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To assess the effects of waiting time for outpatient psychotherapeutic interventions on patient-reported outcomes in adolescents and adults with eating disorders. MEDLINE, Embase, APA PsycInfo, CENTRAL and BASE were searched on 12 August 2025. Quantitative studies of adolescents (≥ 10 years) and adults with eating disorders that examined waitlist conditions prior to outpatient psychotherapeutic interventions and measured eating disorder pathology with the Children's Eating Attitudes Test (chEAT) or Eating Disorder Examination-Questionnaire (EDE-Q) were eligible. Risk of bias was assessed using the RoB 2 and ROBINS-I tools. A within-group random-effects meta-analysis was performed assessing pre-post change scores of the EDE-Q Global Score (primary analysis) and EDE-Q subscales (secondary analyses). A full protocol has been pre-registered on PROSPERO (registration number: CRD420251090691). Nine waitlist-controlled studies (total n = 647, waitlisted n = 283) including adult participants with bulimia nervosa, binge-eating disorder and 'eating disorder not otherwise specified' met our eligibility criteria. Eight studies (waitlisted n = 273) were included in the meta-analysis. Participants entered the waiting period with high EDE-Q Global Scores, ranging from 3.08 to 4.65 across studies. The pooled pre-post effect estimate was Hedges' g = - 0.17 (95% CI - 0.30 to - 0.05), indicating a negligible reduction in eating disorder pathology. Certainty of evidence was rated as moderate, given the high risk of bias across studies. Based on our results, waiting in waitlist control groups represents a period during which substantial eating disorder pathology and associated distress persist without therapeutic intervention. Further research is needed to better understand the effects of waiting time for regular eating disorder treatment outside a study setting. Study participants on a waitlist to be treated for bulimia nervosa, binge-eating disorder, and ‘eating disorder not otherwise specified’ continued to report high levels of eating disorder symptoms while waiting about 10 weeks for psychotherapy. This means that individuals may experience considerable distress during a delay in starting treatment. However, being on a study waitlist is not the same as waiting for treatment in everyday healthcare. In a study, participants know when and what kind of treatment they will get, which might already help reduce symptoms before treatment even starts. We could not find studies that assessed the effects of waiting time in everyday healthcare.
BackgroundMidlife obesity is considered one of the top modifiable risk factors for dementia and Alzheimer's disease (AD). However, body mass index (BMI) on its own does not fully represent obesity-associated risks and it is crucial to disentangle the role of body adiposity and its localization.ObjectiveTo investigate the relationship of MRI-derived body adiposity metrics with AD-related pathology at midlife.MethodsNinety-seven cognitively normal midlife individuals underwent brain amyloid and tau PET, body MRI, and metabolic and cognitive assessments. Key measures included hepatic fat fraction, visceral (VAT) and subcutaneous adipose tissue (SAT) volumes, and thigh muscle and adiposity. The correlation between adiposity/metabolic measurements and amyloid/tau pathologies was investigated.ResultsThe average age of participants was 49.8 years, 65.3% were female and 53.6% had obesity. Amyloid PET burden in Centiloids correlated with VAT (rho = 0.36, p = 0.002), BMI (rho = 0.33, p = 0.002), SAT (rho = 0.33, p = 0.002), and insulin resistance (IR) (rho = 0.34, p = 0.003) in females and Whites, lower high-density lipoprotein (HDL) cholesterol (rho = -0.36, p = 0.002) irrespective of sex and race, and lower MMSE scores (rho = -0.57, p = 0.043) in only in African-Americans, after correction for age, sex, and education. There was no evidence that HDL nor IR mediated VAT-related amyloid. VAT/SAT ratio was significantly associated with mean cortical tau SUVR (β = 0.138, p = 0.030) after adjustment for age, sex, education, and amyloid.ConclusionsAmong fat depots in our study, visceral fat was more strongly correlated to amyloid pathology, and this association is present even independent from BMI. Also, higher visceral compared to subcutaneous fat is related to higher tau pathology.
