bluuebunny/crossref_metadata_2025 huggingface dataset:
Patterns of Treatment and Real‐World Outcomes of Patients With Non‐small Cell Lung Cancer With EGFR Exon 20 Insertion Mutations Receiving Mobocertinib: The EXTRACT Study
Authors: Liu Geoffrey , Nyaw Shi Feng , Mok Tony S. K. , Curcio Hubert , Cortot Alexis B. , Kam Tsz Yeung , Descourt Renaud , Chik Yin Kwan , Cheema Parneet , Gwinnutt James M. , Churchill Eric N. , Nyborn Justin , Curran Eileen , Savell Alexandra , Yin Yu , Chong Katie , Tanaka‐Chambers Yuka , Kretz Julian , Cadranel Jacques
Published: January 2025

Background

Real‐world data regarding patients with non‐small cell lung cancer (NSCLC) with EGFR exon 20 insertion (ex20ins) mutations receiving mobocertinib are limited. This study describes these patients' characteristics and outcomes.

Methods

A chart review was conducted across three countries (Canada, France, and Hong Kong), abstracting data from eligible patients (NCT05207423). The inclusion criteria were: ≥ 18 years old; diagnosis of stage IIIB‐IV NSCLC with EGFR ex20ins between January 1, 2017 and November 30, 2021; received mobocertinib. Data on demographics, clinical parameters, treatment patterns, mobocertinib exposure, real‐world outcomes, and adverse events (AEs) were collected. Results are also reported by Asian/Non‐Asian races.

Results

Overall, 105 patients were enrolled (median [IQR] age at initial diagnosis: 64.0 years [56, 71]; women: 62.9%). The most common first‐line of therapy (LoT) was chemotherapy; the most common second LoT was EGFR tyrosine kinase inhibitors. Most patients received mobocertinib during LoT two and three (74.3%); the maximum dose was 160 mg/day for 67.6% of the cohort (mean [SD] daily dose: 130.6 mg [36.68]). The median real‐world progression‐free survival (PFS) on mobocertinib was 4.76 months (95% CI: 3.98, 6.21). The overall response rate and disease control rate were 20.0% and 48.6%, respectively (median duration of response: 8.34 months [95% CI: 3.61, 9.49]). The median overall survival (OS) was 26.28 months (95% CI: 20.21, 36.44). Asian patients had numerically superior PFS and OS compared with non‐Asian patients. Regarding safety analysis, 73 patients (69.5%) experienced any AE. The most common AE was diarrhea (any grade) (52 patients; 49.5%).

Conclusions

These data illustrate the real‐world effectiveness of mobocertinib.
Characterization of Hospital Admissions During Immune Checkpoint Inhibitor Therapy: Insights From the ICOG Study
Authors: Wiegmann Jonas Paul , Fröhlich Tabea , Möhn Nora , Duzzi Laura , Narten Emily , Aurich Johanna , Thomas Janin , Grote‐Levi Lea , Mahjoub Susann , Berliner Dominik , Wirth Thomas , Golpon Heiko , Bollmann Benjamin‐Alexander , Von Wasilewski Imke , Gutzmer Ralf , Heidel Florian H. , Skripuletz Thomas , Beutel Gernot , Ivanyi Philipp ,   ICOG‐CCCH (Immune Cooperative Oncology Group, Comprehensive Cancer Center Hannover)
Published: January 2025

Introduction

Immune checkpoint inhibitors (ICI) have improved the therapeutic arsenal in outpatient oncology care; however, data on necessity of hospitalizations associated with immune‐related adverse events (irAEs) are scarce. Here, we characterized hospitalizations of patients undergoing ICI, from the prospective cohort study of the immune cooperative oncology group (ICOG) Hannover.

Methods

Between 12/2019 and 06/2022, 237 patients were included. Clinical data and characteristics of ICI were collected during a 6‐month observation period after the initiation of therapy. Descriptive statistics and Kaplan–Meier statistics were administered.

Results

During the observation period, 30/237 patients were hospitalized (HA(+)). Most common underlying tumor entities were malignant melanoma (59.5%), renal cell carcinoma (13.1%), and nonsmall‐cell lung carcinoma (12.7%). HA(+) patients exhibited an increased rate of pulmonary and cerebral metastases. We observed a significantly higher hospitalization rate during dual ICI with Nivolumab and Ipilimumab (p = 0.001). The predominant irAEs for hospitalization were colitis (26.7%), followed by hypophysitis (13.3%), leading to a median hospitalization of 7 (1–34) days. Interdisciplinary consultations were frequent, especially to gastroenterology (46.7%) and neurology (26.7%). Although a trend toward a prolonged overall survival in the HA(+) subgroup was identified, no statistically significant differences were found.

Discussion

The hospitalization rate of 12.6% is comparable to rates reported in previous studies. There was a disproportionate admission of patients with immune‐related colitis and hypophysitis compared to the prevalence described under ICI. We observed a high need for interdisciplinary consultations in line with the heterogeneity of immune‐mediated side effects. Compared to non‐hospitalized patients, there was no survival disadvantage in the HA(+) cohort.

