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Both vascular adventitial fibroblasts (VAFs) and urotensin II (UII) play important roles in vascular remodeling diseases, but the mechanism of UII in VAFs is still unclear. UII inhibited miR-124 expression through up-regulating circ0004372 expression, thereby promoting SERTAD4 expression. UII significantly promoted the generation of ROS, MDA and 4-HNE, reduced the activities of SOD, GST and GR, increased Fe2+ concentration and inhibited GPX4 expression through circ0004372/miR-124/SERTAD4. Both UII and ferroptosis inducer Erastin significantly promoted the expression of α-SMA, Collagen I and TGF-β1 in VAFs, but circ0004372 siRNA, miR-124 mimics, SERTAD4 siRNA or Ferrostatin-1 significantly inhibited the effect of UII and Erastin on cell activation. When co-transfected with circ0004372 siRNA and miR-124 inhibitors or miR-124 mimics and SERTAD4 overexpression vector, UII still significantly increased the expression of α-SMA, Collagen I and TGF-β1. After transfection with circ0004372 overexpression vector, miR-124 inhibitors or SERTAD4 overexpression vector and then treating with UII and Ferrostatin-1, the expression of α-SMA, Collagen I and TGF-β1 was still significant; when the circ0004372 overexpression vector and miR-124 mimics or miR-124 inhibitors and SERTAD4 siRNA were co-transfected and then UII and Ferrostatin-1 were added, the expression of α-SMA, Collagen I and TGF-β1 was not significantly increased. Therefore, these results indicate that UII promotes the activation of VAFs through the circ0004372/miR-124/SERTAD4/ferroptosis pathway.

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.

The application of lithium niobate thin film is a hot topic now. Due to its superior electro-optic modulation properties, it has many popular applications in integrated optics. However, LN thin film’s small size also produces major challenges when attempting to efficiently couple light with optical fibers. Therefore, a trident edge coupler for LN thin-film is proposed in this paper, and its performance is studied in simulation. The trident edge coupler shows

The Jintingling gold deposit, located in the Jiaodong peninsula, north China, contains vein-, dissemination- and stockwork-style ores hosted in the Jurassic Linglong granitic pluton. Hydrothermal activities in this deposit are divided into seven stages, including pre-ore massive K-feldspar alteration, specularite-quartz vein (V1), milky quartz ± sulfide vein (V2), quartz-pyrite vein (V3), massive quartz-sericite-pyrite alteration and gold mineralization, quartz-polymetallic sulfide vein (V4), and quartz-calcite vein (V5). Rhenium-Osmium dating was conducted on molybdenite from V2, yielding an isochron age of 123.3 ± 3.6 Ma. LA-ICP-MS zircon U-Pb dating yielded 121.5 ± 1.5 Ma (1σ, MSWD = 0.010) for a pre-ore diorite porphyrite dyke and 117.6 ± 1.2 Ma (1σ, MSWD = 0.018) for a post-ore diorite porphyry dyke, respectively. Thus, gold mineralization occurred at 122–118 Ma. Four types of fluid inclusions were identified in quartz veins, including CO2-H2O ± CH4 inclusions (type I), pure CO2 inclusions (type II), mineral-bearing inclusions (type III) and aqueous inclusions (type IV). Fluid inclusion studies demonstrate that the primary ore-forming fluids contain CO2-rich vapor (357–420 °C, 7.2–11.3 wt% NaCl equivalent) and critical fluids (368–400 °C). The two phases were likely formed by immiscibility of magmatic-hydrothermal fluids. Later on, the fluids evolved to a H2O-CO2-NaCl ± CH4 system which had temperatures of 300–364 °C and salinities of 2.0–9.7 wt% NaCl equivalent. The H2O-CO2-NaCl ± CH4 fluid system may experience phase separation, forming coexisted CO2-H2O ± CH4 inclusions (homogenized to vapor or liquid at temperature of 265–309 °C and 265–287 °C, salinities of 3.1–7.1 wt% and 4.3–7.1 wt% NaCl equivalent, respectively) and aqueous inclusions (homogenized to liquid at temperature of 255–294 °C and 3.7–7.6 wt% NaCl equivalent). Along with further evolution, the fluids shifted to a H2O-NaCl system, with temperatures of 163–258 °C and salinities of 0.5–9.0 wt% NaCl equivalent. Pyrite from the Jintingling deposit has δ34S values (5.5‰–6.1‰) similar to those of pyrite from other gold deposits in the Jiaodong district, indicating that they were related to the same hydrothermal ore-forming system. The δ13CPDB values of calcite (−4.5‰ to −5.4‰) in V5 are generally located in the range of magmatic-derived carbon. Fluids of V2, V3, V4 have δD from −64.4‰ to −87.1‰, and δ18O from 8.4‰ to 0.2‰, located in the compositional fields between magmatic water and meteoric water. Collectively, microthermonetric results and isotopic data indicate that the primary ore-forming fluids were most probably magmatic in origin, with incorporation of meteoric water in the later ore-forming stage. Precipitation of gold was triggered by cooling of fluids, fluid immiscibility and decrease of sulfur in the fluids.

