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This Phase 1/2 study (NCT02349633) explored the safety and antitumor activity of PF-06747775 (oral, third-generation epidermal growth factor receptor [EGFR] tyrosine kinase inhibitor) in patients with advanced non-small cell lung cancer after progression on an EGFR inhibitor. Phase 1 was a dose-escalation study of PF-06747775 monotherapy (starting dose: 25 mg once daily [QD]). Phase 1b/2 evaluated PF-06747775 monotherapy at recommended Phase 2 dose (RP2D; Cohort 1); PF-06747775 200 mg QD plus palbociclib (starting dose: 100 mg QD orally; Cohort 2A); and PF-06747775 monotherapy at RP2D in a Japanese lead-in cohort. Sixty-five patients were treated. Median treatment duration was 40.1 weeks. Monotherapy maximum tolerated dose was not determined. Two patients in Cohort 2A had dose-limiting toxicities. The monotherapy RP2D was estimated to be 200 mg QD. Most frequently reported adverse events (AEs) were diarrhea (69.2%), paronychia (69.2%), and rash (60.0%). Most AEs were grades 1–3. Overall, objective response rate (90% confidence interval [CI]) was 41.5% (31.2–52.5%). Median (range) duration of response was 11.09 (2.70–34.57) months. Median progression-free survival (90% CI) was 8.1 (5.4–23.3) months. PF-06747775 had a manageable safety profile and the study design highlights important considerations for future anti-EGFR agent development.

An experimental system consisting of a spherical vessel with a horizontal pipe was established. By changing the pipe length, the effect that the ignition position has on methane explosion in an airtight spherical vessel with a pipe was studied, and the regularities of Pmax, (dP/dt)max and flame transmission were analyzed in detail. The results show that different ignition position leading to different propagation of flame and pressure wave. As the ignition position moved from the wall of vessel to the end of pipe, the Pmax in the apparatus first increased, then decreased when ignition occurs behind the center of vessel, and finally increased when ignition occurs behind the middle of pipe. The same trend was observed for (dP/dt)max. When ignited near the end of pipe, the Pmax and (dP/dt)max were large, and the explosion was the most dangerous. In addition, gas oscillation was observed during the explosion process in the pipe, and it was more serious when igniting at the wall of vessel, the center of vessel and the end of pipe. Furthermore, the influence that structure effect had on the gas explosion was determined. With ignition in spherical vessel, the longer the pipe is, the weaker the explosion intensity in vessel is, but the greater the explosion intensity in pipe is. With ignition in the pipe, the longer the pipe is, the greater the explosion intensities are in both the vessel and pipe. The influence that the ignition position has on a gas explosion was revealed, and the reason was analyzed. This research has great theoretical value and practical significance for preventing and controlling potentially disastrous accidents in complex units. The research results provide a theoretical foundation for antiknock and explosion venting in technical vessels and pipes.

Background: Multiple myeloma (MM) is a hematological B-cell malignancy that remains incurable for most patients. Almost all patients, including those who initially respond to treatment, are expected to relapse and subsequently cycle through multiple lines of treatment. The addition of proteasome inhibitors, immunomodulatory drugs and monoclonal antibodies has improved patient outcomes; however, survival of patients after these agents is very poor and highlights an unmet medical need in the relapsed/refractory MM population. Elranatamab (PF-06863135) is a humanized bi-specific antibody that targets both BCMA-expressing MM cells and CD3-expressing T cells, with binding resulting in T-cell mediated cytotoxicity. Elranatamab preclinical studies have demonstrated anti-tumor activity and delayed tumor progression. A Phase 1 study, MagnetisMM-1 (ClinicalTrials.gov ID: NCT03269136), with the aim of characterizing the efficacy, safety, pharmacokinetics, and pharmacodynamics of elranatamab as single agent and in combination with immunomodulatory agents for patients with relapsed/refractory MM is ongoing. Study Design and Methods: MagnetisMM-3 is an open-label, multicenter, non-randomized, Phase 2 study to evaluate the efficacy and safety of elranatamab monotherapy in patients with relapsed/refractory MM who are refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody (ClinicalTrials.gov ID: NCT04649359). Approximately 150 patients will be enrolled to one of two independent parallel cohorts: those naïve to BCMA-directed therapies (Cohort A) and those with previous exposure to BCMA-directed therapy (Cohort B). The primary endpoint is objective response rate, according to International Myeloma Working Group [IMWG] response criteria. Secondary endpoints include duration of response, cumulative complete response (CR) rate, duration of cumulative CR, progression-free survival, time to response, minimal residual disease negativity rate, overall survival, safety, plasma concentrations, and immunogenicity of elranatamab. Key inclusion criteria are age ≥18 years, MM diagnosis according to IMWG criteria and with measurable disease based on IMWG criteria as defined by at least 1 of the following: Serum M-protein ≥0.5 g/dL by SPEP, Urinary M-protein excretion ≥200 mg/24 hours by UPEP; Serum immunoglobulin free light chain ≥10 mg/dL (≥100 mg/L) and abnormal serum immunoglobulin kappa to lambda free light chain ratio (1.65). Eligible patients should also have ECOG performance status ≤2, be refractory to at least one proteasome inhibitor, one immunomodulatory drug, and one anti-CD38 antibody and be relapsed/refractory to their last treatment regimen. Key exclusion criteria are smoldering MM, active plasma cell leukemia, amyloidosis, POEMS syndrome, active, uncontrolled bacterial, fungal or viral infections, stem cell transplant within 12 weeks of enrollment, any other active malignancy within 3 years prior to enrollment (except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ), or having received previous administration of an investigational drug within 30 days or 5 half-lives (whichever is longer) of the first dose of elranatamab. This study is, or is planned to be, open at centers in the USA, Australia, Canada, Belgium, France, Germany, Japan, Poland, Spain, and the UK. Disclosures Lesokhin: Genetech: Research Funding; Serametrix, Inc: Patents & Royalties; pfizer: Consultancy, Research Funding; Behringer Ingelheim: Honoraria; Trillium Therapeutics: Consultancy; bristol myers squibb: Research Funding; Iteos: Consultancy; Janssen: Honoraria, Research Funding. Iida: Ono: Honoraria, Research Funding; Glaxo SmithKlein: Research Funding; Janssen: Honoraria, Research Funding; Abbvie: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Daiichi Sankyo: Research Funding; Amgen: Research Funding. Ma: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Sullivan: Pfizer Inc: Current Employment, Current equity holder in publicly-traded company. Raab: Janssen: Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees.

