bluuebunny/crossref_metadata_2025_split huggingface dataset:
OvaPrint—A Cell-free DNA Methylation Liquid Biopsy for the Risk Assessment of High-grade Serous Ovarian Cancer
Authors: Buckley David N. , Lewinger Juan Pablo , Gooden Gerald , Spillman Monique , Neuman Monica , Guo X. Mona , Tew Ben Yi , Miller Heather , Khetan Varun U. , Shulman Lee P. , Roman Lynda , Salhia Bodour 
Published: October 2023

Abstract

Purpose:
High-grade serous ovarian carcinoma (HGSOC) is the most lethal epithelial ovarian cancer (EOC) and is often diagnosed at late stage. In women with a known pelvic mass, surgery followed by pathologic assessment is the most reliable way to diagnose EOC and there are still no effective screening tools in asymptomatic women. In the current study, we developed a cell-free DNA (cfDNA) methylation liquid biopsy for the risk assessment of early-stage HGSOC.

Experimental Design:
We performed reduced representation bisulfite sequencing to identify differentially methylated regions (DMR) between HGSOC and normal ovarian and fallopian tube tissue. Next, we performed hybridization probe capture for 1,677 DMRs and constructed a classifier (OvaPrint) on an independent set of cfDNA samples to discriminate HGSOC from benign masses. We also analyzed a series of non-HGSOC EOC, including low-grade and borderline samples to assess the generalizability of OvaPrint. A total of 372 samples (tissue n = 59, plasma n = 313) were analyzed in this study.

Results:
OvaPrint achieved a positive predictive value of 95% and a negative predictive value of 88% for discriminating HGSOC from benign masses, surpassing other commercial tests. OvaPrint was less sensitive for non-HGSOC EOC, albeit it may have potential utility for identifying low-grade and borderline tumors with higher malignant potential.

Conclusions:
OvaPrint is a highly sensitive and specific test that can be used for the risk assessment of HGSOC in symptomatic women. Prospective studies are warranted to validate OvaPrint for HGSOC and further develop it for non-HGSOC EOC histotypes in both symptomatic and asymptomatic women with adnexal masses.
Surface and Global Proteome Analyses Identify ENPP1 and Other Surface Proteins as Actionable Immunotherapeutic Targets in Ewing Sarcoma
Authors: Mooney Brian , Negri Gian Luca , Shyp Taras , Delaidelli Alberto , Zhang Hai-Feng , Spencer Miko Sandra E. , Weiner Amber K. , Radaoui Alexander B. , Shraim Rawan , Lizardo Michael M. , Hughes Christopher S. , Li Amy , El-Naggar Amal M. , Rouleau Melanie , Li Wei , Dimitrov Dimiter S. , Kurmasheva Raushan T. , Houghton Peter J. , Diskin Sharon J. , Maris John M. , Morin Gregg B. , Sorensen Poul H. 
Published: October 2023

Abstract

Purpose:
Ewing sarcoma is the second most common bone sarcoma in children, with 1 case per 1.5 million in the United States. Although the survival rate of patients diagnosed with localized disease is approximately 70%, this decreases to approximately 30% for patients with metastatic disease and only approximately 10% for treatment-refractory disease, which have not changed for decades. Therefore, new therapeutic strategies are urgently needed for metastatic and refractory Ewing sarcoma.

Experimental Design:
This study analyzed 19 unique Ewing sarcoma patient- or cell line–derived xenografts (from 14 primary and 5 metastatic specimens) using proteomics to identify surface proteins for potential immunotherapeutic targeting. Plasma membranes were enriched using density gradient ultracentrifugation and compared with a reference standard of 12 immortalized non–Ewing sarcoma cell lines prepared in a similar manner. In parallel, global proteome analysis was carried out on each model to complement the surfaceome data. All models were analyzed by Tandem Mass Tags–based mass spectrometry to quantify identified proteins.

Results:
The surfaceome and global proteome analyses identified 1,131 and 1,030 annotated surface proteins, respectively. Among surface proteins identified, both approaches identified known Ewing sarcoma–associated proteins, including IL1RAP, CD99, STEAP1, and ADGRG2, and many new cell surface targets, including ENPP1 and CDH11. Robust staining of ENPP1 was demonstrated in Ewing sarcoma tumors compared with other childhood sarcomas and normal tissues.

