bluuebunny/crossref_metadata_2025 huggingface dataset:
Reframing Formalin: A Molecular Opportunity Enabling Historical Epigenomics and Retrospective Gene Expression Studies
Authors: Holleley Clare E. , Hahn Erin E.
Published: January 2025

Formalin preservation of museum specimens has long been considered a barrier to molecular research due to extensive crosslinking and chemical modification. However, recent optimisation of hot alkaline lysis and proteinase K digestion DNA extraction methods have enabled a growing number of studies to overcome these challenges and conduct genome‐wide re‐sequencing and targeted locus‐specific sequencing. The newest, and perhaps most unexpected utility of formalin preservation in archival samples is its ability to preserve in situ DNA‐protein interactions at a molecular level. Retrieving this signal provides information about the relative compaction or accessibility of the genome to the transcriptional machinery required for gene expression. Thus, exposure to formalin essentially corresponds to taking a snapshot of organism‐wide gene expression at the time of death. While DNA methylation and RNA‐Seq analyses of dried tissues have provided glimpses into historical gene regulation, these techniques were previously limited to skeletal or desiccated remains, offering only partial insights. By examining fluid‐preserved specimens, molecular tools can now be applied to a broader range of tissues, enabling more detailed tissue‐specific gene regulation profiling across vertebrates. In this review, we chronicle the historical use of formaldehyde in collections and discuss how targeted chromatin profiling with assays like MNase‐seq and FAIRE‐seq are surmounting fixation challenges and unlocking invaluable insights into historical genomes and gene expression profiles. The deeper integration of molecular genetics with museum collections bridges the gap between past and present and provides a vital tool that could help us predict and mitigate some of the impacts of future environmental change, novel pathogens, or invasive species.
Extreme weather events, climate expectations, and agricultural export dynamics
Authors: Nes Kjersti , Schaefer K. Aleks , Gammans Matthew , Scheitrum Daniel Paul
Published: January 2025

Rising temperatures and shifting precipitation patterns threaten agricultural yields in many key global production regions. This paper assesses the impact of growing‐season extreme weather events on agricultural export outcomes in the short run, as well as the association between agricultural exports and long‐run climate expectations and variance. Our analysis matches information on bilateral trade flows with high‐resolution, geospatial data on growing area, planting and harvest dates, and weather for three highly traded staple crops—maize, soybeans, and rice—which together account for almost half of global calorie consumption. We use an econometric gravity model to estimate the short‐run effects of weather volatility and a nonparametric series regression to infer long‐run climate‐export associations. We then use our estimates to simulate the effects of various climate and weather counterfactuals on the agricultural export landscape. We find that 2‐standard‐deviation extreme weather events (measured using the water balance deficit) reduce maize, rice, and soybean bilateral export values by 48.2%, 53.4%, and 21.7%, respectively. Our long‐run results imply that increases in the standard deviation of weather are associated with lower export values across all three crops. An increase in the frequency of extreme events has the potential to greatly shift current commodity export patterns. Understanding these shifting patterns of trade is necessary to implement trade policy that enables countries to leverage their evolving comparative advantages and ensure the effectiveness of trade as a tool mitigating the negative production effect of climate change.
Disparities in healthcare, STI testing, and PrEP access among newcomer sexual minority men in Canada's three largest urban centers
Authors: Palma Paolo A. , Skakoon‐Sparling Shayna , Dawson Jessie , Zandi Reza , Zhang Terri , Campbell Evan , Tan Darrell H. S. , Lachowsky Nathan J. , Cox Joseph , Lambert Gilles , Dvorakova Milada , Lal Allan , Jollimore Jody , Grace Daniel , Hart Trevor A.
Published: January 2025

Gay, bisexual, and other men who have sex with men (GBM) are more likely to be diagnosed with HIV and other sexually transmitted infections (STIs) compared with the general population. Although newcomers generally experience a health advantage in Canada compared with non‐immigrants and more established immigrants (i.e., healthy immigrant effect), they also experience disparities in access to healthcare services. These disparities, in turn, may lead to unique vulnerabilities for the sexual health of GBM immigrants. We examined disparities in healthcare access, STI testing, and HIV pre‐exposure prophylaxis (PrEP) use among immigrant and non‐immigrant GBM. Using baseline data (collected between February 2017 and August 2019) from a multisite cohort study of GBM in Toronto, Vancouver, and Montreal (n = 2449), we found that newcomer GBM (migrated ≤ 5 years prior) were less likely to report having a primary healthcare provider than non‐immigrants. This had a weak indirect effect in mediating both access to STI testing and the use of HIV PrEP. These disparities dissipated after controlling for migration precarity (e.g., refugees and those without permanent residency), suggesting that disparities in newcomer GBM healthcare access may, in part, be driven by the large number of newcomers with precarious migration statuses.