Conclusion

With a relatively low hospitalization rate, short length of stay, and good clinical outcome, our data support the outpatient nature of ICI. The findings underscore the importance of interdisciplinary collaboration and vigilant monitoring of irAEs to ensure timely recognition and management.
Design, Synthesis, and In Silico Molecular Docking Studies of Adamantanyl Hydrazinylthiazoles as Potential Antidiabetic Agents
Authors: Choudhry Sabah Siddique , Mehmood Hasnain , Akhtar Tashfeen , Haroon Muhammad , Musa Mustapha , Sajid Zaroon
Published: January 2025

Diabetes mellitus (DM) is a widespread disease that poses a major threat to millions of people. To address this issue, we have synthesized seventeen new 4‐(adamantan‐1‐yl)‐(2‐(arylidene)hydrazinyl)thiazoles (3a–q) via Hantzsch synthetic approach. The molecular structures of all the compounds were confirmed using FT‐IR, 1H‐ and 13C‐NMR spectroscopy, and HR‐mass spectrometry. Protein kinase, α‐amylase, glycation, and oxidation inhibition potential of all compounds were also investigated, and it was found that compounds 3b, 3c, 3e–3g, and 3i–3q have shown excellent α‐amylase inhibition (IC50 = 7.91 ± 0.07 to 28.57 ± 0.1 µM), compounds 3c, 3e, 3i, 3k, and 3p (IC50 = 30.6 ± 0.06 to 37.8 ± 0.005 ppm) were found to be highly potent anti‐glycating agents, and compounds 3c, 3g, 3h, 3k, and 3m were found to be more potent protein kinase inhibitors as compared to standards. The compounds 3b, 3c, 3d, 3e, 3f, 3g, 3i, 3k, 3l, 3m, 3n, 3p, and 3q have shown good antioxidant potential (IC50 = 27.5 ± 0.09 to 48.8 ± 0.09 µM) as compared to standard ascorbic acid (IC50 = 51.3 ± 0.1 µM). The biocompatibility of all samples was also tested by employing brine shrimp lethality and in vitro hemolytic assays and was found to be safe to human erythrocytes at tested concentrations. Furthermore, the molecular docking simulation study also revealed that almost all synthesized compounds have potential interactions with target proteins at the molecular level.
Acetohydroxyacid Synthase (AHAS) Inhibitors as Antitubercular Agents: Insights From Molecular Docking and Dynamics Simulations
Authors: Gokhale Kunal , Joshi Nachiket , Alavala RajaSekhar Reddy
Published: January 2025

Acetohydroxyacid synthase (AHAS) is a vital enzyme in Mycobacterium tuberculosis, the pathogen causing tuberculosis (TB), involved in branched‐chain amino acid synthesis. Targeting AHAS for drug design against TB offers a promising strategy due to its essentiality in bacterial growth. In current investigation, we have designed 160 novel compounds by leveraging key scaffolds identified through structure‐based drug design (SBDD) methodologies. Subsequently, these compounds underwent molecular docking analysis to elucidate their potential interactions with the AHAS protein. The Top 4 compounds (with docking score above −8.2 kcal/mol) resulting from the docking studies were subjected to rigorous molecular dynamics simulations, spanning a runtime of 100 ns, to assess their stability across various parameters including root mean square deviation (RMSD), root mean square fluctuation (RMSF), secondary structure elements (SSEs), radius of gyration (rGyr), solvent accessible surface area (SASA), and MM‐GBSA free energy values. Remarkably, compounds KG 98 and KG 131 exhibited superior stability profiles across all analyzed parameters. From the detailed interactions analysis, it was found that the nitrogen containing heterocyclic rings (1,3,5‐triazine/imidazole) are essential to have the potential binding interactions with the AHAS enzyme. Some of the interactions were persisted for more than 75% of the simulated time, which shows the strength of the interactions. The findings suggest these lead molecules as promising candidates for AHAS inhibition, a potential avenue for TB treatment and management.
Scrub Typhus Infection Precipitating Hemolysis in a Patient With G6PD Deficiency: A Case Report
Authors: Shukla Ravi , Shrestha Mandira , Bhattarai Chaitanya Darshan , Lamichhane Kiran , Yadav Paras , Tamatta Debendra
Published: January 2025

Glucose‐6‐phosphate dehydrogenase (G6PD) deficiency is a well‐known red blood cell enzymopathy and a cause of intravascular hemolysis. This case report presents a child with underlying G6PD deficiency who experienced an acute episode of extensive intravascular hemolysis induced by a scrub typhus infection. The key takeaway from this report is that scrub typhus infection can trigger extensive hemolysis in patients with even “mild” G6PD deficiency, and normal G6PD levels found during the acute phase of hemolysis do not rule out the possibility of underlying G6PD deficiency.
Aerobiology matters: Why people in the community access pollen information and how they use it
Authors: Medek Danielle E. , Katelaris Constance H. , Milic Andelija , Beggs Paul J. , Lampugnani Edwin R. , Vicendese Don , Erbas Bircan , Davies Janet M.
Published: January 2025

Background

Globally, many pollen monitoring networks provide the community with daily pollen information, but there are limited data on health consumer uses and benefits. This research investigated why individuals in the community access pollen information, how they use it, and the perceived benefits.

Methods

In‐ and post‐pollen season surveys (2017–2018 and 2018–2019) enquired about symptoms, diagnoses, symptom management, access, benefits and usefulness of pollen information provided by the AusPollen Partnership. Open text responses were examined by thematic analysis. Theme frequency and quantitative data were compared across pollen seasons, within and after the season, and between respondents with and without access to AusPollen information.

Results

Surveys were completed 4044 times by 3604 individuals who predominantly self‐reported severe and frequent allergic rhinitis symptoms. Local AusPollen information was accessible to 84.6% of participants, and was reportedly used for preparation and planning (34.6%), guiding activities (32.9%), and medication decisions (28.2%). When asked how pollen information helped, similar themes were evident; but 16.1% also mentioned safety for themselves and others. However, secondary analysis of survey responses indicated that self‐reported medication use did not differ between those with or without access to pollen information or between time points surveyed. Suggestions for improvement included extended duration (16.4%), wider geographic range (13.5%), and information on other taxa (17.2%).

