bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hydroxytyrosol, a Component of Olive Oil for Breast Cancer Prevention in Women at High Risk of Cancer
Authors: Puri Akshjot , Yin Zheng , Granados-Principal Sergio , Ensor Joe , Guzman Liliana , Rosato Roberto , Zhao Hong , Wong Stephen , Wang Lin , Patel Tejal , Chang Jenny C. 
Published: January 2025

Background: This study evaluates the effects of hydroxytyrosol (HT), a component of olive oil, on mammographic breast density reduction. We explored effects of HT on Wnt β‐catenin and other pathways involved in cancer stem cell renewal, DNA repair, cell proliferation, and differentiation.Methods: Twenty‐five milligrams per day oral dose of HT was given for 12 months in pre‐ and postmenopausal women at increased risk of breast cancer. Out of 51 patients enrolled, 41 completed the study. The annualized percent decrease in maximum mammographic volumetric breast density (max VBD%) between baseline (BL) and end of treatment (EOT) was analyzed. RNA sequencing (RNA‐Seq) and multiplex analysis was performed on the breast biopsies to compare the BL with EOT samples.Results: Max VBD% showed a nonsignificant change; however, in women 60 years or older, the max VBD% decrease was significant (3.7%, p = 0.0391), especially in those with high BL mammographic density. Using RNA‐Seq, 3330 unique transcripts were identified (p < 0.05). Mitotic telophase/cytokinesis and DNA damage were upregulated, whereas Wnt, Notch, and oxidative stress–induced senescence pathways were downregulated (p < 0.05). These pathways were confirmed by NanoString nCounter where significant decrease in proliferative genes (RELA and CDK4) and Wnt pathway (R‐HSA‐195721 and R‐HAS‐201681) was observed (p < 0.05).Conclusions: HT reduced breast density only in women over 60 years, especially in those with high BL breast density. HT also reduced proliferation and affected the Wnt signaling pathway. This study lays the foundation for future larger studies in exploring a natural compound with well tolerability and overall nontoxic profile for chemoprevention of breast cancer.Trial Registration: ClinicalTrials.gov identifier: NCT02068092
Characteristics of Workaholism Among Nurses in the Light of Research Conducted in Poland: A Cross‐Sectional Study
Authors: Kunecka Danuta , Milewska Anna Justyna , Iltchev Peter , Kozłowski Remigiusz , Marczak Michał , Kilańska Dorota 
Published: January 2025

Aim: The aim of this study is to analyze the phenomenon of workaholism among Polish nurses.Background: Work may be deemed one of the fundamental or essential forms of human activity. In the case of nurses, the expected level of professional commitment and dedication is above average. This factor may be an important element contributing to developing workaholism, which in turn is a strong prognostic factor for adverse events in the workplace, an especial critical issue in nursing practice.Methods: This cross‐sectional study was conducted from 2016 to 2019. The research material consisted of 454 questionnaire forms completed by nurses with a confirmed high risk of workaholism.Results: The mean values obtained in the study indicate the aspects as significant for characterizing the phenomenon of workaholism among nurses: Need for Predictability, Enthusiasm for Work, Impairment of Alternative, Extreme Dutifulness, Inability to Delegate, and Work Compulsion.Conclusion: The results show that two aspects are particularly significant for characterizing workaholism among Polish nurses: Inability to Delegate and Work as Value. Impairment of Alternative Activities, Extreme Dutifulness, Distributed Social Relations and Awareness, Stress and Anxiety, Enthusiasm for work, Need for predictability, and Work Compulsion proved to be less significant factors of workaholism characteristics in the study group. Therefore, the research attention should primarily focus on two more characteristic areas, e.g., Inability to Delegate and Work as Value, starting with a proper understanding of those concepts.
The Role of Race/Ethnicity on the Association between Neighborhood Deprivation and Breast Cancer Outcomes among Kentucky Patients with Breast Cancer (2010–2022)
Authors: Walker Breyanna , Pollard Elinita , Howard Sydney P. , Jones V. Morgan , O’Connor Kathleen L. , Durbin Eric B. , Hull Pamela C. , Jones Samantha R. , Adegboyega Adebola , Wang Xiaoqin , Owen Wendi A.B. , Szabunio Margaret M. , Williams Lovoria B. , Moore Justin X. 
Published: January 2025

Abstract

Background:
Kentucky is within the top five leading states for breast cancer mortality nationwide. This study investigates the association between neighborhood socioeconomic disadvantage and breast cancer outcomes, including surgical treatment, radiotherapy, chemotherapy, and survival, and how associations vary by race and ethnicity in Kentucky.

