Miracle-dz/UniFAR-FTUs huggingface dataset:
What matters in clinical trial decision-making: a systematic review of interviews exploring cancer patients' experiences.

BACKGROUND Being diagnosed with cancer is an existential challenge and involves difficult treatment decisions, including treatment in clinical trials. Therapy for advanced cancer is potentially life-prolonging and only rarely cures advanced cancer, which often renders these patients in a special situation where dealing with end of life, hope and meaning, become an important part of life. Many existing reviews include both patients with advanced cancer and patients undergoing adjuvant cancer treatment, and there is a lack of reviews with consistent study designs and methods. AIM To systematically review and thematically synthesise the experiences of patients and relatives when they have to decide whether or not to participate in a clinical oncology trial and to provide knowledge about the decision-making process. METHOD A qualitative systematic literature review was conducted based on methods for thematic synthesis by Thomas and Hardens. RESULTS Eleven full-text articles were included in this study. Six descriptive themes appeared and were grouped under two analytical themes: Individualised decisions and Hope and existential matters, which, through discussion, developed into the synthesis of What matters in treatment-related decisions close to the end of life? This review has shown that existential matters are important in the decision-making and that addressing these might be of great importance in medical decision-making, whether it concerns the existential matters of the patients, of their relatives or of the health care professionals. CONCLUSION This review points to existential issues as important contributors in making decisions about treatment. It can be beneficial if health care professionals address the role of existential matters in patients' decision-making in terms of clinical trial participation and involve the relatives more directly to increase individualised decisions. Future research should include the health care professionals' experiences when going in depth with decision-making, with a focus on the existential matters and uncertainties of the health care professionals.
Does having a similar disability matter for match outcomes?: A randomized study of matching mentors and mentees by visual impairment

Abstract Mentoring is modestly effective for youth with a chronic illness or physical disability; however, program effectiveness may be enhanced when mentors and mentees are matched on shared interests and experiences. To test this hypothesis, mentees were randomly assigned to having a mentor with or without visual impairment (VI). Results showed that mentors without VI were younger and more likely to work or be educated in a helping profession and less likely to have a fixed mindset and extremely high positive expectations than mentors with VI. The main analyses on match outcomes showed that mentors with VI had significantly fewer and shorter match meetings, had a weaker relationship with their mentees, and were more likely to end their match prematurely. Mentor age, helping profession background, and fixed mindset were confounds in several analyses and reduced the significance of the relationship between VI group and match meeting quantity. The only relationship that remained significant controlling for covariates showed that matches including a mentor with VI were significantly more likely to end in premature closure than matches including a mentor without VI. Implications of the findings for future research and program practices related to matching were discussed.
Effects of CPAP on the transcriptional signatures in patients with obstructive sleep apnea via coexpression network analysis

A growing number of studies provide epidemiological evidence linking obstructive sleep apnea (OSA) with a number of chronic disorders. Transcriptional analyses have been conducted to analyze the gene expression data. However, the weighted gene coexpression network analysis (WGCNA) method has not been applied to determine the transcriptional consequence of continuous positive airway pressure (CPAP) therapy in patients with severe OSA. The aim of this study was to identify key pathways and genes in patients with OSA that are influenced by CPAP treatment and uncover/unveil potential molecular mechanisms using WGCNA. We analyzed the microarray data of OSA (GSE 49800) listed in the Gene Expression Omnibus database. Coexpression modules were constructed using WGCNA. In addition, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analysis were also conducted. After the initial data processing, 5101 expressed gene profiles were identified. Next, a weighted gene coexpression network was established and 16 modules of coexpressed genes were identified. The interaction analysis demonstrated a relative independence of gene expression in these modules. The black module, tan module, midnightblue module, pink module, and greenyellow module were significantly associated with the alterations in circulating leukocyte gene expression at baseline and after exposure to CPAP. The five hub genes were considered to be candidate OSA‐related genes after CPAP treatment. Functional enrichment analysis revealed that steroid biosynthesis, amino sugar and nucleotide sugar metabolism, protein processing in the endoplasmic reticulum, and the insulin signaling pathway play critical roles in the development of OSA in circulating leukocyte gene expression at baseline and after exposure to CPAP. Using this new systems biology approach, we identified several genes and pathways that appear to be critical to OSA after CPAP treatment, and these findings provide a better understanding of OSA pathogenesis.
Bleeding and safety outcomes in persons with haemophilia A without inhibitors: Results from a prospective non‐interventional study in a real‐world setting