Diabetic retinopathy (DR) and retinal aging, though arising from distinct causes, share converging mechanisms-including oxidative stress, chronic inflammation, mitochondrial dysfunction, and AGE accumulation-that compromise retinal integrity. These overlaps suggest common gene expression patterns, and highlight the contribution of disease-associated or accelerated aging processes to diabetes-induced retinal injury. We systematically retrieved DR- and aging-related human genes from public genetic databases, identified their overlap, and focused on those involved in key metabolic pathways (AGEs, oxidative stress, lipid metabolism, and autophagy). Genes were then cross-validated across multiple databases and filtered by ocular expression to ensure relevance to retinal pathology. Our findings show that although DR and retinal aging arise from distinct etiologies, they converge on four principal metabolic pathways-oxidative stress, AGE accumulation, lipid dysregulation, and impaired autophagy-that collectively drive similar vascular, neuronal, and inflammatory injury within the retina. Shared genes with high ocular expression reinforce the biological relevance of these pathways, while multi-pathway hub genes appear to function as central regulators that integrate redox imbalance, metabolic disruption, and proteostatic failure. These results provide a unified molecular perspective of retinal degeneration and support the potential development of therapeutic approaches designed to simultaneously target age- and diabetes-associated retinal pathology. This review suggests that DR and retinal aging, although initiated by distinct triggers, converge on shared metabolic pathways-oxidative stress, AGE accumulation, lipid dysregulation, and autophagy impairment-mediated by genes expressed in ocular tissues. Within these intersecting pathways, shared hub genes emerge as central control nodes that may amplify molecular dysfunction and represent potential therapeutic entry points. By mapping these molecular intersections, this study may provide a unified mechanistic perspective of retinal degeneration and support the development of dual-purpose strategies aimed at preventing or mitigating both DR and aging-related retinal decline. These findings highlight potential translational opportunities for targeting shared metabolic networks; however, they should be interpreted as hypothesis-generating and require further experimental and clinical validation to establish causal relationships and therapeutic relevance.
Neurodegenerative conditions signify an irreversible, progressive loss of neurons eventually resulting in a wide array of symptoms including cognitive decline, gradual loss of memory, compromised motor functions. Conventional therapies available principally attempt to either restore neurotransmitter levels, or activate its subordinate receptors; while underlying disease pathology of neurodegeneration being overlooked. This narrowed therapeutic approach ultimately results in irreversible, augmented neurodegeneration, leading to hastened disease progression, resulting in long-term complications, and impaired quality of life. This poses an imperative need for newer treatments to curb the progression of the disease. Neurotrophins; NGF and BDNF are proteins that are classically acknowledged during the development of vertebrate nervous system. Proneurotrophins and Mature neurotrophins activate their specific p75NTR and Trk receptors, which initiate intracellular neuronal survival signaling cascades that play an imperative role in maintaining survival of neurons, apoptosis, and synaptic plasticity. Such neuroprotective effects, native neurotrophins could mainly be a potent strategy in the treatment of neurodegenerative disorders. Due to their deprived drugability, neurotrophins failed to pass on further. Hence, small molecule neurotrophin mimetics that corresponds to its receptor domains might show promising results by increasing receptor-induced neuronal survival, differentiation, and initiation of downstream signalling pathways. Prospects that these small molecule mimetics possesses influential neurotrophic effects might as well lead to the application of such compounds that might be crucial to treat the underlying pathology of neurodegeneration that extends beyond the standard symptomatic treatments of neurodegenerative disorders.
One of the important regulators of cellular iron uptake is transferrin receptor 1 (TFRC), which is closely linked to ferroptosis, an iron-dependent form of regulated cell death caused by lipid peroxidation. TFRC and ferroptosis-related biomarkers (including soluble transferrin receptor, labile iron pools, 4-hydroxynonenal, malondialdehyde, glutathione status, GPX4 expression, and oxidized species of phospholipids) can be measured in tissue, blood, and single-cell systems and are beginning to emerge as potential biomarkers in laboratory medicine in oncology. This review considers their analytical and translational applications in human malignancies, focusing on clinical chemistry, diagnostic laboratory medicine, and precision oncology. We combined data showing a relationship between TFRC expression and ferroptosis-related signatures to classify diseases, explore reported associations with prognosis, treatment response, and survival. We also considered their possible uses in stratifying risks, therapies, pharmacodynamic aspects, and longitudinal disease assessment. Emphasis is placed on laboratory variables that influence implementation, such as the selection of matrix specimens, variation in preanalytical factors, assay standardization, platform-dependent cutoff values, calibrations, and cross-platform validation. The review also discusses how digital pathology, artificial intelligence, machine learning, and multimarker analytical frameworks may support biomarker quantification and interpretation after appropriate validation. Overall, a validated analytical workflow, standardized reporting, inter-laboratory harmonization, and prospective clinical validation are required to support the clinical translation of TFRC-ferroptosis biomarker panel tests. This review offers a laboratory medicine-centered framework for understanding the potential and current limitations of TFRC and ferroptosis-related biomarkers as analytical targets in precision oncology.
