bluuebunny/crossref_metadata_2025_split huggingface dataset:
Biological and therapeutic implications of sex hormone-related gene clustering in testicular cancer
Authors: Törzsök Péter , Santer Frédéric R. , Kunz Yannic , van Creij Nils C. H. , Tymoszuk Piotr , Klinglmair Gerald , Culig Zoran , Pichler Renate 
Published: February 2025

Abstract

Background
Gonadotropin dysregulation seems to play a potential role in the carcinogenesis of testicular germ cell tumor (TGCT). The aim of this study was to explore the expression of specific genes related to sex hormone regulation, synthesis, and metabolism in TGCT and to define specific hormonal clusters. Two publicly available databases were used for this analysis (TCGA and GSE99420). By means of hard-threshold regularized KMEANS clustering, we assigned TGCT samples into four clusters defined in respect to different expression of the sex hormone-related genes. We analysed clinical data, protein and gene expression, signaling regarding hormonal clusters. Based on whole-transcriptome gene expression, prediction of anti-cancer drug response was made by RIDGE models.

Results
Cluster #1 (12–16%) consisted primarily of non-seminomatous germ cell tumor (NSGCT), characterized by high expression of PRL, GNRH1, HSD17B2 and SRD5A1. Cluster #2 (42–50%) included predominantly seminomas with high expression of SRD5A3, being highly infiltrated by T and B cells. Cluster #3 (8.3–18%) comprised of NSGCT with high expression of CGA, CYP19A1, HSD17B12, HSD17B1, SHBG. Cluster #4 (23–30%), which consisted primarily of NSGCT with a small fraction of seminomas, was outlined by increased expression of STAR, POMC, CYP11A1, CYP17A1, HSD3B2 and HSD17B3. Elevated fibroblast levels and increased extracellular matrix- and growth factor signaling-related gene signature scores were described in cluster #1 and #3. In the combined model of progression-free survival, S2/S3 tumor marker status, hormonal cluster #1 or #3 and teratoma histology, were independently associated with 25–30% increase of progression risk. Based on the increased receptor tyrosine kinase and growth factor signaling, cluster #1, #3 and #4 were predicted to be sensitive to tyrosine kinase inhibitors, FGFR inhibitors or EGFR/ERBB inhibitors. Cluster #2 and #4 were responsive to compounds interfering with DNA synthesis, cytoskeleton, cell cycle and epigenetics. Response to apoptosis modulators was predicted only for cluster #2.

Conclusions
Hormonal cluster #1 or #3 is an independent prognostic factor regarding poor progression-free survival. Hormonal cluster assignment also affects the predicted drug response with cluster-dependent susceptibility to specific novel therapeutic compounds.
Data-driven projections of candidate enhancer-activating SNPs in immune regulation
Authors: Hoffmann Markus , Vaz Tiago , Chhatrala Shreeti , Hennighausen Lothar 
Published: February 2025

Abstract

Background
Millions of single nucleotide polymorphisms (SNPs) have been identified in humans, but the functionality of almost all SNPs remains unclear. While current research focuses primarily on SNPs altering one amino acid to another one, the majority of SNPs are located in intergenic spaces. Some of these SNPs can be found in candidate cis-regulatory elements (CREs) such as promoters and enhancers, potentially destroying or creating DNA-binding motifs for transcription factors (TFs) and, hence, deregulating the expression of nearby genes. These aspects are understudied due to the sheer number of SNPs and TF binding motifs, making it challenging to identify SNPs that yield phenotypic changes or altered gene expression.

Results
We developed a data-driven computational protocol to prioritize high-potential SNPs informed from former knowledge for experimental validation. We evaluated the protocol by investigating SNPs in CREs in the Janus kinase (JAK) – Signal Transducer and Activator of Transcription (-STAT) signaling pathway, which is activated by a plethora of cytokines and crucial in controlling immune responses and has been implicated in diseases like cancer, autoimmune disorders, and responses to viral infections. The protocol involves scanning the entire human genome (hg38) to pinpoint DNA sequences that deviate by only one nucleotide from the canonical binding sites (TTCnnnGAA) for STAT TFs. We narrowed down from an initial pool of 3,301,512 SNPs across 17,039,967 nearly complete STAT motifs and identified six potential gain-of-function SNPs in regions likely to influence regulation within the JAK-STAT pathway. This selection was guided by publicly available open chromatin and gene expression data and further refined by filtering for proximity to immune response genes and conservation between the mouse and human genomes.

