The anti-diabetic PPARy agonist Pioglitazone inhibits cell proliferation and induces metabolic reprogramming in prostate cancer

Prostate cancer (PCa) and Type 2 diabetes (T2D) often co-occur, yet their relationship remains elusive. While some studies suggest that T2D lowers PCa risk, others report conflicting data. This study investigates the effects of peroxisome proliferator-activated receptor (PPAR) agonists Bezafibrate, Tesaglitazar, and Pioglitazone on PCa tumorigenesis. Analysis of patient datasets revealed that high PPARG expression correlates with advanced PCa and poor survival. The PPAR? agonists Pioglitazone and Tesaglitazar notably reduced cell proliferation and PPAR? protein levels in primary and metastatic PCa-derived cells. Proteomic analysis identified intrinsic differences in mTORC1 and mitochondrial fatty acid oxidation (FAO) pathways between primary and metastatic PCa cells, which were further disrupted by Tesaglitazar and Pioglitazone. Moreover, metabolomics, Seahorse Assay-based metabolic profiling, and radiotracer uptake assays revealed that Pioglitazone shifted primary PCa cells\u27 metabolism towards glycolysis and increased FAO in metastatic cells, reducing mitochondrial ATP production. Furthermore, Pioglitazone suppressed cell migration in primary and metastatic PCa cells and induced the epithelial marker E-Cadherin in primary PCa cells. In vivo, Pioglitazone reduced tumor growth in a metastatic PC3 xenograft model, increased phosho AMPK? and decreased phospho mTOR levels. In addition, diabetic PCa patients treated with PPAR agonists post-radical prostatectomy implied no biochemical recurrence over five to ten years compared to non-diabetic PCa patients. Our findings suggest that Pioglitazone reduces PCa cell proliferation and induces metabolic and epithelial changes, highlighting the potential of repurposing metabolic drugs for PCa therapy

Glycans of parasitic nematodes - from glycomes to novel diagnostic tools and vaccines

Nematodes, commonly known as roundworms, are among the most prevalent and diverse multicellular organisms on Earth, belonging to the large phylum Nematoda. In addition to free-living species, many nematodes are parasitic, infecting plants, animals, and humans. Nematodes possess a wide array of genes responsible for carbohydrate metabolism and glycosylation. The glycosylation processes in parasitic nematodes often result in unique glycan modifications that are not present in their hosts. These distinct glycans can be highly immunogenic to mammalian hosts and play significant immunoregulatory roles during infection. This mini-review article summarises the glycosylation capabilities and characteristics of parasitic nematodes based on glycomic data. It also highlights recent research advances that explore the biological significance of nematode glycans and their potential for diagnostic and vaccine applications

Development and Validation of Targeted Metabolomics Methods Using Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) for the Quantification of 235 Plasma Metabolites

Plasma contains metabolites with diverse physicochemical properties, ranging from highly polar to highly apolar, and concentrations spanning at least nine orders of magnitude. Plasma metabolome analysis is valuable for monitoring health and evaluating medical interventions but is challenging due to the metabolome\u27s diversity and complexity. This study aims to develop and validate targeted LC-MS/MS methods for quantifying 235 mammalian metabolites from 17 compound classes in porcine plasma without prior derivatization. Utilizing reversed-phase and hydrophilic interaction liquid chromatography coupled with tandem mass spectrometry, each analyte is identified and quantified using two selected reaction monitoring (SRM) transitions. Fast polarity switching and scheduled SRM enhance the metabolome coverage and throughput, enabling the analysis of one sample in about 40 min. A simple "dilute and shoot" sample preparation protocol was employed, with samples injected at two dilution levels to align metabolite concentrations within calibration curve ranges. Validation in porcine plasma included assessments of carryover, linearity, detection and quantification limits, repeatability and recovery. The method was further applied to plasma samples from various animal species, demonstrating its applicability to human and animal studies. This study establishes two robust LC-MS/MS methods for comprehensive porcine plasma metabolome quantification, advancing large-scale targeted metabolomics in biomedical research

Imaging and outcome correlates of ctDNA methylation markers in prostate cancer: a comparative, cross-sectional [??Ga]Ga-PSMA-11 PET/CT study

