bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synergistic Effects of Transarterial Chemoembolization and Lenvatinib on HIF-1α Ubiquitination and Prognosis Improvement in Hepatocellular Carcinoma
Authors: Chung Sung Won , Kim Jin Sun , Choi Won-Mook , Choi Jonggi , Lee Danbi , Shim Ju Hyun , Lim Young-Suk , Lee Han Chu , Kim Kang Mo 
Published: February 2025

Abstract
Purpose: A recent trial has shown that adding transarterial chemoembolization (TACE) to lenvatinib therapy results in enhanced therapeutic efficacy in hepatocellular carcinoma (HCC). We aimed to assess the effectiveness of the lenvatinib and TACE combination in a real-world clinical context for managing HCC and to elucidate the molecular pathways involved. Experimental Design: This retrospective analysis included 199 patients diagnosed with HCC and having intrahepatic lesions between 2018 and 2021. The cohort was divided into those who received lenvatinib plus TACE (n=62, combination group) and those who received lenvatinib monotherapy (n=137, monotherapy group). To further explore the underlying mechanisms, Huh-7 cells were exposed to lenvatinib or a vehicle for 48 hours under normoxic or hypoxic condition. Results: Propensity score-matched analysis revealed a significant improvement in both overall survival (adjusted hazard ratio [aHR], 0.38; 95% CI, 0.24–0.59; P&lt;0.001) and progression-free survival (aHR, 0.41; 95% CI, 0.26–0.64; P&lt;0.001) in the combination group compared to the monotherapy group. In laboratory experiments, under hypoxic conditions, lenvatinib notably attenuated hypoxia-inducible factor-1 alpha (HIF-1α) protein levels in Huh-7 cells without altering its mRNA levels. Intriguingly, lenvatinib facilitated the MDM2-mediated ubiquitination and subsequent degradation of HIF-1α. Additionally, cell viability assays confirmed a significant decrease in Huh-7 cell survival following lenvatinib treatment under hypoxic conditions. Conclusions: The combination of lenvatinib and TACE significantly improved survival in HCC patients. The mechanistic foundation appears to be the lenvatinib-triggered degradation of HIF-1α via the MDM2-dependent ubiquitination pathway, highlighting a potential therapeutic target in HCC treatment.
Presence of tertiary lymphoid structures and exhausted tissue-resident T cells determines clinical response to PD-1 blockade in renal cell carcinoma
Authors: Hugaboom Miya B. , Wirth Lena V. , Street Kelly , Ruthen Neil , Jegede Opeyemi A. , Schindler Nicholas R. , Shah Valisha , Zaemes Jacob P. , El Ahmar Nourhan , Matar Sayed , Savla Varunika , Choueiri Toni K. , Denize Thomas , West Destiny J. , McDermott David F. , Plimack Elizabeth R. , Sosman Jeffrey A. , Haas Naomi B. , Stein Mark N. , Alter Robert , Bilen Mehmet A. , Hurwitz Michael E. , Hammers Hans , Signoretti Sabina , Atkins Michael B. , Wu Catherine J. , Braun David A. 
Published: February 2025