Prospectively collected real‐world data on bleeds, haemophilia treatment and safety in persons with haemophilia A (PwHA) without factor VIII (FVIII) inhibitors are limited. A global, non‐interventional study (NIS; NCT02476942) prospectively collected real‐world data in PwHA who were treated per local routine clinical practice.
Toxicity evaluation of monodisperse PEGylated magnetic nanoparticles for nanomedicine

Abstract Innovative nanotechnology aims to develop particles that are small, monodisperse, smart, and do not cause unintentional side effects. Uniform magnetic Fe3O4 nanoparticles (12 nm in size) were prepared by thermal decomposition of iron(III) oleate. To make them colloidally stable and dispersible in water and cell culture medium, they were modified with phosphonic acid- (PA) and hydroxamic acid (HA)-terminated poly(ethylene glycol) yielding PA-PEG@Fe3O4 and HA-PEG@Fe3O4 nanoparticles; conventional γ-Fe2O3 particles were prepared as a control. Advanced techniques were used to evaluate the properties and safety of the particles. Completeness of the nanoparticle coating was tested by real-time polymerase chain reaction. Interaction of the particles with primary human peripheral blood cells, cellular uptake, cytotoxicity, and immunotoxicity were also investigated. Amount of internalized iron in peripheral blood mononuclear cells was 72, 38, and 25 pg Fe/cell for HA-PEG@Fe3O4, γ-Fe2O3, and PA-PEG@Fe3O4, respectively. Nanoparticles were localized within the cytoplasm and in the extracellular space. No cytotoxic effect of both PEGylated nanoparticles was observed (0.12–75 μg/cm2) after 24 and 72-h incubation. Moreover, no suppressive effect was found on the proliferative activity of T-lymphocytes and T-dependent B-cell response, phagocytic activity of monocytes and granulocytes, and respiratory burst of phagocytes. Similarly, no cytotoxic effect of γ-Fe2O3 particles was observed. However, they suppressed the proliferative activity of T-lymphocytes (75 μg/cm2, 72 h) and also decreased the phagocytic activity of monocytes (15 μg/cm2, 24 h; 3–75 μg/cm2, 72 h). We thus show that newly developed particles have great potential especially in cancer diagnostics and therapy.
Epigenetic age is a cell‐intrinsic property in transplanted human hematopoietic cells

The age of tissues and cells can be accurately estimated by DNA methylation analysis. The multitissue DNA methylation (DNAm) age predictor combines the DNAm levels of 353 CpG dinucleotides to arrive at an age estimate referred to as DNAm age. Recent studies based on short‐term observations showed that the DNAm age of reconstituted blood following allogeneic hematopoietic stem cell transplantation (HSCT) reflects the age of the donor. However, it is not known whether the DNAm age of donor blood remains independent of the recipient's age over the long term. Importantly, long‐term studies including child recipients have the potential to clearly reveal whether DNAm age is cell‐intrinsic or whether it is modulated by extracellular cues in vivo. Here, we address this question by analyzing blood methylation data from HSCT donor and recipient pairs who greatly differed in chronological age (age differences between 1 and 49 years). We found that the DNAm age of the reconstituted blood was not influenced by the recipient's age, even 17 years after HSCT, in individuals without relapse of their hematologic disorder. However, the DNAm age of recipients with relapse of leukemia was unstable. These data are consistent with our previous findings concerning the abnormal DNAm age of cancer cells, and it can potentially be exploited to monitor the health of HSCT recipients. Our data demonstrate that transplanted human hematopoietic stem cells have an intrinsic DNAm age that is unaffected by the environment in a recipient of a different age.
The genomic basis for colonizing the freezing Southern Ocean revealed by Antarctic toothfish and Patagonian robalo genomes