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.

OBJECTIVES Activation of coagulation and fibrinolysis is frequently observed in patients with cancer, even with absence of thrombosis. Furthermore, plasma coagulation parameters were associated with tumor progression, metastasis, and prognosis. Few studies have investigated these associations in pancreatic cancer (PA). This study aimed to investigate the clinical and prognostic significance of various plasma coagulation tests in PA patients with absence of venous thromboembolism (VTE). MATERIALS AND METHODS A total of 139 PA patients with the absence of VTE were included in the analysis. Patients were followed up for at least 12 months until death. Pretreatment coagulation parameters including prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), fibrinogen (F), antithrombin-III (AT-III), protein C (PC), factor-VIII (F-VIII), and D-dimer (DD) were evaluated. A total of 40 age-matched and sex-matched healthy individuals without coagulation disorder were enrolled as the control group. RESULTS Patients were inclined to have higher levels of PT, INR, APTT, F, F-VIII, and DD and lower levels of AT-III and PC than the control group (P

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.

This paper develops a requirement modeling language called CosRDL for modeling and analyzing of the time series embedded control systems. The system consists of a series of parallel active task that is composed of the functions for different control behaviors, which is largely applied in the development of embedded control systems. CosRDL can specify the features event-driven behaviors, and each event in CosRDL can contain such as input/output and communication of active objects. The active object is a concept model that expresses a computing or control processing. It contains a set of operation, an event queue and task priority. A requirement model and system model of the CosRDL is proposed for analyzing event-driven control systems. The requirement model of CosRDL is built by directed acyclic graph (DAG) to describe the system behavior. The system model of CosRDL is built by uFusion framework. The uFusion was designed to implement the event-driven system architecture. Meanwhile, a case study is presented to illustrate our approach to requirement modeling in the development of event-driven control systems.

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.

In order to provide effective power for small aerocraft, this paper offers a design of an electromagnetic vibration energy harvester based on MEMS technology, which works in special launching environment. According to "mass-spring-damper" system theory, this paper firstly built a model of the pick-up system, and discussed the pick-up system's response to sinusoidal input and impact load. Then, an energy conversion system was modeled, in order to analyze the system's power output. ANSYS simulation has been done on the pick-up system of different structures & parameters, and the relationship between different structures & parameters and the energy harvester voltage output has been studied. Based on the theoretical analysis and software simulation, the designed energy harvester working high frequency vibration environment can produce voltage over 200mV, which is enough for micro-sensor, low-power circuit in aerocraft.