Public Significance Statement: New immigrants tend to be less likely to have a primary healthcare provider or use other sexual health clinics, which can have adverse consequences for sexual health. This disparity appears to be largely concentrated among temporary foreign workers, international students, and refugees. Interventions should target policies that increase the number of primary healthcare providers, and address immigration policies that lead to fear of deportation due to one's health.
Sciatic Nerve Preservation in Robot‐Assisted Surgery for Initially Unresectable Primary Rectal Cancer: A Case Report
Authors: Mizuno Ryosuke , Okamura Ryosuke , Itatani Yoshiro , Kinoshita Hiromitsu , Aisu Yuki , Maekawa Hisatsugu , Hoshino Nobuaki , Hida Koya , Obama Kazutaka
Published: January 2025

Radical surgery for rectal cancer with bulky lateral pelvic lymph node (LPLN) metastasis involving the sciatic nerve presents both technical and oncological challenges. Preoperative multidisciplinary treatments have recently been anticipated to control the disease as well as to preserve organ function. A 51‐year‐old man, presenting with right buttock pain and impairment of walking, was diagnosed with sciatic nerve impairment due to right LPLN metastasis from rectal cancer. He was initially treated with palliative radiotherapy followed by FOLFOX plus bevacizumab. After 13 cycles of the chemotherapy, his symptoms disappeared and the LPLN shrank. Then, conversion surgery via robot‐assisted low anterior resection with right LPLN dissection was performed. Although he had moderate right leg pain postoperatively, there were no motor deficits or other complications. Pathological examination of the specimen revealed microscopic residual disease at the resection margin, but he is currently surviving recurrence‐free for 1.5 years. Preoperative multidisciplinary treatment enabled the preservation of the sciatic nerve in the robot‐assisted conversion surgery.
A Good Story but not the Whole Story: Stakeholder Theory as an Ethics of Capitalism
Authors: Hargrave Timothy , Smith Jeffery
Published: January 2025

The term “stakeholder capitalism” has become part of our shared business lexicon. This is due in large part to the work of R. Edward Freeman and his collaborators who conceive of stakeholder theory not simply as an approach to ethics in business but also of a new narrative for the ethics of capitalism. We argue that stakeholder thought as it is developed in this literature remains deficient as an ethics of capitalism because it fails to fully appreciate the distinction between business firms as one institution of capitalism and capitalism as an interrelated network of institutions. Failing to appreciate this distinction thwarts any facile movement between the theory's account of the ethics of business, which is concerned with the aims that guide business management, and the ethics of capitalism, which is concerned with how various institutions should be designed as a system with an internal division of moral labor. This difference suggests a prospective way forward for stakeholder theory that focuses more attention on the responsibilities that business firms owe to support the legal and economic institutions of capitalism.
Systemic lupus erythematosus‐associated autoantibodies in sickle cell disease: Spontaneous emergence in a patient and in transgenic sickle mice
Authors: Sinha Urshita , Setty Suman , Pilon Céleste , Brown Julia J. , Ruiz Maria Armila , Ren Guohui , Rauch Joyce , Saraf Santosh L. , Levine Jerrold S.
Published: January 2025

We describe a patient with sickle cell disease (SCD) and elevated antiphospholipid antibodies (aPL) who developed multi‐organ failure resembling catastrophic antiphospholipid syndrome. Autoimmune screening revealed several autoantibodies characteristic of systemic lupus erythematosus (SLE). Notably, routinely housed and unmanipulated transgenic sickle mice displayed significantly elevated titres of aPL‐ and SLE‐associated autoantibodies. We hypothesize that SCD may be a risk factor not only for the development of aPL but also more widespread autoimmunity.
Selective treatment de‐escalation in advanced prostate cancer: have we come full circle?
Authors: Chong Bryan , Saad Marniza , Chong Tsung Wen , Thng John , Tan Yu Guang , Tay Kae Jack , Cheng Christopher , Lin Po‐Hung , Teoh Jeremy , Chiu Peter Ka‐Fung , Lawrentschuk Nathan , Eapen Renu , Murphy Declan , Chan Johan , Chua Melvin L.K. , Tuan Jeffrey , Yuen John , Kanesvaran Ravindran , Chen Kenneth
Published: January 2025

Compelling evidence has solidified the notion of early treatment intensification in managing patients with metastatic hormone‐sensitive prostate cancer (mHSPC). Landmark trials have provided Level 1 evidence for the survival benefits achieved by combining multiple agents. The efficacy of combined therapy relies not only on how treatment is intensified but also on how it is de‐escalated. This underscores the importance of tailored treatment approaches, potentially involving a reduction in therapy for specific patients, to strike a balance between the benefits of hormonal treatment and its associated adverse effects. While de‐escalation of therapy in mHSPC remains challenging due to limited evidence, it is recommended for elderly or frail patients, those with poor performance status, or experiencing significant toxicity. However, for patients with excellent prostate‐specific antigen responses or favourable biomarkers, decisions should be personalised, weighing the potential benefits of continued treatment against the risk of long‐term side effects, using risk stratification tools where appropriate.
Improved Diagnostic Yield in Recessive Intellectual Disability Utilizing Systematic Whole Exome Sequencing Data Reanalysis
Authors: Fattahi Zohreh , Shokouhian Ebrahim , Peymani Fatemeh , Babanejad Mojgan , Beheshtian Maryam , Edizadeh Masoud , Molaei Negar , Alagha Parnian , Ghodratpour Fatemeh , Keshavarzi Fatemeh , Moghadam Masoumeh Goleyjani , Arzhangi Sanaz , Kahrizi Kimia , Najmabadi Hossein
Published: January 2025