Abstract
Immune checkpoint inhibitors (ICI) targeting the PD-1 pathway have transformed treatment of advanced renal cell carcinoma (RCC), but mechanisms underlying therapeutic response remain largely unknown. Herein, we perform transcriptomic analysis on RCC biospecimens from 102 patients enrolled in a phase II clinical trial of frontline nivolumab (NCT03117309) to investigate determinants of response to anti-PD1 monotherapy. Through bulk analysis, we identify an enrichment of genes associated with tertiary lymphoid structures (TLS) in responding patients. Using single-cell transcriptomics and external cohort validation, we identify a population of tissue-resident (ZNF683+ SLAMF7+) exhausted CD8+ T cells enriched in patients with poor clinical outcomes. Integrating these findings, we find tumors with high TLS and low tissue-resident exhausted CD8+ T cells have superior clinical outcomes with nivolumab. Altogether, these analyses contribute to a growing understanding of how the tumor microenvironment drives ICI- resistance and propose possible therapeutic targets to rationally overcome resistance to anti-PD1 monotherapy.
Reactivation of Oxidized Soluble Guanylate Cyclase as a Novel Treatment Strategy to Slow Progression of Calcific Aortic Valve Stenosis: Preclinical and Randomized Clinical Trials to Assess Safety and Efficacy
Authors: Zhang Bin , Enriquez-Sarano Maurice , Schaff Hartzell V. , Michelena Hector I. , Roos Carolyn M. , Hagler Michael A. , Zhang Heyu , Casaclang-Verzosa Grace , Huang Runqing , Bartoo Anna , Ranadive Sushant , Joyner Michael J. , Pislaru Sorin , Nkomo Vuyisile , Kremers Walter K. , Araoz Philip , Singh Gurpreet , Walters Michael A. , Hawkinson Jon , Cunningham Kevin Y. , Sung Jaeyun , Dunagan Brandon , Yi Ze , Miller Jordan D. 
Published: February 2025

BACKGROUND:
Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS.

METHODS:
We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis.

RESULTS:

In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS (
https://www.clinicaltrials.gov
; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS (
https://www.clinicaltrials.gov
; Unique identifier: NCT02481258).

CONCLUSIONS:
Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02049203. URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02481258.
2. CCR II: Pauline Epistles
Authors: Phillips Kim 
Published: February 2025

The first part of the chapter provides a detailed codicological description of the early-period (c. sixth century) CPA Pauline Epistles manuscript: CCR II. Twenty-five bifolia were recycled from this manuscript for use in CCR in the tenth century. The description includes a discussion of the paratextual features of the manuscript, and an initial discussion of the manuscript’s punctuation.
The second part of the chapter provides a fresh transcription of the CPA text of the forty-one folios currently held by Museum of the Bible. Each page includes two brief marginal apparati: the first lists the differences in reading between the current transcription and that of Müller-Kessler and Sokoloff; the second consists of a brief textual apparatus.
Variations in Simulated GMI Brightness Temperatures Due to Varying Particle Size Distribution Models and Hydrometeor Characteristics in a Severe Hailstorm
Authors: Leppert Kenneth D. , Cecil Daniel J. 
Published: February 2025

Abstract
The Atmospheric Radiative Transfer Simulator was used to conduct several simulations of Global Precipitation Measurement Microwave Imager brightness temperatures (BTs; 10.65–183.31±7-GHz) over a severe hailstorm. Simulations were conducted to test the sensitivity of BTs to particle size distribution form and to the size, orientation, and shape of several hydrometeor types assuming constant S-band radar reflectivity. Results show an increase in BT (i.e., less scattering) at most frequencies when changing from a normalized gamma distribution (NGD) to exponential distribution (EXPD). This change causes a decrease in cumulative hydrometeor surface area, but not necessarily a decrease in number concentration, suggesting that surface area exerts a stronger influence on BTs than concentration. Simulated BTs at the highest frequencies (166.0-183.31±7 GHz) agree better with observations when using an EXPD for cloud ice. At lower frequencies, especially 36.5-89.0 GHz, using a NGD for high-density graupel and hail leads to a better match between simulated and observed BTs. No clear preference is seen for low-density graupel, liquid precipitation, or snow. The impact of changing particle shape and/or orientation depends on the hydrometeor type. Changing the orientation of cloud ice from horizontal to a random orientation increases simulated BTs, while having no effect for high-density graupel. Assuming horizontally-oriented, oblate-spheroid cloud ice results in simulated BTs that match better with observed. Finally, under the fixed reflectivity constraint, increasing the diameter of hail from 0.5 to 20 cm results in an increase in minimum BT up to 1.5-cm diameter with near constant BT at all frequencies thereafter.
Mental Health, Mentalising and Empathy in Australian Healthcare Workers During COVID-19: A Cross-Sectional Study
Authors: Soloveva Maria V. , Ravindran Joshua , Sakar Ayse 
Published: February 2025

