Search Results (81,983)

Background/Objectives: Breast cancer recurrence risk stratification has relied on gene expression tests that are limited by long turnaround times and consumption of valuable tissue. Artificial intelligence (AI) utilizing digital pathology images elucidates novel morphological biomarkers with strong prognostic associations, but the use of such AI models requires a modified analytical validation approach. Here, we report analytical validation of a novel breast cancer prognostic test. Methods: Ataraxis Breast RISK (ATX) uses a survival analysis model based upon features from a pan-cancer foundation model. This model extracts morphological features (biomarkers) from H&E-stained slides. These features are combined with clinical variables, and the test outputs a calibrated recurrence risk score. We validated ATX across five axes: intra-operator repeatability, inter-operator reproducibility, limit of blank, limit of detection and inter-laboratory reproducibility. Additionally, we assessed robustness to clinicopathologic data perturbations and conducted a clinical validation bridging study. Experiments were performed in CLIA-certified laboratories. Results: Intra-operator repeatability yielded an intraclass correlation coefficient (ICC) of 0.99 with 100% risk category agreement. Inter-operator reproducibility was concordant (ICC 0.99, 100% agreement). Inter-laboratory reproducibility across multiple scanners showed an ICC of 0.97 with 94.7% agreement. Under simulated clinicopathologic data perturbation, ATX maintained an average C-index of 0.62 with 90.0% agreement. The bridging study confirmed that the performance of the CLIA version was comparable to the prior clinical validation version (C-index 0.63 vs. 0.62). Conclusions: ATX met all predefined analytical acceptance criteria. These results support the analytical readiness of ATX use in clinical testing. Full article

Poisoning caused by Taxus baccata is a well-known cause of sudden death in domestic animals due to the cardiotoxic effects of taxine alkaloids. This study describes two cases of fatal intoxication in donkeys (Equus africanus asinus) and demonstrates a multidisciplinary diagnostic approach combining pathology, botanical identification, and toxicology. Two animals were found dead without prior clinical signs on a farm in north-eastern Italy. Necropsies were performed, and samples were collected for further investigations. Histopathological findings were limited and non-specific, consistent with the hyperacute course typical of yew poisoning. Fragments of plant material resembling yew needles and twigs were identified in the gastric contents. Toxicological analysis using liquid chromatography–electrospray ionization mass spectrometry confirmed the presence of taxane alkaloids, supporting the diagnosis of yew poisoning. These data highlight the importance of integrating necropsy results with botanical examination and targeted toxicological analyses in cases of suspected plant poisoning. This multidisciplinary approach provides a reliable diagnostic framework for confirming yew poisoning in veterinary investigations. Full article

Background and Clinical Significance: Extensive rectal ischemia is exceptionally rare due to the rectum’s robust vascular network, with segmental ischemia being more common. Case Presentation: We report the case of a 69-year-old female who presented with whole-segment rectal ischemia, encompassing the upper, mid, and lower rectum. This severe local ischemic event culminated in full-thickness perforation and extensive fecal peritonitis, which subsequently precipitated postoperative septic shock. The patient underwent emergency low anterior resection with Hartmann’s procedure and received intensive multidisciplinary postoperative care. Conclusions: In this case, we aimed to highlight the importance of early recognition, decisive surgical intervention, and the pathophysiological and diagnostic challenges in managing rare cases of whole-segment rectal ischemia. Full article

Background: Tuberculosis (TB) has long been suspected to contribute to lung carcinogenesis through chronic inflammation and immune dysregulation. However, contemporary controlled evidence quantifying this association remains limited. We aimed to systematically evaluate the relationship between prior TB and subsequent lung malignancy, using recent observational studies and complementary case reports. Methods: A systematic review and random-effects meta-analysis were conducted, including controlled cohort and case–control studies published from 2020 onward. Adjusted effect estimates were converted to the logarithmic scale for pooling. Heterogeneity and small-study effects were assessed using standard meta-analytic techniques. Additionally, published case reports were descriptively analyzed to explore clinicopathological patterns. Results: Across eligible studies, prior TB was consistently associated with an increased risk of subsequent lung cancer (LC). The pooled estimate demonstrated a statistically significant positive association, despite moderate heterogeneity. Larger nationwide cohorts contributed greater statistical weight, while smaller studies showed wider variability. Case reports revealed heterogeneous temporal patterns, including long-latency scar-associated carcinoma and concurrent inflammatory–malignant presentations. Conclusions: Contemporary controlled evidence supports an association between prior tuberculosis and increased risk of subsequent lung malignancy. However, despite strong biological plausibility and the abundant literature on cancer-associated tuberculosis, modern longitudinal studies specifically evaluating tuberculosis as a preceding independent risk factor remain limited. The small number of eligible post-2020 investigations identified in this meta-analysis highlights a significant contemporary research gap and underlines the need for well-designed prospective studies to clarify causality and guide surveillance strategies in TB-exposed populations. Full article

