, we use cell culture models of pancreatic cancer to examine the effects of P-AscH− on DNA damage, and downstream consequences, including changes in bioenergetics. We have found that the high flux of H2O2 produced by P-AscH− induces DNA damage. In response to this DNA damage, we observed that PARP1 is hyperactivated. Using our unique absolute quantitation, we found that P-AscH− mediated the overactivation of PARP1, which results in consumption of NAD+, and subsequently depletion of ATP leading to mitotic cell death. We have also found that Chk1 plays a major role in the maintenance of genomic integrity following treatment with P-AscH−. Hyperactivation of PARP1 and DNA repair are ATP-consuming processes. Using a Seahorse XF96 analyzer, we demonstrated that the severe decrease in ATP after challenging with P-AscH− is because of increased demand, not changes in the rate of production. Genetic deletion and pharmacologic inhibition of PARP1 preserved both NAD+ and ATP; however, the toxicity of P-AscH− remained. These data indicate that disruption of bioenergetics is a secondary factor in the toxicity of P-AscH−; damage to DNA appears to be the primary factor.

Implications:
Efforts to leverage P-AscH− in cancer therapy should first focus on DNA damage.
Outcome of Pancreatic Cancer Surveillance Among High-Risk Individuals Tested for Germline Mutations in BRCA1 and BRCA2
Authors: Saldia Amethyst , Olson Sara H. , Nunes Pamela , Liang Xiaolin , Samson Marguerite L. , Salo-Mullen Erin , Marcell Vanessa , Stadler Zsofia K. , Allen Peter J. , Offit Kenneth , Kurtz Robert C. 
Published: July 2019

Abstract
Germline mutations in BRCA1/2 are risk factors for pancreatic ductal adenocarcinoma (PDAC). The aim of this study was to evaluate whether results of surveillance for PDAC in high risk individuals (HRI) differ between those with and without a pathogenic BRCA1/2 mutation. This prospective study was conducted within the Pancreatic Tumor Registry at a major cancer center. There were 83 HRIs with ≥1 first-degree relative with PDAC who underwent surveillance and testing for pathogenic germline mutations in BRCA1/2. A secondary analysis includes 18 HRIs with known mutations in BRCA1/2 but with weaker family history. HRIs were evaluated over time using magnetic resonance cholangiopancreatography (MRCP) and endoscopic ultrasound when indicated by MRCP findings. We reviewed imaging results, blinded to mutation status. Demographic information was obtained from interviewer-administered questionnaires. The outcome was the proportion with any pancreatic abnormality identified at initial or follow-up surveillance. Among the 83 HRIs in the main analysis, 48 had a mutation in BRCA1/2 and 35 did not. Overall, 16 of 48 (33%) BRCA1/2-positive and 13 of 35 (37%) BRCA1/2-negative participants had pancreatic abnormalities on imaging; in each group, all but one finding was an intraductal papillary mucinous neoplasm. Among those with pathogenic mutations but weaker family history, results were similar: 7 of 18 (39%) with pancreatic abnormalities. Results of surveillance for pancreatic abnormalities on imaging are similar regardless of BRCA1/2 mutation status. While the results from this small study need confirmation in other studies, at present there does not appear to be increased yield from targeting individuals with BRCA1/2 mutations for surveillance.
Uptake of Cervical Cancer Screening in Ethiopia by Self-Sampling HPV DNA Compared to Visual Inspection with Acetic Acid: A Cluster Randomized Trial
Authors: Gizaw Muluken , Teka Brhanu , Ruddies Friederike , Abebe Tamrat , Kaufmann Andreas M. , Worku Alemayehu , Wienke Andreas , Jemal Ahmedin , Addissie Adamu , Kantelhardt Eva Johanna 
Published: July 2019