Geraniin, a typical ellagitannin isolated from Phyllanthus urinaria Linn, has been found to possess a range of bioactive properties. In the present study, we found that Geraniin showed potent anti-proliferative effects on human breast cancer MCF-7 cells. The IC50 values were 9.94, 17.98 and 42.32 µM after 72-, 48- and 24-h treatment, respectively. Meanwhile, Geraniin could remarkably disrupt mitochondrial membrane potential and arrest S phase cell cycle. Western-blot analysis showed that Geraniin induced phosphorylation of the anti-apoptotic Bcl-2, and the cleavage of poly (ADP-ribose) polymerase (PARP) and caspase-3 in MCF-7 cells. Moreover, Geraniin treatment activated p38 mitogen-activated protein kinase (p38 MAPK) and the effect was blunted in MCF-7 cells with the treatment of a specific p38 inhibitor SB203580. Geraniin could generate intracellular reactive oxygen species (ROS), activate p38 MAPK then induce the apoptosis in MCF-7 cells, such phenomena was abrogated by pretreatment with N-acetyl-l-cysteine. In general, these results support the conclusion that Geraniin-induced apoptosis is mediated via ROS-mediated stimulation of p38 MAPK signaling.

Evaluation indexes (monitoring value) set in safety evaluation of dike, it was difficult in conforming the range of evaluation indexes, and could not reflect characteristic of outburst destroy. Catastrophe theory is a kind of mathematical method that problems of transition, discontinuity, and abrupt qualitative change based on analysissitus, problems about how a system of continuous quantitative change to evolving into jumping qualitative change can be analyzed. Firstly, the relation between deformation of dike with components of water pressure, temperature and time effect is analyzed, subdivision lemma of cusp catastrophe theory is cheesed, expression of potential formula on horizontal deformation is carried out based on influence of factor of time, water pressure and temperature. Moreover, normal form of catastrophe is advanced and critical rules of dike safety are put forward, evaluation model based on catastrophe theory is established. Finally, the model is validated with dike of Yellow River. Analysis shows that evaluating conclusion of the model is as the same as the practice, and it can not only reflect outburst destroy character of dike, but also evaluate safety degree in quantity, thus the model is good in adaptability and precision.

The incidence of pancreatic cancer has increased in China in the last decade, though efforts have been made in early detection and multimodality treatment. The aim of this study is to describe the decade-based development in early diagnosis and treatment modalities, as well as outcome for patients with pancreatic ductal adenocarcinoma (PDAC) in a high-volume facility.All the PDAC patients underwent surgery between 1991 and 2009 and were selected from the database of TianJin Cancer Institute and Hospital. Decade-based changes in early diagnosis, treatment modalities, and outcome of the patients were retrospectively analyzed.Of the 565 patients with PDAC, patients in this decade (n = 460) had better overall survival than those in the last decade (n = 105), median survival was 10 months and 3 months, respectively. Patients in this decade had significantly improved in (P 0.001) 2-year (14.7%) and 5-year survival rates (3.5%) as compared to those in the last decade (6.7% and 3.4%, respectively). Patients with metastasis at diagnosis in the last decade and this decade were 54% and 26% (P 0.001), respectively. More patients in this decade had underwent R0/R1 resection (33% vs 20%, P = 0.010), chemotherapy (37% vs 12%, P 0.001), and radical resection (34% vs 21%, P = 0.014) than those in the last decade.Patients operated on for PDAC in this decade had a better outcome than those in the last decade. Early detection, improved resection margin, and development in multimodality treatment contribute to this improvement.

Highly oriented and perovskite structure KTN (potassium tantalate-niobate) thin films were fabricated by pulsed laser deposition technique on Si(100) substrates. The surface of the thin films is homogeneous, crack-free and dense. The ferroelectric measurement was carried out on metal-ferroelectric-metal capacitors and the remanent polarization and the coercive field were 8.66 μC/cm 2 and 7.44 kV/cm, respectively. The effects of the substrate temperature, laser energy density on the target and oxygen pressure during the deposition process on the structure of thin films were discussed.