Methods:
We conducted a retrospective cohort analysis using data from the Kentucky Cancer Registry for patients with breast cancer diagnosed between 2010 and 2017, with follow-up through December 31, 2022. We linked Kentucky Cancer Registry data with census tract data to examine the relationship between area deprivation index (ADI) and breast cancer outcomes. Logistic regression and Cox proportional hazards models analyzed binary outcomes and time-to-event data, respectively.

Results:
Women in the most disadvantaged (ADI fourth quartile) neighborhoods were more likely to be diagnosed at later stages (OR, 1.26; 95% confidence interval, 1.12–1.41) and 34% more likely to die from breast cancer (HR, 1.34; 95% confidence interval, 1.14–1.57) after adjusting for age, race, tobacco use, tobacco pack-years, marital status, insurance status, family history, stage at diagnosis, breast cancer subtype, and residence in Appalachia when compared with women living in the least disadvantaged neighborhoods (ADI first quartile).

Conclusions:
Women in disadvantaged neighborhoods had significantly higher odds of late-stage diagnosis and breast cancer death, regardless of race, indicating that neighborhood factors contribute to breast cancer disparities.

Impact:
Socioeconomic and neighborhood factors may contribute to breast cancer outcomes, suggesting the necessity for targeted interventions. Future research should explore the effectiveness of such interventions and investigate additional social determinants contributing to disparities.
Population Pharmacokinetics of Orvacabtagene Autoleucel, an Autologous BCMA-Directed Chimeric Antigen Receptor T-cell Product, in Patients with Relapsed/Refractory Multiple Myeloma
Authors: Hu Hongxiang , Li Yan , Piasecki Julia , Hosseyni Daniela , Yan Zhicheng , Liu Xianghong , Ogasawara Ken , Zhou Simon , Cheng Yiming 
Published: January 2025

Abstract

Purpose:
Orvacabtagene autoleucel (orva-cel; JCARH125), a chimeric antigen receptor T-cell therapy targeting B-cell maturation antigen, was evaluated in patients with relapsed/refractory multiple myeloma in the EVOLVE phase I/II study (NCT03430011). We applied a modified piecewise model to characterize orva-cel transgene kinetics and assessed the impact of various covariates on its pharmacokinetics (PK).

Experimental Design:
The population PK analysis included 159 patients from the EVOLVE study. Traditional piecewise models, employing a first-order expansion rate with or without lag time followed by a biexponential contraction phase, were compared with a modified model incorporating a cell number-dependent expansion phase aligned with cellular physiology. Covariates assessed encompassed baseline demographics, dose levels (50–600 × 106 CD3+ chimeric antigen receptor+ T cells), prior/concomitant medications, baseline disease burden, and antitherapeutic antibody status.

Results:
Traditional piecewise models failed to accurately describe maximum orva-cel transgene level (Cmax) and underestimated the time to Cmax (Tmax). Our modified model incorporating a cell number–dependent expansion rate outperformed traditional models by (i) more accurately capturing the cellular expansion phase and (ii) yielding a Tmax that closely matches observed values. Additionally, dose level, percentage of plasma cells in bone marrow, and treatment-induced antitherapeutic antibody were identified as statistically significant covariates and associated with orva-cel expansion and/or persistence.

