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Berlin Brandenburg

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  • 1
    Language: English
    In: Cell Reports, 23 October 2018, Vol.25(4), pp.1027-1039.e6
    Description: , which encodes p21, functions as a major route for p53-mediated cell-cycle arrest. However, the consequence of gene dosage on tumor suppression has not been systematically investigated. Here, we employed BAC transgenesis to generate a mouse, which harbors an additional allele within its natural genomic context. We show that these mice display enhanced cell-cycle arrest and reduced apoptosis in response to genotoxic stress. Furthermore, using a chemically induced skin cancer model and an autochthonous -driven lung adenocarcinoma model, we show that mice display a cancer protection phenotype that is indistinguishable from that observed in animals. Moreover, we demonstrate that and cooperate in mediating cancer resistance, using a chemically induced fibrosarcoma model. Overall, our allele enabled us to assess the contribution of to -mediated tumor suppression. Torgovnick et al. create a mouse model, carrying a third copy of (p21), which shows enhanced cell-cycle arrest capacity and protection against DNA damage-induced apoptosis. The animals display delayed epithelial regeneration and a robust cancer resistance phenotype, highlighting the importance of p21 in p53-dependent tumor suppression.
    Keywords: Cdkn1a ; P21 ; P53 ; Mouse Model ; Cancer ; Tumor Suppressor ; Cell Cycle Arrest ; Apoptosis ; Cancer Protection ; Biology
    ISSN: 2211-1247
    E-ISSN: 2211-1247
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  • 2
    Language: English
    In: The Lancet Oncology, July 2018, Vol.19(7), pp.940-952
    Description: Immune checkpoint blockade therapy has shown promising results in patients with advanced hepatocellular carcinoma. We aimed to assess the efficacy and safety of pembrolizumab in this patient population. KEYNOTE-224 is a non-randomised, multicentre, open-label, phase 2 trial that is set in 47 medical centres and hospitals across ten countries. Eligible patients had pathologically confirmed hepatocellular carcinoma; had previously been treated with sorafenib and were either intolerant to this treatment or showed radiographic progression of their disease after treatment; an Eastern Cooperative Oncology Group performance status of 0–1; adequate organ function, and were Child-Pugh class A. Participants received 200 mg pembrolizumab intravenously every 3 weeks for about 2 years or until disease progression, unacceptable toxicity, patient withdrawal, or investigator decision. The primary endpoint was objective response, defined as the proportion of patients with complete or partial response in all patients who received at least one dose of pembrolizumab, which was radiologically confirmed by use of the Response Evaluation Criteria in Solid Tumors version 1.1 by central review. Safety was also assessed in all treated patients. This trial is ongoing but closed to enrolment and is registered with number . Between June 7, 2016, and Feb 9, 2017, we screened 169 patients with advanced hepatocellular carcinoma, of whom 104 eligible patients were enrolled and treated. As of data cutoff on Feb 13, 2018, 17 (16%) patients were still receiving pembrolizumab. We recorded an objective response in 18 (17%; 95% CI 11–26) of 104 patients. The best overall responses were one (1%) complete and 17 (16%) partial responses; meanwhile, 46 (44%) patients had stable disease, 34 (33%) had progressive disease, and six (6%) patients who did not have a post-baseline assessment on the cutoff date were considered not to be assessable. Treatment-related adverse events occurred in 76 (73%) of 104 patients, which were serious in 16 (15%) patients. Grade 3 treatment-related events were reported in 25 (24%) of the 104 patients; the most common were increased aspartate aminotransferase concentration in seven (7%) patients, increased alanine aminotransferase concentration in four (4%) patients, and fatigue in four (4%) patients. One (1%) grade 4 treatment-related event of hyperbilirubinaemia occurred. One death associated with ulcerative oesophagitis was attributed to treatment. Immune-mediated hepatitis occurred in three (3%) patients, but there were no reported cases of viral flares. Pembrolizumab was effective and tolerable in patients with advanced hepatocellular carcinoma who had previously been treated with sorafenib. These results indicate that pembrolizumab might be a treatment option for these patients. This drug is undergoing further assessment in two phase 3, randomised trials as a second-line treatment in patients with hepatocellular carcinoma. Merck & Co, Inc.
    Keywords: Medicine
    ISSN: 1470-2045
    E-ISSN: 1474-5488
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