Abstract
In Ethiopia, the standard method of cervical cancer screening is using Visual Inspection with Acetic Acid (VIA). Self-collection–based human papillomavirus (HPV) testing is assumed to improve the uptake of screening, especially for hard to reach populations. We investigated whether HPV DNA testing with the self-collection of cervical samples would be associated with increased uptake and adherence to procedures at the population level compared with VIA within defined rural population in Ethiopia. A total of 22 clusters (comprising 2,356 women ages 30–49 years) were randomized in two arms. Following the community mobilization, women of the clusters were invited to go either to the local health post for a self-collection–based HPV DNA testing (arm A) or Butajira Hospital for VIA screening (arm B). In the HPV arm, of the 1,213 sensitized women, 1,020 (84.1%) accessed the health post for self-sampling compared with the VIA arm, where 575 of 1,143 (50.5%) visited the hospital for VIA (P &lt; 0.0001). Of those women who attended the VIA and HPV arms, 40% and 65.4% adhered to all procedures expected after screening, respectively. Out of women positive for high risk HPV, 122 (85%) attended VIA as a follow-up test. The trial demonstrated significantly higher levels of population-based uptake and adherence for self-collection HPV testing. Women were more receptive for VIA after their HPV testing result was positive. Self-collection HPV testing can be done at the local health facility and may significantly improve the uptake of cervical cancer screening in Ethiopia.
Early Pregnancy Cardiovascular Health and Subclinical Atherosclerosis
Authors: Benschop Laura , Schalekamp‐Timmermans Sarah , Schelling Sara J. C. , Steegers Eric A. P. , Roeters van Lennep Jeanine E. 
Published: July 2019

Background

Assessing and optimizing cardiovascular health (
CVH
) early in life, such as in pregnancy, could lead to a longer lifetime spent in better
CVH
and reduce the risk of cardiovascular disease. This might especially benefit women with a hypertensive disorder of pregnancy (
HDP
) who are more likely to develop atherosclerosis and cardiovascular disease. We hypothesized that
CVH
in pregnancy is related to later life
CVH
and carotid intima‐media thickness (
CIMT
), and that these associations differ between women with a normotensive pregnancy and women with an
HDP
.

Methods and Results

This study was conducted within the prospective population‐based Generation R Study.
CVH
in pregnancy was based on 5 metrics (blood pressure, total‐cholesterol, glucose, smoking, and body mass index). Postpartum
CVH
additionally included physical activity and diet scores, according to the American Heart Association classification. Postpartum
CVH
and
CIMT
were measured 10 years after pregnancy. Results were analyzed for women with a normotensive pregnancy and those with an
HDP
. Women with a normotensive pregnancy (n=1786) and women with an
HDP
(n=138) were evaluated from early pregnancy until 10 years postpartum. Better
CVH
in early pregnancy was associated with a smaller
CIMT
and better postpartum
CVH
in all women, especially in those with an
HDP
(
CIMT
: −9.82 μm [95%
CI
: −17.98, −1.67]).

Conclusions

Already in pregnancy, better
CVH
is associated with a smaller
CIMT
and better
CVH
10 years postpartum, especially in women with an
HDP
. As pregnancy is an incentive for women to improve lifestyle, assessing
CVH
in pregnancy might help improve postpartum
CVH
and reduce cardiovascular disease risk.
Serum Chemerin as a Novel Prognostic Indicator in Chronic Heart Failure
Authors: Zhou Xiang , Tao Yifei , Chen Yuqi , Xu Weiting , Qian Zhiyuan , Lu Xiang 
Published: July 2019

Background
It has been documented that circulating chemerin is associated with inflammation, metabolic syndrome, and coronary artery disease. The present study was aimed to evaluate the prognostic value of serum chemerin in patients with chronic heart failure.

Methods and Results
We included 834 patients with chronic heart failure in a prospective cohort study and investigated the association between serum chemerin and clinical outcomes using multivariate Cox regression analysis. Patients with higher chemerin levels tended to be older and women and were more likely to experience hypertension, diabetes mellitus, and hyperlipemia. Cox regression analysis showed that chemerin was a significant predictor of major adverse cardiac events (hazard ratio, 1.83; 95% CI, 1.31–2.96) after adjustment for conventional risk factors. Net reclassification and integrated discrimination improvements for major adverse cardiac events were markedly improved by addition of chemerin to the reference model. In addition, chemerin was an independent predictor of all‐cause mortality (hazard ratio, 1.67; 95% CI, 1.21–2.73) after multivariable adjustment. Furthermore, the Kaplan–Meier survival analysis revealed that chemerin was a prognostic indicator of major adverse cardiac events in patients with chronic heart failure and NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide) levels above and below the median.

