Oxide metallurgy technology plays an important role in inclusion control and is also applied to improve the weldability of high strength steel. Based on the requirements of the weldability in high ...strength steel, the influencing factors of weld heat affected zone (HAZ) as well as the development and application status of oxide metallurgy technology are summarized in this review. Moreover, the advantages and difficulties in the application of rare earth (RE) oxide metallurgy technology are analyzed, combined with the performance mechanism of RE and its formation characteristics of fine and high melting point RE inclusions with distribution dispersed in liquid steel. With the weldability diversities of different high strength steels, the research status of weldability of high strength steel with high carbon equivalent and the effects of RE on the microstructure and properties of HAZ are discussed, and some suggestions about further research in the future are proposed.
Bromodomain and extra-terminal (BET) proteins are epigenetic readers that can drive carcinogenesis and therapy resistance. RO6870810 is a novel, small-molecule BET inhibitor.
We conducted a Phase 1 ...study of RO6870810 administered subcutaneously for 21 or 14 days of 28- or 21-day cycles, respectively, in patients with the nuclear protein of the testis carcinoma (NC), other solid tumours, or diffuse large B-cell lymphoma (DLBCL) with MYC deregulation.
Fatigue (42%), decreased appetite (35%) and injection-site erythema (35%) were the most common treatment-related adverse events. Pharmacokinetic parameters demonstrated linearity over the dose range tested and support once-daily dosing. Pharmacodynamic assessments demonstrated sustained decreases in CD11b levels in peripheral blood mononuclear cells. Objective response rates were 25% (2/8), 2% (1/47) and 11% (2/19) for patients with NC, other solid tumours and DLBCL, respectively. Responding tumours had evidence of deregulated MYC expression.
This trial establishes the safety, favourable pharmacokinetics, evidence of target engagement and preliminary single-agent activity of RO6870810. Responses in patients with NC, other solid tumours and DLBCL provide proof-of-principle for BET inhibition in MYC-driven cancers. The results support further exploration of RO6870810 as monotherapy and in combinations.
NCT01987362.
RG7112 is a small-molecule MDM2 antagonist. MDM2 is a negative regulator of the tumor suppressor p53 and frequently overexpressed in leukemias. Thus, a phase I study of RG7112 in patients with ...hematologic malignancies was conducted.
Primary study objectives included determination of the dose and safety profile of RG7112. Secondary objectives included evaluation of pharmacokinetics; pharmacodynamics, such as TP53-mutation status and MDM2 expression; and preliminary clinical activity. Patients were divided into two cohorts: Stratum A relapsed/refractory acute myeloid leukemia (AML; except acute promyelocytic leukemia), acute lymphoblastic leukemia, and chronic myelogenous leukemia and Stratum B (relapsed/refractory chronic lymphocytic leukemia/small cell lymphocytic leukemia; CLL/sCLL). Some Stratum A patients were treated at the MTD to assess clinical activity.
RG7112 was administered to 116 patients (96 patients in Stratum A and 20 patients in Stratum B). All patients experienced at least 1 adverse event, and 3 dose-limiting toxicities were reported. Pharmacokinetic analysis indicated that twice-daily dosing enhanced daily exposure. Antileukemia activity was observed in the 30 patients with AML assessed at the MTD, including 5 patients who met International Working Group (IWG) criteria for response. Exploratory analysis revealed TP53 mutations in 14% of Stratum A patients and in 40% of Stratum B patients. Two patients with TP53 mutations exhibited clinical activity. p53 target genes were induced only in TP53 wild-type leukemic cells. Baseline expression levels of MDM2 correlated positively with clinical response.
RG7112 demonstrated clinical activity against relapsed/refractory AML and CLL/sCLL. MDM2 inhibition resulted in p53 stabilization and transcriptional activation of p53-target genes. We provide proof-of-concept that MDM2 inhibition restores p53 function and generates clinical responses in hematologic malignancies.
