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Systemic immunometabolic profiling classifies cisplatin sensitivity states using interpretable machine learning
No full textCisplatin resistance limits the effectiveness of platinum-based chemotherapy for lung adenocarcinoma, yet practical systemic diagnostics for cisplatin sensitivity are lacking. We developed IMPACT (ImmunoMetabolic Profiling Analysis and Classification Tool), an interpretable machine learning pipeline that selects the best performing model and reduces it to a minimal, mechanistically informative feature set via recursive feature elimination. In a syngeneic orthotopic model, we quantified 25 serum amino acids and 16 immune cell populations across bone marrow, spleen, lung, and mediastinal lymph nodes to capture systemic immunometabolic states. IMPACT classified cisplatin-sensitive versus cisplatin-resistant tumors with high accuracy (AUC = 0.950), driven primarily by bone marrow MDSCs and serum glutamine. Using the same framework, we also classified Cancer (CS+CR) versus No Cancer controls with high accuracy (AUC = 0.955), with lung MDSCs and phosphoserine among the top features.
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•Interpretable machine learning reveal coordinated metabolic and immune interactions•Systemic immunometabolic profiling classifies cisplatin sensitive vs resistant tumors•Systemic immunometabolic profiling classifies cancer from noncancer state
Isolation and Characterization of Marrow-Isolated Adult Multilineage Inducible (MIAMI) Cell-Derived Extracellular Vesicles Demonstrate Multifunctional Therapeutic Potential in Tissue Regeneration and Anti-Inflammatory Immunomodulation
No full textMarrow-isolated adult multilineage inducible (MIAMI) cells are a subpopulation of mesenchymal stem/stromal cells (MSC) with enhanced self-renewal, multilineage plasticity, and anti-inflammatory properties, suggesting that their extracellular vesicles (MIA-EVs) may confer advantages over conventional MSC-EVs. MIAMI cells were transcriptionally profiled and expressed regenerative markers, including PDGFRB, CDX2, and TERT. We report the first successful isolation and characterization of MIA-EVs. EVs were isolated by ultracentrifugation and characterized by nanoparticle tracking analysis, transmission electron microscopy, flow cytometry, and surface markers. Cargo analysis identified growth factors (IGFBP-1, HGF, VEGF-D) and 19 highly expressed miRNA targeting survival, regenerative, and immune regulatory pathways. MIA-EVs were efficiently internalized, enhanced keratinocyte wound closure and suppressed osteosarcoma proliferation in vitro. Conditioned MIA-EVs reshaped pathway weighting without altering core regulatory identity, as a conserved 15-miRNA backbone persisted across naïve, irradiated, and cytokine-primed states. In contrast, a 9-miRNA core shared with MSC-EVs defined a basal mesenchymal framework, while MIA-EVs expanded regenerative, survival, and immune network connectivity. Similar to embryonic stem cell (ESC)-EVs, both MIA- and cytokine-primed EVs promoted M2 macrophage polarization, selectively upregulating IL1R2 and PPARG/STAT1, respectively. Meanwhile, MSC-EVs induced heterogeneous responses. These findings establish MIA-EVs as a conditioning-resistant, systems-regulated, cell-free platform with regenerative, immunomodulatory, and cytoprotective potential under hostile microenvironments
Bypass of blocking lesions by RNAPII reveals a novel stress induced by DNA damage
No full textPlatinum-based compounds and ultraviolet (UV) irradiation produce bulky DNA lesions that stall RNA polymerase II (RNAPII), activating transcription-coupled nucleotide excision repair (TC-NER), RNAPII degradation, and global transcriptional shutdown. However, the consequences of RNAPII bypassing such lesions remain unclear. We identified the acetyltransferase p300 as a key regulator of TC-NER-dependent RNAPII removal from damaged chromatin via a USP7-dependent mechanism. Loss of p300 permits RNAPII to bypass transcription-blocking lesions, sustaining transcription and full-length mRNA production despite DNA damage. This leads to continued translation, endoplasmic reticulum (ER) stress, and activation of the unfolded protein response (UPR), compromising cell viability. Notably, this stress response resensitizes tumors resistant to platinum-based chemotherapy. Our findings reveal a vulnerability in tumor cells that evade transcriptional shutdown and define a synthetic lethal interaction between p300 inhibition and platinum-induced DNA damage, offering a targeted strategy to overcome chemoresistance
Spatially resolved multiomics highlights differential immune responses in atopic eczema skin to blocking IL4Rα