DRG adhesion is a key pathological feature of failed back surgery syndrome and a major cause of neuropathic pain. DRG, or epidural adhesion, commonly results from spinal surgery, leakage of disk material into the epidural space, or inflammation. To better mimic this clinical condition, we developed a novel and reliable animal model of DRG adhesion-induced neuropathic pain. Using this model, we investigated the therapeutic potential and underlying mechanisms of CLARIX FLO, a sterile, particulate human amniotic membrane and umbilical cord tissue product. Our results demonstrate that CLARIX FLO exerts significant analgesic and anti-inflammatory effects in the DRG adhesion model. The application of CLARIX FLO to the injured DRG markedly attenuated mechanical allodynia. CLARIX FLO treatment also reduced outer sheath thickening, suppressed the inflammatory microenvironment, and decreased hypersensitivity of isolectin B4-positive neurons. Mechanistically, CD44 was identified as a potential downstream mediator of CLARIX FLO. Furthermore, a high dose of HC-HA/PTX3, the key bioactive component of CLARIX FLO, effectively reversed mechanical allodynia and inflammation. Notably, CLARIX FLO inhibited the overexpression of TNF-α and TRPV1 adhering to the DRG. In this study, we demonstrated that CLARIX FLO effectively alleviates DRG adhesion-induced neuropathic pain through a CD44–TRPV1-dependent mechanism. Full article

Ulcerative colitis (UC) is a highly prevalent chronic non-specific intestinal inflammatory disorder for which effective therapeutic options are urgently needed. The active component cimigenoside (CIM) possesses promising anti-inflammatory bioactivity; however, its therapeutic efficacy and underlying molecular mechanism against UC remain to be fully elucidated. The present study aimed to investigate the effects and possible mechanisms of CIM on dextran sodium sulfate (DSS)-induced UC. Mice received drinking water containing 2.5% DSS to induce a UC model, and were then treated with different dosages of CIM for 10 consecutive days. The results found that CIM restored the colonic length, alleviated pathological damage to the colon, preserved intestinal mucosal barrier integrity, and inhibited colonic oxidative stress and inflammatory responses in DSS-induced mice. Additionally, DSS induction reduced the expression of sirtuin 3 (SIRT3) protein in the colonic tissues of mice; however, this was improved by treatment with CIM. Notably, the above protective roles of CIM on DSS-induced UC were unavailable in SIRT3-knockout (SIRT3-KO) mice. Notably, the docking score of CIM binding to SIRT3 is −11.3 kcal/mol, suggesting that CIM could directly bind to SIRT3. Collectively, CIM directly binds to SIRT3 and upregulates its protein expression, which in turn inhibits colonic inflammation and oxidative stress, thereby exerting anti-UC effects. Full article

