bluuebunny/crossref_metadata_2025_split huggingface dataset:
Fulvestrant increases the susceptibility of enzalutamide-resistant prostate cancer cells to NK-mediated lysis
Authors: Dahut Madeline , Fousek Kristen , Horn Lucas A , Angstadt Shantel , Qin Haiyan , Hamilton Duane H , Schlom Jeffrey , Palena Claudia 
Published: September 2023

BackgroundEnzalutamide, a next-generation antiandrogen agent, is approved for the treatment of metastatic castration-resistant prostate cancer (CRPC). While enzalutamide has been shown to improve time to progression and extend overall survival in men with CRPC, the majority of patients ultimately develop resistance to treatment. Immunotherapy approaches have shown limited clinical benefit in this patient population; understanding resistance mechanisms could help develop novel and more effective treatments for CRPC. One of the mechanisms involved in tumor resistance to various therapeutics is tumor phenotypic plasticity, whereby carcinoma cells acquire mesenchymal features with or without the loss of classical epithelial characteristics. This work investigated a potential link between enzalutamide resistance, tumor phenotypic plasticity, and resistance to immune-mediated lysis in prostate cancer.MethodsModels of prostate cancer resistant to enzalutamide were established by long-term exposure of human prostate cancer cell lines to the drug in culture. Tumor cells were evaluated for phenotypic features in vitro and in vivo, as well as for sensitivity to immune effector cell-mediated cytotoxicity.ResultsResistance to enzalutamide was associated with gain of mesenchymal tumor features, upregulation of estrogen receptor expression, and significantly reduced tumor susceptibility to natural killer (NK)-mediated lysis, an effect that was associated with decreased tumor/NK cell conjugate formation with enzalutamide-resistant cells. Fulvestrant, a selective estrogen receptor degrader, restored the formation of target/NK cell conjugates and increased susceptibility to NK cell lysis in vitro. In vivo, fulvestrant demonstrated antitumor activity against enzalutamide-resistant cells, an effect that was associated with activation of NK cells.ConclusionNK cells are emerging as a promising therapeutic approach in prostate cancer. Modifying tumor plasticity via blockade of estrogen receptor with fulvestrant may offer an opportunity for immune intervention via NK cell-based approaches in enzalutamide-resistant CRPC.
Application of EULAR and European Society of Cardiology recommendations with regard to blood pressure and lipid management in antiphospholipid syndrome
Authors: Drosos George C , Konstantonis George , Sfikakis Petros P , Tektonidou Maria G 
Published: September 2023

BackgroundTo examine blood pressure (BP) and lipid treatment eligibility in antiphospholipid syndrome (APS) according to European Alliance of Associations for Rheumatology (EULAR) and European Society of Cardiology (ESC) recommendations.MethodsSystematic Coronary Risk Evaluation (SCORE), modified-SCORE, diabetes mellitus (DM)-equivalent risk classifiers (DIME) and disease-related classifiers –type of thrombotic events (APSevents), antiphospholipid-antibody profile (aPLprofile) and adjusted Global APS Score for cardiovascular disease– were used to calculate predicted low-moderate, high and very-high cardiovascular risk (CVR) in 111 patients with APS without prior atherosclerotic cardiovascular events or DM. Actual CVR (AR) was determined according to ESC guidelines, including carotid/femoral plaque presence. In low-moderate SCORE-predicted risk patients, classification ability and agreement for BP or lipid treatment was tested with Matthews’ correlation coefficient (MCC) and Cohen’s kappa, respectively, using the AR classes as reference qualifiers.ResultsSCORE underestimated high/very-high-AR in >50% of cases. SCORE-guided BP/lipid treatment eligibility was 4.2%/12.6% for high, 10.5%/16.8% for very-high AR patients, while 5.3% of low-moderate AR cases were eligible for lipid-lowering therapy. For BP treatment, MCC was higher using DIME for low-moderate and very-high-risk (0.33 and 0.32, respectively), and using modified-SCORE+APSevents(MCC=0.25) for high-risk patients. Eligibility agreement was better with DIME+APSevents or aPLprofile(kappa=0.51) for high-risk, and DIME (kappa=0.31) for very-high-risk patients. For lipid treatment, both classification ability and eligibility agreement were stronger with SCORE (or modified-SCORE)+APSeventsin low-moderate (MCC/kappa=0.43/0.41) and very-high risk (MCC/kappa=0.30/0.30), and with DIME+aPLprofile(MCC/kappa=0.50/0.50) in high-risk patients, respectively.ConclusionMultimodal risk assessment including disease-related and cardiometabolic features used for high-risk diseases such as DM can improve CVR management in APS.
Arbitrary bias control of LiNbO3 based Mach-Zehnder intensity modulators for QKD system
Authors: Teng Jun , Wang Shuang , Yin Zhen-Qiang , Chen Wei , Fan-Yuan Guan-Jie , Guo Guang-Can , Han Zheng-Fu 
Published: September 2023