Conclusions:
Our comprehensive proteomic characterization of the Ewing sarcoma surfaceome provides a rich resource of surface-expressed proteins in Ewing sarcoma. This dataset provides the preclinical justification for exploration of targets such as ENPP1 for potential immunotherapeutic application in Ewing sarcoma.
See related commentary by Bailey, p. 934
Attribution of Seasonal Wildfire Risk to Changes in Climate: A Statistical Extremes Approach
Authors: Wixson Troy P. , Cooley Daniel 
Published: October 2023

Abstract
Wildfire risk is greatest during high winds after sustained periods of dry and hot conditions. This paper is a statistical extreme-event risk attribution study that aims to answer whether extreme wildfire seasons are more likely now than under past climate. This requires modeling temporal dependence at extreme levels. We propose the use of transformed-linear time series models, which are constructed similarly to traditional autoregressive–moving-average (ARMA) models while having a dependence structure that is tied to a widely used framework for extremes (regular variation). We fit the models to the extreme values of the seasonally adjusted fire weather index (FWI) time series to capture the dependence in the upper tail for past and present climate. We simulate 10 000 fire seasons from each fitted model and compare the proportion of simulated high-risk fire seasons to quantify the increase in risk. Our method suggests that the risk of experiencing an extreme wildfire season in Grand Lake, Colorado, under current climate has increased dramatically relative to the risk under the climate of the mid-twentieth century. Our method also finds some evidence of increased risk of extreme wildfire seasons in Quincy, California, but large uncertainties do not allow us to reject a null hypothesis of no change.
Multiproduct Characterization of Surface Soil Moisture Drydowns in the United Kingdom
Authors: Tso Chak-Hau Michael , Blyth Eleanor , Tanguy Maliko , Levy Peter E. , Robinson Emma L. , Bell Victoria , Zha Yuanyuan , Fry Matthew 
Published: October 2023

Abstract
The persistence or memory of soil moisture (θ) after rainfall has substantial environmental implications. Much work has been done to study soil moisture drydown for in situ and satellite data separately. In this work, we present a comparison of drydown characteristics across multiple U.K. soil moisture products, including satellite-merged (i.e., TCM), in situ (i.e., COSMOS-UK), hydrological model [i.e., Grid-to-Grid (G2G)], statistical model [i.e., Soil Moisture U.K. (SMUK)], and land surface model (LSM) [i.e., Climate Hydrology and Ecology research Support System (CHESS)] data. The drydown decay time scale (τ) for all gridded products is computed at an unprecedented resolution of 1–2 km, a scale relevant to weather and climate models. While their range of τ differs (except SMUK and CHESS are similar) due to differences such as sensing depths, their spatial patterns are correlated to land cover and soil types. We further analyze the occurrence of drydown events at COSMOS-UK sites. We show that soil moisture drydown regimes exhibit strong seasonal dependencies, whereby the soil dries out quicker in summer than winter. These seasonal dependencies are important to consider during model benchmarking and evaluation. We show that fitted τ based on COSMOS and LSM are well correlated, with a bias of lower τ for COSMOS. Our findings contribute to a growing body of literature to characterize τ, with the aim of developing a method to systematically validate model soil moisture products at a range of scales.

Significance Statement
While important for many aspects of the environment, the evaluation of modeled soil moisture has remained incredibly challenging. Sensors work at different space and time scales to the models, the definitions of soil moisture vary between applications, and the soil moisture itself is subject to the soil properties while the impact of the soil moisture on evaporation or river flow is more dependent on its variation in time and space than its absolute value. What we need is a method that allows us to compare the important features of soil moisture rather than its value. In this study, we choose to study drydown as a way to capture and compare the behavior of different soil moisture data products.
Future Heavy Rainfall and Flood Risks for Native Americans under Climate and Demographic Changes: A Case Study in Oklahoma
Authors: Li Zhi , Tsoodle Theresa , Chen Mengye , Gao Shang , Zhang Jiaqi , Wen Yixin , Yang Tiantian , King Farina , Hong Yang 
Published: October 2023

