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Angiogenic and immune predictors of neoadjuvant axitinib response in renal cell carcinoma with venous tumour thrombus
No full textVenous tumour thrombus (VTT), where the primary tumour invades the renal vein and inferior vena cava, affects 10-15% of renal cell carcinoma (RCC) patients. Curative surgery for VTT is high-risk, but neoadjuvant therapy may improve outcomes. The NAXIVA trial demonstrated a 35% VTT response rate after 8 weeks of neoadjuvant axitinib, a VEGFR-directed therapy. However, understanding non-response is critical for better treatment. Here we show that response to axitinib in this setting is characterised by a distinct and predictable set of features. We conduct a multiparametric investigation of samples collected during NAXIVA using digital pathology, flow cytometry, plasma cytokine profiling and RNA sequencing. Responders have higher baseline microvessel density and increased induction of VEGF-A and PlGF during treatment. A multi-modal machine learning model integrating features predict response with an AUC of 0.868, improving to 0.945 when using features from week 3. Key predictive features include plasma CCL17 and IL-12. These findings may guide future treatment strategies for VTT, improving the clinical management of this challenging scenario.CC BY 4.0 (Creative Commons Attribution
Congenital Titinopathy: Comprehensive Characterization of the Most Severe End of the Disease Spectrum
No full textCongenital titinopathy has recently emerged as one of the most common congenital muscle disorders. OBJECTIVE: To better understand the presentation and clinical needs of the under-characterized extreme end of the congenital titinopathy severity spectrum. METHODS: We comprehensively analyzed the clinical, imaging, pathology, autopsy, and genetic findings in 15 severely affected individuals from 11 families. RESULTS: Prenatal features included hypokinesia or akinesia and growth restriction. Six pregnancies were terminated. Nine infants were born at or near term with severe-to-profound weakness and required resuscitation. Seven died following withdrawal of life support. Two surviving children require ongoing respiratory support. Most cohort members had at least 1 disease-causing variant predicted to result in some near-normal-length titin expression. The exceptions, from 2 unrelated families, had homozygous truncating variants predicted to induce complete nonsense mediated decay. However, subsequent analyses suggested that the causative variant in each family had an additional previously unrecognized impact on splicing likely to result in some near-normal-length titin expression. This impact was confirmed by minigene assay for 1 variant. INTERPRETATION: This study confirms the clinical variability of congenital titinopathy. Severely affected individuals succumb prenatally/during infancy, whereas others survive into adulthood. It is likely that this variability is because of differences in the amount and/or length of expressed titin. If confirmed, analysis of titin expression could facilitate clinical prediction and increasing expression might be an effective treatment strategy. Our findings also further-support the hypothesis that some near-normal-length titin expression is essential to early prenatal survival. Sometimes expression of normal/near-normal-length titin is due to disease-causing variants having an additional impact on splicing. ANN NEUROL 2025;97:611-628.This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.RDUH staff can access the full-text of this article by clicking on the 'Additional Link' above and logging in with NHS OpenAthens if prompted
The role of molecular pathology in soft tissue tumor diagnosis: what the radiologist needs to know
No full textFor both general radiologists and those specializing in soft tissue sarcoma imaging, understanding the importance and basic concepts of molecular pathology is becoming increasingly relevant to current clinical practice. As molecular research identifies the most fundamental causes and markers of disease, diagnostic testing is increasingly focused on the cell nucleus and its genetic material. Identifying molecular abnormalities, such as mutations, deletions, and amplifications, has advanced our ability to diagnose genetic diseases, including a variety of cancers. Over the past two decades, molecular pathology has rapidly evolved, enhancing our understanding of sarcoma pathogenesis, diagnosis, and classification. This progress forms the foundation of the 2020 WHO classification of soft tissue and bone tumors. This article will highlight cases where molecular diagnostics are crucial for the definitive classification and diagnosis of select soft tissue tumors, with MRI correlation and key teaching points.All rights reserve
The 2025 British Society for Rheumatology guideline for the treatment of axial spondyloarthritis with biologic and targeted synthetic DMARDs
No full textCC BY‑NC‑ND 4.0 (open access
Impact of rapid genomic testing on clinical outcomes of acutely unwell children presenting with severe epilepsy
No full textAbout 30% of epilepsy patients remain unresponsive to standard antiseizure treatment. Increasing evidence suggests that genetic epilepsies may respond better to targeted management. In this study, we therefore evaluate the therapeutic benefits of rapid genetic testing in children with severe epilepsy. METHODS: the clinical data of patients with epilepsy referred for rapid whole-exome sequencing were systematically collected at two large paediatric/neurogenetic centres (Birmingham/Oxford) in the United Kingdom over 3 years (2019-2022), with follow-up at 12 months post-diagnosis. The demographics, diagnostic yield, management by gene function and seizure group (SZ-seizures only or SZ+ seizures with co-morbidities) were explored. RESULTS: among the 106 eligible patients, the age at testing ranged from 0 to 16 years with a median of 7 months. Underserved ethnic groups, e.g., British Asians and Black British, were well-represented. Thirty-nine genes affecting 49 patients were identified, giving an overall diagnostic yield of 46%, which was further enhanced to 51% (31/61) in the SZ+ group. Twenty percent of genes identified affect ion channels and patients were more likely to present early (<6 months old) and respond to a gene-directed treatment (p = 0.004483). Seizures secondary to metabolic disorders responded to bespoke therapy. A fifth (22/106) of tested patients and 45% (22/49) of those diagnosed had their management impacted. At the 12-month follow-up, 9/15 (60%) patients remained seizure-free following gene-targeted management. CONCLUSION: this study demonstrates high diagnostic yield and significant therapeutic benefit from rapid genetic testing in patients with epilepsy. The gene function categories were statistically significant predictors of management change.CC BY 4.0 (Creative Commons Attribution
Do patients with minimally displaced distal radial fractures need a plaster cast?