Background/Objectives: Routine liver biopsies play an important role in monitoring liver allografts but carry non-negligible risks. This pilot study assesses the feasibility of dynamic long-axial field-of-view (LAFOV) [¹⁸F]FDG PET/CT as a non-invasive alternative to biopsy. Methods: Liver transplant (LTx) recipients meeting the inclusion criteria of ≥10 months post-transplantation and scheduled routine biopsy were prospectively enrolled, along with healthy controls. All participants underwent dynamic LAFOV [¹⁸F]FDG PET/CT, followed by biopsy in LTx recipients, who were stratified by inflammatory severity using the BANFF score. Hepatic kinetic parameters (K1, k2, k3, k4) and SUVmean/SUVmax were compared using Mann–Whitney U tests. Correlations were assessed using Spearman’s rank correlation. A p-value < 0.05 was considered significant. Analyses were performed in RStudio (version 2024.12.10563). Results: Sixteen LTx recipients (mean age 48.6 years; seven female, nine male) and eight healthy controls (mean age 35.4 years; six female, two male) were included. Healthy controls had mean k3 and k4 values of 0.0037 min⁻¹ ± 0.0003 min⁻¹ and 0.0019 min⁻¹ ± 0.0011 min⁻¹, respectively. LTx recipients showed significantly higher k3 and k4 values, both when including and excluding patients with biopsy-confirmed inflammation. Descriptive comparisons between LTx recipients with and without significant inflammation (n = 3) showed no clear differences. Spearman analysis showed no significant correlations between the BANFF score and kinetic parameters. The strongest degree of correlation was found between BANFF score and k3, indicating a moderate positive but non-significant association (k3: rs = 0.396, p = 0.128). Conclusions: Elevated k3 and k4 values in LTx recipients were not explained by allograft inflammation, suggesting altered FDG kinetics post-transplant. These differences may confound [¹⁸F]FDG PET interpretation. Larger studies are needed to assess the clinical applicability of dynamic LAFOV [¹⁸F]FDG PET/CT. Full article

Background and Aim: Lymphovascular invasion (LVI) is a negative prognostic factor for gastric cancer, but detection limitations hinder its clinical utility and subtype analysis. This study aimed to explore the predictive value of LVI and its subtypes in the prognosis and recurrence patterns of gastric cancer using our enhanced detection method. Methods: We reviewed 2057 patients who underwent gastrectomy in 2018, of whom 1073 met the inclusion criteria. Propensity score matching (PSM) was performed to balance baseline clinicopathological characteristics. Results: After PSM, 311 patients were assigned to the LVI+ group and 311 to the LVI- group. The LVI+ group demonstrated a poorer prognosis. Subtype analysis revealed that lymphatic invasion (LI), but not venous invasion (VI), was associated with poor prognosis in the matched cohort. Stratified by pathological tumor-node-metastasis (TNM) stage, LVI+ and LI+ patients had worse prognosis in Stages I and III, while VI+ patients had worse prognosis in Stage III. Stratified by lymph node status, LVI+ predicted poorer prognosis in both node-negative (N0) and node-positive (N+) patients, and LI+ was also associated with worse prognosis among N+ patients, whereas VI+ was not significantly associated with prognosis in either subgroup. Recurrence analysis indicated that LVI+ was associated with distant and peritoneal metastases, whereas LI+ was associated with local recurrence, distant and peritoneal metastases. Conclusions: Lymphovascular invasion was associated with adverse prognosis in resectable gastric cancer, with lymphatic invasion showing a stronger prognostic impact than venous invasion. These findings indicate that refined assessment of lymphovascular invasion may complement conventional TNM staging in postoperative risk stratification. Full article

Oxidative stress is no longer viewed as a random imbalance between reactive oxygen species and antioxidants, but as a failure of an integrated redox network that connects metabolism, immunity, and metal homeostasis. Classical markers such as malondialdehyde and 4-hydroxynonenal define oxidative damage, yet they cannot explain how redox adaptation occurs or fails. Over the past decade, the discovery of regulated cell-death pathways (ferroptosis, cuproptosis) and emerging metabolic signals has revealed a new generation of adaptive redox mediators—including itaconate, nitro-fatty acids, reactive sulfur species and succinate—that act as electrophilic or persulfidating regulators rather than passive by-products of oxidation. This review integrates mechanistic, biochemical and clinical evidence to define how these mediators remodel the nuclear factor erythroid 2-related factor 2/Kelch-like ECH-associated protein 1, nuclear factor kappa-light-chain-enhancer of activated B cells, and hypoxia-inducible factor 1-alpha axes, coordinate lipid–metal–sulfur cross-talk, and shape vulnerability or resistance to ferroptosis and cuproptosis. By combining deep molecular research with translational perspectives, we propose a unifying framework for predictive redox medicine based on composite biomarker panels and AI-assisted phenotyping. Understanding and quantifying these next-generation mediators will open new avenues for precision nutrition, drug development, and disease prevention—transforming oxidative-stress biology from a descriptive field into an actionable platform for human health. Full article