Abstract Background The Southern Ocean is the coldest ocean on Earth but a hot spot of evolution. The bottom-dwelling Eocene ancestor of Antarctic notothenioid fishes survived polar marine glaciation and underwent adaptive radiation, forming >120 species that fill all water column niches today. Genome-wide changes enabling physiological adaptations and the rapid expansion of the Antarctic notothenioids remain poorly understood. Results We sequenced and compared 2 notothenioid genomes—the cold-adapted and neutrally buoyant Antarctic toothfish Dissostichus mawsoni and the basal Patagonian robalo Eleginops maclovinus, representing the temperate ancestor. We detected >200 protein gene families that had expanded and thousands of genes that had evolved faster in the toothfish, with diverse cold-relevant functions including stress response, lipid metabolism, protein homeostasis, and freeze resistance. Besides antifreeze glycoprotein, an eggshell protein had functionally diversified to aid in cellular freezing resistance. Genomic and transcriptomic comparisons revealed proliferation of selcys–transfer RNA genes and broad transcriptional upregulation across anti-oxidative selenoproteins, signifying their prominent role in mitigating oxidative stress in the oxygen-rich Southern Ocean. We found expansion of transposable elements, temporally correlated to Antarctic notothenioid diversification. Additionally, the toothfish exhibited remarkable shifts in genetic programs towards enhanced fat cell differentiation and lipid storage, and promotion of chondrogenesis while inhibiting osteogenesis in bone development, collectively contributing to the achievement of neutral buoyancy and pelagicism. Conclusions Our study revealed a comprehensive landscape of evolutionary changes essential for Antarctic notothenioid cold adaptation and ecological expansion. The 2 genomes are valuable resources for further exploration of mechanisms underlying the spectacular notothenioid radiation in the coldest marine environment.
Small Non-Coding RNAs Derived from Eukaryotic Ribosomal RNA

The advent of RNA-sequencing (RNA-Seq) technologies has markedly improved our knowledge and expanded the compendium of small non-coding RNAs, most of which derive from the processing of longer RNA precursors. In this review article, we will present a nonexhaustive list of referenced small non-coding RNAs (ncRNAs) derived from eukaryotic ribosomal RNA (rRNA), called rRNA fragments (rRFs). We will focus on the rRFs that are experimentally verified, and discuss their origin, length, structure, biogenesis, association with known regulatory proteins, and potential role(s) as regulator of gene expression. This relatively new class of ncRNAs remained poorly investigated and underappreciated until recently, due mainly to the a priori exclusion of rRNA sequences—because of their overabundance—from RNA-Seq datasets. The situation surrounding rRFs resembles that of microRNAs (miRNAs), which used to be readily discarded from further analyses, for more than five decades, because no one could believe that RNA of such a short length could bear biological significance. As if we had not yet learned our lesson not to restrain our investigative, scientific mind from challenging widely accepted beliefs or dogmas, and from looking for the hidden treasures in the most unexpected places.
Temporal Impact of Substrate Anisotropy on Differentiating Cardiomyocyte Alignment and Functionality.

Anisotropic biomaterials can affect cell function by driving cell alignment, which is critical for cardiac engineered tissues. Recent work, however, has shown that pluripotent stem cell-derived cardiomyocytes may self-align over long periods of time. To determine how the degree of biomaterial substrate anisotropy impacts differentiating cardiomyocyte structure and function, we differentiated mESCs to cardiomyocytes on non-aligned, semi-aligned, and aligned fibrous substrates and evaluated cell alignment, contractile displacement, and calcium transient synchronicity over time. Although cardiomyocyte gene expression was not affected by fiber alignment, we observed gradient- and threshold-based differences in cardiomyocyte alignment and function. Cardiomyocyte alignment increased with the degree of fiber alignment in a gradient-based manner at early time points and in a threshold-based manner at later time points. Calcium transient synchronization tightly followed cardiomyocyte alignment behavior, allowing highly anisotropic biomaterials to drive calcium transient synchronization within 8 days, while such synchronized cardiomyocyte behavior required 20 days of culture on non-aligned biomaterials. In contrast, cardiomyocyte contractile displacement had no directional preference on day 8 yet became anisotropic in the direction of fiber alignment on aligned fibers by day 20. Biomaterial anisotropy impact on differentiating cardiomyocyte structure and function is temporally-dependent.
Exploring the fate of inhaled monoclonal antibody in the lung parenchyma by microdialysis

