A recent Pathology digest,
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Study Type: Experimental preclinical study (murine in vivo, adoptive transfer and in vitro mechanistic work) with supporting human tissue/sample data.

Key Question: What role do cardiac fibroblasts play in immune-mediated doxorubicin cardiotoxicity?

Key Findings:

• Cardiac fibroblasts upregulate MHC-II at the onset of doxorubicin cardiotoxicity in both humans and mice; this depends on CD8+IFN-γ+ T cells, while doxorubicin-induced fibroblast CXCL9 drives T cell cardiotropism.
• Fibroblast-specific MHC-II deletion in mice reduced systolic dysfunction and cardiac fibrosis (effect sizes not given in the abstract).
• Fibroblast MHC-II was required for cardiac CD4+IFN-γ+ T cell infiltration and proliferation, which in turn supported CD8+ T cell responses and cytotoxicity.

Clinical Relevance: Identifies the fibroblast MHC-II/CXCL9 axis as a candidate biomarker and immunomodulatory target in anthracycline cardiotoxicity, relevant to cardio-oncology and to interpreting cardiac biopsy or immune-profiling findings in NHS practice.

Limitations: Mechanistic evidence is predominantly murine, and the abstract gives no sample sizes or quantitative effect data for the human component, so clinical applicability remains unproven.

Study Type: Preclinical experimental study (in vitro cell assays and orthotopic mouse models).

Key Question: Does inhibiting complement factor B (CFB) with iptacopan suppress pancreatic ductal adenocarcinoma (PDAC) growth and remodel the tumour immune microenvironment?

Key Findings:

• Iptacopan reduced proliferation of human and murine PDAC cells, enhanced gemcitabine cytotoxicity, and induced senescence (increased SA-β-Gal activity, p21 upregulation).
• In vivo, tumour growth fell alongside reduced intratumoral CFB and C5b-9 deposition; Foxp3+ Tregs and the CD8+/Foxp3+ subset decreased while CD8+ tumour-infiltrating lymphocytes increased.
• Adding anti-PD-1/anti-CTLA-4 enhanced effect; triple therapy with gemcitabine/nab-paclitaxel gave greatest tumour suppression. Effect sizes and statistics are not reported in the abstract.

Clinical Relevance: CFB immunohistochemistry and complement profiling could become relevant PDAC biomarkers, and iptacopan's existing licensed use in complement-mediated disease (e.g., PNH) may enable drug repurposing, though this is not yet clinically actionable.

Limitations: Findings are limited to cell lines and mouse models, with no human trial data on efficacy, safety or patient selection in PDAC.

Study Type: In vitro experimental study using primary mouse (E15 C57BL/6J) palatal epithelial cells; no human data.

Key Question: How does TGF-β3 regulate epithelial-mesenchymal transition (EMT) in palatal fusion, and what are the roles of SOX2/OCT4 and canonical versus non-canonical signalling?

Key Findings:

• TGF-β3 at 1-3 ng/mL induced EMT (reduced E-cadherin, increased fibronectin, lower TEER, fibroblast-like morphology) with unchanged phospho-Smad2/3 but upregulated p38 MAPK and Mmp13 (p<0.05), indicating predominantly Smad-independent signalling.
• TGF-β3 downregulated Sox2 and Oct4 (p<0.05); combined Sox2/Oct4 knockdown plus TGF-β3 produced the strongest EMT phenotype, suggesting both act as negative EMT regulators.
• Tgfb3 knockdown substantially attenuated EMT, but partial transition persisted, implying compensatory pathways.

Clinical Relevance: Offers mechanistic insight into cleft palate pathogenesis, which may inform future developmental pathology interpretation and candidate pathway research, though it has no direct diagnostic application.

Limitations: Mouse in vitro findings only, with no in vivo validation or human tissue correlation; abstract gives no effect sizes or sample sizes.

Study Type: Preclinical experimental study (murine and rat sciatic nerve injury models); no human data.

Key Question: Does TAK1 regulate peripheral nerve regeneration after injury, and through what mechanism?

Key Findings:

• TAK1 overexpression impaired nerve regeneration and functional recovery; pharmacological TAK1 inhibition (Takinib) improved both. The abstract gives no effect sizes or confidence intervals.
• TAK1, expressed mainly in Schwann cells and fibroblasts, phosphorylates PPP1R18 at serine 213, relieving its suppression of NF-κB and promoting nuclear p65 accumulation.
• Downstream chemokine induction recruits M1 macrophages, sustaining a proinflammatory microenvironment that impedes remyelination.

Clinical Relevance: Identifies the TAK1–PPP1R18–NF-κB axis as a candidate therapeutic target and potential tissue biomarker pathway in post-traumatic neuropathy, though it is not yet relevant to routine NHS diagnostic practice.

Limitations: Findings are confined to animal models, with no human tissue validation reported and no information on sample sizes, dosing, or long-term outcomes in the abstract.