AbstractQuantum key distribution (QKD) can help distant agents to share unconditional secret keys, and the achievable secret key rate can be enhanced with the help of decoy-state protocol. To implement QKD experimentally, the agents are supposed to accurately transmit a number of different intensity pulses with the LiNbO3 based Mach-Zehnder (LNMZ) intensity modulator. However, the bias drift of LNMZ intensity modulator may affect the performance of a QKD system. In this letter, we reveal a simple RC circuit model to demonstrate the bias drift in the LNMZ intensity modulator. And based on the model, we propose a multi-step bias stable scheme to control the bias working point. Experimental result shows that our scheme can eliminate the bias drift of at arbitrary working point within a long time range. Besides, there is no need of any feedback mechanisms in the scheme. This means our scheme will not lead to any increasement in system complexity, making it more suitable for a QKD system.
A Function-Based Approach to Interactive High-Precision Volumetric Design and Fabrication
Authors: Uchytil Christopher , Storti Duane 
Published: September 2023

We present a novel function representation (F-Rep) based geometric modeling kernel tailor-made to support computer aided design (CAD) and fabrication of high resolution volumetric models containing hundreds of billions of voxel grid elements. Our modeling kernel addresses existing limitations associated with evaluating, storing, and accessing volumetric data produced by F-Reps in contexts outside of rendering. The result is an F-Rep modeling kernel well suited for CAD-based applications.
Our kernel utilizes a sparse volume data structure to manage F-Rep data while efficient F-Rep evaluation is achieved through a combination of interval arithmetic (IA), just-in-time (JIT) compilation of user-defined functions, and massively parallel evaluation on the GPU. We employ IA as the basis for local pruning of the function evaluation tree to minimize total function evaluations, we use a novel JIT compilation scheme to optimize function execution, and we take advantage of GPU-parallelism to enhance computational throughput. We illustrate the kernel’s effectiveness in visualizing and slicing models with complex defining functions and detailed geometry, and utilize the geometry kernel to manufacture a physical part. Additionally, we present performance metrics across multiple hardware configurations demonstrating significant performance improvements over existing F-Rep geometry kernels, and we examine how our geometry kernel scales with computing power.
Evaluation of Platelet Distribution Width as an Early Predictor of Acute Kidney Injury in Extensive Burn Patients
Authors: Jiang Ming , Zhang Qingrong , Zhang Chuwei , Li Zihan , Li Qiqi , Qu Xun , Zhang Yi , Hu Kesu 
Published: September 2023

Background. The extensive burns devastate trauma. The research was designed to analyse the predictive value of early platelet (PLT) indices on the development of acute kidney injury (AKI) after severe burns. Methods and Results. 186 patients with extensive burns (burn area ≥30%) were eventually involved. Multivariate analyses pointed out that platelet distribution width (PDW) in the first 24 h after admission was an independent risk factor for AKI, severe AKI, and RRT requirement in patients with severe burns, and AKI risk showed an increase of 30.9% per increase of 1% in PDW (OR = 1.309, CI, 1.075–1.594, and P = 0.007). It was found that the area under the ROC curve (AUC) of PDW predicting AKI was 0.735 and that the AUC value was 0.81 for AKI after combining PDW and blood urea nitrogen (BUN). Based on the cut-off value PDW = 17.7%, patients were divided into high- (PDW ≥17.7%) and low-risk (PDW <17.7%) groups. In the KM analysis, there was a higher cumulative incidence of AKI if patients were in a high-risk group (in 30 days); and the stages of AKI showed a linear upward trend (chi-square test for linear trend