Since the outbreak of a Coronavirus Disease (COVID-19), healthcare workers have consistently exhibited increased stress, anxiety and depression. However, no study to date, has yet examined whether these symptoms are associated with social cognitive skills, known to be paramount in delivering high quality patient care. This cross-sectional study aimed to investigate whether the symptoms of stress, anxiety and depression were related to both empathy and mentalising in healthcare workers who worked during the COVID-19 outbreak in Australia. Participants were healthcare workers with an average age of 31.9 years ( N = 177). Participants completed the Depression, Anxiety and Stress Scale-21 (DASS-21), the Interpersonal Reactivity Index (IRI) and the Reading the Mind in The Eyes Test (RMET) between May 24th and June 21st, 2021. We found that higher stress levels in healthcare workers were associated with improved abilities in understanding others’ emotions and mental states, showing affective empathy and engaging in imaginative thinking. Conversely, increased anxiety was linked to reduced understanding of others’ emotions and mental states in this cohort. No other significant associations were observed. Our findings suggest that organisational initiatives are needed to deliver targeted interventions and specialised programs to support social cognitive skills in healthcare workers. Future studies with longitudinal designs are needed to better characterise mental health-social cognition associations and disentangle its directionality.
Shared Governance in Wicked Times: Perceptions of Faculty Senate Presidents on Faculty and Administrator Relationships
Authors: McNaughtan Jon , Enright Esther A. , Xie Wu , Billings Meredith S. , Harris Nathan F. 
Published: February 2025

Background: Shared governance is currently under attack by state agencies that seek to limit the power of institutional governing bodies. In addition, the effectiveness has been called into question by practitioners and researchers alike, which creates an additional stress on the prevailing governing structure of higher education. Purpose, Objective, and Focus of Study: Given the challenging context that higher education currently exists in with decreasing financing and desire for more legislative oversight, effective shared governance is critical. In this study, we discuss the importance of shared governance and focus on the critical nature of relationships in the efficacy of shared governance. Research Design: Guided by the shared governance theoretical model, we conducted an embedded qualitative case study on faculty senate presidents’ experiences working with administrators and faculty on issues of shared governance at public four-year regional comprehensive universities. We analyze responses from 13 faculty senate presidents to provide insights on the relationship between administration and faculty senate leaders to better understand how this relationship is perceived, and how it can be improved. Conclusions: We find that faculty senate presidents see challenges in what it means to “have a seat at the table,” and identify important insights for how to strengthen relationships between shared governance leaders and administrators.
Understanding online job search behaviour through the lens of TAM and DTPB: A new-collar job seeker perspective
Authors: Saad Zuria Akmal , Fauzi Muhammad Ashraf , Osman Azim Azuan 
Published: February 2025

Background The industrial revolutions have significantly impacted the labour workforce due to technological changes. Consequently, these changes have reshaped the job search landscape, necessitating a deeper understanding of job search behaviour. Objective This study explores the determinants influencing new-collar job seekers’ use of online job search platforms through an integrated model combining the technology acceptance model (TAM) and decomposed theory of planned behaviour (DTPB). Method Three hundred thirty responses from new-collar job seekers in the East Coast region of Malaysia were analysed using partial least squares-structural equation modelling (PLS-SEM 4). Results Eight of the nine hypotheses developed from the TAM and DTPB variables had a significant impact. The study highlights that sociodemographic factors, digital skills, experience, and platform usability contributed to the insignificance of perceived ease of use in influencing the attitude of new-collar job seekers. Although actual behavioural control failed to moderate the relationship between intention and behaviour, this finding provides valuable insights into the role of this variable in the context of online job search platforms. Conclusion The findings of this study enhance the understanding of new-collar workers’ behaviours in Malaysia. By gaining insights into these behaviours, the study underscores the importance of various stakeholders in the labour market being better prepared for future conditions, ultimately supporting Malaysia’s efforts to achieve developed country status.
Stage pT0–T1 rectal cancers: emphasis on submucosal high intensity on high-resolution T2-weighted imaging and other morphological features
Authors: Zhang Tongyin , Hu Yuwan , Li Haoyu , Wang Juan , Xu Qiaoyu , Xu Yanyan , Sun Hongliang 
Published: February 2025