Conclusions:
Orva-cel PK was adequately described by the modified piecewise model incorporating a cell number–dependent expansion phase, which aligns closely with T-cell biology.
Randomized Phase II Study of Bevacizumab with Weekly Anetumab Ravtansine or Weekly Paclitaxel in Platinum-Resistant/Refractory High-Grade Ovarian Cancer (NCI Trial)
Authors: Alqaisi Husam A. , Cohn David E. , Chern Jing-Yi , Duska Linda R. , Jewell Andrea , Corr Bradley R. , Winer Ira Seth , Girda Eugenia , Crispens Marta A. , Dhani Neesha C. , Madariaga Ainhoa , Grant Robert C. , Malaguti Matthew , Lee Crystal , Bowering Valerie , Wong Horace , Poothullil Andrew , Speers Vanessa , Wang Lisa , Bedard Philippe L. , Brady John C. , Nixon Andrew B. , Chen Li , O’Connor Claire , Zamboni William , McKee Tawyna , Moscow Jeffrey A. , Oza Amit M. , Lheureux Stephanie 
Published: January 2025

Abstract

Purpose:
Mesothelin (MSLN) is highly expressed in high-grade serous/endometrioid ovarian cancers (HGOC). Anetumab ravtansine (AR) is an antibody–drug conjugate directed at the MSLN antigen with a tubulin polymerization inhibitor. We assessed the safety, activity, and pharmacokinetics of the combination AR/bevacizumab (Bev; ARB) versus weekly paclitaxel/Bev (PB) in patients with platinum-resistant/refractory HGOC (prrHGOC).

Patients and Methods:
Following a run-in phase I study to assess ARB safety, patients with prrHGOC with centrally confirmed MSLN-positive expression were randomized to ARB or PB (weekly paclitaxel 80 mg/m2 with Bev 10 mg/kg biweekly). Patients were stratified by platinum resistance/refractory and prior Bev. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall response rate, safety, and blood-based angiome biomarker assessment. A futility analysis was planned after 35 PFS events.

Results:
The combination of Bev (10 mg/kg) biweekly with AR (2.2 mg/kg) weekly was well tolerated. About phase II results, MSLN positivity was 88%, and 57 patients were randomized (28 ARB and 29 PB). Forty-two percentage of patients received prior Bev, and 23% were platinum-refractory. At futility analysis, the median PFS was 5.3 and 12.7 months for ARB and PB, respectively [P = 0.03; HR = 2.02 (1.06–3.86)]. The overall response rate was 21% with ARB and 65% with PB. The most common treatment-related grade ≥3 adverse events were anemia (18%) with ARB and neutropenia (24%) with PB. Higher baseline levels of circulating IL6 were associated with worse PFS, and its levels decreased with PB treatment.

Conclusions:
Our study stopped at interim analysis highlighting the benefit of PB in prrHGOC as the standard of care.
Targeting Monounsaturated Fatty Acid Metabolism for Radiosensitization of KRAS Mutant 3D Lung Cancer Models
Authors: Lu Shan , Pan Xiao , Volckova Eva , Shinde Anjali , Fuller Schuyler R. , Egan Regina , Ma Jianli , Kung Jong , Ott Christopher J. , Hata Aaron N. , Benes Cyril H. , Kang Jing X. , Willers Henning 
Published: January 2025

Abstract
Mutations in the KRAS oncogene can mediate resistance to radiation. KRAS mutation–driven tumors have been reported to express cancer stem cell (CSC)-like features and may harbor metabolic liabilities through which CSC-associated radioresistance can be overcome. We established a radiation/drug screening approach that relies on the growth of 3D spheres under anchorage-independent and lipid-limiting culture conditions, which promote stemness and lipogenesis. In this format, we screened 32 KRAS mutation–enriched lung cancer models. As predicted from published data, CB-839, a glutaminase inhibitor, displayed the highest degree of radiosensitization in KRAS mutant models with LKB1 co-mutations. Radiosensitization by inhibition of stearoyl-CoA desaturase-1 (SCD1) displayed a similar genotype preference though the data also implicated KEAP1 co-mutation and SCD1 expression as potential predictors of radiosensitization. In an isogenic model, KRAS mutant cells were characterized by increased SCD1 expression and a higher ratio of monounsaturated fatty acids to saturated fatty acids. Accordingly, pharmacological inhibition or depletion of SCD1 radiosensitized isogenic KRAS mutant but not wild-type cells. The radiosensitizing effect was notably small, especially compared with several DNA repair inhibitors. As an alternative strategy to targeting monounsaturated fatty acid metabolism, adding polyunsaturated fatty acids phenocopied some aspects of SCD1 inhibition, suppressed tumor growth in vivo, and opposed the CSC-like phenotype of KRAS mutant cells. In conclusion, we report a 3D screening approach that recapitulates clinically relevant features of KRAS mutant tumors and can be leveraged for therapeutic targeting of metabolic vulnerabilities. Our data highlight pronounced intertumoral heterogeneity in radiation/drug responses and the complexity of underlying genomic dependencies.
Age at First Full-term Pregnancy and Other Reproductive Factors Are Associated with Mammographic Breast Density in Postmenopausal Women: A Study in Flanders, Belgium
Authors: Vandeloo Magda J. , Kellen Eliane , Fang Carolyn Y. , Ross Eric A. , Vancoillie Liesbeth , Bruckers Liesbeth M. , Neven Kristof Y. , Bijnens Esmée M. , Nawrot Tim S. , Van Ongeval Chantal 
Published: January 2025