To validate the clinical utility of a previously identified circulating tumor DNA methylation marker (meth-ctDNA) panel for disease detection and survival outcomes, meth-ctDNA markers were compared to PSA levels and PSMA PET/CT findings in men with different stages of prostate cancer (PCa).122 PCa patients who underwent [??Ga]Ga-PSMA-11 PET/CT and plasma sampling (03/2019-08/2021) were analyzed. cfDNA was extracted, and a panel of 8 individual meth-ctDNA markers was queried. PET scans were qualitatively and quantitatively assessed. PSA and meth-ctDNA markers were compared to PET findings, and their relative prognostic value was evaluated.PSA discriminated best between negative and tumor-indicative PET scans in all (AUC 0.77) and hormone-sensitive (hsPC) patients (0.737). In castration-resistant PCa (CRPC), the meth-ctDNA marker KLF8 performed best (AUC 0.824). CHST11 differentiated best between non- and metastatic scans (AUC 0.705) overall, KLF8 best in hsPC and CRPC (AUC 0.662, 0.85). Several meth-ctDNA markers correlated low to moderate with the tumor volume in all (5/8) and CRPC patients (6/8), while PSA levels correlated moderately to strongly with the tumor volume in all groups (all p?<?0.001). CRPC overall survival was independently associated with LDAH and PSA (p?=?0.0168, p?<?0.001).The studied meth-ctDNA markers are promising for the minimally-invasive detection and prognostication of CRPC but do not allow for clinical characterization of hsPC. Prospective studies are warranted for their use in therapy response and outcome prediction in CRPC and potential incremental value for PCa monitoring in PSA-low settings

Beyond symptomatic alignment: evaluating the integration of causal mechanisms in matching animal models with human pathotypes in osteoarthritis research

Osteoarthritis (OA) is a highly prevalent and disabling condition lacking curative treatments, with only symptomatic relief available. Recognizing OA as a heterogenous disorder with diverse aetiologies and molecular foundations underscores the need to classify patients by both phenotypes and molecular pathomechanisms (endotypes). Such stratification could enable the development of targeted therapies to surmount existing treatment barriers. From a scientific, economic, and ethical perspective, it is crucial to employ animal models that accurately represent the endotype of the target patient population, not merely their clinical symptoms. These models must also account for intrinsic and extrinsic factors, like age, sex, metabolic status, and comorbidities, which impact OA\u27s pathogenesis and its clinical and molecular variability and can profoundly influence not only structural and symptomatic disease severity and progression but also the underlying molecular pathophysiology. The molecular definition of the OA subpopulation must also be reflected in the read-outs, as the traditional methods-macroscopic and histological scoring, along with limited gene expression profiling of established biomarkers for cartilage degradation, extracellular matrix (ECM) turnover, and synovial inflammation-are inadequate for discovering new, phenotype- and endotype-specific biomarkers or therapeutic targets. Thus, animal model characterisation should evolve to include both clinically and pathophysiologically pertinent measures of disease progression and response to treatment. This review evaluates the utility and accuracy of current animal models in OA research, focusing on their capacity to replicate the disease\u27s pathophysiological processes

Cyclin C promotes development and progression of B-cell acute lymphoblastic leukemia by counteracting p53-mediated stress responses

Despite major therapeutic advances in the treatment of acute lymphoblastic leukemia (ALL), resistances and long-term toxicities still pose significant challenges. Cyclins and their associated cyclin-dependent kinases are one focus of cancer research when looking for targeted therapies. We discovered cyclin C to be a key factor for B-cell ALL (B-ALL) development and maintenance. While cyclin C is not essential for normal hematopoiesis, Ccnc?/? BCR::ABL1+ B-ALL cells fail to elicit leukemia in mice. RNA sequencing experiments revealed a p53 pathway deregulation in Ccnc?/? BCR::ABL1+ cells resulting in the inability of the leukemic cells to adequately respond to stress. A genome-wide CRISPR/Cas9 loss-of-function screen supplemented with additional knock-outs unveiled a dependency of human B-lymphoid cell lines on CCNC. High cyclin C levels in B-cell precursor (BCP) ALL patients were associated with poor event-free survival and increased risk of early disease recurrence after remission. Our findings highlight cyclin C as a potential therapeutic target for B-ALL, particularly to enhance cancer cell sensitivity to stress and chemotherapy

Testosterone dynamics of migratory birds during stopover

Birds migrating in the spring must balance energy with hormonal preparations in anticipation of the forthcoming breeding season. We investigated the relationships between testosterone, body condition, sociality, territoriality and fueling rates in Western Subalpine Warbler (Curruca iberiae) males during a trans-Saharan stopover. Baseline testosterone was highly variable in correspondence with the transitional nature of spring stopover. Some individuals reached breeding testosterone levels while others had undetectable levels. Testosterone varied with body condition suggesting an endocrine-energy link during migration. Simulated territory intrusions induced an increase of testosterone up to physiological maxima- a similar pattern to breeding contexts. Testosterone was negatively associated with territorial male density, suggesting a \u27dear enemy\u27 effect related to the daily variation in social stability. In repeatedly-sampled individuals, stopover duration and fueling rate were not correlated with baseline testosterone. However, as testosterone decreased, body condition increased. This suggests that stopover territoriality may reduce the reported negative effects of chronically high testosterone. Our data supports the hypothesis that hormonal preparation for breeding may already occur during stopover, and that this is largely linked to body condition. In this system, the endocrine-energy relationship is likely maintained by stopover territoriality. We conclude that male-male social contexts are modulated in similar ways during spring migration as during the breeding life history stage