Conclusion
Our findings highlight the value of combining genomic, epigenomic, and cross-species conservation data to effectively narrow down millions of SNPs to a smaller number with a high potential to induce interferon regulation of nearby genes. These SNPs can finally be reviewed manually, laying the groundwork for a more focused and efficient exploration of regulatory SNPs in an experimental setting.
Impact of perioperative anticoagulation management on free flap survival in reconstructive surgery: a retrospective analysis
Authors: Torabi Saeed , Overbeek Remco , Dusse Fabian , Stoll Sandra E. , Schroeder Carolin , Zinser Max , Zirk Matthias 
Published: February 2025

Abstract

Background
Despite advancements in surgical techniques and perioperative care for free flap reconstructive surgery, concerns persist regarding the risk of free flap failure, with thrombosis and bleeding being the most common complications that can lead to flap loss. While perioperative anticoagulation management is crucial for optimizing outcomes in free flap reconstructive surgery, standardized protocols remain lacking. This study aims to investigate the role of anticoagulation and perioperative practices in free flap reconstructive surgery and their impact on surgical outcomes.

Methods
This retrospective, single-center study included all adult patients undergoing free flap surgery from 2009 to 2020. Patients were retrospectively divided based on intraoperative (UFH or no UFH) and postoperative anticoagulation management (UFH only, Aspirin and UFH, Aspirin only). The relationship between anticoagulation protocols, PTT values, and flap survival was assessed.

Results
A total of 489 free flap surgeries were included. Most flaps were taken from the upper extremity (49.5%), primarily for tumor-related reconstructions (85.7%). Flap loss occurred in 14.5% of cases, with a median time to flap loss of 3 days post-surgery. Intraoperative UFH (20 IU/kg) was administered to 63.6% of patients and significantly predicted flap survival (OR = 0.45, 95% CI [0.24, 0.82]). PTT values on day 1 post-surgery were significantly related to flap survival (P = 0.03), with each unit increase reducing the relative probability of flap loss by 5.2%. There was no significant difference in flap survival between patients treated with heparin alone and those treated with both heparin and aspirin. The small sample size in the aspirin-only group limited the statistical relevance of this subgroup.

Conclusion
Our findings highlight the importance of intraoperative UFH and PTT-guided postoperative management in improving free flap survival. Standardized anticoagulation protocols are essential for enhancing outcomes in free flap reconstructive surgery.
T-cell activation of Toxoplasma gondii positive donors by maltodextrin nanoparticles formulated with killed Toxoplasma gondii
Authors: Vargas-Montes Monica , Fasquelle François , Cardona Nestor Ivan , Gómez-Marín Jorge Enrique , Betbeder Didier 
Published: February 2025

Abstract
Nasal vaccination with killed tachyzoites from Toxoplasma gondii loaded in lipidated maltodextrin nanoparticles (NPL/T.gondii) has been shown to induce protection against lethal T.gondii infection in mice, sheep and squirrel monkeys. This protection was related to a unique T-cell mediated response (Th1 and Th17). In immunocompetent humans T.gondii infection is generally asymptomatic but leads to the formation of cysts in several organs. These cysts may reactivate during episodes of immunosuppression, owing to a Th1 immune exhaustion, leading to numerous complications. The objectives of the current study were to assess whether NPL/T. gondii vaccine can stimulate a specific IFN-γ secretion on peripheral blood mononuclear cells (PBMC) of Toxo-positive donors, in order to potentially prevent reactivation of the parasite. By using enzyme-linked immunospot (ELISpot) assays, the frequency of IFN-γ producing cells was quantified after 72 h of stimulation. This stimulation was specific of the Toxo + donors’ memory T-cells. The uptake of this formulation by PBMCs was evaluated using flow cytometry, more particularly in T lymphocytes (CD3 + CD4 + and CD3 + CD8 +), B lymphocytes (CD3- CD19 +) and natural killer cells (CD3- CD56 +). Surprisingly, a lower antigen uptake was observed in all cell populations from Toxo + donors compared with the seronegative ones. Further in vitro analysis revealed that the early specific IFN-γ secretion by stimulated memory cells from Toxo-positive donors inhibited the endocytosis mechanism, therefore lowering their own vaccine uptake. These results suggest that NPL/T.gondii formulation can specifically trigger the existing Th1 immune response in positive donors, reinforcing their ability to control infection and reactivation.
Prescription of essential medication during the final hospitalization of patients with heart failure or cancer
Authors: González-Jaramillo Valentina , Hagemann Monika , Hunziker Lukas , Maessen Maud , Eychmüller Steffen 
Published: February 2025