No full textThe Automated Vestibular Rehabilitation System: Normative Data From a Machine Vision-Guided Platform
No full textObjective(s): Vestibular rehabilitation therapy (VRT) is an efficient treatment for dizziness and vertigo, but its accessibility remains limited. This study evaluates the feasibility and performance of a machine vision-based automated alternative-the Automated Vestibular Rehabilitation System (AVRS)-as a more accessible approach to delivering VRT.Methods: Forty age- and sex-matched adults without balance disorders or recent head injury completed one standard VRT exercise, X1, in seated and standing positions using the AVRS, which tracked real-time head and eye movements. Gain, the ratio of eye to head velocity near the neutral head position, was calculated using median values and interquartile ranges. Test-retest reliability (TRTR) was assessed in a subset of 20 participants using intraclass correlation coefficients (ICCs) with 95% confidence intervals.Results: All participants successfully completed the AVRS-guided vestibular exercises. The n = 20 person test-retest reliability subset returned after 27 +/- 9 days. Mean VOR gain approximated the expected physiologic norms (similar to-1.0) across sessions irrespective of frequency (Session 1: -0.98 +/- 0.04; Session 2: -0.99 +/- 0.03). Overall reliability between sessions was moderate (ICC (3, 1): 0.59 [95% CI: 0.37-0.75], p Conclusion: The AVRS demonstrated moderate reliability and accurate VOR gain measurement in healthy adults, supporting its potential as a scalable, accessible tool for VRT delivery, with normative data to guide therapeutic progression in clinical populations.Level of Evidence 4.</p
From concept to community of practice in anatomical ethics and professionalism: 5 years of the "Bioethics Unicorns" education initiative
No full textThe topics of ethics and professionalism in anatomy have only recently gained prominence within the discipline, reflecting trends in medical and health professions education and an increasing awareness of societal expectations around the use of the dead. Educators in anatomy have had limited access to specific resources and no established communities of practice to support their understanding and teaching of these subjects. This article traces the journey of three anatomy educators who addressed this gap by developing dedicated educational resources for use in anatomy teaching. The initiative began in 2020 with the creation of a suite of freely available resources designed to provide accessible, engaging content for educators. Next, the project expanded to include quarterly webinars to facilitate dialog and knowledge exchange, as well as in person sessions at anatomical conferences that have fostered professional networking and collaborations. Over time, what began as a resource-driven initiative evolved into a broader movement. By 2025, this journey has culminated in the establishment of an active community of practice and the adoption of the moniker "Bioethics Unicorns" that has come to represent the initiative. This article reflects on the stages of this journey, the development of the resources and community of practice, and provides advice for those wishing to develop educational initiatives for education in their own communities
Changes in the 6th edition of the World Health Organization classification of tumours of the digestive system
No full textThe 6th Edition of the WHO Classification of Digestive System Tumours represents a significant update to the 5th edition. It integrates pathological, new molecular, and clinical insights to refine the taxonomy of digestive system neoplasms. The revised classification continues to emphasise standardisation in terminology, coding, and diagnostic criteria to facilitate global consistency in diagnosis, treatment, epidemiological reporting and research. Structural reorganisation of book chapters describes epithelial tumours by anatomical site, while separating neuroendocrine, mesenchymal and haematolymphoid tumours into dedicated chapters that are aligned with other WHO tumour volumes. Genetic tumour syndromes are classified by mechanisms, pathways and genes, whereas metastatic disease is comprehensively covered under other tumours and metastases. Key structural and diagnostic refinements include consolidation of gastric dysplasia entities; separation of duodenal/ampullary from jejuno-ileal tumours; clearer categorisation of colorectal serrated polyps and novel carcinoma grading; introduction of small- and large-duct intrahepatic cholangiocarcinoma as separate entities, and redefinition of undifferentiated carcinoma to include 'carcinoma with mesenchymal differentiation'. Several new entities are introduced, including oesophageal epidermoid