P

<

0.001

) as there was an increase in the risk level. Conclusion. The PDW level in the early stage serves as an important risk factor for AKI, severe AKI, and RRT requirement in extensive burns. When PDW >17.7%, burn patients are not only at a higher risk for AKI but may also have higher AKI severity. Due to low cost and wide availability, PDW has the potential to be the tool that can predict AKI in extensive burn patients.
Targeting the Metabolic Enzyme PGAM2 Overcomes Enzalutamide Resistance in Castration-Resistant Prostate Cancer by Inhibiting BCL2 Signaling
Authors: Li Zhen , Ning Kang , Zhao Diwei , Zhou Zhaohui , Zhao Junliang , Long Xingbo , Yang Zhenyu , Chen Dong , Cai XinYang , Hong Lexuan , Zhang Luyao , Zhou Fangjian , Wang Jun , Li Yonghong 
Published: September 2023

Abstract

The next-generation androgen receptor (AR) inhibitor enzalutamide is the mainstay treatment for metastatic prostate cancer. Unfortunately, resistance occurs rapidly in most patients, and once resistance occurs, treatment options are limited. Therefore, there is an urgent need to identify effective targets to overcome enzalutamide resistance. Here, using a genome-wide CRISPR-Cas9 library screen, we found that targeting a glycolytic enzyme, phosphoglycerate mutase PGAM2, significantly enhanced the sensitivity of enzalutamide-resistant prostate cancer cells to enzalutamide both in vivo and in vitro. Inhibition of PGAM2 together with enzalutamide treatment triggered apoptosis by decreasing levels of the antiapoptotic protein BCL-xL and increasing activity of the proapoptotic protein BAD. Mechanistically, PGAM2 bound to 14–3-3ζ and promoted its interaction with phosphorylated BAD, resulting in activation of BCL-xL and subsequent resistance to enzalutamide-induced apoptosis. In addition, high PGAM2 expression, which is transcriptionally regulated by AR, was associated with shorter survival and rapid development of enzalutamide resistance in patients with prostate cancer. Together, these findings provide evidence of a nonmetabolic function of PGAM2 in promoting enzalutamide resistance and identify PGAM2 inhibition as a promising therapeutic strategy for enzalutamide-resistant prostate cancer.

Significance:
PGAM2 promotes resistance to enzalutamide by activating antiapoptotic BCL-xL and suppressing apoptosis, indicating that PGAM2 is a potential target for overcoming enzalutamide resistance in prostate cancer.
ADAMTS-7 Modulates Atherosclerotic Plaque Formation by Degradation of TIMP-1
Authors: Sharifi M. Amin , Wierer Michael , Dang Tan An , Milic Jelena , Moggio Aldo , Sachs Nadja , von Scheidt Moritz , Hinterdobler Julia , Müller Philipp , Werner Julia , Stiller Barbara , Aherrahrou Zouhair , Erdmann Jeanette , Zaliani Andrea , Graettinger Mira , Reinshagen Jeanette , Gul Sheraz , Gribbon Philip , Maegdefessel Lars , Bernhagen Jürgen , Sager Hendrik B. , Mann Matthias , Schunkert Heribert , Kessler Thorsten 
Published: September 2023

BACKGROUND:

The
ADAMTS7
locus was genome-wide significantly associated with coronary artery disease. Lack of the ECM (extracellular matrix) protease ADAMTS-7 (A disintegrin and metalloproteinase-7) was shown to reduce atherosclerotic plaque formation. Here, we sought to identify molecular mechanisms and downstream targets of ADAMTS-7 mediating the risk of atherosclerosis.

METHODS:

Targets of ADAMTS-7 were identified by high-resolution mass spectrometry of atherosclerotic plaques from Apoe
−/−
and Apoe
−/−
Adamts7
−/−
mice. ECM proteins were identified using solubility profiling. Putative targets were validated using immunofluorescence, in vitro degradation assays, coimmunoprecipitation, and Förster resonance energy transfer–based protein-protein interaction assays.
ADAMTS7
expression was measured in fibrous caps of human carotid artery plaques.

RESULTS:

In humans,
ADAMTS7
expression was higher in caps of unstable as compared to stable carotid plaques. Compared to Apoe
−/−
mice, atherosclerotic aortas of Apoe
−/−
mice lacking Adamts-7 (Apoe
−/−
Adamts7
−/−
) contained higher protein levels of Timp-1 (tissue inhibitor of metalloprotease-1). In coimmunoprecipitation experiments, the catalytic domain of ADAMTS-7 bound to TIMP-1, which was degraded in the presence of ADAMTS-7 in vitro. ADAMTS-7 reduced the inhibitory capacity of TIMP-1 at its canonical target MMP-9 (matrix metalloprotease-9). As a downstream mechanism, we investigated collagen content in plaques of Apoe
−/−
and Apoe
−/−
Adamts7
−/−
mice after a Western diet. Picrosirius red staining of the aortic root revealed less collagen as a readout of higher MMP-9 activity in Apoe
−/−
as compared to Apoe
−/−
Adamts7
−/−
mice. To facilitate high-throughput screening for ADAMTS-7 inhibitors with the aim of decreasing TIMP-1 degradation, we designed a Förster resonance energy transfer–based assay targeting the ADAMTS-7 catalytic site.

