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Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM. This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual. Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64–75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7–32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8–21·4] vs 14·1 months [12·4–16·2]; hazard ratio 0·74 [96·6% CI 0·60–0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1–46·5) in the nivolumab plus ipilimumab group and 27% (21·9–32·4) in the chemotherapy group. Grade 3–4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression). Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM. Bristol Myers Squibb.

In a randomized study of second-line therapy, treatment with nivolumab, an anti–PD-1 antibody, resulted in responses in more people and in better overall survival than did docetaxel. Squamous-cell carcinoma represents approximately 30% of all cases of non–small-cell lung cancer (NSCLC). 1 Treatment for advanced squamous-cell NSCLC remains an unmet need; little therapeutic progress has been made since the approval of docetaxel for second-line treatment in 1999. 2 – 4 Most new agents for the treatment of NSCLC are not indicated for this subtype because of their toxicity or lack of efficacy or because their activity is limited to tumors with specific genetic alterations that are rarely found in squamous-cell NSCLC. 5 – 7 Furthermore, no single-agent therapy has resulted in better survival than that seen with docetaxel. The programmed death 1 (PD-1) . . .

Background: Approved systemic treatments for malignant pleural mesothelioma (MPM) have been limited to chemotherapy regimens that have moderate survival benefit with poor outcomes. Nivolumab plus ipilimumab has shown clinical benefit in other tumour types, including first-line non-small-cell lung cancer. We hypothesised that this regimen would improve overall survival in MPM.Methods: This open-label, randomised, phase 3 study (CheckMate 743) was run at 103 hospitals across 21 countries. Eligible individuals were aged 18 years and older, with previously untreated, histologically confirmed unresectable MPM, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible participants were randomly assigned (1:1) to nivolumab (3 mg/kg intravenously once every 2 weeks) plus ipilimumab (1 mg/kg intravenously once every 6 weeks) for up to 2 years, or platinum plus pemetrexed chemotherapy (pemetrexed [500 mg/m2 intravenously] plus cisplatin [75 mg/m2 intravenously] or carboplatin [area under the concentration-time curve 5 mg/mL per min intravenously]) once every 3 weeks for up to six cycles. The primary endpoint was overall survival among all participants randomly assigned to treatment, and safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT02899299, and is closed to accrual.Findings: Between Nov 29, 2016, and April 28, 2018, 713 patients were enrolled, of whom 605 were randomly assigned to either nivolumab plus ipilimumab (n=303) or chemotherapy (n=302). 467 (77%) of 605 participants were male and median age was 69 years (IQR 64-75). At the prespecified interim analysis (database lock April 3, 2020; median follow-up of 29·7 months [IQR 26·7-32·9]), nivolumab plus ipilimumab significantly extended overall survival versus chemotherapy (median overall survival 18·1 months [95% CI 16·8-21·4] vs 14·1 months [12·4-16·2]; hazard ratio 0·74 [96·6% CI 0·60-0·91]; p=0·0020). 2-year overall survival rates were 41% (95% CI 35·1-46·5) in the nivolumab plus ipilimumab group and 27% (21·9-32·4) in the chemotherapy group. Grade 3-4 treatment-related adverse events were reported in 91 (30%) of 300 patients treated with nivolumab plus ipilimumab and 91 (32%) of 284 treated with chemotherapy. Three (1%) treatment-related deaths occurred in the nivolumab plus ipilimumab group (pneumonitis, encephalitis, and heart failure) and one (<1%) in the chemotherapy group (myelosuppression).Interpretation: Nivolumab plus ipilimumab provided significant and clinically meaningful improvements in overall survival versus standard-of-care chemotherapy, supporting the use of this first-in-class regimen that has been approved in the USA as of October, 2020, for previously untreated unresectable MPM.

The mammalian heart arises from various populations of Mesp1-expressing cardiovascular progenitors (CPs) that are specified during the early stages of gastrulation. Mesp1 is a transcription factor that acts as a master regulator of CP specification and differentiation. However, how Mesp1 regulates the chromatin landscape of nascent mesodermal cells to define the temporal and spatial patterning of the distinct populations of CPs remains unknown. Here, by combining ChIP–seq, RNA-seq and ATAC-seq during mouse pluripotent stem cell differentiation, we defined the dynamic remodelling of the chromatin landscape mediated by Mesp1. We identified different enhancers that are temporally regulated to erase the pluripotent state and specify the pools of CPs that mediate heart development. We identified Zic2 and Zic3 as essential cofactors that act with Mesp1 to regulate its transcription-factor activity at key mesodermal enhancers, thereby regulating the chromatin remodelling and gene expression associated with the specification of the different populations of CPs in vivo. Our study identifies the dynamics of the chromatin landscape and enhancer remodelling associated with temporal patterning of early mesodermal cells into the distinct populations of CPs that mediate heart development. Lin, Swedlund et al. report that Mesp1 governs the remodelling of the chromatin and enhancer landscape during differentiation of early mesodermal cells into distinct populations of cardiovascular progenitors.

The high-pressure behavior of LuFe2O4 is characterized based on synchrotron X-ray diffraction and neutron diffraction, resistivity measurements, X-ray absorption spectroscopy and infrared spectroscopy studies. The results obtained enabled us to propose a P-T phase diagram. In this study, the low pressure charge-ordering melting could be detected by synchrotron XRD in the P-T space. In addition to the ambient pressure monoclinic C2/m and rhombohedral R 3 ¯ m phases, the possible P 1 ¯ triclinic phase, the monoclinic high pressure form Pm and metastable modulated monoclinic phases were observed; the latter modulated monoclinic phases were not observed in the present neutron diffraction data. Furthermore, the transition to the Pm phase which was already characterized by strong kinetics is found to be favored at high temperature (373 K). Based on X-ray absorption spectroscopy data the Pm phase, which could be recovered at atmospheric pressure, can be explained by a change in the Fe-local environment from a five-fold coordination to a distorted 5 + 1 one.

The simultaneous formation of nanometer sized zinc oxide (ZnO), and acetate zinc hydroxide double salt (Zn-HDS) is described. These phases, obtained using the sol-gel synthesis route based on zinc acetate salt in alcoholic media, were identified by direct characterization of the reaction products in solution using complementary techniques: nephelometry, in situ Small-Angle X-ray Scattering (SAXS), UV-Vis spectroscopy and Extended X-ray Absorption Fine Structures (EXAFS). In particular, the hydrolytic pathway of ethanolic zinc acetate precursor solutions promoted by addition of water with the molar ratio N=[H2O]/[Zn2+] = 0.05 was investigated in this paper. The aim was to understand the formation mechanism of ZnO colloidal suspension and to reveal the factors responsible for the formation of Zn-HDS in the final precipitates. The growth mechanism of ZnO nanoparticles is based on primary particle (radius ≈ 1.5 nm) rotation inside the primary aggregate (radius <3.5 nm) giving rise to an epitaxial attachment of particles and then subsequent coalescence. The growth of second ZnO aggregates is not associated with the Otswald ripening, and could be associated with changes in equilibrium between solute species induced by the superficial etching of Zn-HDS particles at the advanced stage of kinetic.

The evolution of both oxygen and framework tetrahedral shells around Ni2+ cations in faujasite upon rehydration can be described in real time thanks to in situ dispersive-EXAFS. Such type of analysis permits precise experimental description of the coordination environment of cations in zeolite structures under different hydration conditions.