Conclusion

There was a perceived need for localised, detailed and timely pollen information by people with pollen allergy. Whilst responses suggested this helped inform behaviours linked to allergen avoidance, further education strategies on allergic rhinitis control are needed to support patients who self‐manage their condition.
Chronic conditions, cancer disparities, and the unique needs of Black women with ovarian cancer
Authors: Temkin Sarah M.
Published: January 2025

Chronic conditions among women contribute to cancer disparities. Consideration of unique influence sex and gender may be useful in understanding the experiences of Black women with ovarian cancer.
Duration of Time Intervals for Risk Minimization Measure Effectiveness Studies
Authors: Essink Sharon C. M. , Zomerdijk Inge M. , Goedecke Thomas , Straus Sabine M. J. M. , Gardarsdottir Helga , De Bruin Marie L.
Published: January 2025

Insights into the time needed for evaluation of risk minimization measures' (RMMs) effectiveness might identify areas for improvement. We assessed the duration of time intervals between regulatory milestones for RMM effectiveness studies assessed by the Pharmacovigilance Risk Assessment Committee (PRAC) of the European Medicines Agency (EMA). We included completed RMM effectiveness post‐authorization safety studies (PASSs) assessed by PRAC between 2016 and 2022. Regulatory documents submitted by marketing authorization holders and assessment reports were extracted from non‐public EMA databases. To calculate the duration of time intervals, we collected the dates of study request, protocol assessment start, protocol approval, study start, final study report assessment start, and final study report PRAC outcome. We identified 98 PASSs. The median duration from study request to final study report PRAC outcome was 52 months (Q1–Q3: 40–70). The median duration from study request to study start was 21 months (Q1–Q3: 15–30; n = 95) and from study start to final study report assessment start was 21 months (Q1–Q3: 13–36; n = 95). The final study report assessment often comprised <6 months (median: 4; Q1–Q3: 1–6). For PASSs with a PRAC‐approved protocol (n = 80, 81.6%), the median duration of protocol assessment was 7 months (Q1–Q3: 4–10). Concluding, the median duration from study request to RMM effectiveness PASS completion exceeded 4 years. Next to the study conduct duration, the period from study request until study start was the most time‐consuming. The duration of this period might be minimized by improved guidance on RMM effectiveness PASSs and encouraging timely protocol submission.
Characterization, Antibacterial Activity, and Dye Removal Capacity of Green and Hydrothermal Green Synthesized ZnO Nanostructures Using Crataegus Orientalis
Authors: Oke‐Altuntas Feyza , Altuntas Halit , Saritan Selin , Colak Hakan
Published: January 2025

In this study, the cost‐effective and environmentally friendly green synthesis of zinc oxide (ZnO) nanostructures is reported using Crataegus orientalis fruit extract with green synthesis (GS) and hydrothermal‐assisted green synthesis (HTGS) methods. The optical, structural, and morphological characteristics of the synthesized ZnO nanostructures are examined by UV–vis Spectroscopy (UV–vis), X‐ray diffraction (XRD), and field emission scanning electron microscopy (FE‐SEM) supported with energy dispersive X‐ray spectroscopy (EDX). XRD patterns confirmed that the synthesized ZnO nanostructures have a hexagonal single phase. The average crystallite size and optical bandgap values are obtained as 31 and 27 nm, 2.8 and 3.02 eV, for GS‐ZnO and HTGS‐ZnO nanostructures, respectively. The synthesized HTGS‐ZnO and GS‐ZnO nanostructures are used as a catalyst in the photodegradation of methylene blue (MB) dye and show excellent degradation activity of 99% after 120 min of UV illumination. In addition, it is found that HTGS‐ZnO and GS‐ZnO nanostructures have a higher antibacterial effect against Staphylococcus aureus ATCC 25923 than ZnO nanostructures synthesized by chemical methods. Moreover, since both synthesis methods show similar results, the GS method, which is lower cost, simpler, and less time‐consuming than the HTGS technique, can be recommended to synthesize ZnO nanostructures using Crataegus orientalis.
In‐Situ Construction of LiCl‐Rich Artificial Solid Electrolyte Interphase for High‐Performance Lithium Metal Anode
Authors: Chen Zhen , Wang Xi , Qian Shengjie , Liang Hai‐Peng , Chen Minghua , Shen Zexiang
Published: January 2025

In the pursuit of high‐energy‐density lithium metal batteries (LMBs), the development of stable solid electrolyte interphase (SEI) is critical to address issues such as lithium dendrite growth and low Coulombic efficiency. Herein, we propose a facile strategy for the in‐situ fabrication of a LiCl‐rich artificial SEI layer on Li surfaces through reaction of MoCl5 with Li (Li@MoCl5). The resulting artificial SEI significantly enhances the uniformity of Li deposition, effectively suppresses dendrite formation, and improves electrochemical performance. As a result, Li@MoCl5 symmetric cells demonstrate remarkable stability, achieving continuous cycling of 4200 h under a high current density of 10 mA cm−2 with an areal capacity of 1 mAh cm−2. Full‐cells employing Li@MoCl5 exhibit superior cycling stability and rate capability, even at high cathode loading (17 mg cm−2). These results highlight the potential of this interface engineering strategy for advanced practical application of LMBs.
Bi−S Bond Mediated Direct Z‐Scheme BiOCl/Cu2SnS3 Heterostructure for Efficient Photocatalytic Hydrogen Generation
Authors: Sarkar Dipendu , Biswas Maitrayee , Ghosh Swarup , Chowdhury Joydeep , Satpati Biswarup , Ghosh Srabanti
Published: January 2025