CONCLUSIONS:
ADAMTS-7, which is induced in unstable atherosclerotic plaques, decreases TIMP-1 stability reducing its inhibitory effect on MMP-9, which is known to promote collagen degradation and is likewise associated with coronary artery disease. Disrupting the interaction of ADAMTS-7 and TIMP-1 might be a strategy to increase collagen content and plaque stability for the reduction of atherosclerosis-related events.
Undiagnosed Pediatric Elevated Blood Pressure Is Characterized by Induction of Proinflammatory and Cytotoxic Mediators
Authors: Thürmann Loreen , Bauer Mario , Ferland Maike , Messingschlager Marey , Schikowski Tamara , von Berg Andrea , Heinrich Joachim , Herberth Gunda , Lehmann Irina , Standl Marie , Trump Saskia 
Published: September 2023

BACKGROUND:
Inflammatory processes have been suggested as a culprit of vascular damage in pediatric hypertension. We aimed to investigate transcriptional changes of immune modulators and determine their association with office blood pressure in adolescents who were not diagnosed with hypertension at the time of the study visit.

METHODS:
Office blood pressure measurements and blood samples were taken from adolescents of 2 German birth cohorts, GINIplus (The German Infant Study on the Influence of Nutrition Intervention Plus Air Pollution and Genetics on Allergy Development; discovery cohort, n=1219) and LISA (Influences of Lifestyle-related factors on the Immune System and the Development of Allergies in Childhood; validation cohort, n=809), during the 15-year follow-up visit and categorized based on the European Society of Hypertension Guideline. Hs-CRP (high-sensitivity C-reactive protein) and expression of 51 genes encoding cytokines/receptors and transcription factors were analyzed.

RESULTS:

The prevalence of elevated systolic blood pressure (overweight/obese) was 14.0% (5.1%) and 16.4% (5.2%) in the discovery and validation cohorts, respectively. An enhanced cytotoxic (
GZMB, PRF1, IL2RB
) and proinflammatory (
FOS, IL1B
, hs-CRP) immune profile was observed in association with the hypertension class in both cohorts. Expression of hs-CRP and
IL1B
was driven by overweight with
IL1B
being identified as a mediator between body mass index and elevated systolic blood pressure (adj.β/95% CI, 0.01/0.0002–0.02). The association of
GZMB
(adjusted odds ratio/95% CI, 1.67/1.26–2.21;
P
=0.0004) and
PRF1
(adjusted odds ratio/95% CI, 1.70/1.26–2.29;
P
=0.0005) in the hypertension class remained significant in normal-weight individuals without parental predisposition. These effects were confirmed in LISA.

CONCLUSIONS:
Adolescent hypertension is not limited to known risk groups. As adolescents in the hypertension class show an inflammatory profile similar to that of established hypertension in adults, blood pressure monitoring at a young age is critical to ensure early intervention and prevention of adverse sequelae.
The Impact of Emotions on Habitual Inhibition
Authors: Mata-Marín David , Redgrave Peter , Obeso Ignacio 
Published: September 2023

Abstract
Emotional information prioritizes human behavior. How much emotions influence ongoing behavior critically depends on the extent of executive control functions in a given context. One form of executive control is based on stimulus–stop associations (i.e., habitual inhibition) that rapidly and effortlessly elicits control over the interruption of ongoing behavior. So far, no behavioral accounts have explored the emotional impact on habitual inhibition. We aimed to examine the emotional modulation on habitual inhibition and associated psycho-physiological changes. A go/no-go association task asked participants to learn stimulus–stop and stimulus–response associations during 10-day training to form habitual inhibition (without emotional interference). Probabilistic feedback guided learning with varying probabilities of congruent feedback, generating stronger versus weaker pairings. A reversal test measured habitual inhibition strength counteracted by emotional cues (high-arousal positive and negative stimuli compared with neutral ones). Our training protocol induced stable behavioral and psycho-physiological responses compatible with habitual behavior. At reversal, habitual inhibition was evident as marked by significant speed costs of reversed no-go trials for strongly associated stimuli. Positive and negative emotional cues produced larger impact on habitual inhibition. We report first evidence on a cognitive control mechanism that is vulnerable to emotional stimuli and suggest alternative explanations on how emotions may boost or counteract certain behavioral abnormalities mediated by habitual inhibition.
Monastic Authority and Legitimizing Religio-Political Activism: Buddhist Nationalist Monks in Myanmar
Authors: Foxeus Niklas 
Published: September 2023