Conclusions
Our study suggests that chemerin is a novel serum marker for predicting major adverse cardiac events in patients with chronic heart failure.
Sensitivity to Stimulus Irregularity Is Inherent in Neural Networks
Authors: van Gils Teun , Tiesinga Paul H. E. , Englitz Bernhard , Martens Marijn B. 
Published: July 2019

Behavior is controlled by complex neural networks in which neurons process thousands of inputs. However, even short spike trains evoked in a single cortical neuron were demonstrated to be sufficient to influence behavior in vivo. Specifically, irregular sequences of interspike intervals (ISIs) had a more reliable influence on behavior despite their resemblance to stochastic activity. Similarly, irregular tactile stimulation led to higher rates of behavioral responses. In this study, we identify the mechanisms enabling this sensitivity to stimulus irregularity (SSI) on the neuronal and network levels using simulated spiking neural networks. Matching in vivo experiments, we find that irregular stimulation elicits more detectable network events (bursts) than regular stimulation. Dissecting the stimuli, we identify short ISIs—occurring more frequently in irregular stimulations—as the main drivers of SSI rather than complex irregularity per se. In addition, we find that short-term plasticity modulates SSI. We subsequently eliminate the different mechanisms in turn to assess their role in generating SSI. Removing inhibitory interneurons, we find that SSI is retained, suggesting that SSI is not dependent on inhibition. Removing recurrency, we find that SSI is retained due to the ability of individual neurons to integrate activity over short timescales (“cell memory”). Removing single-neuron dynamics, we find that SSI is retained based on the short-term retention of activity within the recurrent network structure (“network memory”). Finally, using a further simplified probabilistic model, we find that local network structure is not required for SSI. Hence, SSI is identified as a general property that we hypothesize to be ubiquitous in neural networks with different structures and biophysical properties. Irregular sequences contain shorter ISIs, which are the main drivers underlying SSI. The experimentally observed SSI should thus generalize to other systems, suggesting a functional role for irregular activity in cortex.
Liberalism and Conservatism in Relation to Psychological Type among Church of England Clergy
Authors: Village Andrew 
Published: July 2019

Abstract
Liberalism and conservatism have been important stances that have shaped doctrinal, moral and ecclesial beliefs and practices in Christianity. In the Church of England, Anglo-catholics are generally more liberal, and evangelicals more conservative, than those from broad-church congregations. This paper tests the idea that psychological preference may also partly explain liberalism or conservatism in the Church of England. Data from 1,389 clergy, collected as part of the 2013 Church Growth Research Programme, were used to categorise individuals by church tradition (Anglo-catholic, broad church or evangelical), whether or not they had an Epimethean psychological temperament, and whether or not they preferred thinking over feeling in their psychological judging process. Epimetheans and those who preferred thinking were more likely to rate themselves as conservative rather than liberal. Conservatism was associated with being Epimethean among those who were Anglo-catholic or broad-church, but with preference for thinking over feeling among evangelicals.
End Time and Emotions: Emotion Regulation Functions of Eschatological Expectations among Jehovah’s Witnesses in Norway
Authors: Ringnes Hege Kristin , Demmrich Sarah , Hegstad Harald , Stålsett Gry , Danbolt Lars Johan 
Published: July 2019

Abstract
The aim of this qualitative interview study was to explore the specific expectations that N = 29 Jehovah’s Witnesses (JWs) had of end times and paradise using an emotion regulation perspective. Beyond the general eschatological doctrine of JWs, the participants were encouraged to report their individual beliefs and connected emotions. Thematic analysis identified forecasting of life in paradise in the form of a continuation of physical life but with an overall positive emotional atmosphere. Emotionally, paradise was often contrasted with the present time, as negative emotions and the downregulation of strong positive emotions dominate the current end time. As an emotion regulation strategy between current end times and future paradise, emotional forecasting, i.e., predicting which emotions would arise in the future to regulate present-day emotions, is used. The results are discussed in the frame of positive and negative psychological implications of JWs’ eschatological beliefs and emotional forecasting.
Customary International Law and the General Principles of Law Recognized by Civilized Nations
Authors: Wood Michael 
Published: July 2019

Abstract
This article looks beyond customary international law and asks whether the source of international law listed in Article 38, paragraph 1(c) of the ICJ Statute (‘the general principles of law recognized by civilized nations’) might join the dance. Is there a risk that general principles of law may be too easily invoked where no applicable treaty or rule of customary international law can be identified? In emphasizing the distinction between customary international law and general principles of law, the article first recalls relevant recent work of the International Law Commission. It then addresses the term ‘general international law’ and certain problems related to it, and raises questions concerning the relationship between customary international law and general principles of law. Before drawing some conclusions, reference is also made to the place of general principles of law within the international legal system.
The Role of Vertical Wind Shear in Modulating Maximum Supercell Updraft Velocities
Authors: Peters John M. , Nowotarski Christopher J. , Morrison Hugh 
Published: July 2019