The advancement of photocatalytic technology for solar‐driven hydrogen (H2) production remains hindered by several challenges in developing efficient photocatalysts. A key issue is the rapid recombination of charge carriers, which significantly limits the light‐harvesting ability of materials like BiOCl and Cu2SnS3 quantum dots (CTS QDs), despite the faster charge mobility and quantum confinement effect, respectively. Herein, a BiOCl/CTS (BCTS) heterostructure was synthesized by loading CTS QDs onto BiOCl 2D nanosheets (NSs), that demonstrated excellent photocatalytic activity under visible light irradiation. The improved hydrogen generation rate (HGR) was primarily due to an interfacial Bi−S bond formation, which facilitates the creation of direct Z‐scheme heterojunction and an internal electric field at the interface, promoting efficient charge transfer between BiOCl and CTS. Moreover, due to the amalgamation of Bi−S bond formation and interfacial electric field, the optimized BCTS‐5% heterostructure exhibited a high HGR of 8.27 mmol g−1 h−1, and an apparent quantum yield (AQY) of 61 %, ~4 times higher than pristine BiOCl. First‐principle density functional theory (DFT) calculations further revealed the presence of a Bi−S bond with a bond length of ~2.85 Å and a minimal work function of 2.37 eV for the heterostructure, both of which are critical for enhancing H2 generation efficiency.
Functional genomics pipeline identifies CRL4 inhibition for the treatment of ovarian cancer
Authors: Claridge Sally E. , Nath Shalini , Baum Anneliese , Farias Richard , Cavallo Julie‐Ann , Rizvi Nile M. , De Boni Lamberto , Park Eric , Granados Genesis Lara , Hauesgen Matthew , Fernandez‐Rodriguez Ruben , Kozan Eda Nur , Kanshin Evgeny , Huynh Khoi Q. , Chen Peng‐Jen , Wu Kenneth , Ueberheide Beatrix , Mosquera Juan Miguel , Hirsch Fred R. , DeVita Robert J. , Elemento Olivier , Pauli Chantal , Pan Zhen‐Qiang , Hopkins Benjamin D.
Published: January 2025

Background

The goal of precision oncology is to find effective therapeutics for every patient. Through the inclusion of emerging therapeutics in a high‐throughput drug screening platform, our functional genomics pipeline inverts the common paradigm to identify patient populations that are likely to benefit from novel therapeutic strategies.

Approach

Utilizing drug screening data across a panel of 46 cancer cell lines from 11 tumor lineages, we identified an ovarian cancer‐specific sensitivity to the first‐in‐class CRL4 inhibitors KH‐4‐43 and 33‐11. CRL4 (i.e., Cullin‐4 RING E3 ubiquitin ligase) is known to be dysregulated in a variety of cancer contexts, making it an attractive therapeutic target. Unlike proteasome inhibitors that are associated with broad toxicity, CRL4 inhibition offers the potential for tumor‐specific effects.

Results

We observed that CRL4 inhibition negatively regulates core gene signatures that are upregulated in ovarian tumors and significantly slowed tumor growth as compared to the standard of care, cisplatin, in OVCAR8 xenografts. Building on this, we performed combination drug screening in conjunction with proteomic and transcriptomic profiling to identify ways to improve the antitumor effects of CRL4 inhibition in ovarian cancer models. CRL4 inhibition consistently resulted in activation of the mitogen‐activated protein kinase (MAPK) signaling cascade at both the transcriptomic and protein levels, suggesting that survival signaling is induced in response to CRL4 inhibition. These observations were concordant with the results of the combination drug screens in seven ovarian cancer cell lines that showed CRL4 inhibition cooperates with MEK inhibition. Preclinical studies in OVCAR8 and A2780 xenografts confirmed the therapeutic potential of the combination of KH‐4‐43 and trametinib, which extended overall survival and slowed tumor progression relative to either single agent or the standard of care.

Conclusions

Together, these data demonstrate the prospective utility of functional modeling pipelines for therapeutic development and underscore the clinical potential of CRL4 inhibition in the ovarian cancer context.

Highlights

A precision medicine pipeline identifies ovarian cancer sensitivity to CRL4 inhibitors.

CRL4 inhibition induces activation of MAPK signalling as identified by RNA sequencing, proteomics, and phosphoproteomics.

Inhibitor combinations that target both CRL4 and this CRL4 inhibitor‐induced survival signalling enhance ovarian cancer sensitivity to treatment.
Development and Characterization of Potato Starch–Pectin‐Based Active Films Enriched With Juniper Berry Essential Oil for Food Packaging Applications
Authors: Bhatia Saurabh , Jawad Muhammad , Chinnam Sampath , Al‐Harrasi Ahmed , Shah Yasir Abbas , Khan Talha Shireen , Al‐Azri Mohammed Said , Koca Esra , Aydemir Levent Yurdaer , Dıblan Sevgin , Mohan Syam , Najmi Asim , Khalid Asaad , Khan Mahbubur Rahman
Published: January 2025

The increasing demand for sustainable food packaging has driven the development of films based on biopolymers. However, enhancing their functional properties remains a challenge. In the current study, potato starch–pectin (PSP) composite films were fabricated and enriched with juniper berry essential oil (JBEO) to improve their physicochemical properties. The effects of incorporating different concentrations of JBEO (0.1%–1% v/v) on various properties of PSP‐based films were evaluated, including surface color, transparency, barrier properties, scanning electron microscopy (SEM), X‐ray diffraction (XRD), Fourier transform infrared spectroscopy (FTIR), thermal analysis (TGA and DTA), antioxidant activity, and antimicrobial effectiveness. Increasing the level of JBEO led to a significant decrease in the moisture content, film transparency, and mechanical attributes, while an increase in thickness, water permeability, and film elongation was observed. SEM analysis also revealed morphological properties such as some spherical, bubble‐like configuration and cracks on the surface due to an increase in JBEO concentration. TGA and DTA revealed lower weight loss in the initial cycles due to the addition of JBEO, and the thermal stability of the films improved. The antioxidant assays revealed a concentration‐dependent increase in the radical scavenging capacity of the films from 11.31% to 17.28% for DPPH and from 3.06% to 25.53% for ABTS. Moreover, significant antibacterial and antifungal activity of the bioactive films was observed against P. aeruginosa, S. aureus, and C. albicans. These findings suggest that JBEO enhances the functional properties of PSP films, making them suitable for active food packaging applications.
Psoralen and Isopsoralen Activate Nuclear Factor Erythroid 2‐Related Factor 2 Through Interaction With Kelch‐Like ECH‐Associated Protein 1
Authors: Lv Chengyu , Wang Song , Sun Chang , Liu Jing , Chen Yihao , Wang Chao , Yuan Cuiping , Qin Fengxian , Li Tiezhu
Published: January 2025