metaplasia, colorectal intramucosal adenocarcinoma, low-grade tubuloglandular adenocarcinoma and lymphoglandular complex-like adenocarcinoma, intraductal tubulopapillary and intraductal oncocytic papillary neoplasms of the bile ducts and sonic hedgehog hepatocellular adenoma. The concept of amphicrine-like carcinoma (ALC) is distinguished from MiNEN and broadens the understanding of tumours with dual neuroendocrine-non-neuroendocrine differentiation. Grading systems are simplified to two-tier classifications (low/high grade) across precursor lesions, with enhanced criteria for neuroendocrine tumour grading. Anal canal neoplasia terminology is harmonised with human papillomavirus (HPV) related Lower Anogenital Squamous Terminology (LAST) and mass-forming biliary and gallbladder cancer precursors share similar terminology. Finally, carcinoma of unknown primary (CUP) is included in a separate section for the first time, classified by molecular and immunophenotypic profiles to guide therapy. Overall, the 6th edition strengthens tumour diagnostic precision and molecular alignment across the digestive system
Characterization and propagation of partially coherent fields radiated by sources with univariable cross-spectral density
No full textA new class of partially coherent light sources, the sources with uni-variable cross-spectral density, has been recently introduced. Their cross-spectral density is obtained starting from any function of a single complex argument having non-negative Taylor coefficients. This allows the conception of a virtually infinite number of physically realizable partially coherent sources. Here, the main characteristics of sources of this class are investigated through examples, with particular reference to the irradiance and coherence properties across the source plane and upon propagation, both in the near and in the far field. Furthermore, since the coherent modes of such sources present optical vortices, parameters quantifying the vortex structure of the field across the source plane are also evaluated for the presented cases
Bimanual angle surgery: Gonioscopy-assisted canaloplasty and transluminal trabeculotomy using an illuminated microcatheter
No full textThis manuscript presents an innovative technique for performing an ab interno canaloplasty and transluminal trabeculotomy using the iTrackTM Advance (Nova Eye Medical), an advanced illuminated microcatheter specifically designed for ab interno canaloplasty. Unlike traditional methods, this procedure does not require forceps to advance the microcatheter; instead, it uses the slider system of the device for smooth, continuous movement of the catheter. The technique integrates viscodilation of Schlemm’s canal and the possibility of creating a trabeculotomy with a hands-free goniolens, allowing the surgeon to use both hands when needed, improving surgical efficiency while manipulating the anterior chamber. This approach, which can be performed during cataract surgery or as a standalone procedure, offers a promising treatment for glaucoma patients
Tyrosine-Peptide Analog Modulates Extracellular Vesicles miRNAs Cargo from Mesenchymal Stem/Stromal and Cancer Cells to Drive Immunoregeneration and Tumor Suppression
No full textSoft tissue sarcoma remains challenging to treat due to its heterogeneity, stemness-associated survival programs, and resistance to conventional therapies. Extracellular vesicles (EVs) mediate tumor-stroma communication, yet how stemness-targeted therapies reshape EVs-associated miRNAs networks remains unclear. This study profiled EVs miRNAs cargo from infrapatellar fat pad mesenchymal stem/stromal cells (IFP-MSCs) and sarcoma cells (SCs) under basal conditions and following treatment with a synthetic tyrosine peptide analog (TPA). EVs were isolated, characterized, and subjected to miRNAs profiling and pathway enrichment analyses. TPA induced ≥2-fold regulation of 182 miRNAs, including 49 upregulated and 24 downregulated in IFP-MSC-EVs and 86 upregulated and 23 downregulated in SC-EVs. A conserved core of 149 miRNAs (67.1%) was shared across all EVs groups. Abundant species included miR-3960 and miR-21-5p, while TPA reduced tumor-associated miRNAs such as miR-1246 (~10-fold decrease in IFP-MSC-EVs). Pathway enrichment revealed consistent targeting of cancer, MAPK, Wnt, TGF-β, and immune signaling pathways, with modest increases in mapped gene coverage following TPA treatment. In silico analysis identified distinct EVs miRNA-gene interaction profiles, with VEGFA emerging as a recurrent predicted target. These results demonstrate that stemness-targeted modulation quantitatively reprograms EVs miRNA cargo in a cell-type-dependent manner, reshaping vesicle-mediated signaling networks in sarcoma