Recent advances in next generation sequencing (NGS) have positioned whole exome sequencing (WES) as an efficient first‐tier method in genetic diagnosis. However, despite the diagnostic yield of 35%–50% in intellectual disability (ID) many patients still remain undiagnosed due to inherent limitations and bioinformatic short‐comings. In this study, we reanalyzed WES data from 159 Iranian families showing recessively inherited ID. The reanalysis was conducted with an initial clinical re‐evaluation of the patients and their families, followed by data reanalysis using two updated bioinformatic pipelines. In the first phase, the BWA‐GATK pipeline was utilized for alignment and variant calling, with subsequent variant annotation by the ANNOVAR tool. This approach yielded causative variants in 17 families (10.6%). Among these, six genes (MAZ, ACTR5, AKTIP, MIX23, SERPINB12, and CDC25B) were identified as novel candidates potentially associated with ID, supported by bioinformatics functional annotation and segregation analysis. In the second phase, families with negative results were reassessed using the Illumina DRAGEN Bio‐IT platform for variant‐calling, and Ilyome, a newly developed web‐based tool, for annotation. The second phase identified likely pathogenic variants in two additional families, increasing the total diagnostic yield to 11.9% which is consistent with other studies conducted on cohorts of patients with ID. In conclusion, identification of co‐segregating variants in six novel candidate genes in this study, emphasizes once more on the potential of WES reanalysis to uncover previously unknown gene‐disease associations. Notably, it demonstrates that systematic reanalysis of WES data using updated bioinformatic tools and a thorough review of the literature for new gene‐disease associations while performing phenotypic re‐evaluation, can improve diagnostic outcome of WES in recessively inherited ID. Consequently, if performed within a 1–3 year period, it can reduce the number of cases that may require other costly diagnostic methods such as whole genome sequencing.
Contemporary practices in abdominoperineal resection for early‐stage rectal cancer in the United States
Authors: Dhimal Totadri , Hilty Chu Bailey K. , Loria Anthony , Boyer Megan , Cai Xueya , Li Yue , Colugnati Fernando , Cupertino Paula , Ramsdale Erika E. , Fleming Fergal J.
Published: January 2025

Aim

In contrast to significant advances in organ preservation in locally advanced rectal cancer, the contemporary management of early‐stage rectal cancer, including the frequency of abdominoperineal resections, remains largely unexplored in the United States. Therefore, we assessed the utilization of neoadjuvant therapy and oncological resections in early‐stage rectal cancer patients.

Study design

This is a retrospective cohort study of patients with cT1–T3N0 rectal cancer who underwent proctectomies between 2016 and 2022 in the National Surgical Quality Improvement Project proctectomy files. Multivariable logistic regression was used to identify factors associated with abdominoperineal resections and Kendall's tau statistics to evaluate clinical‐pathological staging agreement.

Results

In all, 3078 patients (29.6% cT1–2N0, 70.4% cT3N0) were included with 55.3% of tumours <5 cm from the anal verge. Overall, 58.2% received neoadjuvant therapy within 3 months of surgery (30.6% for cT1–T2N0 vs. 69.8% for cT3N0, P < 0.001), and 58.6% underwent abdominoperineal resection (55.5% for cT1–T2N0 vs. 59.9% for cT3N0, P = 0.058). The adjusted odds of undergoing abdominoperineal resection were associated with increasing age (OR 1.4 per every 10‐year increase; 95% CI 1.2–1.5), cT3N0 tumours (OR 1.7; 95% CI 1.1–2.7) and tumour location <5 cm from the anal verge (OR 10.6; 95% CI 7.7–14.7). There was a weak clinical‐pathological T staging correlation (Kendal tau coefficient 0.25; 95% CI 0.20–0.29).

Conclusion

In this large cohort of patients with early‐stage rectal cancer with high rates of neoadjuvant therapy, over half of patients underwent abdominoperineal resection and one in five had a pathological complete response. These findings underscore opportunities for organ preservation in early‐stage rectal cancer, suggesting that treatments typically reserved for locally advanced disease may extend to early stages with the completion of ongoing clinical trials.
The Diagnostic Utility of PRAME in Primary Cutaneous Dedifferentiated and Transdifferentiated Melanomas
Authors: Choy Audrey , Wang Alex , Thayaparan Ganesha K. , Beaumont Luke , Williams Richard , Diab Sara , Tzaikou George , Ajmal Ayesha , Nirenberg Alexander
Published: January 2025

Melanomas show a wide spectrum of clinical, morphological, immunohistochemical, and molecular features, which can impact treatment and prognosis. Dedifferentiated and transdifferentiated melanomas (DTM) are defined as melanomas which have lost conventional melanocytic morphologic and immunohistochemical features, showing sarcomatous morphology and/or immunohistochemical staining of other cell lineages, and as such, can be mistaken for other entities such as collision tumors and undifferentiated spindle cell tumors. In this series, we highlight the utility of preferentially expressed antigen in melanomas (PRAME) in diagnosing undifferentiated/dedifferentiated melanomas. Case 1 is a lentigo maligna melanoma with dedifferentiation on the scalp of an 85‐year‐old. Case 2 is a desmoplastic melanoma with leiomyosarcomatous transdifferentiation on the cheek of an 80‐year‐old. Case 3 is a desmoplastic melanoma with rhabdomyosarcomatous transdifferentiation arising from the temple of an 88‐year‐old. In all cases, conventional melanocytic immunohistochemical markers were positive in the conventional melanoma and negative in the dedifferentiated/transdifferentiated areas. However, PRAME was positive in both the conventional and dedifferentiated areas with varying intensity. Although PRAME immunoreactivity can be seen in other malignant spindle cell tumors, this study highlights the potential utility of PRAME immunohistochemistry when considering a diagnosis of DTM.
Real‐world management of patients with complete response under immune‐checkpoint inhibition for advanced melanoma
Authors: Reitmajer Markus , Livingstone Elisabeth , Thoms Kai‐Martin , Heppt Markus V. , Meiss Frank , Gesierich Anja , Drexler Konstantin , Heinzerling Lucie , Meier Friedegund , Menzer Christian , Schlaak Max , Zimmer Lisa , Forschner Andrea
Published: January 2025

Background

Up to now, the optimal duration of immune checkpoint inhibitors (ICI) has not been evaluated in prospective studies. However, current clinical practice requires decisions to be made regarding the duration of ICI in complete responders.

