Search Results (48)

Preeclampsia (PE), a pregnancy complication characterized by high blood pressure and organ damage, has been suggested to be associated with mitochondrial dysfunction, although evidence remains limited. This study aimed to investigate the activity of oxidative phosphorylation (OXPHOS) enzymes and the expression of related proteins in placental tissues from women diagnosed with early-onset preeclampsia (eoPE, <34 weeks of gestation), late-onset preeclampsia (loPE, ≥34 weeks of gestation), and normotensive controls. Placental samples were analyzed using immunohistochemistry, western blotting, and enzymatic activity assays to assess the activity and expression of OXPHOS complexes. Complex I activity was increased by 80% in eoPE and 56% in loPE, with positive correlations between normalized complex I expression, gestational age at delivery (r = 0.85, p = 0.01), and birth weight (r = 0.88, p = 0.004) in loPE. Relative complex II expression in loPE showed positive correlations with pregnancy duration (r = 0.76, p = 0.03) and birth weight (r = 0.77, p = 0.03), while in controls, complex II expression correlated with pregnancy duration (r = 0.64, p = 0.03). Additionally, complex IV enzyme activity in eoPE was negatively correlated with maternal age at birth (r = −0.69, p = 0.03). The observed correlations highlight mitochondrial metabolism as a promising biomarker for predicting disease progression and guiding therapeutic interventions in preeclampsia. Unraveling its precise role in PE pathogenesis is critical to advancing diagnostic precision and improving maternal-fetal outcomes. Full article

Clear and accessible lay summaries are essential for enhancing the public understanding of scientific knowledge. This study aimed to evaluate whether ChatGPT-4 can generate high-quality lay summaries that are both accurate and comprehensible for prostate cancer research in Current Oncology. To achieve this, it systematically assessed ChatGPT-4’s ability to summarize 80 prostate cancer articles published in the journal between July 2022 and June 2024 using two distinct prompt designs: a basic “simple” prompt and an enhanced “extended” prompt. Readability was assessed using established metrics, including the Flesch–Kincaid Reading Ease (FKRE), while content quality was evaluated with a 5-point Likert scale for alignment with source material. The extended prompt demonstrated significantly higher readability (median FKRE: 40.9 vs. 29.1, p < 0.001), better alignment with quality thresholds (86.2% vs. 47.5%, p < 0.001), and reduced the required reading level, making content more accessible. Both prompt designs produced content with high comprehensiveness (median Likert score: 5). This study highlights the critical role of tailored prompt engineering in optimizing large language models (LLMs) for medical communication. Limitations include the exclusive focus on prostate cancer, the use of predefined prompts without iterative refinement, and the absence of a direct comparison with human-crafted summaries. These findings underscore the transformative potential of LLMs like ChatGPT-4 to streamline the creation of lay summaries, reduce researchers’ workload, and enhance public engagement. Future research should explore prompt variability, incorporate patient feedback, and extend applications across broader medical domains. Full article

Background: The urinary microbiota of healthy children has rarely been studied, and potential differences between boys and girls have not been addressed. Thus, this study aimed to compare the urinary microbiota of healthy prepubescent girls and boys. Methods: We included healthy children aged between 4 and 10 years who were free of functional or organic urinary tract diseases and had no history of urinary tract infection. We collected the mean portion of morning urine during natural micturition and determined aerobic and anaerobic microbiota using HiCrome™ chromogenic growth media. We identified microorganisms on the basis of morphotinctural properties and analyzed α- and β-diversity of microorganisms isolated from the urine of boys and girls. Results: Mean age of the children was 6.1 ± 3.2 years. In general, four-component (28.1%) as well as two-component (15.6%), three-component (15.6%), and six-component (12.5%) combinations of microorganisms prevailed in the urine of children. The urine of boys exhibited four-component combinations significantly more often than that of girls (p ˂ 0.05), while the urine of girls contained seven-component microbial combinations significantly more often than that of boys (p ˂ 0.05). Comparison of multicomponent combinations of microorganisms in boys and girls revealed an overrepresentation of Enterococcus spp. in girls (p < 0.05). Furthermore, there was a trend towards higher microbial α-diversity in the urine of girls, but the difference between girls and boys was not significant. Conclusions: The urine of healthy prepubescent children contained various aerobic–anaerobic combinations of microorganisms. Their diversity in the urine of girls and boys did not differ significantly. However, the level of α-diversity of microorganisms was higher in girls than in boys. We noted differences in the prevalence of certain taxa of microorganisms in the urine of boys and girls. Our study showed a close functional relationship between aerobic and anaerobic microorganisms detected in the urine of children in more than half of the cases. Full article