Abstract
The Buddhist nationalist movements that emerged during the political and economic liberalization of the second parliamentarian period (2011–2021) in Burma/Myanmar provide unique material for the study of monastic authority. The aim of this article is to examine two overlapping dynamics regarding how monastic authority is established and undermined. As for the first dynamic, the article examines three strategies in Buddhist nationalist sermons aiming to provide legitimacy for the nationalist monks. The second dynamic is a political outgroup criticism that became more common during the period in question. The article makes a distinction between generic monastic authority, which is the fundamental one, and nationalist monastic authority, as they are legitimized and established in different ways. Finally, the article argues that recognition of monastic authority by laypeople is based not merely on trust and respect but tends to be a more complex process.
What is “Race” in Algorithmic Discrimination on the Basis of Race?
Authors: Hu Lily 
Published: September 2023

Abstract
Machine learning algorithms bring out an under-appreciated puzzle of discrimination, namely figuring out when a decision made on the basis of a factor correlated with race is a decision made on the basis of race. I argue that prevailing approaches, which are based on identifying and then distinguishing among causal effects of race, in their metaphysical timidity, fail to get off the ground. I suggest, instead, that adopting a constructivist theory of race answers this puzzle in a principled manner. On what I call a “thick constructivist” account of race, to be raced is to be socially positioned in the way indicated by a certain set of statistical regularities on the basis of particular phenotypical traits. A thick constructivist sees that acting on the basis of correlations that constitute race qua social position just is acting on the basis of race, because races just are social positions that subject their member individuals to a particular matrix of social relations that define the raced position. This conclusion has considerable ramifications for our understanding of discrimination, algorithms and beyond.
The Pendulum that Diagnoses and Cures
Authors: Guillemain Hervé , Morfee Adrian 
Published: September 2023

Abstract
The example of medical radiesthesia illustrates how a new discipline may be elaborated and taken up by amateurs on the fringes of official academic science. Driven by scholarly discoveries about waves, it broke with the long tradition of dowsing while expanding its initial ambition, that of discovering hidden things by using an object to prolong the individual’s sensitivity. This break was materialised by the shift from rods to pendulums in the 1930s. Medical radiesthesia consists in using a pendulum—a simple object made of a solid or hollow ball of varying material oscillating on a cord—for diagnosis and therapy. It may be characterized as an amateur practice because radiesthesia was devised in the 1930s as a new discipline on the margins of professional scientific circles; and because it was theorised by non-doctors and practised mainly by people not involved in the world of professional healthcare.
Diagnosing Mechanisms of Hydrologic Change under Global Warming in the CESM1 Large Ensemble
Authors: Siler Nicholas , Bonan David B. , Donohoe Aaron 
Published: September 2023

Abstract
Global warming is expected to cause significant changes in the pattern of precipitation minus evaporation (P − E), which represents the net flux of water from the atmosphere to the surface or, equivalently, the convergence of moisture transport within the atmosphere. In most global climate model simulations, the pattern of P − E change resembles an amplification of the historical pattern—a tendency known as “wet gets wetter, dry gets drier.” However, models also predict significant departures from this approximation that are not well understood. Here, we introduce a new method of decomposing the pattern of P − E change into contributions from various dynamic and thermodynamic mechanisms and use it to investigate the response of P − E to global warming within the CESM1 Large Ensemble. In contrast to previous decompositions of P − E change, ours incorporates changes not only in the monthly means of atmospheric winds and moisture, but also in their temporal variability, allowing us to isolate the hydrologic impacts of changes in the mean circulation, transient eddies, relative humidity, and the spatial and temporal distributions of temperature. In general, we find that changes in the mean circulation primarily control the P − E response in the tropics, while temperature changes dominate at higher latitudes. Although the relative importance of specific mechanisms varies by region, at the global scale departures from the wet-gets-wetter approximation over land are primarily due to changes in the temperature lapse rate, while changes in the mean circulation, relative humidity, and horizontal temperature gradients play a secondary role.