Parkinson's disease (PD) is featured by progressive neurodegeneration linked to iron-dependent ferroptosis, yet the functions of m6A RNA-binding proteins and deubiquitinating enzymes in this process remain poorly understood. This work investigates the functional interplay between the m6A reader YTHDF2 and deubiquitinase CYLD in PD-associated ferroptosis and delineates their downstream molecular mechanisms. PD models were established using MPTP-treated C57BL/6 mice and MPP+-exposed SH-SY5Y neuroblastoma cells. Behavioral assessments (open field, rotarod, and pole tests) and pain sensitivity assays (mechanical allodynia, thermal hyperalgesia) were performed. Molecular analyses included qRT-PCR, Western blot, RNA immunoprecipitation (RIP), co-immunoprecipitation (Co-IP), and ubiquitination assays. Ferroptosis markers (Fe2+, ROS, MDA, and GSH) and key regulators (ACSL4, GPX4, SLC7A11, and FTL) were quantified. Gain- and loss-of-function experiments for YTHDF2, CYLD, and NOX4 were conducted to validate regulatory relationships. MPTP/MPP+ treatment downregulated YTHDF2 and upregulated CYLD, exacerbating ferroptosis, as evidenced by mitochondrial damage, elevated Fe2+/ROS/MDA, reduced GSH, and altered level of ferroptosis-associated proteins (ACSL4 increased, GPX4/SLC7A11/FTL decreased). YTHDF2 overexpression suppressed ferroptosis, at least in part, by recognizing m6A-modified CYLD mRNA and promoting its degradation. Moreover, CYLD stabilized NOX4 by inhibiting its ubiquitination. Rescue experiments confirmed that CYLD depletion attenuated ferroptosis, an effect that was rescued by NOX4 overexpression. In MPTP-induced mice, YTHDF2 overexpression alleviated motor deficits (improved locomotion, rotarod performance), and reduced pain hypersensitivity, while mitigating ferroptosis markers and nigral mitochondrial pathology. Our study uncovered the YTHDF2/CYLD/NOX4 axis as a novel ferroptosis regulator in PD, revealing a dual epitranscriptomic-posttranslational therapeutic target for neuroprotection.
Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis rarely presents with severe inflammatory cardiac involvement. Valvuloaortic disease with high-grade atrioventricular block is particularly uncommon. A 53-year-old woman was referred with a presumptive diagnosis of non-ST-segment elevation myocardial infarction. Coronary angiography showed no obstructive epicardial coronary artery disease. Multimodality imaging demonstrated severe aortic regurgitation, inflammatory valvuloaortic thickening with cusp retraction, moderate pericardial effusion, nonischemic septal late gadolinium enhancement, and progressive high-grade atrioventricular block. Rheumatologic assessment supported myeloperoxidase-positive ANCA-associated vasculitis. She underwent mechanical aortic valve replacement and cardiac resynchronization therapy pacemaker implantation. Rituximab was subsequently initiated as immunosuppressive therapy. Histopathology showed active inflammatory valvulitis without detectable microorganisms. This case highlights a rare but clinically important inflammatory cardiac phenotype and underscores the value of multimodality imaging and multidisciplinary evaluation. ANCA-associated vasculitis may rarely present as multicompartment cardiac involvement and should be considered in severe inflammatory valvuloaortic disease with conduction abnormalities.
