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Drug-induced liver injury (DILI) is a patient-specific, temporal, multifactorial pathophysiological process that cannot yet be recapitulated in a single in vitro model. Current preclinical testing regimes for the detection of human DILI thus remain inadequate. A systematic and concerted research effort is required to address the deficiencies in current models and to present a defined approach towards the development of new or adapted model systems for DILI prediction. This Perspective defines the current status of available models and the mechanistic understanding of DILI, and proposes our vision of a roadmap for the development of predictive preclinical models of human DILI.Current preclinical models poorly predict the potential of a new drug candidate to cause drug-induced liver injury (DILI) in humans. Here, Park and colleagues discuss current understanding of the mechanisms mediating DILI and, through an academic–industry collaboration, propose a roadmap for the development of predictive preclinical models of human DILI.

Assessing the potential of a new drug to cause drug-induced liver injury (DILI) is a challenge for the pharmaceutical industry. We therefore determined whether cell models currently used in safety assessment (HepG2, HepaRG, Upcyte and primary human hepatocytes in conjunction with basic but commonly used endpoints) are actually able to distinguish between novel chemical entities (NCEs) with respect to their potential to cause DILI. A panel of thirteen compounds (nine DILI implicated and four non-DILI implicated in man) were selected for our study, which was conducted, for the first time, across multiple laboratories. None of the cell models could distinguish faithfully between DILI and non-DILI compounds. Only when nominal in vitro concentrations were adjusted for in vivo exposure levels were primary human hepatocytes (PHH) found to be the most accurate cell model, closely followed by HepG2. From a practical perspective, this study revealed significant inter-laboratory variation in the response of PHH, HepG2 and Upcyte cells, but not HepaRG cells. This variation was also observed to be compound dependent. Interestingly, differences between donors (hepatocytes), clones (HepG2) and the effect of cryopreservation (HepaRG and hepatocytes) were less important than differences between the cell models per se. In summary, these results demonstrate that basic cell health endpoints will not predict hepatotoxic risk in simple hepatic cells in the absence of pharmacokinetic data and that a multicenter assessment of more sophisticated signals of molecular initiating events is required to determine whether these cells can be incorporated in early safety assessment.

Drug-induced liver injury (DILI) is a major cause of late-stage clinical drug attrition, market withdrawal, black-box warnings, and acute liver failure. Consequently, it has been an area of focus for toxicologists and clinicians for several decades. In spite of considerable efforts, limited improvements in DILI prediction have been made and efforts to improve existing preclinical models or develop new test systems remain a high priority. While prediction of intrinsic DILI has improved, identifying compounds with a risk for idiosyncratic DILI (iDILI) remains extremely challenging because of the lack of a clear mechanistic understanding and the multifactorial pathogenesis of idiosyncratic drug reactions. Well-defined clinical diagnostic criteria and risk factors are also missing. This paper summarizes key data interpretation challenges, practical considerations, model limitations, and the need for an integrated risk assessment. As demonstrated through selected initiatives to address other types of toxicities, opportunities exist however for improvement, especially through better concerted efforts at harmonization of current, emerging and novel in vitro systems or through the establishment of strategies for implementation of preclinical DILI models across the pharmaceutical industry. Perspectives on the incorporation of newer technologies and the value of precompetitive consortia to identify useful practices are also discussed.

Brain metastases occur in 30–50% of patients with metastatic HER2-positive breast cancer. In the case of diffuse brain metastases, treatment is based on whole brain radiotherapy (WBRT). Few systemic options are available. We aimed to investigate the combination of lapatinib plus capecitabine for the treatment of previously untreated brain metastases from HER2-positive breast cancer. In this single-arm phase 2, open-label, multicentre study, eligible patients had HER2-positive metastatic breast cancer with brain metastases not previously treated with WBRT, capecitabine, or lapatinib. Tretament was given in 21 day cycles: patients received lapatinib (1250 mg, orally) every day and capecitabine (2000 mg/m2, orally) from day 1 to day 14. The primary endpoint was the proportion of patients with an objective CNS response, defined as a 50% or greater volumetric reduction of CNS lesions in the absence of increased steroid use, progressive neurological symptoms, and progressive extra-CNS disease. All responses had to be confirmed 4 weeks after initial response. Efficacy analyses included all patients who received the study drugs and were assessable for efficacy criteria. This trial is registered with ClinicalTrials.gov, number NCT00967031. Between April 15, 2009, to Aug 2, 2010, we enrolled 45 patients, 44 (98%) of whom were assessable for efficacy, with a median follow-up of 21·2 months (range 2·2–27·6). 29 patients had an objective CNS response (65·9%, 95% CI 50·1–79·5); all were partial responses. Of all 45 treated patients, 22 (49%) had grade 3 or grade 4 treatment-related adverse events, of which the most common were diarrhoea in nine (20%) patients and hand-foot syndrome in nine (20%) patients. 14 (31%) patients had at least one severe adverse event; treatment was discontinued because of toxicity in four patients. No toxic deaths occurred. The combination of lapatinib and capecitabine is active as first-line treatment of brain metastases from HER2-positive breast cancer. A phase 3 trial is warranted. GlaxoSmithKline-France and UNICANCER.