Abstract
Climate change has posed inequitable risks to different communities. Among communities of color in the United States, Native Americans stand out because 1) they desire resources to sustain resilient nations and 2) they have developed nature-based solutions through experiences with local climate-related challenges, which can provide deep insight for the whole society. Projection of climate risks for Native Americans is essential to assess future risks and support their climate-ready nations, yet there has been lack of useable information. In this study, we projected three climate hazards—heavy rainfall, 2-yr floods, and flash floods—for tribal nations in Oklahoma. To break down into tribal jurisdictions, we utilize a coupled regional climate model at 4 km and flash-flood forecast model at 1 km. A hazard–exposure–vulnerability risk framework is applied to integrate both climate and demographic changes in a high-emissions scenario. It is found that 1) Indigenous people are the most vulnerable community in Oklahoma; 2) heavy rainfall and 2-yr floods have marked increases in risks at 501.1% and 632.6%, respectively, while flash floods have a moderate increase (296.4%); 3) Native Americans bear 68.0%, 64.3%, and 64.0% higher risks in heavy rainfall, 2-yr flooding, and flash flooding, respectively, than the general population in Oklahoma; 4) in comparing climate and demographic changes, it is seen that population growth leads to greater climate hazard risks than does climate change; and 5) emerging tribal nations are projected to have 10 times as much population, resulting in great exposures to climate extremes. This study can raise awareness of the impact of climate changes and draw attention to address climate injustice issues for minoritized communities.

Significance Statement
This study examines the impact of climate change on a marginalized community—Native Americans in Oklahoma, home to 39 federally recognized tribal nations. We utilized the high-resolution climate simulation at 4-km resolution and hydrologic simulation at 1-km resolution to aggregate three climate extremes to tribal jurisdictions. We find that climate and demographic changes disproportionately put many Native Americans at risk. The heavy rainfall, 2-yr floods, and flash floods are all projected to have increased risks by 501.1%, 632.6%, and 296.4%, respectively. Those risks are 68.0%, 64.3%, and 64.0% higher than the state average for the general population, respectively. We urge proper attention to tribal nations to address climate injustice issues as a whole with the acknowledgment of their distinct relationships to their homelands as sovereign peoples.
Studying moral distress and moral injury among inpatient and outpatient healthcare professionals during the COVID-19 pandemic
Authors: Whitehead Phyllis B. , Haisch Carl E. , Hankey Maria S. , Mutcheson Ryan B. , Dewitt Sarah A. , Stewart Christi A. , Stewart Jonathan D. , Bath Jennifer L. , Boone Sherry M. , Jileaeva Ilona , Faulks Emily R. , Musick David W. 
Published: October 2023

Objective: COVID-19 increased moral distress (MD) and moral injury (MI) among healthcare professionals (HCPs). The purpose of this study was to examine MD and MI among inpatient and outpatient HCPs during March of 2022. The study sought to examine (1) the relationship between MD and MI; (2) the relationship between MD/MI and pandemic-related burnout and resilience; and (3) the degree to which HCPs experienced pandemic-related MD and MI based on background characteristics. Methods: A survey was conducted to measure MD, MI, burnout, resilience, and intent to leave healthcare at two academic medical centers during a 4-week period. A convenience sample of 184 participants (physicians, nurses, residents, respiratory therapists, advanced practice providers) completed the survey. In this mixed-methods approach, researchers analyzed both quantitative and qualitative survey data and triangulated the findings. Results: A moderate association was found between MD and MI (r = .47, P < .001). Regression results indicated that burnout was significantly associated with both MD and MI ( P = .02 and P < .001, respectively), while intent to leave was associated only with MD ( P < .001). Qualitative results yielded eight sources of MD and MI: workload, distrust, lack of teamwork/collaboration, loss of connection, lack of leadership, futile care, outside stressors, and vulnerability. Conclusions: While interrelated conceptually, MD and MI should be viewed as distinct constructs. Many HCPs were significantly impacted by the COVID-19 pandemic, with MD and MI being experienced by those in all HCP categories. Understanding the sources of MD and MI among HCPs could help to improve well-being, work satisfaction, and the quality of patient care.
Public Disclosure of Tax Strategies and Firm’s Actual Tax Policy
Authors: Blaufus Kay , Jarzembski Janine K. , Reineke Jakob , Trenn Ilko 
Published: October 2023