Ischemic cardiomyopathy (ICM), a leading cause of heart failure, is characterised by complex cellular heterogeneity and a dysregulated microenvironment. A systematic computational dissection of its molecular mechanisms and a coherent pipeline from discovery to potential therapeutics is currently lacking. We integrated single-cell RNA sequencing (scRNA-seq) data from ICM patients with four independent bulk transcriptomic cohorts. A cardiac cellular atlas was constructed, and candidate genes were filtered through differential expression analysis. Subsequently, a benchmark of 127 machine learning algorithm-feature selection combinations was performed to identify robust diagnostic hub genes. Their functions were validated at single-cell resolution via UCell scoring, pseudotime trajectory analysis, and virtual knockout perturbations using scTenifoldKnk. The immune infiltration landscape was assessed using CIBERSORT and MCP-counter. Finally, computational drug repositioning and molecular docking were employed to screen for potential compounds targeting the hub genes. Machine learning identified a core 5-gene signature (NPPA, HTRA1, LUM, ASPN, and OGN) demonstrating excellent diagnostic performance across independent datasets (AUC > 0.83). Single-cell analysis revealed that these genes were most abundantly expressed in fibroblasts and were consistently upregulated in ICM. Pseudotemporal trajectory analysis illustrated their dynamic expression patterns. Virtual knockout and functional enrichment indicated that four of these genes (ASPN, HTRA1, LUM, OGN) significantly perturbed pathways related to the regulation of inflammatory response. Immune profiling revealed increased infiltration of fibroblasts and plasma cells in ICM. Molecular docking identified the compound LDN-193189 as a potential lead molecule with high predicted binding affinity (binding energy < -9 kcal·mol-1) for ASPN, LUM, and OGN. Through multi-omics integration and computational biology, this study systematically delineates a fibroblast-centric molecular network involving key hub genes and an altered immune microenvironment in ICM and computationally proposes a potential therapeutic candidate. These findings provide a crucial computational foundation and experimental direction for understanding ICM pathology and developing novel therapeutic strategies.
Breast cancer is the most prevalent malignancy worldwide. Beyond genetic factors, dietary components like palmitic acid (PA) and sucrose modulate tumor progression and microenvironment dynamics. However, their combined mechanistic impacts on tumor-stroma crosstalk remain undefined. We investigated how dietary PA and sucrose affect breast cancer growth and the tumor microenvironment using a murine model. Mice received Control, high-PA (HPOD), high-sucrose (HCD), or combined (HPCD) diets. We assessed tumor growth, metabolic parameters, membrane fatty acids, histopathology, proliferative indices, and microenvironment markers (CD8, F4/80, α-SMA, HIF-1α, FASN). In vitro assays evaluated PA and fructose effects on LM3 cells and fibroblasts. HCD and HPCD markedly promoted tumor growth versus Control and HPOD. HPOD increased membrane saturated fatty acids, whereas HCD elevated ω-6 PUFAs. Both HCD and HPCD increased macrophage infiltration (F4/80 +), while HPCD specifically activated cancer-associated fibroblasts (α-SMA). HIF-1α protein increased across all experimental diets without mRNA alterations, suggesting post-transcriptional stabilization. FASN protein upregulation occurred in HCD and HPCD, while Fasn mRNA increased specifically in HCD. In vitro, combining PA and fructose enhanced LM3 cell proliferation and viability while reducing apoptosis. Additionally, this co-treatment specifically increased fibroblast viability. Diets rich in PA and sucrose drive breast cancer progression through distinct mechanisms. Carbohydrates transcriptionally activate FASN-mediated lipogenesis, whereas their combination with PA remodels the tumor microenvironment via CAF activation and HIF-1α post-transcriptional stabilization. These findings highlight specific dietary components as critical variables in cancer progression, offering potential implications for nutritional interventions and targeted therapies.
Congenital neuroblastoma is the most common malignant fetal tumor, yet placental metastases are exceptionally rare. We report a fetus with a right-sided suprarenal mass, hydrops, and marked placentomegaly that progressed to intrauterine demise at 26 weeks. Histopathology confirmed widespread metastatic neuroblastoma involving fetal organs and placental fetal vessels while sparing maternal intervillous spaces. This case is unique due to extensive involvement of placental fetal vessels with complete sparing of the maternal intervillous space. It highlights the importance of considering metastatic neuroblastoma when fetal abdominal masses coexist with hydrops and placentomegaly.
