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Olszewski, Michael W., Samara J. Danan, and Thomas J. Boerth. "Effects of Enhanced APG Surfactant on Leaching and Wettability of Six Bark Substrates." HortTechnology 18, no. 2 (January 2008): 295–300. http://dx.doi.org/10.21273/horttech.18.2.295.
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Alkyl phenol ethoxylate (APE) surfactants are used in horticultural substrates but are considered nonbiodegradable, whereas others such as alkyl polyglucoside (APG) are derived from biodegradable sugar compounds. APE reduced total porosity (TP), container capacity (CC), and aeration porosity (AP) whereas APG with polyalkylene oxide block copolymer surfactant (APG/BLK) increased TP, CC, and AP for some substrates but other substrates remained unaffected by either surfactant. We determined substrate leaching fraction (LF) and wettability rating (WR) after drenches of 0.003 to 0.2 mL·L−1 APG/BLK for six bark substrates for three wetting cycles. After the third wetting cycle, five substrates had reduced LF and increased WR. Drenches of 0.2 mL·L−1 APE or APG/BLK for three wetting cycles indicated that APE was more efficacious than APG/BLK for reducing LF or increasing WR. APE was determined to be an effective surfactant for difficult-to-wet substrates, but drenching sometimes reduced TP. No reductions in TP were noted when using APG/BLK. Drenching rates of 0.003–0.2 mL·L−1 APG/BLK for three successive wetting cycles reduced LF and increased WR for most substrates, indicating potential usage for some horticultural applications.
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Vicens, Margarita, Amparo Caubet, and Virtudes Moreno. "Interaction of Pd(II) and Pt(II) Amino Acid Complexes With Dinucleotides." Metal-Based Drugs 4, no. 1 (January 1, 1997): 43–50. http://dx.doi.org/10.1155/mbd.1997.43.
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The interaction of the dinucleotides d(ApG) and d(ApA) with [Pd(aa)Cl2], where aa = L- or D-histidine or the methyl ester of L-histidine, and with [Pt(Met)Cl2], where Met = L-methionine was studied by H1 and C13 NMR and CD measurements. In the case of the L-histidine and L-histidineOMe, the reaction with d(ApG) appeared to give the bifunctional adducts Pd(L-Histidine)N1(1)N7(2) and Pd(L-HisOMe)N1(1)N7(2), but the behavior with D-histidine suggested the formation of the monofunctional adduct Pd(D-His)N7(2). The reaction of L-histidine with d(ApA) seemed to form the bimetallic adduct (L-His)PdN7(1)N7(2)Pd(L-His). The Pt(II)-L-methionine complex in both reactions with d(ApG) and d(ApA) seemed to yield mainly adducts Pt(L-Met)N7(1)N7(2) but the existence of adducts Pt(L-Met)N1(1)N7(2) cannot be ruled out.
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Modeß, Johannes M. "Apg 4,32–37 14.6.2020 1. Sonntag nach Trinitatis." Göttinger Predigtmeditationen 74, no. 3 (March 31, 2020): 332–36. http://dx.doi.org/10.13109/gpre.2019.74.3.332.
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Modeß, Johannes M. "Apg 4,32–37 14.6.2020 1. Sonntag nach Trinitatis." Pastoraltheologie 109, no. 5 (March 31, 2020): 332–36. http://dx.doi.org/10.13109/path.2020.109.5.332.
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Chen, Lihong, Chun Wang, Hengchuan Liu, Guanjian Liu, and Xingwu Ran. "Antibacterial Effect of Autologous Platelet-Rich Gel Derived from Subjects with Diabetic Dermal Ulcers In Vitro." Journal of Diabetes Research 2013 (2013): 1–5. http://dx.doi.org/10.1155/2013/269527.
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Background. Autologous platelet-rich gel (APG) is an effective method to improve ulcer healing. However, the mechanisms are not clear. This study aimed to investigate the antibacterial effect of APG in vitro.Methods. Platelet-rich plasma (PRP), platelet-poor plasma (PPP) and APG were prepared from whole blood of sixteen diabetic patients with dermal ulcers. Antibacterial effects againstStaphylococcus aureus,Escherichia coli, andPseudomonas aeruginosawere evaluated by bacteriostasis assay of APG, PRP, and APG-APO (APG combined with apocynin), with phosphate-buffered saline (PBS) and PPP as the control group.Results. (1) Compared to the PBS and PPP, the APG and APG-APO groups showed strong antibacterial activity againstStaphylococcus aureus. There was no significant difference(P>0.05)between APG and APG-APO. (2) Compared to PBS, APG, APG-APO, and PRP showed obvious antibacterial effects againstEscherichia coliandPseudomonas aeruginosa. No significant difference(P>0.05)was revealed among the three groups. Compared to the PPP group, they did not show antibacterial effect againstEscherichia coliandPseudomonas aeruginosa(P>0.05).Conclusions. APG has antibacterial effect againstStaphylococcus aureusmediated by platelet activation in the diabetic patients with dermal ulcer, and does not present obvious antibacterial effect againstEscherichia coliorPseudomonas aeruginosa. Combination of APG and antibiotics may have synergistic antibacterial effect.