The integration of artificial intelligence, particularly Large Language Models (LLMs), has the potential to significantly enhance therapeutic decision-making in clinical oncology. Initial studies across various disciplines have demonstrated that LLM-based treatment recommendations can rival those of multidisciplinary tumor boards (MTBs); however, such data are currently lacking for urological cancers. This preparatory study establishes a robust methodological foundation for the forthcoming CONCORDIA trial, including the validation of the System Causability Scale (SCS) and its modified version (mSCS), as well as the selection of LLMs for urological cancer treatment recommendations based on recommendations from ChatGPT-4 and an MTB for 40 urological cancer scenarios. Both scales demonstrated strong validity, reliability (all aggregated Cohen’s K > 0.74), and internal consistency (all Cronbach’s Alpha > 0.9), with the mSCS showing superior reliability, internal consistency, and clinical applicability (p < 0.01). Two Delphi processes were used to define the LLMs to be tested in the CONCORDIA study (ChatGPT-4 and Claude 3.5 Sonnet) and to establish the acceptable non-inferiority margin for LLM recommendations compared to MTB recommendations. The forthcoming ethics-approved and registered CONCORDIA non-inferiority trial will require 110 urological cancer scenarios, with an mSCS difference threshold of 0.15, a Bonferroni corrected alpha of 0.025, and a beta of 0.1. Blinded mSCS assessments of MTB recommendations will then be compared to those of the LLMs. In summary, this work establishes the necessary prerequisites prior to initiating the CONCORDIA study and validates a modified score with high applicability and reliability for this and future trials. Full article

Large cities are typically characterized by a mosaic of green spaces that hold a remarkable variety of native and “exotic” plants. Urban beekeeping has gained increasing popularity. In order to characterize the “urban” in the honey, pollen diversity in 50 honey samples from 18 apiary locations in Vienna, Austria, was microscopically analyzed. The relative abundances of each plant taxon were determined by counting out 500 individual pollen grains per sample. In total, 202 taxa could be identified, with a median of 46 per sample. Taxa richness and diversity differed significantly across three years but did not so between urban and suburban apiaries. Despite trees comprising only roughly a quarter of all taxa, the amount of tree pollen was disproportionally high. The invasive Ailanthus altissima was predominant in 15 out of 50 samples. Other important non-native and/or ornamental trees included Sophora japonica, Gleditsia triacanthos, Castanea sativa, Koelreuteria paniculata, and Liriodendron tulipifera. Urban honey from Central Europe may typically comprise pollen taxa from Europe, East Asia, and North America alike. The results of this study show that intentionally planted, managed urban green spaces can support stable foraging resources for pollinators in cities. Full article

The available randomised controlled trials (RCTs) assessing the influence of peritoneal interposition flaps (PIF) on the reduction of symptomatic lymphoceles (sLCs) post robot-assisted radical prostatectomy (RARP) do not constitute a sufficient follow-up (FU) to assess the long-term effects. The PIANOFORTE trial was the first of these RCTs, showing no sLC reduction at the 3-month FU. Therefore, all 232 patients from the PIANOFORTE trial were invited for long-term FU. One hundred seventy-six patients (76%) presented themselves for FU and constituted the study group (SG). The median FU duration was 43 months. No significant differences in group allocation or LC endpoints at 90 days were observed between SG patients and patients not presenting themselves for the FU. During the FU period, four patients (2.3%) in the SG developed sLCs, and six patients (3.4%) developed asymptomatic lymphoceles (aLCs), which persisted in five patients (2.9%). There were no significant differences between PIF and non-PIF regarding sLC/aLC formation or persistence, newly developed complications, stress urinary incontinence or biochemical/clinical tumour recurrence. Therefore, this long-term FU confirms the primary outcomes of the PIANOFORTE trial that, while PIF does not impact complications or functionality, it does not reduce sLC/aLC rates. Furthermore, it shows the potential occurrence of LC after the third postoperative month. Full article