As natural furocoumarins, psoralen and its isomer isopsoralen are widely distributed in various fruits including Ficus carica L., vegetables including celery, and medicinal herbs including Psoralea corylifolia L. Although psoralen and isopsoralen have been used as dietary supplements because of their bioactivities such as antibacterial and anti‐inflammatory properties; however, the potential mechanisms underlying the antioxidant activities of these two furocoumarins still need to be explored. Hence, the aims of this work were to examine the activation of nuclear factor erythroid 2‐related factor 2 (Nrf2) by psoralen and isopsoralen, as well as the binding interaction of Kelch‐like ECH‐associated protein 1 (Keap1) with these two furocoumarins. Interestingly, both psoralen and isopsoralen induced Nrf2 nuclear translocation in a dose‐dependent manner in HEK293T cells. These two furanocoumarins also activated antioxidant response element (ARE)‐driven luciferase activity. The mRNA expression of GCLM, HO‐1, and NQO1 genes was significantly upregulated by treatment of HEK293T cells with psoralen and isopsoralen, respectively. Similarly, the expression of proteins can be promoted. Both psoralen and isopsoralen were located in the top of the central pocket of the Keap1 Kelch domain, suggesting that they were natural ligands of Keap1. In conclusion, both psoralen and isopsoralen activate Nrf2 through interaction with Keap1, thereby serving as natural antioxidants.
Daylight Saving Time and Automobile Accidents: Evidence From Chile
Authors: Gillmore Roberto
Published: January 2025

Under the evidence that the Daylight Saving Time (DST) regime does not accomplish its primary goal of saving energy, I analyze one of the main side effects, automobile accidents in Chile between 2002 and 2018. I use a Regression Discontinuity Design (RDD) exploiting the discrete nature of the transition into DST and a Difference‐in‐Difference (DID) approach, taking advantage of the changes in dates that the policy starts and ends over the years. I find a 2.7% reduction in automobile accidents under the DST regime. I isolate the two main mechanisms: sleep disruption and the reallocation of light. I find suggestive evidence that the sleep disruption effect plays a relevant role at both transitions: it increases automobile accidents by 6% the first week following the transition into DST and decreases them by 3.9% the first week following the transition into Standard Time (ST). I also find evidence that ambient light reduces serious and fatal accident risk.
Clinico‐Pathological Significance of Tumor Infiltrating Immune Cells in Oral Squamous Cell Carcinoma—Hope or Hype?
Authors: Seenivasagam Rajkumar K. , Singh Ashok , Gowda Vinay N. , Poonia Dharma R. , Majumdar Kinjal S. , Abhinav Thaduri , Kaul Pallvi , Panuganti Achyuth , Kailey Vikramjit S. , Kumar Rahul , Chowdhury Nilotpal
Published: January 2025

Background

To correlate between immunohistochemical expression of tumor‐infiltrating lymphocytes (TILs), tumor‐associated macrophages (TAMs), and natural killer (NK) cells with the AJCC 8th edition TNM staging system and other disease‐modifying clinico‐pathological variables.

Methods

The representative histology sections of tumor invasive margin (IM) and tumor core (TC) were selected according to the International Immuno‐Oncology Biomarker Working Group and were subjected to immunohistochemistry with antibodies for TILs (CD3, CD8, FOXP3), NK Cells (CD57), TAMs (CD68, CD163) and pan‐leukocyte marker (CD45). Histo‐immuno‐density‐intensity (HIDI) scoring was calculated as a product of the proportion and intensity of staining. Ordinal‐ordinal and continuous‐ordinal variables were correlated using Kendall's tau‐b (τb), and binary‐ordinal variables were correlated using Rank‐Biserial (rrb) statistics.

Results

A total of 111 patients were included in the study. None of the clinical and pathological parameters showed a strong correlation with any of the immune infiltrates including TNM staging.

Conclusion

We hypothesize an independent activity of tumor immunology in the disease prognosis.

Trial Registration

CTRI/2020/07/026335
Effect of Particle Size and Alloying with Gallium and Zinc in Copper Nanoparticles from Ab Initio Molecular Dynamics
Authors: Müller Andreas , Comas‐Vives Aleix , Copéret Christophe
Published: January 2025

Supported nanoparticles (NPs) are an intense field of research in industry and academia due to their unique catalytic properties. Yet, establishing relationships between structure and activity is challenging due to multiple possible compositions, interfaces, and alloy formation. This is especially pronounced for bimetallic NPs used in the CO2‐hydrogenation‐to‐methanol, where the structure responds dynamically to the chemical potential of the reactants and products, resulting in distinct surface structures depending on the exact reaction conditions. These phenomena have been highlighted by combining ab initio Molecular Dynamics (AIMD) and Metadynamics (MTD) with in situ X‐ray absorption spectroscopy, chemisorption, and CO‐IR. Here, we aim to understand how particle size and simulation temperature influence the structure and dynamics of small Cu NPs using the diffusion coefficients and the radial distribution function/atomic pair density function as descriptors using AIMD simulations. We found that decreasing the particle size or increasing the simulation temperature results in increased atom mobility, highlighted by the increased metal diffusion and resulting in reduced particle crystallinity. We also find that alloying Cu with Ga significantly increases the diffusion of both elements in the particle compared to the monometallic ones. In contrast, such diffusion lies in between the individual elements composing the CuZn particles.
Socio‐economic inequalities in second primary cancer incidence: A competing risks analysis of women with breast cancer in England between 2000 and 2018
Authors: Golani Ruchika , Kagenaar Eva , Jégu Jérémie , Belot Aurélien , Ling Suping
Published: January 2025