Uncovering the full potential of attitude measures in navigating human-wolf coexistence

Attitudes towards wolves are important indicators of what wolf presence means to people and whether they lean towards support or opposition. Over the past 50 years, attitude surveys and interviews have uncovered that the polarisation between social groups is not only driven by tangible impacts. Moreover, uneven distribution of intangible costs fostered feelings of marginalisation, and socio-cultural divides create different perceptions of wolves and their management. Despite these revelations, little emphasis has been placed on the intricate psychological mechanisms underlying attitude polarisation and behavioural implications. This Perspective drafts a framework around the roles of attitude strength, accessibility, and ambivalence in attitude and behaviour formation, and emphasizes the potential role of unconscious, implicit attitudes beyond explicit self-report in how humans perceive and react to wolves. It explores how these factors may explain polarisation, sudden attitude shifts, mismatches between reported attitudes and behaviours, and the unexpected ineffectiveness of some interventions. Under the assumption of this framework, approaches are discussed that could help navigate attitude shifts amid expanding wolf populations and emotional conflicts between groups and species. Though speculative for now, we hope that this bottom-up approach will guide and inspire research to further explore the proposed mechanisms and improve our understanding about how latent attitudes, ambivalence, and experiences may shape attitudes towards wolves. Rather than advocating for nationwide shifts towards positive views of wolves, we stress the importance of recognizing the full spectrum of attitudes, contexts, and social group settings in managing conflict sustainably, particularly considering expanding and increasingly urbanized wolf populations

Dexamethasone: a double-edged sword in the treatment of osteoarthritis

Glucocorticoids are widely used to manage osteoarthritis (OA) symptoms, but long-term safety concerns exist. This study investigates the therapeutic potential of dexamethasone (DEX) and triamcinolone acetonide (TA) in chondrocytes, evaluating their anti-inflammatory effects and potential detrimental actions. This study evaluated the effects of DEX and TA on the expression of pro-inflammatory genes in inflamed chondrocytes. In addition, the effects of DEX treatment on chondrocytes were analyzed using next-generation sequencing, high-resolution mass spectrometry, proliferation and metabolic rate, wound healing capacity and senescence-associated B-galactosidase assays. A single therapeutic dose of DEX (40nM) effectively reduced the expression of inflammatory genes in chondrocytes, while TA showed no such effect. DEX significantly reduced inflammation but also ECM production in inflamed chondrocytes. At 24 h, DEX treatment led to 168 differentially expressed genes (DEGs) compared to untreated inflamed cells, decreasing to 5 DEGs by 48 h, indicating a rapidly diminishing anti-inflammatory effect. Conversely, the difference between DEX-treated and healthy cells increased over time, from 666 DEGs at 24 h to 1317 DEGs at 48 h. Pathway analysis revealed potential disruptions in cell cycle, mitosis, and ECM homeostasis in DEX-treated cells compared to both healthy and inflamed controls. Interestingly, repeated DEX administration at both a therapeutic (40nM) and a high dose (1µM) induced senescence in healthy cells but not in inflamed cells. In contrast, repeated high-dose DEX reduced apoptosis marker Caspase 3/7 in inflamed but not healthy cells. Despite the transient suppression of inflammation achieved with DEX treatment, the observed decrease in ECM production and induction of senescence in healthy chondrocytes at therapeutic doses, along with apoptosis in inflamed cells at higher doses, underscore the need for caution in its intra-articular administration

Improvement in the Usability of Meat Inspection Findings for Swine Herd Health Management

Data from post-mortem inspections conducted using official controls on the meat production of slaughtered pigs are generally considered valuable for identifying herd health issues and ensuring meat safety. However, several studies highlighted that a multi-stage assessment of lung changes would provide more useful information on animal health than the implemented binary (yes/no) recording. For this purpose, a new scheme was developed and subsequently used by trained official veterinarians at four slaughterhouses in Austria. Implementation of the multi-stage assessment was carried out in parallel with the conventional assessment, and data collected from both schemes were analyzed and compared to evaluate effectiveness. The analysis of the data (n = 20,345) showed that the most common alteration was low-grade (28.4%), followed by moderate-grade (11.3%,) and then high-grade pneumonia (5.2%). In the case of pleurisy, 88.9% of the carcasses showed no alterations of the pleura, and 11.1% had pathological changes (low-grade pleurisy = 4.7%, moderate-grade pleurisy = 2.7%, high-grade pleurisy = 3.7%). Analysis of the results showed a strong heterogeneity of the frequency of alterations between the batches reflecting various underlying animal health issues. Among the influencing factors, the origin of the pigs had the greatest influence. The project demonstrated that the new evaluation can be carried out easily with no extra time effort once staff are trained and the technological platform for reporting is adapted. The more detailed information ensures more useful feedback is provided to the farmers and supervising veterinarians, thereby ensuing animal welfare and contributing to sustainable, improved animal husbandry