To evaluate whether an age < 55 years is independently associated with early urinary continence recovery after robot-assisted radical prostatectomy (RARP) in a large multi-institutional Japanese cohort. The cohort comprised 5349 patients aged < 75 years with clinically localized prostate cancer (cT1-2N0M0) who underwent RARP at Japanese tertiary care centers from August 2011 to April 2023. The primary analysis consisted of a 1:1 propensity score-matched comparison between men aged < 55 and 55-74 years. Covariates used for matching included American Society of Anesthesiologists physical status, clinical T stage, biopsy International Society of Urological Pathology grade group, prostate-specific antigen, prostate volume, nerve-sparing status, pelvic lymph node dissection, and surgical approach. Early urinary continence, biochemical recurrence-free survival, and surgical outcomes were evaluated using logistic regression and Cox proportional hazards models in the matched cohort. After propensity score matching, 158 well-balanced matched pairs were generated. A younger age (< 55 years) was significantly associated with higher odds of early continence at 1 month (odds ratio: 1.66, 95% confidence interval [CI]: 1.04-2.65) and 3 months (odds ratio: 2.22, 95% CI: 1.32-3.73). Five-year biochemical recurrence-free survival was similar between men aged < 55 and 55-74 years (86.2% vs. 84.8%). In an exploratory three-group analysis, continence recovery showed a graded age-related pattern. In this large Japanese cohort, an age < 55 years was independently associated with early urinary continence recovery after RARP without compromising oncological outcomes. These findings provide age-specific evidence to support preoperative counseling and surgical decision-making in younger patients.
Toxoplasma gondii (T. gondii) is a globally prevalent parasite that poses significant medical and veterinary challenges. Although current therapies such as pyrimethamine and sulfadiazine are effective, they often cause severe adverse effects, including myelosuppression, highlighting the need for safer and more effective alternatives. In this study, we evaluated the immunostimulatory and antiparasitic activities of three traditional herbal extracts, Stellaria dichotoma L. var. lanceolata Bge. (LDS), Stellaria aquaatic (SA) and Gypsophila oldhamiana (GO), in a murine model of T. gondii infection. To investigate mechanisms, bone marrow-derived dendritic cells (BMDCs) were treated in vitro. For the in vivo model, C57BL/6 mice received oral extracts (100 mg/kg/day) for 13 days, starting six days prior to intraperitoneal challenge with T. gondii (ME49). Parasite burden and splenic immune profiles were analyzed at 7 days post-infection to assess acute-phase containment. The findings of this study show that in vitro, GO extract promoted the maturation of BMDCs, significantly increasing CD11c+CD11blo mature dendritic cell subset and the expression of costimulatory molecules (CD40/CD80). Notably, GO simultaneously upregulated PD-L1 and PD-L2 on DCs, indicating a balanced Th1 response that prevents excessive immunopathology through checkpoint regulation while preserving strong effector functions. In vivo, GO-treated mice exhibited significantly lower splenic parasite loads than those in the control, LDS, or SA groups. GO significantly increased the frequency of IL-12-producing MHC II⁺ DCs and conventional DC type 1 (cDC1). This activation expanded IFN-γ -producing CD8⁺ and double-negative T cells, while NK cell responses were lower. Therefore, our findings show that GO extract limits acute T. gondii infection by modulating the DC-IL-12-CD8⁺ T cell axis. This study provides a modern immunological basis for the traditional use of Yinchaihu and highlights GO as a promising plant-based candidate for preventing and maintaining immunological balance during intracellular parasitic challenges.