We aimed to investigate socio‐economic inequalities in second primary cancer (SPC) incidence among breast cancer survivors. Using Data from cancer registries in England, we included all women diagnosed with a first primary breast cancer (PBC) between 2000 and 2018 and aged between 18 and 99 years and followed them up from 6 months after the PBC diagnosis until a SPC event, death, or right censoring, whichever came first. We used flexible parametric survival models adjusting for age and year of PBC diagnosis, ethnicity, PBC tumour stage, comorbidity, and PBC treatments to model the cause‐specific hazards of SPC incidence and death according to income deprivation, and then estimated standardised cumulative incidences of SPC by deprivation, taking death as the competing event. Multiple imputation was performed to account for missing data. Among 649,905 included women, 47,399 SPCs and 171,223 deaths occurred during 4,269,042 person‐years of follow‐up. Income deprivation was consistently associated with an increased rate of SPC incidence (cause‐specific hazard ratio for the most vs. least deprived quintile: 1.29; 95% CI: 1.25, 1.33) and of death (1.36; 1.34, 1.38), translating into an absolute risk difference (the most vs. least deprived quintile) of 1.3% (95% CI: 1.0, 1.5) for SPC incidence and 4.9% (95% CI: 4.6, 5.1) for death at 10 years. Women with PBC from deprived areas in England faced a substantially higher risk of SPC than their counterparts. Future research is warranted to understand mechanisms for observed inequalities to inform strategies to monitor, prevent, and identify SPC in women with PBC.
ESG Rating Uncertainty and the Cost of Debt Financing
Authors: Chen Jinyu , Guo Xinyu , Liu Ran
Published: January 2025

Using A‐share listed companies in 2011–2022 as a research sample, this study manually calculates and constructs Environment, Social and Government (ESG) rating uncertainty at the level of Chinese listed companies and examines whether and how ESG rating uncertainty affects firms' cost of debt financing. The empirical results demonstrate that ESG rating uncertainty raises firms' debt financing costs. After a string of robustness tests, the results are still robust. Mechanism analysis identifies credit risk and corporate reputation as the primary channels driving this relationship. Furthermore, high levels of firm's internal control, region's public environmental concerns and the level of financial agglomeration are conducive to mitigating the adverse effects of ESG rating uncertainty. This article enriches the research on the impact of ESG rating uncertainty on microeconomic agents in emerging markets and provides new perspectives to alleviate corporate financing constraints.
Meta‐analysis of the ability of mutational profiles on the cancer genome atlas to predict prognosis in endometrial carcinoma
Authors: Li Yi‐xiang , Fan Yu , Cao Si‐yu , Zhang Yu‐fei , Li Jin‐ke
Published: January 2025

Background

In 2013, The Cancer Genome Atlas Research Network suggested that endometrial carcinoma patients may be reclassified into four molecular prognostic groups.

Objective

To compare survival of endometrial carcinoma patients with different mutational profiles.

Search Strategy

Studies reporting survival of endometrial carcinoma patients were identified through systematic searches of four databases.

Selection Criteria

We included relevant studies based on the literature type, data integrity and the methodological quality.

Data Collection and Analysis

The pooled survival data were compared among patients with different mutational profiles. Heterogeneity in the pooled data was assessed using the I2 statistic.

Main Results

Data were meta‐analyzed from nine studies involving 4755 patients, who were classified into the following mutational profiles: p53abn, 745 patients (15.6%); MMRd, 1454 patients (30.6%); POLEmut, 351 patients (7.4%); and p53wt, 2205 patients (46.4%). Compared to the p53wt group, the p53abn group showed significantly worse overall survival (OS) (HR 2.31, 95% CI: 1.67–3.19), progression‐free survival (PFS) (HR 2.86, 95% CI: 1.45–5.64) and disease‐specific survival (HR 2.60, 95% CI: 1.41–4.79); and the MMRd group showed significantly worse OS (HR 1.30, 95% CI: 1.11–1.53) and PFS (HR 1.27, 95% CI: 1.01–1.59). The POLEmut group, in contrast, showed similar survival as the p53wt group.

Conclusions

The four mutational profiles for patients with endometrial carcinoma in the Cancer Genome Atlas for Endometrial Cancer are associated with worse to better survival in the trend: p53abn < MMRd < POLEmut ≈ p53wt. Mutational profiling may be useful for stratifying endometrial carcinoma patients by survival risk, which in turn may improve their management.
Anti‐Müllerian hormone regulates ovarian granulosa cell growth in PCOS rats through SMAD4
Authors: Dong Anqi , Yu Xiaomeng , Zhang Yun , Liu Lili , Liu Fanglin , Song Wei , Zheng Jindan
Published: January 2025

Objective

Polycystic ovary syndrome (PCOS) is a diverse condition with an unknown cause. The precise mechanism underlying ovulatory abnormalities in PCOS remains unclear. It is widely believed that malfunction of granulosa cells is the primary factor contributing to aberrant follicular formation in PCOS.

