Telomere biology disorder presenting acutely with pulmonary fibrosis and hepatopulmonary syndrome in a young adult male.

A 33-year-old man presented with acute dyspnoea and profound hypoxaemia, and had clubbing, greying of hair, orthodeoxia and fine inspiratory crackles. CT chest showed established pulmonary fibrosis in a usual interstitial pneumonia pattern. Additional investigations revealed a small patent foramen ovale, pancytopenia, and oesophageal varices and portal hypertensive gastropathy from liver cirrhosis. Telomere length testing demonstrated short telomeres (<1st percentile), confirming the diagnosis of a telomere biology disorder. An interstitial lung disease gene panel identified a pathogenic variant in TERT (c.1700C>T, p.(Thr567Met)) and a variant of uncertain significance in PARN (c.1159G>A, p.(Gly387Arg)). Combined lung and liver transplantation was deemed not suitable due to frailty and severe hepatopulmonary syndrome, and he died 56 days after presentation. Early recognition of the short telomere syndrome is important, and its multi-organ involvement poses challenges to management. Genetic screening may be important in younger patients with pulmonary fibrosis or in unexplained liver cirrhosis.

Estimating Effects of Sea Level Rise on Benthic Biodiversity and Ecosystem Functioning in a Large Meso-Tidal Coastal Lagoon.

Estuaries are among the world's most productive ecosystems, but due to their geographic location, they are at the forefront of anthropogenic pressures. Sea level rise (SLR) is one major consequence of climate change that poses a threat to estuaries with extensive intertidal habitats. The ecological implications of intertidal habitat loss have been largely overlooked despite their likely significance. We aimed to address this knowledge gap by investigating how benthic macroinvertebrate communities and their contributions to ecosystem function are likely to respond to SLR. Based on a spatially extensive dataset (119 sites) from a large coastal lagoon, depth, sediment chlorophyll concentrations, mud content, and average current speed were identified as the main drivers of community compositional turnover. Shifts in benthic community structure and associated functional implications were then evaluated using depth as a proxy for SLR. Three main macrofaunal groups representing intertidal, shallow subtidal, and deep subtidal habitats were identified. Functional trait analysis indicated low functional redundancy for a key intertidal suspension-feeding bivalve (Austrovenus stutchburyi) and the lack of a shallow subtidal functional replacement should intertidal habitats become inundated. These findings strongly suggest SLR and the associated environmental changes will alter estuarine macroinvertebrate communities, with implications for future ecosystem function and resilience.

The spleen as an organ at risk in paediatric radiotherapy: A SIOP-Europe Radiation Oncology Working Group report.

BACKGROUND: Radiation may cause long-term splenic dysfunction, risking potentially fatal late sepsis. We aimed to review this complication's magnitude in paediatric radiotherapy and gauge the level of awareness of the spleen as an organ at risk. METHODS: Clinical trial protocols and radiotherapy guidelines, patient/parent information sheets, and professional guidance documents were reviewed to assess the perceived risk of radiotherapy-related splenic dysfunction. Paediatric oncologists and paediatric radiation oncologists across Europe were surveyed to estimate the level of understanding of this risk and to ascertain current practice. Spleen doses received in practice were examined. A systematic review of relevant publications was undertaken. RESULTS: The risk is not mentioned in most clinical trials, patient information leaflets, or professional guidance documents. When mentioned, a threshold dose of 40 Gy is cited. The survey showed only limited awareness. More than half of patients assessed received spleen doses in excess of 10 Gy. The systematic review identified one paper reporting a relative mortality risk of 5.5 with spleen doses in the 10-20 Gy range. CONCLUSIONS: The risk of mortality from overwhelming infection is poorly recognised. We therefore recommend routine delineation of the spleen. Protocols and guidelines should give a spleen dose objective as low as reasonably achievable, ideally mean <10 Gy without compromise to target volumes. Revised evidence-based guidelines and continuing professional development activities should inform oncologists. Patient/parent information should mention the risk and the dose received be communicated to colleagues. Antibiotic prophylaxis and/or (re)vaccination should be considered if the mean spleen dose is ≥10 Gy.

The PTTG1-binding factor (PBF/PTTG1IP) regulates p53 activity in thyroid cells.

The PTTG1-binding factor (PBF/PTTG1IP) has an emerging repertoire of roles, especially in thyroid biology, and functions as a protooncogene. High PBF expression is independently associated with poor prognosis and lower disease-specific survival in human thyroid cancer. However, the precise role of PBF in thyroid tumorigenesis is unclear. Here, we present extensive evidence demonstrating that PBF is a novel regulator of p53, a tumor suppressor protein with a key role in maintaining genetic stability, which is infrequently mutated in differentiated thyroid cancer. By coimmunoprecipitation and proximity-ligation assays, we show that PBF binds specifically to p53 in thyroid cells and significantly represses transactivation of responsive promoters. Further, we identify that PBF decreases p53 stability by enhancing ubiquitination, which appears dependent on the E3 ligase activity of Mdm2. Impaired p53 function was evident in a transgenic mouse model with thyroid-specific PBF overexpression (transgenic PBF mice), which had significantly increased genetic instability as indicated by fluorescent inter simple sequence repeat-PCR analysis. Consistent with this, approximately 40% of all DNA repair genes examined were repressed in transgenic PBF primary cultures, including genes with critical roles in maintaining genomic integrity such as Mgmt, Rad51, and Xrcc3. Our data also revealed that PBF induction resulted in up-regulation of the E2 enzyme Rad6 in murine thyrocytes and was associated with Rad6 expression in human thyroid tumors. Overall, this work provides novel insights into the role of the protooncogene PBF as a negative regulator of p53 function in thyroid tumorigenesis, in which PBF is generally overexpressed and p53 mutations are rare compared with other tumor types.