Background Identification and staging of rectal cancer are mainly based on the difference in signal intensity (SI) between the tumor and normal structures of the intestinal wall on T2-weighted imaging. However, differentiating stage pT0–T1 from pT2 rectal tumors is difficult using routine magnetic resonance imaging (MRI) sequences. Purpose To summarize and explore whether MRI findings from routine imaging can help differentiate pT0–T1 from pT2 rectal tumors. Material and Methods A total of 110 patients with pT0–T2 rectal cancer underwent preoperative pelvic MRI examinations and tumor resection without preoperative chemoradiotherapy. MRI findings of rectal lesions (including tumor location, shape, longitudinal length, maximum cross-section, submucosal high intensity [SHI], extramural fibrotic scarring, wall shrinkage, lesion-to-wall signal intensity ratio, and presence of lymph node with short axis over 3 mm) and clinical characteristics were analyzed by univariate and multivariate analyses to screen the independent factors associated with pathological results. Results Of all the lesions, 32 tumors were proved to be pT0–T1 and 78 tumors were pT2. Univariate and multivariate logistic regression analyses revealed that tumor shape (odds ratio [OR] = 24.607, P < 0.001), SHI (OR = 6.129, P = 0.002), and extramural fibrotic scarring (OR = 0.110, P = 0.007) were independent factors distinguishing pT0–T1 tumors from pT2 tumors. If the rectal lesion has a cauliflower-like shape with SHI and no extramural fibrotic scarring, it is more likely to be a pT0–T1 tumor. Conclusion The imaging features obtained from the routine MRI sequence showed potential value for differentiating pT0–T1 from pT2 rectal tumors.
These Thy Libations, Osiris! A Reconsideration of the Four Clay Troughs from the Tomb of Tutankhamun (KV62)
Authors: Brown Nicholas 
Published: February 2025

While excavating the tomb of Tutankhamun, an enigmatic set of objects was discovered in the Burial Chamber: four clay troughs, also known as mud trays. Originally, these clay troughs were believed to be stands for the emblems found nearby and in close association to them. However, closer examination of the religious and archaeological context of the artefacts enables another interpretation of their function. First, the author compares the four troughs from KV62 with other known examples from the Valley of the Kings, along with previous hypotheses as to the function(s). The article continues with an analysis of the Burial Chamber’s association to Osirian funerary rites, and the long-standing traditions of funerary offerings and rites for the deceased present there. The research concludes with the author’s proposal that the mud trays functioned instead as libation offering basins for a funerary rite likely associated with Osiris. [Formula: see text]
Combined effects of cannabidiol and Δ9-tetrahydrocannabinol alleviate migraine-like symptoms in mice
Authors: Zorrilla Erik , Krivoshein Georgii , Kuburas Adisa , Schenke Maarten , Piña Cassandra L. , van Heiningen Sandra H. , Waite Jayme S. , Dehghani Anisa , Castonguay William C. , Flinn Harold C. , van den Maagdenberg Arn M.J.M. , Russo Andrew F. , Tolner Else A. , Wattiez Anne-Sophie 
Published: February 2025