Methods

A DHEA‐induced PCOS rat model was established, and ovarian granulosa cells were extracted and identified. Anti‐Müllerian hormone (AMH) and SMAD family member 4 (SMAD4) expression was detected in the serum, ovarian tissue and ovarian granulosa cells of each group, and proliferating cell nuclear antigen (PCNA), BCL2‐associated 2 (BAX), cleaved caspase‐3 and BCL‐2 protein expression was detected by Western blot in ovarian granulosa cells. Recombinant anti‐Müllerian hormone (rAMH) was administered at different concentrations to act on normal rat ovarian granulosa cells, cell proliferation was detected by cell counting kit‐8 (CCK‐8), apoptosis was detected by flow cytometry, and SMAD4, caspase‐3, BCL‐2 and cyclin A proteins were detected by Western blot. SMAD4‐siRNA was transfected into rat ovarian granulosa cells of the PCOS group, and PCNA and BAX were detected by Western blot.

Results

Compared with those in the control group, the expression of AMH and SMAD4 was increased in the ovarian tissues and granulosa cells of rats in the PCOS group, the expression of PCNA and BCL‐2 proteins was decreased in the ovarian granulosa cells of the PCOS group, the expression of BAX proteins was increased, and the expression of cleaved caspase‐3 was increased. Western blot results indicated that rAMH upregulated SMAD4 and caspase‐3 protein expression in granulosa cells and downregulated cyclin A and BCL‐2 protein expression. CCK‐8 and flow cytometry results indicated that AMH decreased granulosa cells proliferation and increased apoptosis. SiRNA knockdown of SMAD4 gene increased PCNA and BCL‐2 protein expression in the granulosa cells of PCOS rats and decreased BAX and cleaved caspase‐3 protein expression.

Conclusion

AMH may be involved in regulating impaired ovarian granulosa cells development in PCOS rats via SMAD4.
Optical Based Methods for Water Monitoring in Biological Tissue
Authors: Perkov Sergei , Cvjetinovic Julijana , Sydygalieva Altynai , Gorodkov Sergey , Li Guoqiang , Gorin Dmitry
Published: January 2025

Skin homeostasis is strongly dependent on its hydration levels, making skin water content measurement vital across various fields, including medicine, cosmetology, and sports science. Noninvasive diagnostic techniques are particularly relevant for clinical applications due to their minimal risk of side effects. A range of optical methods have been developed for this purpose, each with unique physical principles, advantages, and limitations. This review provides an in‐depth examination of optical techniques such as diffuse reflectance spectroscopy, optoacoustic spectroscopy, optoacoustic tomography, hyperspectral imaging, and Raman spectroscopy. We explore their efficacy in noninvasive monitoring of skin hydration and edema, which is characterized by an increase in interstitial fluid. By comparing the parameters, sensitivity, and clinical applications of these techniques, this review offers a comprehensive understanding of their potential to enhance diagnostic precision and improve patient care.
Regulatory Fragmentation and Operational Efficiency
Authors: Xu Hongkang
Published: January 2025

This study employs a fragmentation index derived from Federal Register data to explore the relationship between regulatory fragmentation and operational efficiency. I find a positive association between regulatory fragmentation and operational efficiency, validated through various robustness checks, including entropy balancing, instrumental variable methods, fixed effects at different levels, change specification models, and alternative measures of operational efficiency. Additional analyses indicate that this positive association is more pronounced in firms exhibiting internal control weaknesses and facing higher operational uncertainty. Overall, my results suggest that although regulatory fragmentation poses challenges, it also creates opportunities for firms to enhance their operation efficiency. This research sheds light on the multifaceted effects of regulatory environments, providing valuable insights for policymakers and corporate strategists in managing regulatory complexities.
The Degree and Origin of the Cooperativity of the Chalcogen (Ch···N) and Dihydrogen (H···H) Bonds in Some Triad Systems
Authors: Soufi Aboulfazl , Salehzadeh Sadegh
Published: January 2025

The strength and cooperative energy of chalcogen and dihydrogen bonds in some ABC triad systems of the types XHTe…NCH…HY (X = F, Cl, Br, I, H; Y = Li, Na, BeH, MgH) and FHCh…NCH…HNa (Ch = Te, Se, S) were computed and compared at several levels of theory. All resulting data showed that the strengths of chalcogen (Te…N) and dihydrogen (H…H) bonds increase in the order of H < I < Br < Cl < F, and Be < Mg < Li < Na, respectively. Then, the comparison of data for the FHTe…NCH…HY, FHSe…NCH…HNa, and FHS…NCH…HNa triads indicated that the interaction, stabilization, and cooperativity energies decrease in the order of Te > Se > S. The data show that in all cases the chalcogen and dihydrogen bonds change the bond dissociation energies (BDEs) and interaction energies (IEs) of each other by the same quantitative value. However, the relative impact of the above bonds on BDEs and IEs of each other depends on the relative strength of these bonds. Finally, the nature of both dihydrogen and chalcogen bonds and the origin of the cooperativity of bonds were evaluated by NBO and energy decomposition analysis (EDA) analyses.
Computational Insights Into Corrosion Inhibition Mechanism: Dissociation of Imidazole on Iron Surface
Authors: Zhao Weina , Shen Chang , Tummanapelli Anil Kumar , Wong Ming Wah
Published: January 2025

Corrosion inhibitors are widely used to mitigate safety risks and economic losses in engineering, yet post‐adsorption processes remain underexplored. In this study, we employed density functional theory calculations with a periodic model to investigate the dissociation mechanisms of imidazole on the Fe(100) surface. Imidazole was found to adsorb optimally in a parallel orientation, with an adsorption energy of −0.88 eV. We explored two dissociation pathways: CH and NH bond cleavages and found CH dissociation having a lower activation barrier of 0.46 eV. Intriguingly, an alternative indirect route CH dissociation pathway involving a tilted intermediate state was found to be competitive. Both indirect and direct CH dissociation pathways are energetically more favorable than NH cleavage. Molecular dynamics simulations reveal that indirect CH dissociation occurs rapidly. This study proposes an alternative protective mechanism involving dissociated imidazole inhibitors, offering new insights for corrosion inhibitor design.
Emotion and peer problems in autistic adolescents: The role of puberty, school adjustment and bullying
Authors: Dawe‐Lane Erin O. , Saunders Rob , Flouri Eirini , Mandy William P. L.
Published: January 2025

Background

Emotion and peer problems tend to increase in autistic young people during adolescence. However, the extent to which endogenous (e.g., pubertal maturation) and exogenous (e.g., school adjustment, bullying) factors contribute to trajectories of emotion and peer problems in autistic young people is unclear.