Abstract

Background
Four medication types—opioids, benzodiazepines, anticholinergics, and antipsychotics—have been proposed as essential for patients in their final days, regardless of their primary diagnosis. These drugs are typically prescribed for individuals with cancer who are under specialized palliative care (PC+). However, it is not known whether their usage is equally common for patients with other chronic and progressive conditions, such as heart failure (HF), or for those who are not under specialized palliative care (PC-).

Aim
To assess the prescription frequency of each of the four medication types during the final hospitalization of patients with HF and compare it with the prescription frequency in patients with cancer (CA), considering both PC + and PC- patients in each disease group.

Methods
A retrospective cohort study included all patients dying in a tertiary hospital between 2016 and 2022. We created three disease groups – “HF,” “CA,” and “HF&CA” – splitting each of them into two groups, depending on whether they received PC. So there were a total of six groups – “HF PC+”, “HF PC-“, “CA PC+”, “CA PC-”, “HF&CA PC+”, and “HF&CA PC-”.

Results
Of the 3,874 patients, 1,921 (59%) had cancer exclusively, 371 (10%) had heart failure exclusively, and 691 (18%) had both. The median length of stay was 9 days (IQR 2–16). Within each diagnosis group, PC + patients had a higher prescription frequency for each medication type than PC- patients. For example, patients who received PC had 12 times the odds of being prescribed opioids than those who did not receive it (p < 0.05). Among the six groups, the highest prescription frequency of opioids, benzodiazepines, and anticholinergics was seen in the “HF PC+” group and the lowest in the “HF PC-” group. Antipsychotics were prescribed less frequently in the “HF PC-” and the “CA PC-” groups and were mainly prescribed in the “CA PC+” group.

Conclusion
Across the diagnostic groups, a notable difference in the prescription of the four medication types was observed between PC + and PC- patients. This difference was more pronounced among patients with HF (without cancer).
Context sensitive mindfulness: lessons from graduates of a professional training in South Africa
Authors: Whitesman Simon , Mash Robert 
Published: February 2025

Abstract

Objective
The study aimed to evaluate the implementation of mindfulness based interventions, in different community settings in South Africa, by graduates of a two-year mindfulness training course, and to explore the challenges involved in adapting to the local context.

Methods
This was a descriptive exploratory qualitative study using semi-structured interviews. Ten graduates of a two-year training in mindfulness-based interventions (MBIs) were identified using purposeful criterion-based sampling based on their implementation of adapted MBIs in communities that represented the systemic social, economic and health challenges affecting a majority of South Africans.

Results
Previous and ongoing trauma is pervasive in South Africa which significantly affects the quality of lived experience for many individuals and families. Teachers who offered mindfulness-based approaches within these communities needed to hold a high level of sensitivity to pre-existing and ongoing trauma and signs of traumatic abreaction to effectively and skilfully deliver these interventions. Context sensitive adaptations needed to be implemented to programme structure, such as length of sessions, prioritisation of curricular elements and duration of mindfulness practices, along with in-the-moment flexible responsiveness such as ending a formal practice ealier than planned, or responding to the emotional needs of an individual. This was supported by the creation of a robust and compassionate holding environment, a safe and secure space in which attuned relationality supported co- and self-regulation and the internalisation of mindfulness skills.