Material and Methods

A survey was sent to 80 DeCOG skin cancer centers to assess how decisions are made on treatment duration of ICI in melanoma after having reached complete response, and staging intervals after ICI discontinuation. All responses received by March 10, 2024 (51 centers) were included.

Results

The duration of ICI after having achieved complete remission varies between centers from three to 36 months. In total, 66% of the DeCOG centers continue treatment for up to 6 months, after having achieved complete remission (CR) with ICI. In the first year after discontinuation of ICI, most centers perform staging intervals (CT/MRI) every 3 months. More than 60% of centers continue staging at least once per year even in the 4th and 5th year after discontinuation.

Conclusions

There are significant differences between the centers regarding staging intervals and duration of ICI upon CR. Prospective studies are necessary to determine the optimal time point of ICI discontinuation and follow‐up.
The Mortality of Adults With Sickle Cell Disease at a Comprehensive Sickle Cell Center
Authors: Afranie‐Sakyi Jennifer A. , Randall Eldrida , Fasano Ross , McLemore Morgan L. , El Rassi Fuad
Published: January 2025

Introduction

Sickle cell disease (SCD) is the most common hemoglobinopathy in North America. The life expectancy of SCD has extended into adulthood with screenings, preventative care, and hydroxyurea. However, comorbidities arise as adults with SCD age, leading to early mortality.

Methods

We conducted a retrospective chart review of the Georgia Comprehensive Sickle Cell Center at Grady Health System, analyzing records of deceased SCD patients from 2013 to 2020.

Results

Amongst the 72 patients analysed, majority had severe complications from SCD and at least 1 cardiovascular comorbidity. The median age of death was 44 (STD = 15.5) for all genotypes with the median age of death at 39 (STD = 14.26) for SS and Sβ0 genotypes (n = 51). There was no difference in the median age of death for patients who maintained regular clinic visits (a visit in the last 6 months prior to death) compared to those who did not. Despite hydroxyurea's known benefits in reducing SCD morbidity and mortality, less than 50% of patients had a prescription.

Conclusion

As new therapies are approved, their impact on SCD‐related morbidity and mortality must be evaluated. Improving access to, and education about, disease‐modifying therapies like hydroxyurea for both patients and clinicians is essential to improving outcomes.
The EU interinstitutional body for ethical standards: A legal and policy analysis
Authors: Alemanno Alberto
Published: January 2025

Amid several high‐profile ethical scandals, the EU has been discussing since the early 2000s the establishment of a dedicated EU ethics authority capable of restoring trust in its institutions. This article provides one of the first assessments of the newly adopted EU Interinstitutional Body for Ethical Standards by examining whether and how it can contribute to strengthening the existing EU public integrity system. After tracing its genesis and evolution, it first identifies the major structural limitations of the extant EU ethical framework, ranging from its high fragmentation across EU institutions, weak enforcement of its underlying standards to its limited awareness within both the EU institutional setting and wider public. Second, it assesses whether the newly adopted EU ethical body may address and overcome those structural limitations and how it may do so. It concludes that, despite its limited investigative and sanctioning powers, the first dedicated Interinstitutional Body for Ethical Standards carries the potential to mark a qualitative difference in the development of the EU public integrity system as we know it. Through a combination of its standard‐setting, advisory and awareness‐raising functions, the Body may profoundly alter both the ethical standards and their enforcement for participating institutions' members and beyond.
Soft palate angle and basihyoid depth increase with tongue size and with body condition score in horses
Authors: Talbot Alison M. , Shanks‐Boon Hannah , Baldwin Christopher M. , Barnes Harriet , Maddox Thomas W.
Published: January 2025

Background

Obesity has been associated with human obstructive sleep apnoea and canine brachycephalic obstructive airway syndrome. The effect of body condition score (BCS) on structures of the oropharynx, nasopharynx and upper airway of the horse has not been investigated.

Objectives

To investigate the effect of BCS on tongue measurements, soft palate angle and basihyoid depth in horses.

Study design

Retrospective, analytical, cross‐sectional.

Methods

Computed tomographic (CT) images of the head of 58 horses were assessed. DICOM viewing software was used to measure head length, basihyoid‐skin depth, soft palate angle (SPA), midline tongue area, dorsoventral height (DVH) of the tongue in two locations and head angle. BCS were assigned during CT examinations. Associations between measurements were tested and following initial calculations, further associations with tongue measurements as a ratio of head length were assessed.

Results

For initial measurements, 44 horses met the inclusion criteria. Addition of head length ratios to tongue measurements resulted in 24 of 44 horses meeting the inclusion criteria for the second set of calculations. Increased BCS led to an increased mean SPA (mean difference = 2.56; p = 0.02) and increased median basihyoid depth (mean difference = 0.246 cm; p = 0.006). Following adjustments made for the effect of head length on tongue measures, significant correlation was identified between SPA and tongue area (Spearman's r = 0.544; p = 0.007); SPA and DVH of the tongue at the level of the hard palate (Spearman's r = 0.562; p = 0.004) and SPA and DVH of the tongue at the lingual process of the basihyoid bone (Spearman's r = 0.690; p < 0.001). No significant correlation was identified between variables and sex.

Main limitations

The sample size was small and the effect of breed on measures was not studied. Measurements were acquired on a single sagittal CT plane. The investigator collecting CT measures was not blinded to BCS. All horses were sedated for the CT procedure which may have affected measures obtained.