We use a sample of 248 tax strategies published by U.K. companies listed on the Financial Times Stock Exchange (FTSE) 100 and FTSE 250 to examine (a) how companies present themselves—more as “responsible taxpayers” who view taxes as a meaningful contribution to society, or more as “tax planners” who view taxes primarily as a cost, and (b) whether these presentations correspond to actual tax avoidance behavior. Our results show that, on average, firms tend to portray themselves as “responsible taxpayers,” but that this portrayal is consistent with firms’ tax avoidance behavior only when firms are subject to above-average external monitoring by financial analysts. The results suggest that firms manage the content of qualitative tax disclosures to sway public opinion as long as the probability of detecting misstatements is sufficiently low. This raises doubts as to whether mandatory qualitative information provides added value for stakeholders if it is not under external review. JEL Classification: H25; H20; M40; M48
Cost-Effectiveness Analysis for Therapy Sequence in Advanced Cancer: A Microsimulation Approach with Application to Metastatic Prostate Cancer
Authors: Handorf Elizabeth A. , Beck J. Robert , Correa Andres , Ramamurthy Chethan , Geynisman Daniel M. 
Published: October 2023

Purpose Patients with advanced cancer may undergo multiple lines of treatment, switching therapies as their disease progresses. We developed a general microsimulation framework to study therapy sequence and applied it to metastatic prostate cancer. Methods We constructed a discrete-time state transition model to study 2 lines of therapy. Using digitized published survival curves (progression-free survival, time to progression, and overall survival [OS]), we inferred event types (progression or death) and estimated transition probabilities using cumulative incidence functions with competing risks. We incorporated within-patient dependence over time; first-line therapy response informed subsequent event probabilities. Parameters governing within-patient dependence calibrated the model-based results to a target clinical trial. We applied these methods to 2 therapy sequences for metastatic prostate cancer, wherein both docetaxel (DCT) and abiraterone acetate (AA) are appropriate for either first- or second-line treatment. We assessed costs and quality-adjusted life-years (5-y QALYs) for 2 treatment strategies: DCT → AA versus AA → DCT. Results Models assuming within-patient independence overestimated OS time, which corrected with the calibration approach. With generic pricing, AA → DCT dominated DCT → AA, (higher 5-y QALYs and lower costs), consistent for all values of calibration parameters (including no correction). Model calibration increased the difference in 5-y QALYs between treatment strategies (0.07 uncorrected v. 0.15 with base-case correction). Applying the correction decreased the estimated difference in cost (−$5,360 uncorrected v. −$3,066 corrected). Results were strongly affected by the cost of AA. Under a lifetime horizon, AA → DCT was no longer dominant but still cost-effective (incremental cost-effectiveness ratio: $19,463). Conclusions We demonstrate a microsimulation approach to study the cost-effectiveness of therapy sequences for advanced prostate cancer, taking care to account for within-patient dependence. Highlights We developed a discrete-time state transition model for studying therapy sequence in advanced cancers. Results are sensitive to dependence within patients. A calibration approach can introduce dependence across lines of therapy and closely match simulation outcomes to target trial outcomes.
Proliferation and differentiation of MC3T3‐E1 cells on polymethyl methacrylate cements containing Fe3O4 and TiO2 for hyperthermic treatment of metastatic bone tumors
Authors: Kubota Moe , Furuya Maiko , Yokota Kotone , Kanetaka Hiroyasu , Ogawa Tomoyuki , Saito Shin , Jeyadevan Balachandran , Shimabukuro Masaya , Yokoi Taishi , Kawashita Masakazu 
Published: October 2023

Polymethyl methacrylate (PMMA) bone cement is widely used to relieve pain caused by metastatic bone tumors. We previously found that PMMA bone cement containing 15 mass% or more of TiO2 showed good apatite-forming ability, and 25 mass% or more of Fe3O4 generated sufficient heat for hyperthermia under an alternating current (AC) magnetic field. In this study, the cytocompatibility of PMMA bone cement with Fe3O4:TiO2 weight ratios of 25:15 (F25T15-3/2-42) and 30:15 (F30T15-3/2-42) was evaluated using osteoblastic cells (MC3T3-E1). The proliferation and differentiation of MC3T3-E1 cells were suppressed for F25T15-3/2-42 and F30T15-3/2-42 compared to PMMA bone cement without Fe3O4 and TiO2 (F0T0-3/2-42). The release of methyl methacrylate (MMA) monomers from F25T15-3/2-42 and F30T15-3/2-42 at 7 days was about 33 and 50 times higher than that from F0T0-3/2-42, respectively. The remarkable release of MMA monomers from F25T15-3/2-42 and F30T15-3/2-42 may be responsible for the suppressed proliferation and differentiation of MC3T3-E1 cells. The release of MMA monomers was not reduced when the MMA/PMMA weight ratio was decreased from 3/2 to 1/1, however, it was significantly reduced by increasing the content of benzoyl peroxide (BPO) and N, N-dimethyl- p-toluidine (DMPT) to 8 and 4 mass% against MMA, respectively. Proliferation and differentiation of MC3T3-E1 cells on PMMA-type cements containing Fe3O4 and TiO2 with increased BPO and DMPT contents need to be investigated in the future; however, our findings will be useful for designing PMMA cements for the hyperthermic treatment of metastatic bone tumors.
Rhamnazin ameliorates 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin-evoked testicular toxicity by restoring biochemical, spermatogenic and histological profile in male albino rats
Authors: Ijaz Muhammad Umar , Mustafa Shama , Ain Qurat Ul , Hamza Ali , Ali Shafaqat 
Published: October 2023