Methods

Using data from the Millennium Cohort Study (MCS), we fitted latent growth curves to model initial levels and growth in emotion and peer problems during adolescence. We used generalised structural equation models to investigate whether pubertal maturation, school adjustment, bullying, and timing of autism diagnosis (none, early [<8 years] or late [≥8 years]) predict initial levels and growth of emotion and peer problems in autistic and non‐autistic young people, separately for males (n = 780) and females (n = 172).

Results

In females, there were significant interactions between timing of diagnosis and (a) school adjustment and (b) bullying. In females with a late diagnosis of autism, lower school adjustment and greater bullying were associated with greater growth of emotion problems during adolescence. Furthermore, in females with an early diagnosis, lower school adjustment was associated with greater initial levels of peer problems. In males, later pubertal maturation was associated with greater growth of emotion and peer problems during adolescence, irrespective of autism diagnosis. In males with an early diagnosis of autism, greater bullying was associated with greater growth of emotion problems during adolescence.

Conclusion

School adjustment and bullying were associated with increasing emotion and peer problems in autistic adolescents, but their relative contribution varied according to timing of autism diagnosis and sex. Overall, this study supports the need for early identification and intervention for young autistic people experiencing poor school adjustment and bullying during adolescence.
Leadership Training for Department Chairs: Integrating Formal Training, Experiential Learning, and Mentorship
Authors: Stawnychko Leda
Published: January 2025

The study explores the link between formal training, experiential learning, mentorship, and the leadership development of department chairs at a Canadian university. Employing a framework analysis approach grounded in transformative learning theory, data from 17 semi‐structured interviews revealed that formal training imparted essential knowledge and skills to new chairs. However, the training's influence on the chairs' development varied, depending on individual career stages and previous leadership experiences. Participants identified experiential learning as a vital element of their leadership development, with prior leadership roles providing a solid base for a successful transition. Mentorship emerged as a transformative instrument, offering timely developmental opportunities through exchanges with experienced leaders. The study concludes that strategically combining learning approaches can enhance institutional leadership capacity and facilitate faculty members' transition into department chair roles, particularly in the context of the post‐COVID‐19 pandemic and the ongoing leadership crisis.
The Development of Creativity: From Self‐to Socially‐Referenced
Authors: Dumas Denis
Published: January 2025

How does creativity develop from a nearly ubiquitous and domain‐general capacity associated with playfulness and openness to experience to a highly rarified and domain‐specific ability associated with invention and innovation? In this short report, I describe creativity along two dimensions: self‐ and socially referenced creativity. In self‐referenced creativity, only the creators themselves judge the novelty and usefulness of an idea, while in socially referenced creativity, others make the judgments. For education to support creativity, it should therefore leverage (not squash) the self‐referenced creativity that learners enter schooling with, while simultaneously supporting learners in a transition to more socially referenced creativity within a domain. Based on the psychological characteristics of learners at different points in their academic development, I suggest activities that would be maximally fruitful in the process of developing domain creativity. Because these activities allow learners to engage their self‐referenced creativity but also require them to apply their domain knowledge to predict what others in the domain would view as novel or useful, they support the development of socially referenced creativity and exemplify the goals of creative education.
Circulating Tumor DNA as a Marker of Recurrence Risk in Stage III Colorectal Cancer: The α‐CORRECT Study
Authors: Diergaarde Brenda , Young Greg , Hall David W. , Mazloom Amin , Costa Gina L. , Subramaniam Soma , Palomares Melanie R. , Garces Jorge , Baehner Frederick L. , Schoen Robert E. ,   Exact Sciences MRD Group
Published: January 2025

Background and Objectives

Identification of colorectal cancer (CRC) patients at high risk of recurrence could be of substantial clinical use. We evaluated the association of ctDNA status, using a tumor‐informed assay, with recurrence‐free survival (RFS).

Methods

Stage III CRC patients were enrolled between 2016 and 2020. Tumor tissue and serial (every 3 months for years 1–3, biannually for years 4–5) blood samples were collected. Utilizing whole‐exome sequencing and selection of 50–200 variants for tumor informed assays, ctDNA status was determined using plasma cell‐free DNA.

Results

Of 137 patients enrolled, 124 with 1029 ctDNA results were included in the analyses. Median follow‐up was 4.8 years. Plasma ctDNA status was strongly associated with risk of recurrence during the surveillance period (hazard ratio (HR) 49.6, 95% CI: 16.6–148.3; p < 0.0001), and at the postsurgical (HR 9.6, 95% CI: 3.2–29.5) and postdefinitive therapy timepoints (HR: 16.7, 95% CI: 6.9–40.3). The estimated 3‐year RFS for ctDNA positive and ctDNA negative patients were, respectively, 54.5% and 96.1% after surgery, and 18.2% and 90.0% after definitive therapy. Multivariable analysis indicated ctDNA but not CEA was strongly prognostic for recurrence.

Conclusions

Our tumor‐informed ctDNA assay was strongly prognostic for recurrence in patients with stage III colorectal cancer at all timepoints.