Conclusions

Increased BCS increases SPA and basihyoid bone depth. Increases in tongue size measurements increase SPA. Results from this study warrant further investigation into the clinical significance of the effects of BCS on the upper airways of the horse.
Review of biological variation and its applications in interpretation of equine clinical pathology results
Authors: Fernandes T. , Robin Matthew , Freeman Kathleen P.
Published: January 2025

Biological variation in laboratory results refers to physiological fluctuations that occur around a homeostatic setpoint (HSP) for various laboratory measurands. Assessment of biological variation includes determining individual variation (CVI), group variation (CVG), and analytical variation (CVA). Reference change value (RCV) is an objective tool for an evidence‐based approach to interpret data by assessing the significance of consecutive results in an individual for the diagnosis, prognosis, and monitoring of disease. The individualised reference intervals (iRI) are derived from the determination of the HSP for an individual and the RCV. Evaluation of dispersion (DI) of results around any numerical result, reference interval limit, or recommended cut‐off value can help define grey zones in clinical data interpretation. The Index of Individuality (II), which compares the amount of biological variation in a group (CVG) relative to the amount of biological variation in an individual (CVI), is useful to determine if 95% population‐based or iRI would be more valuable to detect a significant change in a measurand. The critical number of specimens provides confidence in a defined probability needed for the estimation of the HSP for laboratory measurands. Biological variation data may help support or disprove empirically derived or consensus‐derived interpretation recommendations. Biological variation data has the potential to improve the diagnostic accuracy of clinical laboratory testing. Examples of these applications are included.
Knockdown of RFC3 enhances the sensitivity of colon cancer cells to oxaliplatin by inducing ferroptosis
Authors: Wu Youyi , Chen Tingting , Wu Songsong , Huang Yiwei , Li Fuyao
Published: January 2025

Background

The development of resistance to oxaliplatin is a multifaceted process, often involving modifications in drug transport, DNA repair mechanisms, and the ability of cells to evade drug‐induced apoptosis.

Objective

To evaluate whether knocking down RFC3 promotes the sensitivity of colorectal cancer (CRC) cells to oxaliplatin, potentially offering a new approach to combat drug resistance.

Methods

siRNA‐mediated knockdown of RFC3 was employed in colorectal cancer cell lines to assess the impact on oxaliplatin responsiveness. Cell viability assays, clonogenic survival assays, and flow cytometry were conducted to evaluate the effects on cell growth and apoptosis. Additionally, immunoblot analysis was used to scrutinize modifications in the expression of pivotal protein expression in the Wnt/β‐catenin/GPX4 axis.

Results

RFC3 is highly expressed in CRC tissues and associated with prognosis. Knocking down RFC3 enhances the sensitivity of CRC cells to oxaliplatin. Additionally, the reduction of RFC3 promotes the susceptibility of chemoresistant tumor cells to oxaliplatin by inducing ferroptosis. Furthermore, the knockdown of RFC3 disrupts the Wnt/β‐catenin/GPX4 axis.

Conclusion

Depletion of RFC3 enhances the sensitivity of CRC cells to oxaliplatin via inducing ferroptosis.
A novel naphthylchalcone ([E]‐4‐(3‐[naphthalen‐2‐yl]‐3‐oxoprop‐1‐en‐1‐yl) induces intrinsic and extrinsic apoptosis in human acute leukemia cell lines
Authors: Jacques Amanda V. , Stefanes Natália M. , Walter Laura O. , Syracuse Stephanie M. , Bigolin Alisson , Chiaradia‐Delatorre Louise D. , de Souza Luiz F. S. , de Moraes Ana C. R. , Nunes Ricardo J. , Santos‐Silva Maria C.
Published: January 2025

Background

Chalcones have been described in the literature as promising antineoplastic compounds.

Objectives

Therefore, the objective of this study was to analyze the cytotoxic effect of 23 synthetic chalcones on human acute leukemia (AL) cell lines (Jurkat and K562).

Methods

Cytotoxicity assessment was performed using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide (MTT) method. Cell death was evaluated using fluorescence microscopy, the DNA fragmentation technique, and the assessment of proteins involved in apoptosis by flow cytometry.

Results

The most cytotoxic chalcone (R32) showed no cytotoxicity towards peripheral blood mononuclear cells (PBMC). It exhibited no hemolytic activity, did not alter platelet aggregation after adenosine diphosphate (ADP) and epinephrine stimulation, and did not affect blood coagulation as measured by prothrombin time (PT) and activated partial thromboplastin time (APTT). R32 demonstrated cytotoxic activity by inducing both intrinsic and extrinsic apoptosis, leading to caspase‐3 activation and DNA fragmentation. In Jurkat and K562 cells, intrinsic apoptosis was associated with changes in mitochondrial membrane potential (MMP). There was a decreased expression of Bcl‐2, increased expression of Bax, decreased expression of survivin, and increased expression of apoptosis‐inducing factor (AIF). Extrinsic apoptosis involvement was also observed in both cell lines, characterized by increased expression of the Fas receptor. Additionally, Jurkat cells exhibited decreased expression of the KI‐67 cell proliferation marker.

Conclusion

These findings suggest R32 as a potential compound for the development of novel drugs for the treatment of AL.
Long‐term evaluation of rheumatoid arthritis activity with erythrocyte methotrexate‐polyglutamate 3
Authors: Escal Jean , Poudret Marion , Hodin Sophie , Neel Tiphany , Coman Irina , Locrelle Hervé , Amouzougan Adamah , Thomas Thierry , Delavenne Xavier , Marotte Hubert
Published: January 2025

Background

Methotrexate (MTX) is the first‐line treatment for Rheumatoid Arthritis (RA), yet 30%–50% of RA patients develop resistance to MTX, which can manifest several years after treatment initiation.