Conclusion
Mindfulness can be a valuable practice in diverse settings in South Africa, including communities affected by previous and current trauma, and the training curriculum in this context requires high levels of sensitivity to these conditions and must prioritise a safe and compassionate environment in which to learn.
Minimum and optimal combined variations in sleep, physical activity, and nutrition in relation to all-cause mortality risk
Authors: Stamatakis Emmanuel , Koemel Nicholas A. , Biswas Raaj K. , Ahmadi Matthew N. , Allman-Farinelli Margaret , Trost Stewart G. , Inan-Eroglu Elif , del Pozo Cruz Borja , Bin Yu Sun , Postnova Svetlana , Duncan Mitch J. , Dumuid Dorothea , Brown Helen , Maher Carol , Fontana Luigi , Simpson Stephen , Cistulli Peter A. 
Published: February 2025

Abstract

Background
Sleep, physical activity, and nutrition (SPAN) are critical behaviours for health, although they have traditionally been studied separately. We examined the combined associations of SPAN and the minimum between-individual variations associated with meaningfully lower all-cause mortality risk.

Methods
This prospective cohort analysis included 59,078 participants from the UK Biobank (median age: 64.0 years; 45.4% male) who wore trackers for 7 days and self-reported dietary data. Wearable-measured sleep (hours/day) and moderate to vigorous physical activity (MVPA; mins/day) were calculated using a machine learning based schema. A 10-item diet quality score (DQS) assessed the intake of vegetables, fruits, fish, dairy, whole grains, vegetable oils, refined grains, processed and unprocessed meats, and sugary beverages (0–100 for all components with higher values indicating higher quality). Cox proportional hazards models were used to estimate hazard ratios (HR) for all-cause mortality risk across 27 separate joint tertile combinations of SPAN behaviours with the lowest tertile for all three as the referent group. For more granular clinical interpretations, we examined combined incremental dose–response changes of the SPAN behaviours using the 5th percentile of each behaviour as the referent point.

Results
Over the 8.1-year median follow-up time, 2,458 mortality events occurred. Compared to the referent group of combined SPAN exposure (lowest tertiles for all three), the optimal SPAN combination involving moderate sleep duration (7.2–8.0 h/day), high MVPA (42–103 min/day), and a DQS between 57.5 and 72.5 was associated with an HR of 0.36 (95% CI: 0.26–0.50). Relative to the 5th percentile of sleep (5.5 h/day), physical activity (7.3 min/day), and nutrition (36.9 DQS), a theoretical minimum combined increase of 15 min/day of sleep, 1.6 min/day MVPA, and 5 DQS points (corresponding to e.g., extra 1/2 serving of vegetables per day or 1 less serving of processed meat per week) was associated with 10% lower all-cause mortality risk (0.90; 0.88–0.93). Combined increases of 75 min/day of sleep, 12.5 min/day MVPA, and 25 DQS points were associated with 50% lower all-cause mortality risk (0.50; 0.44–0.58).

Conclusions
This study highlights the potential health value of subtle combined SPAN modification in relation to mortality risk and expands opportunities for more holistic recommendations.
Pig tail length is associated with the prevalence of tail malformations but not with inflammation of the tail
Authors: Egerer Christiane , Gerhards Katharina , Becker Sabrina , Engel Petra , König Sven , Reiner Gerald 
Published: February 2025

Abstract

Background
Assuming that tail length is associated with the prevalence of tail biting, attempts are being made to shorten tails by genetic selection in order to avoid the painful procedure of docking. However, undesirable side effects such as kinky tails and inflammatory changes may occur. The aim of the present study was to clinically quantify in a population with known segregation of tail length, i) its variability, ii) possible associations with kinked tails and iii) possible associations of tail length and kinks with inflammation of the tail using 348 piglets at day 3 (undocked) and 39 (docked tails) of life.

Results
The relative tail length (tail tip to tail base/tail tip to ear base × 100) varied between 20.3 and 31.3%. A reduced tail length was associated with kinked tails. Piglets with the shortest tails had 28% kinked tails, 5.6 times more than the piglets with the longest tails. The tails showed high prevalence of inflammation both on day 3 and on the docked tails on day 39. Overall, these were not associated with tail length or kinked tails. Only necrosis of the tail was significantly more frequent in the kinked tails than in the normal tails. Sow line, sow ID and boar ID significantly affected relative tail length, which may suggest a genetic cause.