Knowledge communication in cultural heritage and digital humanities currently faces two challenges, which this paper addresses: On the one hand, data-driven storytelling in these fields has mainly focused on human protagonists, while other essential entities (such as artworks and artifacts, institutions, or places) have been neglected. On the other hand, storytelling tools rarely support the larger chains of data practices, which are required to generate and shape the data and visualizations needed for such stories. This paper introduces the InTaVia platform, which has been developed to bridge these gaps. It supports the practices of data retrieval, creation, curation, analysis, and communication with coherent visualization support for multiple types of entities. We illustrate the added value of this open platform for storytelling with four case studies, focusing on (a) the life of Albrecht Dürer (person biography), (b) the Saliera salt cellar by Benvenuto Cellini (object biography), (c) the artist community of Lake Tuusula (group biography), and (d) the history of the Hofburg building complex in Vienna (place biography). Numerous suggestions for future research arise from this undertaking. Full article

Citric acid cycle deficiencies are extremely rare due to their central role in energy metabolism. The ACO2 gene encodes the mitochondrial isoform of aconitase (aconitase 2), the second enzyme of the citric acid cycle. Approximately 100 patients with aconitase 2 deficiency have been reported with a variety of symptoms, including intellectual disability, hypotonia, optic nerve atrophy, cortical atrophy, cerebellar atrophy, and seizures. In this study, a homozygous deletion in the ACO2 gene in two brothers with reduced aconitase 2 activity in fibroblasts has been described with symptoms including truncal hypotonia, optic atrophy, hyperopia, astigmatism, and cerebellar atrophy. In an in vivo trial, triheptanoin was used to bypass the defective aconitase 2 and fill up the citric acid cycle. Motor abilities in both patients improved. Full article

Background: X-linked myotubular myopathy (XLMTM) is a rare congenital myopathy resulting from dysfunction of the protein myotubularin encoded by the MTM1 gene. XLMTM has a high neonatal and infantile mortality rate due to a severe myopathic phenotype and respiratory failure. However, in a minority of XLMTM cases, patients present with milder phenotypes and achieve ambulation and adulthood. Notable facial dysmorphia is also present. Methods: We investigated the genotype–phenotype correlations in newly diagnosed XLMTM patients in a patients’ cohort (previously published data plus three novel variants, n = 414). Based on the facial gestalt difference between XLMTM patients and unaffected controls, we investigated the use of the Face2Gene application. Results: Significant associations between severe phenotype and truncating variants (p < 0.001), frameshift variants (p < 0.001), nonsense variants (p = 0.006), and in/del variants (p = 0.036) were present. Missense variants were significantly associated with the mild and moderate phenotype (p < 0.001). The Face2Gene application showed a significant difference between XLMTM patients and unaffected controls (p = 0.001). Conclusions: Using genotype–phenotype correlations could predict the disease course in most XLMTM patients, but still with limitations. The Face2Gene application seems to be a practical, non-invasive diagnostic approach in XLMTM using the correct algorithm. Full article