Summary Background We report a proof-of-mechanism study of RG7112, a small-molecule MDM2 antagonist, in patients with chemotherapy-naive primary or relapsed well-differentiated or dedifferentiated ...MDM2 -amplified liposarcoma who were eligible for resection. Methods Patients with well-differentiated or dedifferentiated liposarcoma were enrolled at four centres in France. Patients received up to three 28-day neoadjuvant treatment cycles of RG7112 1440 mg/m2 per day for 10 days. If a patient progressed at any point after the first cycle, the lesion was resected or, if unresectable, an end-of-study biopsy was done. The primary endpoint was to assess markers of RG7112-dependent MDM2 inhibition and P53 pathway activation (P53, P21, MDM2, Ki-67, macrophage inhibitory cytokine-1 MIC-1, and apoptosis). All analyses were per protocol. This trial is registered with EudraCT, number 2009-015522-10. Results Between June 3, and Dec 14, 2010, 20 patients were enrolled and completed pretreatment and day 8 biopsies. 18 of 20 patients had TP53 wild-type tumours and two carried missense TP53 mutations. 14 of 17 assessed patients had MDM2 gene amplification. Compared with baseline, P53 and P21 concentrations, assessed by immunohistochemistry, had increased by a median of 4·86 times (IQR 4·38–7·97; p=0·0001) and 3·48 times (2·05–4·09; p=0·0001), respectively, at day 8 (give or take 2 days). At the same timepoint, relative MDM2 mRNA expression had increased by a median of 3·03 times (1·23–4·93; p=0·003) that at baseline. The median change from baseline for Ki-67-positive tumour cells was −5·05% (IQR −12·55 to 0·05; p=0·01). Drug exposure correlated with blood concentrations of MIC-1 (p<0·0001) and haematological toxicity. One patient had a confirmed partial response and 14 had stable disease. All patients experienced at least one adverse event, mostly nausea (14 patients), vomiting (11 patients), asthenia (nine patients), diarrhoea (nine patients), and thrombocytopenia (eight patients). There were 12 serious adverse events in eight patients, the most common of which were neutropenia (six patients) and thrombocytopenia (three patients). Discussion MDM2 inhibition activates the P53 pathway and decreases cell proliferation in MDM2 -amplified liposarcoma. This study suggests that it is feasible to undertake neoadjuvant biopsy-driven biomarker studies in liposarcoma. Funding F Hoffmann-La Roche.
The effects of Cerium (Ce) were studied on the casting slab quality, microstructure, and inclusion evolution of cryogenic vessel steel. An optical metallographic microscope, scanning electron ...microscope, energy dispersive spectrometer, and Thermo-calc thermodynamic software were used for characterization and analysis. The results indicated that the central segregation was significantly improved after adding Ce and reached the lowest level when the content of Ce was 0.0009 wt.%. Meanwhile, the presence of Ce reduces the size of ferrite and improves pearlite morphology. Ce also enables the modification of Al2O3 and MnS + Ti4C2S2 inclusions into ellipsoid CeAlO3 and spherical Ce2O2S + Ti4C2S2 composite inclusions, respectively, which are easier to remove. The formed Ce2O2S inclusions are fine and can work as heterogeneous nucleation points to refine the microstructure of steel.
Impact toughness, tensile properties, grains, and inclusions of industrial Al-killed steel Q355B were investigated by adding cerium (Ce) from 0, 0.0028%–0.0048%. The results revealed that: (1) With ...the increase of Ce additions, the size of inclusions decreased and the oxide inclusions significantly decreased while oxide-sulfide inclusions significantly increased; (2) Inclusions of sample without Ce were Al2O3 and Mn(Ca)S, inclusions of sample with adding 0.0028% Ce were CeAlO3, Mn(Ca)S, and Ce2O2S, and inclusions of sample with adding 0.0048% Ce were CeAlO3, Ce2S3, Ce2O2S, and Mn(Ca)S; (3) Grains of sample with Ce were refined. Microstructure with 0.0028% Ce addition displayed a more uniform ferrite and microstructure with 0.0048% Ce addition exhibited a more uniform pearlite, which was due to Ce2O2S as effective nucleating agent for α-Fe and MnS as effective nucleating agent for γ-Fe; (4) Impact toughness and yield strength of sample with 0.0028% Ce addition was highest in the three samples, because of the microstructure of refining and uniform ferrite grains and small Ce-based inclusions.