Study Type: Narrative review (no systematic methodology or quantitative synthesis described in the abstract).

Key Question: How does gut microbiome dysbiosis contribute to MASLD progression and malignant transition to HCC, and can microbiome-targeted therapies modify this?

Key Findings:

• Dysbiosis is proposed to drive MASLD progression via intestinal barrier disruption, systemic inflammation, and altered hepatic metabolic and immune responses, mediated by microbial metabolites and host genetic factors.
• Therapeutic strategies reviewed include pro-/pre-/syn-/postbiotics, faecal microbiota transplantation, engineered bacteria, bacteriophage therapy, small molecule inhibitors, and microbiota-derived metabolites.
• No effect sizes or clinical outcome data are reported in the abstract.

Clinical Relevance: With MASLD affecting over one-third of adults globally and a growing driver of HCC, this offers a mechanistic framework relevant to NHS liver pathology and emerging biomarker and therapeutic research.

Limitations: As a narrative review, it provides no quantitative evidence, and most microbiome-targeted interventions appear to remain preclinical or early-stage.

Study Type: Preclinical experimental study (transgenic mouse model with in vitro work, spatial transcriptomics and human liver transcriptomic analysis).

Key Question: Does constitutive Wnt/β-catenin signalling alter fibrosis and hepatocyte reprogramming in cholestasis, and does it act via or independently of Yap signalling?

Key Findings:

• Transgenic mice expressing non-degradable β-catenin (S45D) showed less fibrosis but more inflammation than wild-type during prolonged cholestasis, with increased ductular reaction and hepatocyte reprogramming.
• Yap was not required for Wnt-mediated hepatocyte reprogramming in vitro. Reporter mice showed enhanced Wnt activation in both pericentral and periportal hepatocytes, with Yap activity unchanged between genotypes.
• Wnt/β-catenin and Yap target genes mapped to distinct cell compartments in human cholestatic liver transcriptomes, consistent with the murine data.

Clinical Relevance: The findings identify Wnt/β-catenin as a candidate antifibrotic, pro-regenerative pathway in cholestatic disease (e.g. PBC, PSC), which may inform future biomarker or immunohistochemical interpretation of biliary repair, though no direct diagnostic application exists yet.

Limitations: Evidence is predominantly from a constitutive-activation mouse model; the abstract gives no quantitative effect sizes or human sample details, and translation to patients remains unproven.

Study Type: Preclinical experimental study (in vitro exosome characterisation plus in vivo mouse model; streptozotocin-induced diabetic and normoglycaemic C57BL/6J mice).

Key Question: Do exosomes from mouse corneal epithelial cells influence wound healing, and does this differ between diabetic and normoglycaemic corneas?

Key Findings:

• Exosomes from wounded (healing) cultures, but not quiescent cultures, accelerated delayed epithelial closure in diabetic corneas, with little effect in normoglycaemic corneas. Vesicles were taken up by corneal epithelial cells and trigeminal sensory neurons.
• HTRA1, enriched in healing exosomes, was required for wound closure in normoglycaemic but not diabetic mice.
• STAT3 inhibition of healing exosomes partially reduced their pro-healing effect in diabetic corneas. Effect sizes were not reported in the abstract.

Clinical Relevance: Identifies exosomal cargo as a potential biomarker or therapeutic target in diabetic keratopathy, though this is far from clinical application.

Limitations: Findings derive from a mouse cell line and rodent model, with no human tissue validation, so translatability to human diabetic keratopathy is unproven.

Study Type: Retrospective cohort study (single-centre series; 1,449 radical prostatectomies with multifocal disease)

Key Question: In multifocal prostate cancer where the dominant tumour is excised with clear margins, does a positive margin in a secondary tumour independently predict biochemical recurrence (BCR)?

Key Findings:

• Secondary tumour M+ occurred in 74/1,449 cases (5.1%), mostly GG1–2; BCR occurred in 137 (9.4%), with a further 62 (4.3%) showing persistent PSA.
• On adjusted Cox analysis, secondary tumour M+ predicted BCR (HR 3.14, P=0.0002), alongside GG3 (HR 9.53), GG4 (HR 16.4), GG5 (HR 14.2), tumour volume (HR 1.16/unit) and SV+ (HR 3.03). GG2 and EPE were not significant.
• Authors conclude secondary tumour M+ carries less prognostic weight than dominant tumour features (grade, SV+, volume).

Clinical Relevance: Supports reporting margin status for each tumour focus in multifocal RP specimens, as secondary tumour M+ may warrant closer PSA surveillance despite a clear dominant tumour margin.

Limitations: Short median follow-up (~2 years), very few secondary M+ cases (n=74) and wide likelihood of unstable estimates; also, the abstract's statement that secondary M+ has "lesser effect" is not supported by a direct comparison with dominant tumour M+ (excluded by design).