Objective

This study investigates the relationship between erythrocyte methotrexate polyglutamates (MTX‐PGs) subtype concentrations and clinical disease activity in RA patients undergoing long‐term MTX treatment.

Methods

In this cross‐sectional study, patients on a stable dose of subcutaneous MTX for several years were included. The study protocol was registered in the European Medicines Agency's clinical trials register (n°2017‐004348‐39). Patients were classified as either in clinical remission (DAS28 <2.6) or having active disease (DAS28 >3.2). Erythrocyte MTX‐PGs concentrations were measured using liquid chromatography coupled with mass spectrometry. Multivariate logistic regression analysis assessed the probability of remission status based on MTX‐PG3 concentrations.

Results

The study included 34 patients with active RA and 25 in remission. The remission group had a median MTX treatment duration of 6.4 years compared to 2.6 years for the active group (p = 0.001). Patients in remission had a longer median disease duration (p = 0.02) and a lower Body Mass Index (BMI) (p = 0.03) than those with active RA. A positive correlation was found between remission status and high MTX‐PG3 concentrations in patients with a BMI <25 kg/m2.

Conclusion

Erythrocyte MTX‐PG3 concentrations may serve as a marker for RA activity after prolonged treatment. However, BMI could limit their utility as a biomarker.
Transitions in treatment: A systematic review and meta‐aggregation of preferences and barriers in switching from oral to long‐acting injectable antiretroviral therapy among people living with HIV and stakeholders
Authors: Hu Tiantian , Yang Shuqi , Yu Junwen , Yang Zhongfang , Jin Yilin , Zhu Zheng
Published: January 2025

Introduction

Antiretroviral treatment (ART) has significantly enhanced health outcomes for people living with HIV (PLWH). With the evolution of treatment options, there is an increasing interest in the development of long‐acting injectable formulations of antiretroviral drugs. These formulations present a promising alternative to oral ART.

Methods

The methodology and reporting of this systematic review followed the guidance of the Joanna Briggs Institute Reviewer's Manual and Enhancing Transparency in Reporting the Synthesis of Qualitative Research (ENTREQ). The comprehensive searches involved multiple databases, including PubMed, MEDLINE (Ovid), Embase (Ovid), CINHAL (EBSCO), ProQuest Dissertations and Theses, Web of Science, Wanfang (Chinese), CNKI (Chinese), Google Scholar and Baidu Scholar (Chinese).

Results

In all, 142 studies were identified and 20 eligible studies were included in the meta‐aggregation. A total of 141 findings, 20 categories and nine synthesized findings were extracted from 20 studies. The nine synthesized findings identified from the 20 studies focused on the following topics: benefits, flexibility and practicality of long‐acting injectable (LAI) treatment; scepticism about the use of LAI treatment; management challenges; logistical challenges; potential for protecting marginalized populations; concerns about side effects; financial issue; suggestions for improvement. PLWH's geographical distribution, backgrounds, demographics and clinical characteristics were limited.

Conclusion

We recommend considering the needs and experiences of PLWH in the transition from oral ART to LAI treatment. For marginalized populations, it is crucial to maintain regular communication with healthcare providers and institutions. Additionally, at the community level, engaging diverse stakeholders with valuable insights is vital, as is enhancing health education programmes and intensifying efforts to combat discrimination. These measures will play a key role in addressing the needs of PLWH, enhancing public awareness and promoting better understanding of LAI treatment.
The β Common Cytokine Receptor Family Reveals New Functional Paradigms From Structural Complexities
Authors: Kan Winnie L. , Weekley Claire M. , Nero Tracy L. , Hercus Timothy R. , Yip Kwok Ho , Tumes Damon J. , Woodcock Joanna M. , Ross David M. , Thomas Daniel , Terán David , Owczarek Catherine M. , Liu Nora W. , Martelotto Luciano G. , Polo Jose M. , Pant Harshita , Tvorogov Denis , Lopez Angel F. , Parker Michael W.
Published: January 2025

Cytokines are small proteins that are critical for controlling the growth and activity of hematopoietic cells by binding to cell surface receptors and transmitting signals across membranes. The β common (βc) cytokine receptor family, consisting of the granulocyte‐macrophage colony‐stimulating factor (GM‐CSF), interleukin (IL)‐3, and IL‐5 cytokine receptors, is an architype of the heterodimeric cytokine receptor systems. We now know that signaling by cytokine receptors is not always an “all or none” phenomenon. Subtle alterations of the cytokine:receptor complex can result in differential or selective signaling and underpin a variety of diseases including chronic inflammatory conditions and cancers. Structural biology techniques, such as X‐ray crystallography and cryo‐electron microscopy alongside cell biology studies, are providing detailed insights into cytokine receptor signaling. Recently, we found that the IL‐3 receptor ternary complex forms higher‐order assemblies, like those found earlier for the GM‐CSF receptor, and demonstrated that functionally distinct biological signals arise from different IL‐3 receptor oligomeric assemblies. As we enhance our understanding of the structural nuances of cytokine–receptor interactions, we foresee a new era of theranostics whereby structurally guided mechanism‐based manipulation of cytokine signaling through rational/targeted protein engineering will harness the full potential of cytokine biology for precision medicine.
Enhanced temperature stability of colossal‐permittivity Ce‐doped SrTiO3 ceramics designed by defect engineering
Authors: Zhu Mingliang , Liu Kang , Meng Yingzhi , Qiang Xuerui , Xia Xiyue , Cao Xueli , Lei Xiuyun , Wang Dawei , Liu Laijun
Published: January 2025