ABSTRACT Therapeutic antibodies (Abs) are emerging as major drugs to treat respiratory diseases, and inhalation may provide substantial benefits for their delivery. Understanding the behavior of Abs after pulmonary deposition is critical for their development. We investigated the pharmacokinetics of a nebulized Ab by continuous sampling in lung parenchyma using microdialysis in non-human primates. We defined the optimal conditions for microdialysis of Ab and demonstrated that lung microdialysis of Ab is feasible over a period of several days. The concentration-profile indicated a two-phase non-linear elimination and/or distribution of inhaled mAbX. Lung exposition was higher than the systemic one over a period of 33 hours and above MabX affinity for its target. The microdialysis results were supported by an excellent relationship with dosages from lung extracts.
Threshold values affect predictive accuracy of caries risk assessment

Abstract Objective: To evaluate effects of thresholds on estimates of predictive accuracy of methods for caries risk assessment. Material and methods: Adolescents, aged 12 visiting two dental clinics, were examined by visual/tactile examination and bitewing radiography at baseline and after one year. Three methods for caries risk assessment were applied: previous caries experience, dentists’ risk assessment according to set criteria (presence or absence of caries lesion) and acid tolerance of dental biofilm. The measure for validity (the reference standard) comprised caries lesion progression at 1 year. Predictive accuracy estimates were calculated for several thresholds. Results: Accuracy estimates changed with threshold values of the methods and the reference standard. Patient spectrum differed between the clinics, which resulted in different accuracy estimates for the two samples. Generally, negative predictive values were high while positive ones were low indicating that these methods were more efficient in finding individuals who are at low risk of developing caries lesions than those with increased risk. Conclusions: As thresholds and patient spectrum affected predictive accuracy, it may be difficult to design a universal model with set thresholds for caries risk assessment. Foremost, a model should consider the level of aspiration for prediction and clinical decisions that will be made based on the risk assessment in the actual clinical setting.
Fifty Years of Research in ARDS., Cell‐based Therapy for Acute Respiratory Distress Syndrome. Biology and Potential Therapeutic Value

&NA; On the basis of several preclinical studies, cell‐based therapy has emerged as a potential new therapeutic for acute respiratory distress syndrome (ARDS). Of the various cell‐based therapy options, mesenchymal stem/stromal cells (MSCs) from bone marrow, adipose tissue, and umbilical cord have the most experimental data to support their potential efficacy for lung injury from both infectious and noninfectious causes. Mechanistically, MSCs exert their beneficial effects by release of paracrine factors, microvesicles, and transfer of mitochondria, all of which have antiinflammatory and pro‐resolving effects on injured lung endothelium and alveolar epithelium, including enhancing the resolution of pulmonary edema by up‐regulating sodium‐dependent alveolar fluid clearance. MSCs also have antimicrobial effects mediated by release of antimicrobial factors and by up‐regulating monocyte/macrophage phagocytosis. Phase 2a clinical trials to establish safety in ARDS are in progress, and two phase 1 trials did not report any serious adverse events. Several issues need further study, including: determining the optimal methods for large‐scale production, reconstitution of cryopreserved cells for clinical use, defining cell potency assays, and determining the therapeutic potential of conditioned media derived from MSCs. Because ARDS is a heterogeneous syndrome, targeting MSCs to patients with ARDS with a more hyperinflammatory endotype may further enhance their potential for efficacy.
Abuse, invalidation, and lack of early warmth show distinct relationships with self-criticism, self-compassion, and fear of self-compassion in personality disorder.