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.

P2P traffic has taken up the most significant portion of the network traffic. Effective identification of P2P traffic becomes an important role for network traffic management. However, with the wide application of dynamic port and content encrypted techniques, traditional P2P identification methods are powerless. To address the issues of port hopping and unconspicuous application characters, a fast identification method of P2P flow is proposed in this study, in which the connection degree distribution of network nodes is used to judge the effective character of P2P flow. At the same time, some common P2P protocols are tested with the method, including HTTP, OICQ, DNS and Edonkey. Experimental results show that using this identification method can quickly and effectively judge P2P flow. The method can also deal with network congestion to a certain extent by identifying and monitoring P2P traffic.

Cyclin B1, a positive regulator, controls mitosis occurrence, plays an important role in cell proliferation. To investigate the clinical significance of cyclin B1, the expression of cyclin B1 in acute leukemia (AL) patients was measured; the expression of cyclin B1 and p21(cipl), and their cell cycle distribution were assayed by flow cytometry in 136 adult patients with newly diagnosed AL, 10 continuous complete remission (CCR) AL and 17 normal controls; the mRNA of cyclin B1 and p21(cipl), and the proliferation cell nuclear antigen (PCNA) in patients and normal controls were detected with semi-quantitative reverse transcription polymerase chain reaction (RT-PCR). The results showed that the expression of cyclin B1 in newly diagnosed AL patients was significantly higher than that in normal controls. For the relapsed AL patients, the cyclin B1 expression was also higher than that in normal controls, but lower than that in newly diagnosed cases, there was no significant difference between the remission cases and normal controls, nor difference between CCR AL patients and normal controls. All patients with high cyclin B1 expression had an unscheduled expression manner, that cyclin B1 protein appeared in G(1) phase, and in some case it even higher than that of G(2) phase. The response rate (partial remission + complete remission) and survival rate in the cyclin B1 high expressed patients were higher than that of cyclin B1 low expressed patients. The relapse rate in cyclin B1 high expressed patients was higher than that in cyclin B1 normally expressed patients. The survival rate in cyclin B1 high expressed patients was higher than that in cyclin B1 low expression patients. A negative correlation between the expression of cyclin B1 and p21(cipl) was observed. Additionally, cyclin B1 protein expression was generally correlated with proliferation index (PI) and proliferation cell nuclear antigen (PCNA). It is concluded that this study demonstrates for the first time cyclin B1 overexpression and abnormally distribution in cell cyclin of newly diagnosed AL patients. It was considered that cyclin B1 may play an important role in leukemic pathogeneses and can be one of the factors influencing the prognosis of AL patients.

Etoposide (VP-16) is one of the most common chemotherapy drugs, but its usage is limited by drug resistance. Some researches on solid tumors show that cisplatin (DDP) have synergetic effect with VP-16. This study was to evaluate synergetic cytotoxicity of VP-16 and DDP to leukemia cell line K562, and explore the mechanism.K562 cells were treated with VP-16 (0 or 5 microg/ml) and DDP (0, 0.3, 3, 15, or 30 microg/ml) in different combination patterns. Inhibitory effect of VP-16 and DDP on survival of K562 cells was measured by MTT assay. Cell apoptosis was evaluated by AO/EB double fluorescent labeling. The expression of topoisomerase (TOPO) II alpha and II beta, and transcription factor Sp1 and Sp3 were measured by semi-quantitive reverse transcription-polymerase chain reaction (RT-PCR) and Western blot.MTT assay showed significant synergetic cytotoxicity of VP-16 and DDP. VP-16 in combination with DDP obviously enhanced cell apoptosis. RT-PCR showed that DDP significantly up-regulated the expression of TOPO II and Sp1 in concentration-dependent manners (TOPO II alpha, II beta, and Sp1 were up-regulated by 36%, 25%, and 75% of control, respectively, when treated with 30 microg/ml of DDP), and down-regulated Sp3 by 49% of control; VP-16 (5 microg/ml) down-regulated TOPO II alpha by 71.9%, and up-regulated Sp3 by 14%; VP-16 (5 microg/ml) in combination with DDP (30 microg/ml) up-regulated TOPO II alpha by 83%, II beta by 11%, and Sp1 by 58% when compared with using VP-16 alone (but the levels were lower than using DDP alone), and down-regulated Sp3 by 61.3% when compared with using DDP alone. Western blot showed similar results to RT-PCR.Through up-regulating TOPO II, DDP could enhance the chemotherapeutic effect of VP-16 on K562 cells by provide more target enzyme to act on.