To evaluate intravoxel incoherent motion diffusion-weighted imaging (IVIM-DWI) for preoperative diagnosis of perineural invasion (PNI) in rectal cancer (RC). A total of 148 patients with pathology-confirmed RC (PNI+, n = 72; PNI-, n = 76) were enrolled. Parameters from mono-exponential (ADC), bi-exponential (D, D*, f), and stretched-exponential (DDC, α) IVIM models were analyzed. Univariate and multivariate logistic regression analyses were used to construct diagnostic models. Diagnostic performance was evaluated using receiver operating characteristic (ROC) curve analysis. The DeLong test was used to compare the AUC of the models. Internal validation was employed to assess model performance. Net reclassification improvement (NRI) and integrated discrimination improvement (IDI), along with calibration metrics and decision curve analysis, were used to further evaluate model performance. P-value < 0.05 was considered statistically significant. ADC, D, f, and DDC differed significantly between groups. Multivariate analysis identified ADC and D as independent PNI predictors. The D value yielded the highest AUC (0.84), while ADC showed the highest sensitivity (81.94%). A combined model (ADC + D) achieved an AUC of 0.85, sensitivity of 86.10%, specificity of 73.70%, and accuracy of 77.00%. The fivefold internal validation mean AUC was 0.84 ± 0.04. No significant AUC differences were found among parameters or models (DeLong test, P > 0.05). Further analyses revealed that the combined model provided significant improvements over the ADC model in individual risk reclassification (continuous NRI = 0.65, 95% CI 0.33-0.95), overall predictive accuracy (IDI = 0.07, 95% CI excluding 0), and calibration (Brier score: 0.16 vs. 0.17; MAE: 0.01 vs. 0.04; MSE: 2.3×10⁻⁴ vs. 1.91×10⁻³). Decision curve analysis demonstrated consistently higher net benefit for the combined model across threshold probabilities of 0-0.50. IVIM-DWI demonstrates potential value for the preoperative assessment of PNI status in rectal cancer and may facilitate individualized treatment planning.
Thin-slice MRI may improve appendix visualization in children with suspected appendicitis, but reducing slice thickness decreases signal-to-noise ratio (SNR) and can degrade image quality. Deep learning reconstruction (DLR) enables denoising of thin-slice images and may mitigate these limitations. To evaluate whether 2-mm T2-weighted magnetic resonance imaging (MRI) with DLR improves appendix visualization and diagnostic performance compared with conventional 4-mm MRI in pediatric appendicitis. In this prospective, Institutional Review Board-approved, single-center study (January 2022-June 2025), 82 pediatric patients (mean age 9.6 years; age range 5-20 years) undergoing MRI for suspected appendicitis were included. MRI protocols contained both standard 4-mm and thin-slice 2-mm single-shot T2-weighted images; DLR was applied to 2-mm images (2-mm+DLR). Three blinded radiologists independently assessed paired series for appendix visualization, confidence, appendicitis diagnosis, ancillary findings, and overall image quality. Objective SNR was measured in psoas muscle, bladder, and fat. Diagnostic performance was calculated against surgical or clinical reference standards using paired statistical tests. In the first 16 exploratory cases, quantitative analysis showed that the signal-to-noise ratio of 2-mm+DLR images was comparable to that of standard 4-mm images. Across the full cohort, pooled analysis showed improved appendix visualization with 2-mm+DLR compared with standard 4-mm MRI (88.2% [217/246] vs 83.3% [205/246], P=0.006). Overall diagnostic image quality was also higher with 2-mm+DLR (median 5 vs 4, P<0.001), while confidence in appendix visualization and appendicitis diagnosis was similar between techniques (both medians 4, P>0.1). Exploratory pooled diagnostic performance numerically favored 2-mm+DLR, with higher sensitivity (89% [78/87] vs 81% [71/87]) and accuracy (89% [218/246] vs 86% [210/246]), although paired comparisons did not reach statistical significance (Table 4). DLR-enhanced 2-mm MRI improves appendix visualization and overall diagnostic image quality in pediatric appendicitis without reducing reader confidence or specificity. Thin-slice DLR MRI supports improved depiction of the appendix and alternative abdominal pathology in children.