Abstract
This study evaluated the association between age at first full-term pregnancy (FFTP) and mammographic breast density (MBD) in postmenopausal women. A total of 1,034 women, ages 50 to 69 years, were recruited from the Flemish (Belgium) population–based breast cancer screening program. Participants completed a questionnaire on lifestyle and reproductive factors. From mammography, we assessed the percentage glandular tissue of the total breast volume (GLAND), the volumetric breast density (VBD), and the Breast Imaging Reporting and Data System (BI-RADS) density classification. For statistical analysis, we used the piecewise linear regression model. The average age at FFTP was 26.1 years. Among women with an FFTP &gt; 25.7 years, an each year increase in FFTP age was associated with a 1.17% increase in GLAND [95% confidence interval (CI), 0.20%–2.46%; P = 0.041] and a 1.45% increase in VBD (95% CI, 0.18%–2.75%; P = 0.026). Similarly, the odds of a higher BI-RADS classification increased by 5.0% (95% CI, 0.0%–11.0%; P = 0.059) for each year increase in FFTP age after 25.7 years. For every year delay in age at menarche, a 2.48% higher GLAND (95% CI, 0.43%–4.57%; P = 0.017) and a 2.45% higher VBD (95% CI, 0.38%–4.56%; P ≤ 0.020) were observed. Ever use of oral contraceptive resulted in a 12.24% decrease in GLAND (95% CI, −20.90% to −2.63%; P = 0.014) and a 13.48% decrease in VBD (95% CI, −22.1% to −3.91%; P = 0.007). MBD is significantly higher when FFTP takes place after 25.7 years. Later age at menarche is associated with higher MBD, whereas ever use of oral contraceptive is associated with lower MBD at postmenopause.

Significance:
We consider our findings to be highly novel, and to the best of our knowledge, our study is one of the first to investigate associations between age at FFTP and three markers of MBD (GLAND, VBD, and BI-RADS), uncovering that MBD is significantly higher when FFTP occurs after 25.7 years.
Non-Canonical TERT Activity Initiates Osteogenesis in Calcific Aortic Valve Disease
Authors: Cuevas Rolando A. , Hortells Luis , Chu Claire C. , Wong Ryan , Crane Alex , Boufford Camille K. , Regan Cailyn , Moorhead William J. , Bashline Michael J. , Parwal Aneesha , Parise Angelina M. , Behzadi Parya , Brown Mark J. , Gurkar Aditi U. , Bruemmer Dennis , Sembrat John , Sultan Ibrahim , Gleason Thomas G. , Billaud Marie , St. Hilaire Cynthia 
Published: January 2025

BACKGROUND:
Calcific aortic valve disease is the pathological remodeling of valve leaflets. The initial steps in valve leaflet osteogenic reprogramming are not fully understood. As TERT (telomerase reverse transcriptase) overexpression primes mesenchymal stem cells to differentiate into osteoblasts, we investigated whether TERT contributes to the osteogenic reprogramming of valve interstitial cells.

METHODS:

Human control and calcific aortic valve disease aortic valve leaflets and patient-specific human aortic valve interstitial cells were used in in vivo and in vitro calcification assays. Loss of function experiments in human aortic valve interstitial cells and cells isolated from
Tert

−/−

and
Terc

−/−

mice were used for mechanistic studies. Calcification was assessed in
Tert

+/+

and
Tert

−/−

mice ex vivo and in vivo. In silico modeling, proximity ligation, and coimmunoprecipitation assays defined novel TERT interacting partners. Chromatin immunoprecipitation and cleavage under targets and tagmentation sequencing defined protein-DNA interactions.