AbstractObserved supercell updrafts consistently produce the fastest mid- to upper-tropospheric vertical velocities among all modes of convection. Two hypotheses for this feature are investigated. In the dynamic hypothesis, upward, largely rotationally driven pressure gradient accelerations enhance supercell updrafts relative to other forms of convection. In the thermodynamic hypothesis, supercell updrafts have more low-level inflow than ordinary updrafts because of the large vertical wind shear in supercell environments. This large inflow makes supercell updrafts wider than that of ordinary convection and less susceptible to the deleterious effects of entrainment-driven updraft core dilution on buoyancy. These hypotheses are tested using a large suite of idealized supercell simulations, wherein vertical shear, CAPE, and moisture are systematically varied. Consistent with the thermodynamic hypothesis, storms with the largest storm-relative flow have larger inflow, are wider, have larger buoyancy, and have faster updrafts. Analyses of the vertical momentum forcing along trajectories shows that maximum vertical velocities are often enhanced by dynamic pressure accelerations, but this enhancement is accompanied by larger downward buoyant pressure accelerations than in ordinary convection. Integrated buoyancy along parcel paths is therefore a strong constraint on maximum updraft speeds. Thus, through a combination of processes consistent with the dynamic and thermodynamic hypotheses, supercell updrafts are able to realize a larger percentage of CAPE than ordinary updrafts.
Assessing the Influence of Convective Downdrafts and Surface Enthalpy Fluxes on Tropical Cyclone Intensity Change in Moderate Vertical Wind Shear
Authors: Nguyen Leon T. , Rogers Robert , Zawislak Jonathan , Zhang Jun A. 
Published: July 2019

AbstractThe thermodynamic impacts of downdraft-induced cooling/drying and downstream recovery via surface enthalpy fluxes within tropical cyclones (TCs) were investigated using dropsonde observations collected from 1996 to 2017. This study focused on relatively weak TCs (tropical depression, tropical storm, category 1 hurricane) that were subjected to moderate (4.5–11.0 m s−1) levels of environmental vertical wind shear. The dropsonde data were analyzed in a shear-relative framework and binned according to TC intensity change in the 24 h following the dropsonde observation time, allowing for comparison between storms that underwent different intensity changes. Moisture and temperature asymmetries in the lower troposphere yielded a relative maximum in lower-tropospheric conditional instability in the downshear quadrants and a relative minimum in instability in the upshear quadrants, regardless of intensity change. However, the instability increased as the intensification rate increased, particularly in the downshear quadrants. This was due to increased boundary layer moist entropy relative to the temperature profile above the boundary layer. Additionally, significantly larger surface enthalpy fluxes were observed as the intensification rate increased, particularly in the upshear quadrants. These results suggest that in intensifying storms, enhanced surface enthalpy fluxes in the upshear quadrants allow downdraft-modified boundary layer air to recover moisture and heat more effectively as it is advected cyclonically around the storm. By the time the air reaches the downshear quadrants, the lower-tropospheric conditional instability is enhanced, which is speculated to be more favorable for updraft growth and deep convection.
Comparing Hematoma Incidence between Hemostatic Devices in Total Thyroidectomy: A Systematic Review and Meta‐analysis
Authors: Hua Nadia , Quimby Alexandra Elizabeth , Johnson‐Obaseki Stephanie 
Published: July 2019

ObjectiveAlternative energy devices have become a popular alternative to conventional hemostasis in thyroid surgery. These devices have been shown to reduce operative time and thermal nerve injury. As hemostasis is paramount in thyroid surgery, we sought to examine the relative efficacy of 2 alternate energy devices compared to conventional hemostasis in preventing postoperative hematoma following total thyroidectomy.Data SourcesOvid MEDLINE, EMBASE, PubMed, and Cochrane Central Register of Controlled Trials.Review MethodsA systematic literature search was performed for all relevant English‐language studies published between 1946 and July 2018. Two authors independently extracted data and analyzed articles for quality using the National Institute of Health Quality Assessment Scale. Our primary outcome of interest was hematoma requiring reoperation.ResultsA total of 348 studies were screened, with 23 meeting the inclusion criteria. We found no significant difference in postoperative hematoma rates using alternate energy devices compared to conventional hemostasis (P =. 370,. 317). Network meta‐analysis echoed the results of conventional meta‐analysis, demonstrating no significant difference in hematoma rates.ConclusionsWe found no significant difference in postoperative hematoma rates following total thyroidectomy for any indication with the use of alternate energy devices compared to conventional hemostatic techniques. This suggests that hematoma occurrence does not necessarily need to be considered when choosing between these hemostatic devices. This information may help guide surgeons’ decisions regarding choice of hemostatic technique during thyroid surgery.