To investigate the clinical significance of cyclin B1 expression in adult acute leukemia (AL) patients.The expression of cyclin B1 and p21 and their cell cycle distribution were measured by flow cytometry in 85 adult patients with de novo AL, 10 continuous complete remission (CCR) AL and 17 normal controls (NC). The mRNAs of cyclin B1, p21 cip1 and proliferation cell nuclear antigen (PCNA) in patients and NCs were measured with semi-quantity reverse transcription polymerase chain reaction (RT-PCR).Cyclin B1 protein expression in de novo AL patients was significantly higher than that in NC (P0.001). It was higher in relapsed patients than in NC (P0.05) but was lower than in de novo AL (P0.01). There was no difference between the remission cases and NC (P = 0.21), and between CCR patients and NC (P0.05). The cyclin B1 overexpression ratio was higher than that of NC. A negative correlation between the expression levels of cyclin B1 and P21 was observed (r = -0.266, P0.05). The cyclin B1 protein expression level was positively correlated with its mRNA level. The expression of cyclin B1 was positively correlated with proliferation index (PI) levels, and with PCNA levels (rPI = 0.7314, rPCNA = 0.7152). Remission rate was higher in high cyclin B1 expression patients than in normal cyclin B1 expression patients (P0.01), so did the relapse rate (P0.01). Patients with higher cyclin B1 expression had higher survival rate.Cyclin B1 was overexpressed and abnormally distributed in cell cycle phases in de novo AL patients. Overexpression of cyclin B1 might be a favorable prognostic factor for patients with AL.

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.

To investigate the relation between the expression of cyclin B1 and multidrug resistance in adult patients with acute leukemia.The proteins expression of cyclin B1, p170 was measured with flow cytometric analysis in 85 adult de novo acute leukemia patients (AL) and 17 normal control (NC). The expression of cyclin B1, multidrug resistance gene (mdr-1), topoisomerase IIalpha, beta (TOPOIIalpha, beta) and bcl-2 mRNA in these patients was measured with semi-quantify reverse transcription polymerase chain reaction (RT-PCR).(1) The expression of cyclin B1 protein (M = 12.3%) and mRNA (M = 0.217) in the treatment resistance group was significantly lower than the sensitive group cyclin B1 protein (M = 22.7%) and mRNA (M = 0.563) (P0.05), so was the mRNA of TOPOIIalpha (M = 0.236), TOPOIIbeta (M = 0.328) than the sensitive group TOPOIIalpha (M = 0.514), TOPOIIbeta (M = 0.635) (P0.01). Cyclin B1 protein expression was lower than 5% and there were no expression of cyclin B1, TOPOIIalpha, mdr-1 mRNA in the NC group under the same condition. (2) The p170 protein (M = 14.3%) and mdr-1 (M = 1.071), bcl-2 (M = 0.941) mRNA expression in the resistant group was significant higher than the sensitive group p170 protein (M = 3.6%) and mdr-1 (M = 0.094), bcl-2 (M = 0.153) (P0.01). (3) The expression of cyclin B1 protein and TOPOIIalpha, TOPOIIbeta mRNA was positive correlated (r(TOPOIIalpha) = 0.472, P0.01; r(TOPOIIbeta) = 0.683, P0.01), so was the cyclin B1 mRNA (r(TOPOIIalpha) = 0.319, P0.05; r(TOPOIIbeta) = 0.527, P0.05). (4) There was no correlation between cyclin B1 and p170, mdr-1, bcl-2. (5) By Binary logistic forward conditional analysis we concluded that cyclin B1 correlated with atypital mutidrug resistance.Low expression of cyclin B1 might be a unfavorable prognostic factor for patients with AL and measurement of both cyclin B1 and TOPOIIalpha, TOPOIIbeta gene expression would predict drug resistance in adult acute leukemia patients.