Two siblings showed increased galactose and galactose-related metabolites in neonatal screening. Diagnostic workup did not reveal abnormalities in any of the known disease-causing enzymes involved in galactose metabolism. Using whole-exome sequencing, we identified a homozygous missense variant in PPA1 encoding the cytosolic pyrophosphatase 1 (PPA1), c.557C>T (p.Thr186Ile). The enzyme activity of PPA1 was determined using a colorimetric assay, and the protein content was visualized via western blotting in skin fibroblasts from one of the affected individuals. The galactolytic activity of the affected fibroblasts was determined by measuring extracellular acidification with a Seahorse XFe96 analyzer. PPA1 activity decreased to 22% of that of controls in the cytosolic fraction of homogenates from patient fibroblasts. PPA1 protein content decreased by 50% according to western blot analysis, indicating a reduced stability of the variant protein. The extracellular acidification rate was reduced in patient fibroblasts when galactose was used as a substrate. Untargeted metabolomics of blood samples revealed an elevation of other metabolites related to pyrophosphate metabolism. Besides hyperbilirubinemia in the neonatal period in one child, both children were clinically unremarkable at the ages of 3 and 14 years, respectively. We hypothesize that the observed metabolic derangement is a possible mild manifestation of PPA1 deficiency. Unresolved abnormalities in galactosemia screening might result in the identification of more individuals with PPA1 deficiency, a newly discovered inborn metabolic disorder (IMD). Full article

Background: Heterozygous, large-scale deletions at 14q24.3-31.1 affecting the neurexin-3 gene have been associated with neurodevelopmental disorders such as autism. Both “de novo” occurrences and inheritance from a healthy parent suggest incomplete penetrance and expressivity, especially in autism spectrum disorder. NRXN3 encodes neurexin-3, a neuronal cell surface protein involved in cell recognition and adhesion, as well as mediating intracellular signaling. NRXN3 is expressed in two distinct isoforms (alpha and beta) generated by alternative promoters and splicing. MM/Results: Using exome sequencing, we identified a monoallelic frameshift variant c.159_160del (p.Gln54AlafsTer50) in the NRXN3 beta isoform (NM_001272020.2) in a 5-year-old girl with developmental delay, autism spectrum disorder, and behavioral issues. This variant was inherited from her mother, who did not have any medical complaints. Discussion: This is the first detailed report of a loss-of-function variant in NRXN3 causing an identical phenotype, as reported for heterozygous large-scale deletions in the same genomic region, thereby confirming NRXN3 as a novel gene for neurodevelopmental disorders with autism. Full article

Background: Liquid biopsy diagnostic methods are an emerging complementary tool to imaging and pathology techniques across various cancer types. However, there is still no established method for the detection of molecular alterations and disease monitoring in MB, the most common malignant CNS tumor in the pediatric population. In the presented study, we investigated droplet digital polymerase chain reaction (ddPCR) as a highly sensitive method for the detection of MYC amplification in bodily fluids of group 3 MB patients. Methods: We identified a cohort of five MYC-amplified MBs by methylation array and FISH. Predesigned and wet-lab validated probes for ddPCR were used to establish the detection method and were validated in two MYC-amplified MB cell lines as well as tumor tissue of the MYC-amplified cohort. Finally, a total of 49 longitudinal CSF samples were analyzed at multiple timepoints during the course of the disease. Results: Detection of MYC amplification by ddPCR in CSF showed a sensitivity and specificity of 90% and 100%, respectively. We observed a steep increase in amplification rate (AR) at disease progression in 3/5 cases. ddPCR was proven to be more sensitive than cytology for the detection of residual disease. In contrast to CSF, MYC amplification was not detectable by ddPCR in blood samples. Conclusions: ddPCR proves to be a sensitive and specific method for the detection of MYC amplification in the CSF of MB patients. These results warrant implementation of liquid biopsy in future prospective clinical trials to validate the potential for improved diagnosis, disease staging and monitoring. Full article