The Xiadian gold deposit, located in the Zhaoyuan–Laizhou belt of the Jiaodong gold province, is a typical Jiaojia-type gold deposit, which is characterized by disseminated and stockwork ores enclosed by hydrothermally altered wall rocks. The exact age and the genesis of the gold deposit remain controversial. Here, we present precise in-situ monazite U-Pb dating to constrain the age of the gold mineralization, which we integrate with published geochronological work on the associated geological events to understand the genesis of the gold deposit. The Linglong granite represents the earliest magmatic event at Xiadian, and yielded a zircon LA–ICPMS U-Pb age of 159.5 ± 0.9 Ma (2σ, MSWD = 0.63). Subsequent geologic events were recorded by minor amounts of quartz–pyrite–molybdenite veins which are dated at 124.8 ± 2.1 Ma (2σ, MSWD = 0.01) by molybdenite Re–Os dating in a granitic pegmatite. The formation of such veins was close to the emplacement of adjacent Guojialing granodiorite (~130 Ma), and thus may be considered as a product of post–magmatic hydrothermal activity. It is proposed that the molybdenum–bearing hydrothermal fluids acted as a prelude to gold mineralization and participated in the formation of the latter ore fluids. Gold mineralization took place at 120.0 ± 1.4 Ma (2σ, MSWD = 0.59), determined by LA–ICPMS U–Pb dating on hydrothermal monazite from quartz–polymetallic sulfide veins. Prior to and post mineralization, voluminous hydrothermally altered porphyritic diorite and fresh quartz diorite porphyry dykes were emplaced, which yielded U–Pb ages of 121.3 ± 1.4 Ma (2σ, MSWD = 0.28) and 115.8 ± 1.9 Ma (2σ, MSWD = 0.71), respectively. Based on these geochronological data, we have established a comprehensive geochronologic framework, which suggests that the genesis of the Xiadian deposit might be related to the craton destruction and lithosphere thinning in the North China Craton.

The material source, fluid evolution and mineralizing mechanism in the Jiaodong gold province have been hotly debated for several decades. The Sizhuang gold deposit provides an excellent object for studying these issues. Gold in this deposit mainly precipitated in the quartz–Au–pyrite (stage II) and quartz–Au–polymetallic (stage III) stages. Stage III can be further subdivided into the early stage III (chalcopyrite, galena with minor amounts of electrum, pyrrhotite, pyrite, siderite and sphalerite) and the late stage III (chalcopyrite, magnetite, siderite with a little pyrrhotite). Pyrite from stage II and stage III contains consistent δ34S signatures (8.1‰–9.6‰ and 7.5‰–9.8‰, respectively) as well as trace elements (e.g. Co: 8.19 vs. 2.63 ppm, Ni: 3.54 vs. 0.74 ppm, As: 29.95 vs. 5.78 ppm, and Bi: 3.18 vs. 7.81 ppm). These consistent geochemical features combined with previous fluid inclusion and C-H-O isotope studies argue for a common source for ore-forming materials and fluids of the stage II and III at Sizhuang deposit. During the stage II and III, reduced sulfur species may have been lost from ore-forming fluids in response to pyrite precipitation (HS- being scavenged by pyrite) and fluid immiscibility (H2S entering vapor phase), which led to the total sulfur concentration (∑Stotal) decrease in the ore-forming fluids. Thermodynamic calculations at different ∑Stotal and constant pressure (2000 bar) and temperature (300 °C) in Fe-Cu-O-S-H system reveal that ∑Stotal decrease can lead to first enlargement and then shrinkage of pyrrhotite stability field with magnetite stability field being broadened to more acidic field; that sulfur species is dominated by H2S (>90 mol%) under the bornite–pyrite phase boundaries in the acidic ore-forming fluids; and that decreases in H2S concentration can efficiently cause gold precipitation by reducing gold bisulfide solubility up to 2–3 orders of magnitude while ∑Stotal just decreases ~50 times. Pyrrhotite and magnetite precipitated due to enlarged stability field during this physicochemical process, which is in line with geologic observations. It is proposed that the two-stage gold deposition by H2S loss from a single ore-forming fluid could account for gold precipitation coupling with occurrence of pyrrhotite and magnetite in the mineral assemblage at Sizhuang deposit.

