Exposure to aristolochic acid (AA) is associated with human nephropathy and urothelial cancer. The tumour suppressor TP53 is a critical gene in carcinogenesis and frequently mutated in AA-induced urothelial tumours. We investigated the impact of p53 on AAI-induced nephrotoxicity and DNA damage in vivo by treating Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice with 3.5 mg/kg body weight (bw) AAI daily for 2 or 6 days. Renal histopathology showed a gradient of intensity in proximal tubular injury from Trp53(+/+) to Trp53(−/−) mice, especially after 6 days. The observed renal injury was supported by nuclear magnetic resonance (NMR)-based metabonomic measurements, where a consistent Trp53 genotype-dependent trend was observed for urinary metabolites that indicate aminoaciduria (i.e. alanine), lactic aciduria (i.e. lactate) and glycosuria (i.e. glucose). However, Trp53 genotype had no impact on AAI-DNA adduct levels, as measured by 32P-postlabelling, in either target (kidney and bladder) or non-target (liver) tissues, indicating that the underlying mechanisms of p53-related AAI-induced nephrotoxicity cannot be explained by differences in AAI genotoxicity. Performing gas chromatography–mass spectrometry (GC–MS) on kidney tissues showed metabolic pathways affected by AAI treatment, but again Trp53 status did not clearly impact on such metabolic profiles. We also cultured primary mouse embryonic fibroblasts (MEFs) derived from Trp53(+/+), Trp53(+/−) and Trp53(−/−) mice and exposed them to AAI in vitro (50 μM for up to 48 h). We found that Trp53 genotype impacted on the expression of NAD(P)H:quinone oxidoreductase (Nqo1), a key enzyme involved in AAI bioactivation. Nqo1 induction was highest in Trp53(+/+) MEFs and lowest in Trp53(−/−) MEFs; and it correlated with AAI-DNA adduct formation, with lowest adduct levels being observed in AAI-exposed Trp53(−/−) MEFs. Overall, our results clearly demonstrate that p53 status impacts on AAI-induced renal injury, but the underlying mechanism(s) involved remain to be further explored. Despite the impact of p53 on AAI bioactivation and DNA damage in vitro, such effects were not observed in vivo.

Lymphoepithelioma-like carcinoma of the endometrium is a very rare variant of endometrial carcinoma characterized by syncytial nests of pleomorphic epithelial cells and heavy infiltration of the stroma by lymphocytes (in particular CD8 cytotoxic T-lymphocytes) and plasma cells. Until now, only five cases have been characterized in this location. This report describes the clinicopathological and the molecular features of this unusual tumor. In particular, using the next generation sequencing (NGS) technique, we have demonstrated that this tumor could be associated with PIK3CA and p53 gene mutations. These data have not been reported to date and suggest that lymphoepithelioma-like carcinoma of the endometrium shares common molecular features with high grade endometrioid and serous-like endometrial carcinoma which are associated with poor outcome. Nevertheless, in endometrial lymphoepithelioma-like carcinoma, the alterations on cell cycle, apoptosis, and/or senescence secondary to p53 mutations could potentially be counterbalanced by the antitumoral response induced by CD8 cytotoxic T-lymphocytes numerous in these tumors.

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Background Acute kidney injury (AKI) requiring renal replacement therapy (RRT) in the ICU portends a poor prognosis. We aimed to better characterize predictors of survival and the mechanism of kidney failure in these patients. Methods Retrospective observational study using clinical and radiological electronic health records, analysed by univariable and multivariable binary logistic regression. Histopathological examination of post-mortem renal tissue was performed. Results Among 157 patients with AKI requiring RRT, higher serum creatinine at RRT initiation associated with increased ICU-survival (OR 0.33, 95%CI 0.17–0.62, p = 0.001) however, muscle mass (a marker of frailty) interacted with creatinine (p = 0.02) and superseded creatinine as a predictor of survival (OR 0.26 95%CI 0.08–0.82; p = 0.02). Achieving lower cumulative fluid balance (mls/kg) predicted ICU-survival (OR 1.01 95%CI 1.00 -1.01, p < 0.001), as supported by sensitivity analyses showing improved ICU-survival with the use of furosemide (OR 0.40, 95%CI 0.18–0.87, p = 0.02) and increasing net-ultrafiltration (OR 0.97, 95%CI 0.95–0.99, p = 0.02). A urine output of > 500mls/24 hours strongly predicted successful liberation from RRT (OR 0.125, 95%CI 0.05–0.35, p < 0.001). Post-mortem reports were available for 32 patients; clinically unrecognized renal findings were described in 6 patients, one of whom had interstitial nephritis. Experimental staining of renal tissue from patients with sepsis-associated AKI (S-AKI) showed glomerular loss of synaptopodin (p = 0.02). Conclusions Confounding of creatinine by muscle-mass undermines its use as a marker of AKI severity in clinical studies. Volume management and urine-output are key determinants of outcome. Loss of synaptopodin implicates glomerular injury in the pathogenesis of S-AKI.