Background/Objectives: Drug repurposing offers a time- and cost-efficient strategy for accelerating the development of anticancer therapies by leveraging the established safety profiles of existing pharmaceuticals. This study aimed to investigate the anticancer potential of three tetracycline analogues chemically modified tetracycline-3 (COL-3), doxycycline (DOX), and minocycline (MIN) in leukemia models, with a particular focus on their cytotoxic effects and modulation of the JAK2/STAT3 signaling pathway. Methods: Cytotoxicity was evaluated in K562, KG-1a and Jurkat cell lines using luminescence-based viability assays, whereas the mechanisms of cell death were analyzed by Annexin-V/7-AAD staining and Western blotting. Results: COL-3 displayed the highest cytotoxic potency across all cell lines, with Jurkat cells showing the greatest overall sensitivity. Flow cytometry revealed that tetracycline analogues primarily induced apoptosis, although the molecular mechanisms differed between cell lines. In K562 and KG-1a cells, apoptosis occurred largely through JAK2/STAT3-independent mechanisms, involving differential regulation of BCL-2 family proteins: COL-3 reduced BCL-2 expression, whereas DOX and MIN increased BAX expression. In contrast, Jurkat cell apoptosis correlated with suppression of phosphorylated JAK2 and STAT3 and downregulation of BCL-2, implicating a JAK2/STAT3-dependent mechanism. Conclusions: Taken together, these findings demonstrate that tetracycline analogues exert cell line-specific anticancer activities through distinct molecular pathways. Among them, COL-3 emerges as the most potent analogue and acts through both JAK/STAT-dependent and -independent mechanisms. This work supports further investigation of COL-3 as a candidate for drug repurposing strategies in hematological malignancies. Full article

Background/Objectives: Natural killer (NK) cells are key innate lymphoid cells that restrict tumour progression by secreting proinflammatory cytokines and directly lysing malignant cells, with their activity tightly regulated by a balance of activating and inhibitory surface receptors. The natural cytotoxicity receptor NKp44 is induced on NK cells following stimulation with IL-2 or IL-15 and recognizes platelet-derived growth factor D (PDGF-DD) as a ligand. Mechanistic interpretation of NKp44 signalling upon PDGF-DD engagement is confounded by the existence of three distinct NKp44 isoforms (NKp44-1, -2, and -3), each capable of initiating divergent intracellular signalling cascades. Unlike NKp44-2 and -3, NKp44-1 encodes a cytoplasmic tyrosine residue (Y238) that conforms to a putative immunoreceptor tyrosine-based inhibition motif (ITIM) and has been reported to suppress NK cell effector functions in some contexts. However, it remains unclear whether the NKp44 isoforms are translated and expressed in NK cells, and formal evidence defining NKp44-1 signalling in response to engagement by PDGF-DD is lacking. Methods: In this study, we used C-terminal targeting monoclonal antibodies (mAbs) and a NFAT-GFP reporter system to define the expression and signalling properties of NKp44 isoforms in response to PDGF-DD. Results: We demonstrate protein expression of NKp44-1 and NKp44-2-/3 receptors in IL-2 expanded NK cells. We further show that NKp44-1 transduces activating rather than inhibitory signals when engaged by PDGF-DD ligand, albeit weaker than NKp44-3. Intriguingly, we find that Y238 is dispensable for NKp44-1 activating signalling and instead functions as a YXXΦ internalisation motif. Conclusions: Collectively, these findings provide the first evidence that the NKp44-1 and NKp44-2/3 isoforms are expressed in NK cells and establish that PDGF-DD activates signalling through NKp44-1 independently of Y238. This work lays the foundations for future studies investigating how PDGF-DD sensing by the different NKp44 isoforms shapes immune functions in different physiological and pathological contexts. Full article

The human pineal gland (PG) undergoes structural and cellular changes during the aging process, yet the underlying patterns and mechanisms remain insufficiently understood. In this study, we analyzed the lobular architecture and astrocytic network of the PG and identified two distinct pathways associated with normal aging. The first is characterized by an increase in astrocyte number within the pineal parenchyma, suggesting a compensatory role in supporting pinealocyte function. The second pathway involves disruption of the lobular structure, leading to a decline in the functional integrity of the gland. While pathological conditions such as neurodegenerative and psychiatric disorders may accelerate pineal degeneration and reduce melatonin production, our results suggest that normal aging is the principal factor driving this involutional process. These findings contribute to a deeper understanding of the morphological aging pathways of the pineal gland and their potential functional implications. Full article