Modern software systems are growing ever more complex, and the component-based software engineering (CBSE) is viewed as an opportunity to deal with the increasing complexity of measurement and control system. This paper analyzes the task profile of measurement and control system (GMCS) and discusses the component-based design methods. The paper submits a novel model called CV-MDN for software of GMCS that includes five parts: user controller, display views, domain model, data services and network service. The five parts provide cooperation method with software buses. Finally, the paper introduces the architecture of software design and it analyzes the software system functions. The CV-MDN model can be formed a general method for design of GMCS.

In this letter, we address the problem of wideband sources localization in the near field of the sensor array. It is shown that the spatial sampling rate can be considered as a function of temporal frequency so that wideband sources can be represented in the spatial frequency domain. A computationally efficient localization method is then developed based on the Toeplitz matrices constructed from the frequency-dependent cross-correlation between sensors. This allows us to resolve near field sources with quite a few numbers of sensors. Indeed, the sources can be located with fewer sensors. Finally, the simulation results are presented to validate the performance of the proposed method.

Chimaphilin, 2,7-dimethyl-1,4-naphthoquinone, is extracted from pyrola [Passiflora incarnata Fisch.]. In this study, the anticancer activity and underlying mechanisms of chimaphilin toward human breast cancer MCF-7 cells are firstly investigated. Chimaphilin could inhibit the viability of MCF-7 cells in a concentration-dependent manner, and the IC50 value was 43.30μM for 24h. Chimaphilin markedly induced apoptosis through the investigation of characteristic apoptotic morphological changes, nuclear DNA fragmentation, annexin V-FITC/propidium iodide (PI) double staining. Flow cytometry assay revealed that chimaphilin triggered a significant generation of ROS and disruption of mitochondrial membrane potential. Additionally, western blotting assay showed that chimaphilin suppressed Bcl-2 level and enhanced Bad level, then activated caspase-9 and caspase-3, and further activated the poly ADP-ribose polymerase (PARP), finally induced cell apoptosis involving the mitochondrial pathway. Furthermore, free radical scavengers N-acetyl-L-cysteine (NAC) pretreatment test testified that chimaphilin could increase the generation of ROS, then induce cell apoptosis. In general, the present results demonstrated that chimaphilin induced apoptosis in human breast cancer MCF-7 cells via a ROS-mediated mitochondrial pathway.

To investigate the clinical significance of cyclin A expression in adult patients with acute leukemia (AL).4 ml bone marrow was extracted from 100 AL patients and 10 normal controls to isolate the mononuclear cells (MNCs). The cyclin A mRNA levels in these MNCs were measured by RT-PCR. The cyclin A protein level and cell cycle in 75 randomly selected AL patients and 10 normal controls were examined by flow cytometric analysis.(1) The distribution of cyclin A protein was normal in cell cycle in AL patients. The positive rates of cyclin A protein and mRNA were 66.7% and 59%, significantly higher than those in the normal controls (0 and 1.4% respectively, both P0.01). The median expression levels of cyclin A protein and mRNA of cyclin A in AL patients were 18.5% and 0.539 +/- 0.490 respectively, significantly higher than those in the normal controls (both P0.01). Sequence analysis showed a complete consistency between the positive segment of cyclin A and the objective gene in GeneBank. (2) The levels of cyclin A protein and mRNA were positively correlated with the cumulative percentages of cells in S and G(2)/M phases (P0.01). (3) The expression level of cyclin A protein in the recurrent acute lymphoblastic leukemia (ALL) group was 15.4%, significantly lower than those of de novo group (29.5%, t = 14.418, P = 0.022). (4) The complete remission (CR) rates in the AL patients with high expression levels of cyclin A protein and mRNA group were 87.9% and 85.7% respectively, significantly higher than those in the AL patients with low expression levels (38.2% and 53.5% respectively, both P0.01). Multivariate regression analysis showed that cyclin A was one of the influencing factors of CR rate of AL patients (P0.05).Cyclin A expression contributes to the high proliferative activity in leukemia cells. The abnormal expression of cyclin A might be a prognostic marker of CR rate in AL patients.