The aim of this study was to investigate whether and how phosphodiesterase (PDE) inhibitors modulate the proliferation, cell cycle and apoptosis in lymphoma cells. The effects of aminophylline (AM), a non-specific PDE inhibitor, on Raji cells were explored in vitro. MTT assay, light and transmission electron microscopy and annexin V staining were used to observe cell proliferation, morphologic changes and apoptosis rate in AM-treated cells, and FCM and RT-PCR techniques were adopted to detect the effect on cell cycle, the expression of cyclin B1 and Bcl-2 and mitochondrial transmembrane potential in AM-treated cells. The results showed that AM inhibited the growth of Raji cells in a concentration-dependent manner. Morphologic observations showed apoptosis changes in AM-treated cells, including cytoplamic shrinkage, cytoplasmic bubbling, karyopyknosis and nuclear fragmentation. FCM and RT-PCR detection showed that AM intervention increased the fraction of annexin V(+) cells, reduced the value of mitochondrial transmembrane potential, induced S phase arrest, and down-regulated the expression of Bcl-2 at both mRNA and protein level and cyclin B1 protein in a concentration-dependent manner. It is concluded that PDE inhibitor aminophylline may induce Raji cell growth inhibition, S phase arrest, apoptosis via down-regulation of Bcl-2 and reduction of mitochondrial transmembrane potential.

In order to investigate the role and the mechanism of protein tyrosine phosphatase (PTPase) signaling pathway in the regulation of proliferation, cell cycle and apoptosis in lymphoma cells, the effects of sodium orthovanadate, Na(3)VO(4), a specific PTPase inhibitor, were explored on Raji lymphoblast-like cell line by MTT assay and CFU-Raji culture, morphologic observation, DNA gel electrophoresis, FCM and RT-PCR. Results showed that MTT assay and CFU-Raji culture demonstrated that sodium or thovanadate inhibited the growth of Raji cells in a concentration-dependent fashion; morphologic observations showed that Raji cells exhibited cytoplasm shrinkage, cytoplasm membrane blebbing, nuclear fragmentation and chromatin condensation forming crescents along nuclear membrane characteristic of apoptosis in the presence of Na(3)VO(4); DNA gel electrophoresis revealed typical DNA ladder reminiscent of DNA cleavage at internucleosomal sites in Na(3)VO(4) treated cells; FCM and RT-PCR indicated that Na(3)VO(4) intervention increased the fraction of annexin V(+) PI(-) cells, reduced the value of mitochondrial transmembrane potential, induced G(2)/M arrest and down-regulated the expression of Bcl-2 and cyclin B1 at both mRNA and protein level in a concentration-dependent manner. It was concluded that PTPase pathway might be implicated in the regulation of cell proliferation, cell cycle and apoptosis, and PTPase specific inhibitor Na(3)VO(4) could induce Raji cell growth inhibition, G(2)/M arrest and apoptosis via down-regulation of Bcl-2 and cyclin B1, and reduction of mitochondrial transmembrane potential.

The I-V characteristics of K(Ta 0.65 Nb 0.35 )O 3 thin films being prepared by PLD method on Si(100) were found to be Ohmic at low fields and space-charge-limited at higher fields, and this phenomena was correctly explained by SCLC theory.