2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD) is a potential environmental toxin that has the ability to affect male reproductive tract. Rhamnazin is a naturally present flavone that displays multiple medicinal properties. Therefore, the current study was designed to determine the mitigative role of rhamnazin against TCDD induced reproductive damage. 48 adult male albino rats were randomly separated into four groups: control, TCDD (10 µgkg−1), TCDD + rhamnazin (10 µgkg−1 + 5 mgkg−1 respectively) and rhamnazin (5 mgkg−1). The trial was conducted for 56 days. TCDD intoxication notably affected superoxide dismutase (SOD), glutathione peroxidase (GPx), glutathione reductase (GSR) and catalase (CAT) activities, besides reactive oxygen species (ROS) and malondialdehyde (MDA) concentrations were augmented. TCDD administration also lowered sperm motility, viability, sperm number, while it augmented the sperm morphological (tail, neck/midpiece and head) anomalies. Moreover, it decreased the levels of follicle-stimulating hormone (FSH), luteinizing hormone (LH) and plasma testosterone. Moreover, TCDD reduced steroidogenic enzymes i.e., 17-beta hydroxysteroid dehydrogenase (17β-HSD), steroidogenic acute regulatory protein (StAR) and 3-beta hydroxysteroid dehydrogenase (3β-HSD) as well as B-cell lymphoma 2 (Bcl-2) expressions, but increased the expressions of Bcl-2-associated X protein (Bax) and cysteine–aspartic acid protease (Caspase-3). Furthermore, TCDD exposure also induced histopathological anomalies in testicular tissues. However, the supplementation of rhamnazin recovered all the mentioned damages in the testicles. The outcomes revealed that rhamnazin can ameliorate TCDD induced reproductive toxicity due to its anti-oxidant, anti-apoptotic and androgenic nature.
A single-center model for implementation of SLEDAI documentation adherence in childhood-onset systemic lupus erythematosus (cSLE)
Authors: Nelson Meghan Corrigan , Mosley Colleen , Bennett Tonya , Orenstein Evan , Rouster-Stevens Kelly 
Published: October 2023

Background Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune disease with variable disease expression but noted association with significant disease-related damage, morbidity, and mortality. The European Alliance of Associations for Rheumatology (EULAR) recommends routine monitoring of SLE through validated disease activity and chronicity indices, including the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Despite this, physician adherence with SLEDAI documentation remains elusive at various academic institutions. The aim of our study was to determine baseline SLEDAI documentation rates at our center and assess the change in adherence in SLEDAI documentation rate with electronic clinical decision support (CDS) reminders facilitated through the electronic medical record (EMR) over a 2-year period. Methods All SLE encounters over a 24-month period at a pediatric academic center were reviewed in order to obtain baseline SLEDAI documentation percentages. Physicians subsequently received monthly email reminders, initiated at month 4 of project initiation, with subsequent CDS reminder 13 months after project initiation prompted by anti-dsDNA lab result. Chart review was repeated continuously for each provider, and SLEDAI documentation rates were emailed to each provider monthly. Physicians completed a post-intervention survey regarding barriers to SLEDAI documentation at the end of the study. Results A total of 1980 SLE encounters were reviewed for this study. Baseline SLEDAI documentation rates were 10%. Following the introduction of monthly emails reminding physicians to document SLEDAI, rates increased to 55%. After the initiation of electronic in-basket reminders prompted by lab results, rates increased to 60%. Noted barriers to documentation were cited to be forgetfulness (67%) and lack of time (33%). Conclusion Our study demonstrates that monthly email reminders as well as EMR-mediated electronic in-basket reminders increased SLEDAI documentation rates at an academic center. Noted barriers to documentation were reported to be forgetfulness (67%) and lack of time (33%).