BACKGROUND Cultivating self-compassion is increasingly recognized as a powerful method to regulate hyperactive threat processes such as shame and self-criticism, but fear of self-compassion (FSC) can inhibit this. These difficulties are underexplored in personality disorder (PD) despite their prevalence. Furthermore, little evidence exists regarding how these factors relate to adverse childhood experiences (ACEs) and attachment. METHOD Fifty-three participants with a diagnosis of PD completed measures including childhood abuse/neglect, invalidation, early warmth, self-compassion, shame, self-criticism, FSC, and anxious/avoidant attachment. RESULTS Self-compassion was predicted uniquely by low early warmth; self-inadequacy by invalidation and abuse; and FSC by multiple ACEs. FSC and self-compassion were significantly correlated with self-criticism and shame, but not with one another. CONCLUSIONS Low self-compassion and high FSC appear to be distinct problems, substantiating physiological models proposing distinct threat and soothing systems. Results are consistent with theories positing that low self-compassion has distinct origins to shame, self-criticism, and FSC.
Conformational sampling and polarization of Asp26 in pKa calculations of thioredoxin

Thioredoxin is a protein that has been used as model system by various computational methods to predict the pKa of aspartate residue Asp26 which is 3.5 units higher than a solvent exposed one (eg, Asp20). Here, we use extensive atomistic molecular dynamics simulations of two different protonation states of Asp26 in combination with conformational analysis based on RMSD clustering and principle component analysis to identify representative conformations of the protein in solution. For each conformation, the Gibbs free energy of proton transfer between Asp26 and Asp20, which is fully solvated in a loop region of the protein, is calculated with the Amber99sb force field in alchemical transformations. The varying polarization of the two residues in different molecular environments and protonation states is described by Hirshfeld‐I (HI) atomic charges obtained from the averaged polarized electron density. Our results show that the Gibbs free energy of proton transfer is dependent on the protein conformation, the proper sampling of the neighboring Lys57 residue orientations and on water molecules entering the hydrophobic cavity upon deprotonating Asp26. The inclusion of the polarization of both aspartate residues in the free energy cycle by HI atomic charges corrects the results from the non‐polarizable force field and reproduces the experimental ΔpKa value of Asp26.
Protective effects of low-intensity pulsed ultrasound on mandibular condylar cartilage exposed to mechanical overloading

The aim of this study was to examine the role of low-intensity pulsed ultrasound (LIPUS) exposure in the onset and early progression of temporomandibular joint (TMJ) osteoarthritis (TMJ-OA) induced by mechanical overloading. Fifteen-week-old male Wistar rats were divided into two experimental groups and a control group (n = 5 each). In the experimental groups, both TMJs were subjected to mechanical overloading by forced mouth opening using a jaw-opening device for 3 h/day for 5 continuous days. After mechanical overloading, TMJs in one experimental group were exposed to LIPUS for 20 min/day. After the experiments, mandibles were resected from the rats, and the condyles were processed. The bones were analyzed using high-resolution microcomputed tomography (micro-CT). The resected TMJs were also subjected to histological analysis and immunohistochemical staining. Micro-CT images of the mandibular condyle showed severe subchondral trabecular bone loss in the experimental group with overloading. Treatment with LIPUS after overloading resulted in decreased subchondral trabecular bone resorption. In TMJ sections from the experimental group with overloading, cell-free regions and proteoglycan loss characterized the cartilage degradation; LIPUS exposure restricted these changes in the mandibular condyle. Furthermore, the number of tartrate-resistant acid phosphatase-positive osteoclasts in the mineralized layer of the condylar cartilage increased after mechanical overloading and decreased after LIPUS treatment. Our findings suggest that LIPUS exposure after mechanical TMJ overloading downregulates subchondral trabecular bone resorption and proteoglycan loss in the mandibular condylar cartilage. Thus, it may prove to be protective effects of LIPUS exposure on onset and early progression of TMJ-OA induced by mechanical overloading.