Background The therapeutic use of cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) to treat migraine has been understudied. Using three mouse models, we examined the impact of CBD and THC on migraine-relevant behaviors triggered by: 1) calcitonin gene-related peptide (CGRP), 2) sodium nitroprusside (SNP), and 3) cortical spreading depolarization (CSD). Methods Both male and female CD1 mice were treated with CBD (100 mg/kg) or THC (1 mg/kg) alone or in combinations of CBD (1, 30 or 100 mg/kg) and THC (1 mg/kg) prior to injection of CGRP or SNP. The mice were assessed for light aversion (photophobia), squint (non-evoked pain), and periorbital tactile hypersensitivity, as well as possible adverse effects. In a separate set of experiments, CSD events were optogenetically induced in familial hemiplegic migraine 1 (FHM1) mutant and wildtype littermates (WT) mice (C57BL/6 background), followed by grimace and motor assessments with and without combinations of CBD (30 or 100 mg/kg) and THC (1 mg/kg). Results In CD1 mice, a 100:1 CBD:THC combination mitigated light aversion induced by CGRP and SNP in males and females. Rescue of CGRP- and SNP-induced squint was observed only in male mice with 100:1 CBD:THC. None of the treatments rescued periorbital tactile hypersensitivity in either sex. In FHM1 mutant and WT mice, the 100:1 CBD:THC ratio did not affect CSD characteristics but did reduce CSD-induced grimace features (i.e., head pain mimic). No adverse effects of any of the cannabinoid treatments were observed using cognitive, emotional, or motor tests. Conclusions A 100:1 ratio of CBD:THC has a beneficial effect on some of the most bothersome migraine-related symptoms in three mouse models. Our findings support a potential therapeutic efficacy of combined CBD and THC treatments.
Increased Tibial Tubercle–Trochlear Groove Distance and Sulcus Angle Are Associated With Patellar Osteochondritis Dissecans in Pediatric Patients
Authors: Lijesen Emilie , Adhiyaman Akshitha , Tracey Olivia C. , Bram Joshua T. , Oji Nnaoma M. , Chipman Danielle E. , Simpson Shae K. , Mintz Douglas N. , Fabricant Peter D. , Green Daniel W. 
Published: February 2025

Background: Osteochondritis dissecans (OCD) lesions in the knee are most commonly found in the medial femoral condyle (MFC). However, a paucity of literature has explored the characteristics or morphology of patellar OCD lesions. Purpose/Hypothesis: The purpose of this study was to analyze patellar tracking and patellofemoral measurements of pediatric patients with patellar OCD compared with patients with MFC OCD. It was hypothesized that the patients with patellar OCD would demonstrate an increased bony sulcus angle, cartilaginous sulcus angle, and tibial tubercle–trochlear groove (TT-TG) distance compared with patients with MFC OCD. Study Design: Case series; Level of evidence, 3. Methods: Patients aged ≤18 years diagnosed with either a patellar or MFC OCD lesion at a single tertiary care hospital between January 2016 and May 2023 were analyzed. Patients with a history of patellar instability were excluded. The Caton-Deschamps index, cartilaginous bony height, trochlear depth, patellar tilt, lateral patellar displacement, cartilaginous sulcus angle, bony sulcus angle, and TT-TG distance were assessed on magnetic resonance imaging (MRI). Patients were matched 1:2 based on sex and chronological age within 2 years between the patellar and MFC OCD groups. Results: A total of 40 extremities in 34 patients with patellar OCD were matched to 80 extremities in 73 patients with MFC OCD. The mean age at the time of MRI was 14.1 ± 2.3 years, and 23% were female. Compared with patients with MFC OCD, patients with patellar OCD had a significantly greater TT-TG distance (11.55 ± 4.15 vs 13.35 ± 4.07 mm, respectively; P = .03). The cartilaginous sulcus angle (150.63°± 7.20° vs 128.09°± 14.07°, respectively; P < .001) and bony sulcus angle (144.70°± 7.78° vs 137.37°± 9.62°, respectively; P < .001) were higher in the patellar OCD group compared with the MFC OCD group. Of patients with patellar OCD, 40% had a TT-TG distance >15 mm, and of patients with MFC OCD, 20% had a TT-TG distance >15 mm. The patellar OCD group had 3.7 times the risk of having a patellar dislocation compared with the MFC OCD group. Conclusion: An increased TT-TG distance and sulcus angle were associated with patellar OCD in pediatric patients. Patients with abnormal patellofemoral morphology who undergo treatment for a patellar OCD lesion may subsequently develop a patellar dislocation; in this study, patients with patellar OCD without a history of patellar dislocations demonstrated a nearly 4-fold higher dislocation rate compared with an age- and sex-matched group of patients with MFC OCD.