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Background: Many metastatic prostate cancer prognostics have been suggested, but few are validated. Nodal metastasis burden and baseline biochemical characteristics are overlooked in the currently accepted stratifications for metastatic hormone-sensitive prostate cancer (mHSPC). Prostate-specific membrane antigen positron emission tomography/computed tomography (PSMA PET/CT) is likely to increase the incidence of pelvic nodal and mHSPC undetected by conventional scans. However, there is no consensus on managing regional nodal metastasis (N1M0) and no separate guidelines for non-regional nodal (M1a) and low-volume bone (M1b) spread but collectively as a part of low-volume CHAARTED disease. Objectives: To assess the different prognostic factors for stage IV disease classified as CHAARTED low-volume on a real-world series of patients and to examine treatment preference for each of the disease subcategories. Methods and design: This retrospective cross-sectional study included patients diagnosed with HSPC at stage IV, with low-volume disease according to the CHAARTED criteria. Data were collected from the database of Portsmouth and St. Mary NHS Hospitals between February 2017 and August 2023. Patient characteristics were analysed, and prognostic factors were evaluated using Cox regression analysis. 5-year progression-free survival (PFS) was the primary outcome measure. Results: Data on 126 patients were analysed. Seven patients (6%) had N1M0, 28 (22%) M1a, and 91 (72%) M1b. 5-year PFS was 80.9% for M1a and 54.9% for M1b metastases, p = 0.3. High prostate-specific antigen (PSA) value (⩾25) was identified as an independent prognostic factor for PFS with HR = 2.80 (95% CI: 1.19–6.56), p = 0.0179. Variable treatment preference for each subclass reflects the uncertainty regarding the best regimen and the importance of consolidation prostate radiotherapy (cRT) in clinical practice. Conclusion: Early results of our data analysis underscore the significance of baseline PSA as an independent prognostic factor alongside anatomical tumour extent of spread in stage IV low-volume metastasis prostate cancer. There is no agreement on treatment for each subcategory, necessitating further real-world studies and clinical trials. Further follow-up would assess the prognostic benefit of cRT. [ABSTRACT FROM AUTHOR]

In situ hybridization studies of human skeletal muscle reveal the expression of fast myosin heavy chair (MHC) II a and IIx transcripts and the beta/slow MHC gene in these muscles. IIa MHC transcripts are expressed in primary in histochemical type IIa fibers while IIx MHC transcripts are found in histochemical type IIb fibers. The MHC transcripts present in these fibers are similar to the IIx MHC mRNA in the 3'-translated and untranslated region.

Objective: The molecular mechanisms that regulate the formation of the conduction system are poorly understood. We studied the developmental expression pattern and functional aspects of the T-box transcription factor Tbx3, a novel marker for the murine central conduction system (CCS). Methods: The patterns of expression of Tbx3, and of Cx40, Cx43, and Nppa, which are markers for atrial and ventricular chamber-type myocardium in the developing heart, were analyzed in mice by in situ hybridization and three-dimensional reconstruction analysis. The function of Tbx3 in regulating Nppa and Cx40 promoter activity was studied in vitro. Results: In the formed heart, Tbx3 is expressed in the sinoatrial node (SAN), atrioventricular node (AVN), bundle and proximal bundle branches (BBs), as well as the internodal regions and the atrioventricular region. Throughout cardiac development, Tbx3 is expressed in an uninterrupted myocardial domain that extends from the sinoatrial node to the atrioventricular region. This expression domain is present in the looping heart tube from E8.5 onwards. Expression of the chamber-type myocardial markers is specifically absent from the Tbx3 expression domain. Tbx3 is able to repress Nppa and Cx40 promoter activity and abolish the synergistic activation of the Nppa promoter by Tbx5 and Nkx2.5. Conclusion: We identified the T-box transcription factor Tbx3 as a novel and accurate marker for the central conduction system. Our analysis implicates a role for Tbx3 in repressing a chamber-specific program of gene expression in regions from which the components of the central conduction system are subsequently formed. [Copyright &y& Elsevier]

Reports on the cooperative action of TBX2 and NKX2.5 which inhibits atrial natriuretic factor (ANF) expression in the atrioventricular canal. Effect of action on cardiac chamber formation; Investigation of the regulatory mechanism underlying the selective expression; Provision of a potential mechanism for chamber restricted gene activity.

Aims: Increased Ankyrin Repeat Domain 1 (ANKRD1) levels linked to gain of function mutations have been associated to total anomalous pulmonary venous return and adult cardiomyopathy occurrence in humans. The link between increased ANKRD1 level and cardiac structural and functional disease is not understood. To get insight into this problem, we have generated a gain of function ANKRD1 mouse model by overexpressing ANKRD1 in the myocardium., Methods and Results: Ankrd1 is expressed non-homogeneously in the embryonic myocardium, with a dynamic nucleo-sarcomeric localization in developing cardiomyocytes. ANKRD1 transgenic mice present sinus venosus defect, which originates during development by impaired remodelling of early embryonic heart. Adult transgenic hearts develop diastolic dysfunction with preserved ejection fraction, which progressively evolves into heart failure, as shown histologically and haemodynamically. Transgenic cardiomyocyte structure, sarcomeric assembly, and stability are progressively impaired from embryonic to adult life. Postnatal transgenic myofibrils also present characteristic functional alterations: impaired compliance at neonatal stage and impaired lusitropism in adult hearts. Altogether, our combined analyses suggest that impaired embryonic remodelling and adult heart dysfunction in ANKRD1 transgenic mice present a common ground of initial cardiomyocyte defects, which are exacerbated postnatally. Molecular analysis showed transient activation of GATA4-Nkx2.5 transcription in early transgenic embryos and subsequent dynamic transcriptional modulation within titin gene., Conclusions: ANKRD1 is a fine mediator of cardiomyocyte response to haemodynamic load in the developing and adult heart. Increased ANKRD1 levels are sufficient to initiate an altered cellular phenotype, which is progressively exacerbated into a pathological organ response by the high ventricular workload during postnatal life. Our study defines for the first time a unifying picture for ANKRD1 role in heart development and disease and provides the first mechanistic link between ANKRD1 overexpression and cardiac disease onset., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)