The rapid integration of generative artificial intelligence (AI) into scientific writing has ignited intense debate across biomedical publishing, with journals adopting divergent and often contradictory policies ranging from outright prohibition to conditional acceptance with disclosure. In this Perspective, we examine the ethical and practical implications of AI‑assisted authorship specifically as they relate to Head & Neck Pathology and Springer Nature publishing policies. We examine whether AI‑assisted writing truly represents an ethical threat to scientific integrity, or whether the current controversy reflects a misplaced focus on the mechanics of writing rather than on scientific substance. We argue that efforts to regulate AI use are fundamentally undermined by the inability to reliably detect AI‑generated text and by the growing convergence between human and machine writing styles. More importantly, we contend that authorship should remain grounded in intellectual contribution, intent, and responsibility for scientific claims and not in the tools used to draft prose. By contextualizing generative AI as a natural extension of long‑accepted assistive technologies, we highlight the ethical risks of over‑enforcement, including false accusations and barriers to dissemination of valid science. Ultimately, we call for a recalibration of editorial priorities toward scientific rigor, accountability, and public benefit, rather than fixation on the provenance of text.
A consensus classification for idiopathic interstitial pneumonias was first published in 2002, providing terminology for clinicians, radiologists and pathologists as well as highlighting that a multidisciplinary approach was best clinical practice. This comprised seven histological patterns that had corresponding idiopathic multidisciplinary diagnoses. This classification was updated in 2013, with the addition of an eighth histological pattern. Since 2013, there have been further advances in our understanding of interstitial pneumonias, in particular relating to idiopathic versus secondary disease, advances in molecular pathology and recognition of progressive pulmonary fibrosis (PPF), which have led to a further update in 2025. This review highlights the changes relevant to pathologists reporting interstitial pneumonias. Major changes include (1) expansion beyond idiopathic interstitial pneumonias to also include secondary causes, (2) subclassification as interstitial (fibrotic vs non-fibrotic) and alveolar filling disorders, (3) expansion to include additional patterns (e.g. bronchiolocentric interstitial pneumonia), (4) improved terminology that better reflects histogenesis and (5) consideration of diagnostic confidence in biopsy evaluation. Pathologists also need to be aware of the advantages and limitations of cryobiopsy interpretation and the importance of reporting features that point towards a secondary cause rather than idiopathic disease. The 2025 classification provides a framework for a methodological approach to reporting biopsies in patients with interstitial pneumonia, which should be used prospectively for both diagnosis and research.
Background With the widespread availability of whole-slide imaging, many studies have utilized digital images of hematoxylin and eosin (H&E)-stained breast cancer tissues and applied convolutional neural networks (CNNs) for pathological diagnosis. However, CNN-based diagnosis is largely a black box and may be limited in quantitative morphological research. In this study, we developed a simple algorithm for morphometric analysis of three nuclear atypia features on H&E-stained whole-slide images to predict nuclear grade, hormone receptor status, and Ki-67 levels in breast cancer.Materials and Methods Using 43,183 H&E-stained nuclear images larger than 20 µm2 from 131 invasive ductal breast carcinomas, we calculated the following features of nuclear atypia using a computer vision algorithm: anisonucleosis (variation in nuclear size), inhomogeneous chromatin density, and the average size of prominent nucleoli. Anisonucleosis was quantified as the percentage of nuclei larger than 47 μm². Inhomogeneous chromatin was defined as the percentage of blue-saturated structures with 0.92-fold luminance or less than the average nuclear luminance. Prominent nucleoli were identified based on blue-saturated structures with 0.87-fold luminance or less, circularity greater than 0.65, and size greater than 1.15 μm². Using these values of nuclear atypia features, the thresholds that were the most associated with grade and biomarkers were calculated using receiver operating characteristic curves by Youden index.Results The morphometric algorithm using these thresholds predicted nuclear grade (grade 1 and 3), Ki-67 index ≧ 20%, and hormone receptor negative status with sensitivities of 52.1 to 100% and specificities from 34.3 to 85.3%. Two multivariable logistic regression models combining these three thresholds predicted nuclear grade, Ki-67, and hormone receptor negative with much better accuracy, sensitivities ranging from 57.1 to 91.3%, specificities from 50.9 to 82.2%, and area under curve of 0.70-0.82. The algorithm was applied to an independent set of 42 tumors.Conclusion The present morphological algorithm of nuclear atypia might provide new insights into the computational grading of invasive breast cancer.