Cerium‐doped SrTiO3 ceramics (Sr1‐3x/2CexTiO3, x = 0, 0.005, 0.0075, 0.01, 0.0125, and 0.015) were prepared by a burying sintering process. The sample with x = 0.0075 exhibits a colossal permittivity (∼ 21,000) and ultra‐low dielectric loss (∼ 0.0073) at room temperature (at 1 kHz). Furthermore, the x = 0.0075 sample maintains high permittivity (ε′ ≥ 15,000) and low dielectric loss (tanδ ≤ 0.018) in a wide temperature range (−60°C to 250°C). X‐ray photoelectron spectroscopy and electron paramagnetic resonance indicate the coexistence of Ce3+ and Ti3+. According to equation , synergetic effects from defect dipoles and interfacial polarization are responsible for the observed high‐performance giant permittivity behaviors with pronounced temperature stability and ultralow tanδ. The dielectric behaviors under different DC biases evidence the minor contribution from the interfacial polarization and reflect the dominant contribution from defect dipoles. The dielectric properties of dielectric ceramics are mainly influenced by oxygen vacancy clusters and defect dipoles ((Ti3+ − − Ti3+) and ( − )). The excellent thermal stability of permittivity is also attributed to the pinning effect of defect dipoles from the charged defects which prohibit the long‐range movement of free carries. The obtained colossal permittivity and low dielectric loss SrTiO3‐based ceramics with high‐frequency/temperature stabilities are suitable for the application of single‐layer ceramic capacitors.
Analysis of Changes in Home‐ and Community‐Based Service Utilisation Among Chinese Older Adults: A National Cohort Study
Authors: Yu Yushan , Zheng Xiaoying , Petrovic Mirko , Zhang Wei‐Hong
Published: January 2025

Aim

To explore changes in home‐ and community‐based service utilisation and its associated factors among Chinese older adults between 2016 and 2018.

Design

A national cohort study.

Methods

This study included 6924 older adults from the China Longitudinal Aging Social Survey 2016 and 2018 waves, examining the changes in service utilisation among four groups: continuous users, former users, new users and nonusers. Multinomial logistic models were employed to identify the determinants of service utilisation changes, and dominance analysis was performed to compare the relative contribution of the main variables associated with utilisation changes.

Results

Overall, there was an approximate 6% increase in the utilisation of any services among the study population from 2016 to 2018. The changes in service utilisation among four groups were 6.9% as continuing users, 4.2% as former users, 10.1% as new users and 78.8% as nonusers from 2016 to 2018, respectively. Factors associated with utilisation changes, ranked from the most to the least relative contribution, included availability of services, living region, type of pension, activities and instrumental activities of daily living, personal income, age and living alone.

Conclusions

Despite an increase in service utilisation, low services utilisation remains a concern. Strengthening policy support and boosting financial investments in home‐ and community‐based services to enhance availability across all regions would be an effective measure to improve service utilisation.

Implications for the Profession and/or Patient Care

The study highlights the need for long‐term care professionals and policymakers to increase availability to home‐ and community‐based services, especially in underserved areas.

Impact

Identifying key factors associated with changes in service utilisation, such as service availability and living region, can guide targeted strategies to improve access and equity.

Patient or Public Contribution

No patient or public contribution.

Reporting Method

STROBE statement (Table S5).
Intersectional marginalized identities as predictors of time until first reported suicide attempt among preadolescent youth using survival analysis
Authors: Mournet Annabelle M. , Kellerman John K. , Hamilton Jessica L. , Kleiman Evan M.
Published: January 2025

Background

Suicide attempts and deaths among children are increasing in the United States, yet suicide in this preadolescent population remains understudied. A clearer understanding of which youth experience early onset of suicidal behavior is crucial for predicting risk and identifying youth best suited to early intervention. This paper examines how intersectional marginalized identities may predict the onset of suicidal behaviors among preadolescent youth.

Methods

The Adolescent Brain and Cognitive Development (ABCD) Study is a prospective cohort study with annual assessments of youth ages 9 and 10 and their caregivers. Lifetime suicide attempts and preparatory suicidal behaviors were assessed annually. Survival models examined overall trends and demographic differences in the onset of suicidal behaviors.

Results

The final sample included 11,223 participants (mean age = 9.9 years old, SD = 7.5 months). 5,280 (47%) reported a minoritized racial/ethnic identity, and 1,410 (12.6%) were categorized as sexual or gender minorities. 208 suicide attempts and 143 instances of preparatory suicidal behaviors were reported across the study period. An interaction effect was found such that youth who hold multiple minoritized identities (i.e., sexual and gender minority youth from minoritized racial/ethnic backgrounds) were at elevated risk for onset of both suicide attempts (HR = 2.97, 95% CI = 1.59–5.56, p = .001) and preparatory suicidal behaviors (b = 3.09, 95% CI = 1.38–6.93, p = .006).

