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One of the main challenges for a skilful Limited Area Model Ensemble Prediction System (LAMEPS) is the generation of appropriate initial perturbations. In most operational LAMEPSs, the initial perturbations are provided by a global Ensemble Prediction System (EPS). Molteni et al. (2001) proposed clustering analysis as an objective selection criterion to choose a member from the global European Centre for Medium-range Weather Forecasts (ECMWF)-EPS model as initial perturbations in LAMEPS. In this article, another strategy for using the clustering method is investigated which ensures that initial perturbations are centred on the control analysis. The main purpose of this article is to study the benefit of cluster analysis and to validate the effect of different clustering strategies on the performance of a 17-member LAMEPS. The system used in this study is the operational Aire Limitée Adaptation Dynamique Développement InterNational-Limited-Area Ensemble Forecasting (ALADIN-LAEF) model.Three experiments were carried out over a 50-day period to validate different clustering strategies: i) representative members of 16 clusters from the 50-member ECMWF-EPS, where initial perturbations are not necessarily centred; ii) representative members from eight clusters and the symmetric pairs from ECMWF singular vector analysis; and iii) eight arbitrarily chosen ECMWF-EPS singular vector pairs. Results of the verified experiments show that the statistical reliability of ALADIN-LAEF improves when clustering is applied, but no clear improvement can be seen in the skill of LAMEPS. A case study of a heavy precipitation event confirms the result of the 50-day verification. The validation shows that none of the clustering strategies outperforms any other. Nous avons mené trois expériences sur une période de 50 jours pour valider différentes stratégies de groupement: i) membres représentatifs de 16 groupements d'un ECMWF-EPS de 50 membres, où les perturbations initiales ne sont pas nécessairement centrées; ii) membres représentatifs de huit groupements et les paires symétriques issues de l'analyse par vecteurs singuliers du ECMWF; et iii) huit paires issues de l'analyse par vecteurs singuliers du ECMWF-EPS choisies au hasard. Les résultats des expériences vérifiées montrent que la fiabilité statistique du ALADIN-LAEF s'améliore lorsqu'un groupement est appliqué, mais on ne perçoit aucune amélioration nette dans l'habileté du LAMEPS. Une étude de cas d'un événement de fortes précipitations confirme le résultat de la vérification de 50 jours. La validation montre qu'aucune des stratégies de groupement ne surpasse les autres.

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AR signalling pathway reactivation plays a key role in the development of castration-resistant prostate cancer (CRPC). High-mobility group protein B1 (HMGB1) is an important factor involved in the occurrence and development of a variety of tumours by regulating gene transcription. In the present study, the association between HMGB1 and prostate cancer (PCa) and the effects of HMGB1 on androgen receptor (AR) transcription and signalling pathway reactivation in PCa cells in vitro and in vivo were evaluated. A bioinformatics method was used to determine the mRNA expression level of HMGB1 in PCa specimens and its correlation with the mRNA expression of AR. Immunohistochemical staining was used to detect the expression of these proteins in clinical PCa samples. Reporter gene and ChIP assays were performed to determine the activity of AR and the effect of HMGB1 on the ability of AR to bind to the promoters of prostate specific antigen and transmembrane protease, serine 2. A bioluminescence resonance energy transfer assay was employed to observe the direct interaction between HMGB1 and AR protein. Additionally, a castrated nude mouse xenograft tumour model was established to verify the effect of HMGB1 on PCa. The results revealed that HMGB1 expression was significantly increased in PCa specimens, which may have a strong correlation with AR expression. Moreover, HMGB1 could reactivate the AR signalling pathway, directly interact with AR, and promote the development of CRPC in an androgen-independent manner. The results of the present study indicated that HMGB1 promoted the development of CRPC by interacting with AR, which inferred that decreasing the expression of HMGB1 may be a potential effective method for CRPC prevention and treatment.

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Background Lung cancer is one of the most lethal cancers worldwide. Cisplatin, a widely used anti‐lung cancer drug, has been limited in clinical application due to its drug resistance. Medicines targeting mitochondrial electron transport chain (ETC) complexes may be effective candidates for cisplatin‐based chemotherapy. Methods In this study, the small molecule drug library from Food and Drug Administration FDA was used to screen for medicines targeting ETC. MTT and colony formation assays were used to investigate cell proliferation. Flow cytometry was employed to analyze cell cycle, apoptosis, reactive oxygen species (ROS), and mitochondrial membrane potential. Wound scratch and transwell assays were used to detect migration and invasion abilities. The activities of the ETC complex were tested using kits. Western blot analysis was used to investigate the expressions of related proteins. A mouse xenograft model was constructed to verify the antitumor effect in vivo. Results The results showed that mubritinib can reduce the activation of the PI3K/mTOR signal pathway, disrupt mitochondrial function, significantly increase ROS levels and induce oxidative stress, and ultimately exert its antitumor effect against non‐small cell lung cancer (NSCLC) both in vivo and in vitro. In addition, the combination of cisplatin and mubritinib can improve the tumor‐suppressive effect of cisplatin. Conclusion Mubritinib can upregulate intracellular ROS concentration and cell apoptosis, inhibit the PI3K signaling pathway and interfere with the function of mitochondria, thus reducing cell proliferation and increasing ROS induced apoptosis by reducing the activation of Nrf2 by PI3K.