Nasopharyngeal carcinoma (NPC) remains a therapeutically challenging malignancy due to its late diagnosis and limited treatment efficacy. Although metabolic reprogramming is a hallmark of cancer, the ubiquitin-mediated mechanisms underlying NPC progression are incompletely understood. Here, we demonstrate that tripartite motif-containing protein 47 (TRIM47) is significantly upregulated in NPC tissues and drives tumor aggressiveness. Through integrated in vitro and in vivo approaches, we found that TRIM47 promotes proliferation, migration, epithelial-mesenchymal transition (EMT), and tumor growth. Mechanistically, TRIM47 directly interacts with succinate dehydrogenase subunit B (SDHB)-a key component of mitochondrial complex II-via its B30.2/SPRY domain and catalyzes K48-linked polyubiquitination, leading to SDHB proteasomal degradation. This degradation induces metabolic reprogramming characterized by enhanced aerobic glycolysis, as evidenced by increased glucose consumption and lactate production. Critically, the oncogenic effects of TRIM47 were reversed by SDHB reconstitution. Moreover, supplementation with succinate, the enzymatic product of SDH, counteracted the tumor-suppressive effects of TRIM47 knockdown. Furthermore, exploiting the metabolic vulnerability induced by TRIM47, ascorbate treatment effectively suppressed TRIM47-driven tumor growth. Our results identify TRIM47 as a novel E3 ligase responsible for SDHB ubiquitination and degradation, thereby promoting Warburg-like metabolism and NPC progression. These findings unveil the TRIM47-SDHB axis as a promising therapeutic target and support metabolic intervention with ascorbate as a potential precision strategy for NPC treatment.
Proteins function not only through intramolecular folding and intermolecular complex formation but also through phase transitions driven by intermolecular interactions. Such phases, including liquid-like condensates, amorphous aggregates (AAs), and amyloid fibrils, are linked to distinct biological functions and pathologies. Although the transition from liquid-like condensates to amyloids has been extensively studied, the kinetic relationships between amyloids and other metastable solid states under cell-sized confinement remain unclear, which may hinder the establishment of effective therapeutic strategies. This knowledge gap arises because bulk-scale experiments inevitably lead to the conversion of metastable phases into the most stable phase. We developed a droplet-based microfluidic system that quantifies amyloid nucleation and metastable AA formation. Using the yeast prion protein Sup35, we found that condensates convert into both amyloids and AAs and that AA formation imposes a kinetic barrier that suppresses amyloid formation in a size-dependent manner at the micrometer scale, highlighting the importance of size effects in condensate-to-amyloid transitions. Furthermore, we demonstrated that the well-known amyloid inhibitor (-)-epigallocatechin-3-gallate paradoxically promoted amyloid formation at low concentrations by modulating the AA and amyloid nucleation kinetics. This phenomenon cannot, in principle, be observed in bulk-scale experiments and became apparent only under micrometer-scale confinement in the present system. These findings provide fundamental insights into protein phase transitions in cellular environments and may guide the development of novel therapeutic strategies targeting the metastable aggregates of amyloidogenic proteins.
Benign metastasizing leiomyoma is a rare entity characterized by the metastasis of histologically benign smooth muscle tumors that originate from uterine leiomyomas. Patients are typically women with a history of uterine leiomyomas for which they have undergone operative treatment. Benign metastasizing leiomyoma most frequently involves the lungs but has been described in other locations. Osseous involvement is rare, with less than 20 cases reported in literature, the majority occurring in the spine. The current case is that of a 67-year-old female with a history of breast carcinoma with multiple lytic osseous lesions involving the pelvis and scapula, initially suspected to represent metastatic disease. Following multi-modality imaging workup including radiographs, CT, MRI, and PET/CT, biopsy revealed benign metastasizing leiomyoma. This case illustrates the multimodality imaging appearance of this rare entity. Radiographs and CT typically show well-defined lytic lesion(s) without aggressive periosteal reaction. On MRI, lesions are often T1 and T2 hypointense, with diffuse enhancement following the administration of contrast. Lesions typically display no or mild FDG uptake on PET/CT, however, varying levels of FDG uptake have been reported in literature. Benign metastasizing leiomyoma with osseous involvement is a rare but clinically significant entity that requires a high index of suspicion in women with a history of uterine leiomyomas and new bone lesions. Radiologists should be aware of this entity so that they may include benign metastasizing leiomyoma in the differential diagnosis when appropriate.