Conclusion
Based on the phenotypic variation found in the present study, it seems possible to influence tail length through breeding. It remains to be seen whether the available potential is sufficient to actually reduce tail biting. At the same time, a higher incidence of kinked tails and necrosis is to be expected.
The blood–brain barriers: novel nanocarriers for central nervous system diseases
Authors: Liu Jiajun , Wang Ting , Dong Jian , Lu Yuan 
Published: February 2025

Abstract
The central nervous system (CNS) diseases are major contributors to death and disability worldwide. However, the blood–brain barrier (BBB) often prevents drugs intended for CNS diseases from effectively crossing into the brain parenchyma to deliver their therapeutic effects. The blood–brain barrier is a semi-permeable barrier with high selectivity. The BBB primarily manages the transport of substances between the blood and the CNS. To enhance drug delivery for CNS disease treatment, various brain-based drug delivery strategies overcoming the BBB have been developed. Among them, nanoparticles (NPs) have been emphasized due to their multiple excellent properties. This review starts with an overview of the BBB’s anatomical structure and physiological roles, and then explores the mechanisms, both endogenous and exogenous, that facilitate the NP passage across the BBB. The text also delves into how nanoparticles' shape, charge, size, and surface ligands affect their ability to cross the BBB and offers an overview of different nanoparticle classifications. This review concludes with an examination of the current challenges in utilizing nanomaterials for brain drug delivery and discusses corresponding directions for solutions. This review aims to propose innovative diagnostic and therapeutic approaches for CNS diseases and enhance drug design for more effective delivery across the BBB.

Graphical abstract
The properties of TREM1 and its emerging role in pain-related diseases
Authors: Fan Zhenzhen , Sun Songtang , Wang Longde , Ge Zhaoming 
Published: February 2025

Abstract
The TREM1 receptor, a member of the TREMs family, is expressed by myeloid cells and functions as an initiator or enhancer of the inflammatory response, playing a pivotal role in the regulation of inflammation. In recent years, it has been found that TREM1-mediated inflammatory response is involved in the regulation of pain-related diseases. This article provides an extensive review on the structural characteristics and distribution patterns, ligand, signaling pathways, inhibitors, and pathophysiological roles of TREM1 in pain disorders aiming to further elucidate its biological function and offer novel insights for clinical interventions targeting pain-related diseases.
Draft genome of pin nematode Paratylenchus projectus recovered from rhizosphere of blueberry
Authors: Liu Liang-Qin , Fu Wei-Qi , Ma Yuan-Yuan , Liu Zhi-Yin , Ge Chun-feng , Yang Yi-Ru , Qing Xue , Zeng Qi-Long 
Published: February 2025

Abstract

Background
The pin nematode, belonging to the genus Paratylenchus, parasitizes higher plants, often causing reduced or inhibited root tip development.

Methods
Pin nematodes were isolated from the roots and rhizosphere of blueberry plants and subsequently identified as representatives of Paratylenchus projectus based on morphological characteristics and molecular barcoding. The P. projectus draft genome was sequenced using the Illumina platform.

Results
Phylogenetic analysis based on 18S, 28S and ITS rRNA placed this species in highly supported clades alongside other P. projectus specimens. The draft genome of P. projectus was sequenced and assembled, representing the first genomic data for both the genus Paratylenchus and the family Tylenchulidae. The assembled genome, though fragmented, had a total length of 191.36 Mb and an estimated genome size of 64.9 Mb. Protein-coding genes were predicted using four different databases, with particular focus on carbohydrate-active enzymes from the GH5 and GH18 families. The recovered GH5 genes were distributed among three distinct clades: one forming a basal group relative to other nematodes, one as a sister clade to the fungivorous nematode Aphelenchus avenae and one nested within a fungal clade. The GH18 chitinase genes were grouped into two clades: one closely related to sedentary plant-parasitic nematodes of the genera Heterodera and Globodera and the other closely related to the fungivorous nematode Ditylenchus.

Conclusions
The draft genome of Paratylenchus projectus was sequenced and assembled, representing the first genomic data for both the genus Paratylenchus and the family Tylenchulidae to our knowledge.

Graphical Abstract