Objectives: The study aimed to examine the association between a dietary index for gut microbiota (DI-GM) and the risk of incident colorectal cancer (CRC). Clarifying the role of diet-induced alterations in the composition and function of gut microbiota on the development of CRC can contribute to prevention efforts. Methods: Participants from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening trial enrolled in the intervention arm and who completed baseline assessments were included in the analysis (n = 55,685). The DI-GM is a literature-derived index used to score diet quality in terms of maintaining healthy gut microbiota. A time-dependent Cox model stratified by follow-up years (<5 and ≥5 person-years) was used to evaluate the relationships between the dietary patterns and risk of incident CRC. Results: A total of 735 incident CRC were identified over 650,470 person-years of follow-up. During < 5 years of follow-up, those with higher diet quality (DI-GM scores above 67th percentile) had an 18% lower risk of incident CRC (HR_adjusted = 0.82, 95% CI: 0.63, 1.07) compared with those with lower diet quality (DI-GM scores below the 67th percentile), though effect estimates were imprecise. During ≥ 5 years of follow-up, there was no association between incident CRC and DI-GM (HR_adjusted = 1.01, 95% CI: 0.80, 1.26). Conclusions: Diet quality measured using the DI-GM was associated with the risk of CRC in the first five years of follow-up in a large prospective cohort study. A diet that enhances the composition and function of gut microbiota may contribute to reduction in CRC risk. Full article

Treatment-associated regression of tumors outside the irradiated field has occasionally been reported, but the underlying mechanisms remain unclear, particularly in the context of central nervous system (CNS)–directed therapy. Glioblastoma (GBM) is commonly treated with radiotherapy and temozolomide, both of which may influence tumor biology and the systemic environment. We report a patient with synchronous primary GBM and early-stage lung adenocarcinoma who underwent craniotomy followed by intensity-modulated radiotherapy with concurrent temozolomide for GBM. During GBM-directed chemoradiotherapy, the untreated pulmonary lesion demonstrated progressive regression without any lung-specific therapy, temporally coinciding with CNS-targeted treatment. Although comprehensive immunophenotyping was not feasible, longitudinal changes in the proportion of peripheral blood lymphocytes were observed during therapy. These findings represent a clinical observation characterized by a temporal association between CNS-directed treatment and regression of a distant, non-irradiated tumor. However, the underlying mechanism remains uncertain, and a contribution from systemic temozolomide exposure cannot be excluded. While treatment-related systemic effects may be considered, no specific causal mechanism can be established based on this single case. This case highlights an unusual clinical observation that may warrant further investigation. Further studies are needed to clarify the relationship between CNS-directed therapies and systemic tumor behavior. Full article

Yeast models are widely used to study molecular chaperones from diverse organisms, including plants, because of their well-characterized genetics and the conservation of the protein-folding machinery among eukaryotes. Cross-species complementation studies in yeast have yielded valuable insights into conserved biochemical activity and molecular functions that manage protein folding, assembly, and repair during stress. This study evaluated the functional capacity of three potato StBiP isoforms (StBiP1, StBiP2, and StBiP3) to complement the kar2 deletion (kar2Δ) strain under a range of environmental and ER stress conditions. All three StBiPs partially restored colony growth under normal conditions, demonstrating that they are functional orthologs of yeast KAR2 and can support core ER housekeeping functions. Under severe stress, however, the isoforms diverged: StBiP3 most effectively complemented the kar2Δ strain during heat- and chemically induced ER stress, whereas StBiP1 and StBiP2 provided weaker protection. Unfolded protein response (UPR) activation, monitored via HAC1 mRNA splicing, further highlighted isoform-specific differences in how the StBiPs support IRE1-HAC1 signaling under ER stress and oxidative stress. A conserved cysteine in the nucleotide-binding domain, previously implicated in Kar2 redox control, was also critical for StBiP3-mediated protection in yeast, although the same mutation led to different consequences in plant tissues. Together, these findings provide evidence of subfunctionalization among potato BiP isoforms, with StBiP3 emerging as a stress-specialized chaperone that is a promising target for improving ER stress resilience in solanaceous crops. Full article