No full textTraditionally, patients with a fracture of the distal radius are treated in a cast if they do not require surgery. If the fracture requires manipulation, the cast is moulded to hold the reduction and maintain normal anatomical alignment during healing. However, is a cast necessary for patients whose fracture does not require manipulation? Removable splints are an alternative treatment option. Such splints have the advantage that they can be adjusted to improve fit around the wrist as swelling reduces, and can be removed and reapplied for the purpose of washing or, in some cases, exercise. However, evidence for their safety and effectiveness in the management of distal radius fractures is lacking. DRAFT3 is a multicentre randomized non-inferiority trial and economic analysis designed to determine the safety and effectiveness of removable splints as an alternative to casts in the treatment of distal radius fractures that do not require manipulation.Not hel
Interleukin-1β Stimulates Matrix Metalloproteinase 10 Secretion: A Possible Mechanism in Trophoblast-Dependent Spiral Artery Remodeling
No full textMaternal uterine spiral arteries (SpA) undergo significant structural changes in early pregnancy, resulting in increased blood flow to the developing fetus. Endothelial cells (EC) and vascular smooth muscle cells (VSMC) are lost from the SpA wall and are replaced by trophoblasts. We have previously shown that matrix metalloproteinase 10 (MMP-10) and Heparin binding-EGF like growth factor (HB-EGF) gene expression is increased in a 3D EC/VSMC co-culture system in response to trophoblast secreted factors. This study investigated trophoblast mediated MMP-10 and HB-EGF expression and determined if there was a relationship between the secretion of MMP-10 and the release of soluble HB-EGF (sHB-EGF) from EC. MMP-10 was widely expressed in first trimester decidual tissue including trophoblast, and EC, but not VSMC. MMP-10 expression was significantly lower in decidual tissue from pregnancies at increased risk of developing pre-eclampsia compared to low-risk pregnancies. In vitro, SGHEC-7 cells, a human EC line, but not SGHVMC-9, a human VSMC cell line, secreted MMP-10 in response to trophoblast conditioned medium (TCM). TCM contains several growth factors and cytokines, but only interleukin-1β (IL1β) significantly stimulated MMP-10 secretion by SGHEC-7 cells. Interleukin-1 receptor antagonist (IL-1Ra) significantly inhibited TCM-induced MMP-10 secretion. Interrogation of intracellular pathways established the involvement of MEK and JNK in TCM and IL-1β stimulated MMP-10 secretion. Although IL-1β also significantly increased sHB-EGF, inhibition of MMP-10 activity using a broad spectrum MMP inhibitor had no effect on sHB-EGF. Western blot analysis indicated that MMP-10 secreted by EC in response to IL-1β stimulation was the enzymatically inactive pro form.CC BY 4.0 (Creative Commons Attribution
An oligodendrocyte silencer element underlies the pathogenic impact of lamin B1 structural variants
No full textThe role of non-coding regulatory elements and how they might contribute to tissue type specificity of disease phenotypes is poorly understood. Autosomal Dominant Leukodystrophy (ADLD) is a fatal, adult-onset, neurological disorder that is characterized by extensive CNS demyelination. Most cases of ADLD are caused by tandem genomic duplications involving the lamin B1 gene (LMNB1) while a small subset are caused by genomic deletions upstream of the gene. Utilizing data from recently identified families that carry LMNB1 gene duplications but do not exhibit demyelination, ADLD patient tissues, CRISPR edited cell lines and mouse models, we have identified a silencer element that is lost in ADLD patients and that specifically targets expression to oligodendrocytes. This element consists of CTCF binding sites that mediate three-dimensional chromatin looping involving LMNB1 and the recruitment of the PRC2 transcriptional repressor complex. Loss of the silencer element in ADLD identifies a role for non-coding regulatory elements in tissue specificity and disease causation.Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
CIROZ is dispensable in ancestral vertebrates but essential for left-right patterning in humans
No full textFour genes-DAND5, PKD1L1, MMP21, and CIROP-form a genetic module that has specifically evolved in vertebrate species that harbor motile cilia in their left-right organizer (LRO). We find here that CIROZ (previously known as C1orf127) is also specifically expressed in the LRO of mice, frogs, and fish, where it encodes a protein with a signal peptide followed by 3 zona pellucida N domains, consistent with extracellular localization. We report 16 individuals from 10 families with bi-allelic CIROZ inactivation variants, which cause heterotaxy with congenital heart defects. While the knockout of Ciroz in mice also leads to situs anomalies, we unexpectedly find that its targeted inactivation in zebrafish and Xenopus does not lead to observable LR anomalies. Moreover, CIROZ is absent or obsolete in select animals with motile cilia at their LRO, including Carnivora, Atherinomorpha fish, or jawless vertebrates. In summary, this evo-devo study identifies CIROZ as an essential gene for breaking bilateral embryonic symmetry in humans and mice, whereas we witness its contemporary pseudogenization in discrete vertebrate species.Journal content freely available via Open Access. Some content may be unavailable due to publisher embargo. Click on the 'Additional link' above to access the full-text