RESULTS:

TERT protein was highly expressed in calcified valve leaflets without changes in telomere length, DNA damage, or senescence markers, and these features were retained in isolated primary human aortic valve interstitial cells.
TERT
expression increased with osteogenic or inflammatory stimuli, and knockdown or genetic deletion of
TERT
prevented calcification in vitro and in vivo. Mechanistically, TERT was upregulated via NF-κB (nuclear factor-kappa B) and required to initiate osteogenic reprogramming, independent of its canonical reverse transcriptase activity and the long noncoding RNA
TERC
. TERT exerts non-canonical osteogenic functions via binding with STAT5 (signal transducer and activator of transcription 5). Depletion or inhibition of STAT5 prevented calcification. STAT5 was found to bind the promoter region of RUNX2 (runt-related transcription factor 2), the master regulator of osteogenic reprogramming. Finally, we demonstrate that TERT and STAT5 are upregulated and colocalized in calcific aortic valve disease tissue compared with control tissue.

CONCLUSIONS:
TERT’s non-canonical activity is required to initiate calcification. TERT is upregulated via inflammatory signaling pathways and partners with STAT5 to bind the RUNX2 gene promoter. These data identify a novel mechanism and potential therapeutic target to decrease vascular calcification.
Localizing hierarchical prediction errors and precisions during an oddball task with volatility: Computational insights and relationship with psychosocial functioning in healthy individuals
Authors: Charlton Colleen E. , Hauke Daniel J. , Wobmann Michelle , de Bock Renate , Andreou Christina , Borgwardt Stefan , Roth Volker , Diaconescu Andreea O. 
Published: January 2025

Abstract
The auditory mismatch negativity (MMN) has been widely used to investigate deficits in early auditory information processing, particularly in psychosis. Predictive coding theories suggest that impairments in sensory learning may arise from disturbances in hierarchical message passing, likely due to aberrant precision-weighting of prediction errors (PEs). This study employed a modified auditory oddball paradigm with varying phases of stability and volatility to disentangle the impact of hierarchical PEs on auditory MMN generation in 43 healthy controls (HCs). Single-trial EEG data were modeled with a hierarchical Bayesian model of learning to identify neural correlates of low-level PEs about tones and high-level PEs about environmental volatility. Our analysis revealed a reduced expression of the auditory MMN in volatile compared to stable phases of the paradigm. Additionally, lower Global Functioning (GF): Social scores were associated with a reduced difference waveform at 332 ms after stimulus presentation across the entire MMN paradigm. Further analysis revealed that this association was present during the volatile phase but not the stable phase of the paradigm. Source reconstruction suggested that the association between the stable difference waveform and psychosocial functioning originated in the left superior temporal gyrus. Finally, we found significant EEG signatures of both low- and high-level PEs and precision ratios. Our findings highlight the value of computational models in understanding the neural mechanisms involved in early auditory information processing and their connection to psychosocial functioning.
Exploring professional reasoning in occupational therapy: A scoping review of recent research
Authors: Sánchez-Zamorano Soledad , Rolack-Jaramillo Samanta , Ossandón-Pérez MaríaPaz , Moruno-Miralles Pedro 
Published: January 2025

Background: Professional reasoning in occupational therapy has become a key line of research. Updating and analyzing recent publications is crucial for the discipline. The objective of the research was to describe new findings and changes in the characteristics of research on professional reasoning in occupational therapy between 2019 and 2023. Method: A scoping review was used with the aim of identifying the development and scope of the literature on professional reasoning in occupational therapy from 2019 to 2023. The review was conducted in five stages following the PRISMA-ScR guidelines. Results: Seventy-six articles were described in terms of their nature and volume under the following categories: specific fields of practice, educational strategies for professional reasoning, theoretical discussions, and instruments related to professional reasoning. New findings include two professional reasoning modalities, five practice-related areas, and intervention programs that had not been previously described. Additionally, there has been an increase in the use of mixed methods. Conclusion: This scoping review identifies the nature and volume of literature on professional reasoning in recent years. The study reveals consolidated research lines focused on practice and teaching, alongside new findings and changes observed in recent studies.