Conclusions

Intersectional marginalized identities were associated with earlier onset of suicide attempts and preparatory suicidal behaviors. Findings suggest that early interventions for minoritized youth may be important to reduce the rapidly increasing suicide rate among preadolescent youth.
Temperature‐Driven Variations in Fitness and Physiological Responses of Aphis craccivora Koch and Aphis gossypii Glover (Hemiptera: Aphididae) on Lablab purpureus subsp. Bengalensis (Jacq.) Verdc
Authors: Kumbhakar Sanoj , Das Susmita , Bhattacharyya Bhramar , Barik Anandamay
Published: January 2025

Temperature, an important abiotic factor, alters physiological processes in insects. This study includes effect of temperatures under laboratory (7°C, 12°C, 17°C, 22°C, 27°C and 32°C) and field (10°C–26°C) conditions on the life table parameters, total reactive oxygen species (ROS), hydrogen peroxide (H2O2), malondialdehyde (MDA) content and activities of antioxidative [superoxide dismutase (SOD), catalase (CAT) and ascorbate peroxidase (APX)], detoxifying [acetylcholinesterase (AChE), β‐glucosidase and glutathione‐S‐transferase (GST)] and oxidoreductive [peroxidase (POD) and polyphenol oxidase (PPO)] enzymes of Aphis craccivora Koch and A. gossypii Glover (Hemiptera: Aphididae) on Lablab purpureus subsp. bengalensis (Jacq.) Verdc. plants. The longevity and fecundity of both aphids were highest at 22°C, and A. craccivora showed similarity between 22°C and field condition but A. gossypii showed similarity between 17°C and field condition, suggesting that A. craccivora is able to withstand more fluctuating temperature stress than A. gossypii. Total ROS, H2O2 and MDA content were increased at low (7°C) or high (32°C) temperature but these parameters were more increased at high temperature than low temperature, suggesting that high‐temperature stress is more harmful for both aphids. Under low (7°C) or high (32°C) temperature stress, the levels of antioxidative, detoxifying and oxidoreductive enzymes were increased in both adult aphids compared to 22°C or field condition, implicating that both these aphids are trying to detoxify excess ROS by producing more antioxidative, detoxifying and oxidoreductive enzymes. The mortality of both aphids was higher at low (7°C) and high (32°C) temperatures, implicating that both aphids could not detoxify excess ROS by the coordinated action of antioxidative, detoxifying and oxidoreductive enzymes. The findings of this study can assist to envisage the population dynamics of these two important aphids, which can assist in management of these two sucking insect pests in the crop field.
Can maternal serum soluble fms‐like tyrosine kinase‐1 to placental growth factor levels at term anticipate adverse pregnancy outcomes?
Authors: Corker Sarah A. , Cade Thomas J. , Brennecke Shaun P.
Published: January 2025

Aim

To evaluate if maternal serum soluble fms‐like tyrosine kinase‐1(sFlt‐1) to placental growth factor (PlGF) ratio levels at term can anticipate the following adverse pregnancy outcomes: small for gestational age neonates; operative delivery for suspected fetal welfare compromise; and neonatal compromise.

Methods

A retrospective analysis of a single hospital database containing antenatal soluble fms‐like tyrosine kinase‐1 to placental growth factor (sFlt‐1/PlGF) ratio results together with associated demographic, clinical and investigative information. Subjects with antenatal sFlt‐1/PlGF measurements taken ≥37 weeks' gestation were analyzed. sFlt‐1/PlGF ratio cut‐offs of <38, 38–110, 111–201 and >201 were tested against the following outcomes: birthweight ≤10th and ≤3rd centiles; operative delivery for suspected fetal welfare compromise; 5 min Apgar score; and neonatal admissions for extra care.

Results

Statistically significant associations were found between sFlt‐1/PlGF ratios 111–201 and birthweights ≤10th centile (p < 0.01, odds ratio [OR] 3.04, 95% confidence interval [CI] 1.52–6.10), and between operative delivery for suspected fetal welfare compromise and sFlt‐1/PlGF ratios 111–201 (p = 0.04, OR 2.21, 95% CI 1.03–4.75) and >201 (p = 0.01, OR 4.73, 95% CI 1.45–15.4).

Conclusions

This study indicates that maternal serum sFlt‐1/PlGF ratios performed at term may subsequently help identify significantly small‐for‐gestational age fetuses and operative delivery for suspected fetal welfare compromise. Further prospective studies may confirm these findings and substantiate the clinical importance of sFlt‐1/PlGF measurements in assisting the management of pregnancies at term.
Working from home and bi‐directional work–family conflict: Longitudinal evidence from Australian parents
Authors: Laß Inga , Wooden Mark
Published: January 2025

Objective

This study investigates the effects of working from home (WFH) on both work‐to‐family conflict (WTFC) and family‐to‐work conflict (FTWC) among parents, and whether family demands and the COVID‐19 pandemic moderate these effects.

Background

The COVID‐19 pandemic saw a marked increase in the incidence of WFH in many countries, which many argue has been beneficial for families. Convincing evidence in support of this hypothesis, however, is scarce.

Method

Panel data from 19 waves of the Household, Income and Labour Dynamics in Australia (HILDA) Survey (covering the period 2001 to 2021) are used to estimate fixed effects regression models of both FTWC and WTFC where the explanatory variable of interest is the share of usual weekly work hours worked from home. The sample is restricted to working parents aged between 18 and 64 years (9850 persons; 54,764 observations).

Results

For both genders, the level of WTFC declines with the proportion of time worked from home. By contrast, the association between WFH and FTWC differs between mothers and fathers, with FTWC lower for mothers but higher for fathers (and especially for single fathers and those with young children) when working mostly from home. These associations remained largely unchanged during the pandemic.

Conclusion

WFH is particularly beneficial for mothers' reconciliation of work and family life but has ambivalent effects for fathers. This, in turn, may mean mothers will be more likely than fathers to have preferences for continuing WFH post pandemic.