The effect of Ce content on the precipitation behavior of rare earth inclusions in Al-killed HSLA steel was investigated by SEM-EDS and automatic inclusion analysis system. The type, morphology, ...number and size of rare earth inclusions were observed and counted. The mode of precipitation of the rare earth inclusions were predicted by Factsage 8.0 thermodynamics software and confirmed by experimental observations. The results indicate that the typical inclusions of HSLA steel change in composition from Ce–O to Ce–O–S and finally to CeS with increase in Ce content. Importantly the inclusions are small and spheroid and decrease in size with increase in Ce content up to 0.036%, and their size is considerably less than the 5 μm blocky Al
2
O
3
inclusions formed in the absence of Cerium. This should improve their weldability. Most Ce–O and Ce–O–S inclusions were formed in the steel molten, while Ce–S was mainly formed during solidification.
Two submerged entry nozzles (SENs) used for casting 1300 tons and 260 tons of Al-killed steel were dissected. Several parameters including block rate, nozzle clog angle, port width, and port height ...of the clogged nozzle were introduced to describe the geometry of clogs in the SENs based on the dissection; furthermore, a geometry model was established to describe the characteristics of the nozzle clogging of the SENs. A large-eddy simulation (LES) coupled with the volume of fraction (VOF) method was adopted to simulate the steel–slag interface’s interaction behavior. The vortex visualization and rotation magnitude were characterized by the Liutex method. Quantitatively, the influence of nozzle clogging resulted in block rates of 0% to 45.9% on the flow and vortex distribution in the mold, and the characteristics of the steel–slag interface fluctuation were well verified in the industrial experiment.
With the continuous expansion of the application field of low alloy wear-resistant steel, higher processing plasticity and toughness are prioritized on the basis of ensuring strength and hardness. In ...this article, a low alloy wear-resistant steel Hardox400 was studied: by adding a mass fraction of 0.0030% of rare earth cerium as microalloying treatment, the pilot scale simulation of the rare earth wear-resistant steel was carried out using vacuum induction furnace and a four-high reversible laboratory mill. The effects of the rare earth on the occurrence state of the inclusions, microstructure, mechanical properties and wear resistance of the steel were studied by means of optical microscope (OM), scanning electron microscope (SEM) and wet sand/rubber wheel wear tester. The results show that the fine spherical CeAlO3, CeAlO3-MnS and elliptical Ce2S2O-CaO are formed by adding 0.0030% Ce, which enhances the binding force between the inclusions and matrix. The addition of rare earth Ce helps to refine the as-cast structure, prevent the transformation of proeutectoid ferrite of overcooled austenite and promotes the formation of bainite ferrite, whilst simultaneously increasing the yield strength, yield ratio and surface hardness, especially the low-temperature impact toughness approximately between −40 °C~−20 °C of the tested steel. Simultaneously, the ability to resist abrasive embedment and crack propagation is enhanced, and the wear resistance is obviously improved. The research results will provide a reference for the development of high-quality rare earth wear-resistant steel utilizing national featured resources.
CeO2 can be applied to refining slag to minimize the size of inclusions, speed up the deoxidization process, and adsorb Al2O3 inclusions. The impact through which CeO2 content affects slag’s melting ...efficiency is still uncertain. The thermal analyzer was used to measure the thermogravimetric analysis (TG) and differential scanning calorimetry (DSC) curves of the slag melting process. According to the study results, with the increase in CeO2 content, the melting temperature of slag decreased first and then increased. The slag’s melting point fell from 1364 °C to 1324 °C and then rose to 1503 °C. XRD and SEM were used to analyze the CaO-Al2O3-SiO2-MgO-CeO2 slag’s microstructure. The mineral-phase structure of CeO2-containing refining slag was primarily composed of Ca2SiO4 and 3CaO·Al2O3, MgO, SiO2, CaO·Al2O3, and Ca8Ce6Al6O26. The proportion of 3CaO·Al2O3, CaO·Al2O3, and Ca2SiO4 decreased as the rare-earth-oxide content increased, while the proportion of Ca8Ce6Al6O26 increased. FactSage was used to estimate the equilibrium-phase compositions of slags with various compositions, and a model for predicting melting points was carried out by a linear regression model. Results were obtained through the analysis of equilibrium-phase composition and crystal structure transformation. The main reasons for the melting point decrease were the change of degree of polymerization and the decrease in contents and complete melting temperature of high-melting-point Ca3Al2O6 and Ca2SiO4 compounds. The latter increase in melting point was due to the number of Ca8Ce6Al6O26 compounds and precipitation temperature increases and the complexity of the structural-network increases.
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