Background: We assessed a wide array of body composition parameters to identify those most relevant as prognostic tools for patients undergoing radical cystectomy (RC) due to bladder cancer (BC). Methods: In this retrospective, single-center study, preoperative computed tomography (CT) scans of 657 patients were measured at the level of the 3rd lumbar vertebra (L3) to determine common body composition indices including sarcopenia, myosteatosis, psoas muscle index (PMI), subcutaneous and visceral fat index (SFI and VFI), visceral-to-subcutaneous fat ratio (VSR), and visceral obesity. Predictors of overall survival (OS) and cancer-specific survival (CSS) were identified in univariate and multivariate survival analysis. Results: Sarcopenia and a low PMI were independently associated with shorter OS (Sarcopenia: HR 1.30; 95% CI 1.02–1.66; p = 0.04 and a low PMI: HR 1.32; 95% CI 1.02–1.70; p = 0.03) and CSS (Sarcopenia: HR 1.64; 95% CI 1.19–2.25; p < 0.01 and a low PMI: HR 1.41; 95% CI 1.02–1.96; p = 0.04). Myosteatosis, measured as decreasing average Hounsfield units of skeletal muscle, was an independent risk factor for OS (HR 0.98; 95% CI 0.97–1.00; p = 0.01) and CSS (HR 0.98; 95% CI 0.96–1.00; p < 0.05). The assessed adipose tissue indices were not significant predictors for OS and CSS. Conclusions: Sarcopenia, a low PMI, and myosteatosis are independent predictors for OS and CSS in patients undergoing radical cystectomy for bladder cancer. Full article

Biliary tract cancer (BTC) is a gastrointestinal malignancy associated with a poor survival rate. Current therapies encompass palliative and chemotherapeutic treatment as well as radiation therapy, which results in a median survival of only one year due to standard therapeutic ineffectiveness or resistance. Tazemetostat is an FDA-approved inhibitor of enhancer of Zeste homolog 2 (EZH2), a methyltransferase involved in BTC tumorigenesis via trimethylation of histone 3 at lysine 27 (H3K27me3), an epigenetic mark associated with silencing of tumor suppressor genes. Up to now, there are no data available regarding tazemetostat as a possible treatment option against BTC. Therefore, the aim of our study is a first-time investigation of tazemetostat as a potential anti-BTC substance in vitro. In this study, we demonstrate that tazemetostat affects cell viability and the clonogenic growth of BTC cells in a cell line-dependent manner. Furthermore, we found a strong epigenetic effect at low concentrations of tazemetostat, which was independent of the cytotoxic effect. We also observed in one BTC cell line that tazemetostat increases the mRNA levels and protein expression of the tumor suppressor gene Fructose-1,6-bisphosphatase 1 (FBP1). Interestingly, the observed cytotoxic and epigenetic effects were independent of the mutation status of EZH2. To conclude, our study shows that tazemetostat is a potential anti-tumorigenic substance in BTC with a strong epigenetic effect. Full article

Mutations in the COL7A1 gene lead to malfunction, reduction or complete absence of type VII collagen (C7) in the skin’s basement membrane zone (BMZ), impairing skin integrity. In epidermolysis bullosa (EB), more than 800 mutations in COL7A1 have been reported, leading to the dystrophic form of EB (DEB), a severe and rare skin blistering disease associated with a high risk of developing an aggressive form of squamous cell carcinoma. Here, we leveraged a previously described 3′-RTMS6m repair molecule to develop a non-viral, non-invasive and efficient RNA therapy to correct mutations within COL7A1 via spliceosome-mediated RNA trans-splicing (SMaRT). RTM-S6m, cloned into a non-viral minicircle-GFP vector, is capable of correcting all mutations occurring between exon 65 and exon 118 of COL7A1 via SMaRT. Transfection of the RTM into recessive dystrophic EB (RDEB) keratinocytes resulted in a trans-splicing efficiency of ~1.5% in keratinocytes and ~0.6% in fibroblasts, as confirmed on mRNA level via next-generation sequencing (NGS). Full-length C7 protein expression was primarily confirmed in vitro via immunofluorescence (IF) staining and Western blot analysis of transfected cells. Additionally, we complexed 3′-RTMS6m with a DDC642 liposomal carrier to deliver the RTM topically onto RDEB skin equivalents and were subsequently able to detect an accumulation of restored C7 within the basement membrane zone (BMZ). In summary, we transiently corrected COL7A1 mutations in vitro in RDEB keratinocytes and skin equivalents derived from RDEB keratinocytes and fibroblasts using a non-viral 3′-RTMS6m repair molecule. Full article