Coral reefs are of major ecological and socio-economic interest. They are threatened by global warming and natural pressures such as solar ultraviolet radiation. While great efforts have been made to understand the physiological response of corals to these stresses, the signalling pathways involved in the immediate cellular response exhibited by corals remain largely unknown. Here, we demonstrate that c-Jun N-terminal kinase (JNK) activation is involved in the early response of corals to thermal and UV stress. Furthermore, we found that JNK activity is required to repress stress-induced reactive oxygen species (ROS) accumulation in both the coral Stylophora pistillata and human skin cells. We also show that inhibiting JNK activation under stress conditions leads to ROS accumulation, subsequent coral bleaching and cell death. Taken together, our results suggest that an ancestral response, involving the JNK pathway, is remarkably conserved from corals to human, protecting cells from the adverse environmental effects.

Arpp19 is a potent PP2A-B55 inhibitor that regulates this phosphatase to ensure the stable phosphorylation of mitotic/meiotic substrates. At G2-M, Arpp19 is phosphorylated by the Greatwall kinase on S67. This phosphorylated Arpp19 form displays a high affinity to PP2A-B55 and a slow dephosphorylation rate, acting as a competitor of PP2A-B55 substrates. The molecular determinants conferring slow dephosphorylation kinetics to S67 are unknown. PKA also phosphorylates Arpp19. This phosphorylation performed on S109 is essential to maintain prophase I-arrest in Xenopus oocytes although the underlying signalling mechanism is elusive. Here, we characterize the molecular determinants conferring high affinity and slow dephosphorylation to S67 and controlling PP2A-B55 inhibitory activity of Arpp19. Moreover, we show that phospho-S109 restricts S67 phosphorylation by increasing its catalysis by PP2A-B55. Finally, we discover a double feed-back loop between these two phospho-sites essential to coordinate the temporal pattern of Arpp19-dependent PP2A-B55 inhibition and Cyclin B/Cdk1 activation during cell division. Progression of the cell division cycle requires feedback loops including those of phosphorylation and dephosphorylation; however the precise regulation of phosphorylation kinetics of Arpp19, an inhibitor of protein phosphatase 2A, is unclear. Here, the authors report that feedback between phosphorylation states of Ser67 and Ser109 of Arpp19 coordinates Arpp19-dependent inhibition of PP2A-B55 and Cyclin B activation during cell cycle progression.

The Allier River and its alluvial aquifer constitute a shallow but highly productive water resource due to their hydrodynamic properties. This hydrosystem provides almost all of the water requirements for domestic supply and irrigation. Recent dry summers (such as those in 2015, 2019, and 2022) and the lack of winter recharge have led managers to question the sustainability of this resource. We proposed the use of hydrological modelling with Gardenia with which the water balance can be determined at the watershed scale (7020 km2) and with which forecasting simulations can be performed for 2030–2070. Thus, this work was divided into (1) model calibration (2000–2020), (2) the determination of the main drivers of the water balance (2000–2020), (3) and river flow and groundwater level simulation (2030–2070). For the latter, Gardenia was used considering a “better case”, using the RCM Aladin63 in RCP2.6, and considering a “worst case”, using the RCM RegCM4-6 in RCP8.5. The calibration for 2000–2014 showed good reproducibility of river flows (NSE = 0.91) and groundwater levels (NSE = 0.85). The model showed that the major drivers in 2000–2020 were actual evapotranspiration and effective precipitation, which, respectively, represented 68% and 32% of mean annual precipitation. Water withdrawals did not significantly contribute to the water balance with the exception of those in very dry summers, such as those in 2003, 2005, 2015, and 2019. Climate appeared, therefore, as a prevalent factor of the Allier hydrosystem functioning compared to global withdrawals except for that during these dry years. Prospective simulations showed a decline in annual river flows and groundwater levels by a maximum of −15% and −0.08 m asl (“worst case”), respectively. These simulations showed that the Allier hydrosystem will be able to meet the water needs for various uses until 2070. In detail, it is likely that summer shortages will no longer be compensated by the Naussac Dam if the hydrosystem faces more than two years of drought. In this case, water-saving solutions will have to be found. This study is, thus, a good example of the application of hydrological modelling to address management issues in such a hydrosystem.

Background The effect of cataract surgery on IOP in patients with primary open-angle glaucoma (POAG) is a subject of debate. We investigated the effect of cataract surgery by phacoemulsification on intraocular pressure (IOP) in patients with medically POAG . Methods Seventy eyes of 40 POAG patients undergoing cataract surgery by phacoemulsification were retrospectively evaluated. All patients had their POAG medically controlled without prior glaucoma surgery. Baseline demographics and clinical characteristics were recorded. IOP and the number of glaucoma medications were evaluated before and for 1 year after cataract surgery. We analyzed IOP variations from baseline with a Student t -test for a paired sample. We used a Pearson correlation coefficient and linear regression to study the relation between IOP change from baseline and preoperative characteristics. Results One year after phacoemulsification, IOP decreased by a mean 1.15 ± 3 mmHg (6.8 ± 18.1%) ( P  = 0.01) and the number of glaucoma medications remained unchanged with a difference of − 0.1 ± 0.43 ( P  = 0.09). Higher preoperative IOP was associated with a greater IOP decrease after 1 year of follow-up ( P  < 0.001). One and 7 days after cataract surgery, 12.9 and 4.2% of the eyes had IOP spikes > 30 mmHg, respectively. One year after cataract surgery, 75.7% of the POAG eyes maintained the same number of glaucoma medications while 17.1% had a decrease and 7.2% of the eyes required adding glaucoma medications. Conclusion Cataract surgery by phacoemulsification in eyes with medically controlled POAG resulted at 1 year in a very small IOP decrease without a change in the number of glaucoma medications. A drop in IOP should not be expected after performing phacoemulsification alone in POAG patients.