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Plasger, Georg. "Apg 6, 1–7 17.8.2008 13. Sonntag nach Trinitatis." Göttinger Predigtmeditationen 62, no. 3 (April 2007): 364–69. http://dx.doi.org/10.13109/gpre.2007.62.3.364.
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Hadem, Eva. "Apg 3, 1-10 26.8.2012 12. Sonntag nach Trinitatis." Göttinger Predigtmeditationen 66, no. 3 (April 2011): 370–75. http://dx.doi.org/10.13109/gpre.2011.66.3.370.
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Gehring, Hans-Ulrich. "Apg 12, 1-11 23.9.2012 16. Sonntag nach Trinitatis." Göttinger Predigtmeditationen 66, no. 4 (July 2011): 406–12. http://dx.doi.org/10.13109/gpre.2011.66.4.406.
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Tsapara, Anna, Karl Matter, and Maria S. Balda. "The Heat-Shock Protein Apg-2 Binds to the Tight Junction Protein ZO-1 and Regulates Transcriptional Activity of ZONAB." Molecular Biology of the Cell 17, no. 3 (March 2006): 1322–30. http://dx.doi.org/10.1091/mbc.e05-06-0507.
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The tight junction adaptor protein ZO-1 regulates intracellular signaling and cell proliferation. Its Src homology 3 (SH3) domain is required for the regulation of proliferation and binds to the Y-box transcription factor ZO-1-associated nucleic acid binding protein (ZONAB). Binding of ZO-1 to ZONAB results in cytoplasmic sequestration and hence inhibition of ZONAB's transcriptional activity. Here, we identify a new binding partner of the SH3 domain that modulates ZO-1–ZONAB signaling. Expression screening of a cDNA library with a fusion protein containing the SH3 domain yielded a cDNA coding for Apg-2, a member of the heat-shock protein 110 (Hsp 110) subfamily of Hsp70 heat-shock proteins, which is overexpressed in carcinomas. Regulated depletion of Apg-2 in Madin-Darby canine kidney cells inhibits G1/S phase progression. Apg-2 coimmunoprecipitates with ZO-1 and partially localizes to intercellular junctions. Junctional recruitment and coimmunoprecipitation with ZO-1 are stimulated by heat shock. Apg-2 competes with ZONAB for binding to the SH3 domain in vitro and regulates ZONAB's transcriptional activity in reporter gene assays. Our data hence support a model in which Apg-2 regulates ZONAB function by competing for binding to the SH3 domain of ZO-1 and suggest that Apg-2 functions as a regulator of ZO-1–ZONAB signaling in epithelial cells in response to cellular stress.
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Bastian, Februadi, Ani Suryani, and Titi Candra Sunarti. "PENINGKATAN KECERAHAN PADA PROSES SINTESIS SURFAKTAN NONIONIK ALKIL POLIGLIKOSIDA (APG) BERBASIS TAPIOKA DAN DODEKANOL." Reaktor 14, no. 2 (August 8, 2012): 143. http://dx.doi.org/10.14710/reaktor.14.2.143-150.
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Alkylpolyglycosides (APG) is a nonionic surfactant that has been getting some green labels such asEcocert, EU Eco-flower and Green Seal as an environmentally friendly surfactant. Sugar is the mainraw material which is supplied the hydrophilic group, and fatty alcohol as hydrophobic group. Someundesirable compounds formed during the APG production and caused low quality. The aim of thisresearch to increase the quality and performance of APG, by controlling its process. Addition 0-10%of activated carbon and 0-0.3% of NaBH4 in APG pre-purification process; 2% (w/w) of H2O2, 35%and 500 ppm of MgO in the bleaching process were examined to process high quality and highperformance of APG. The best APG was obtained from purification step by addition 0% of activatedcarbon and 0.2% of NaBH4, with the characteristics of clarity of 59.02(%T); the ability to reducesurface and interfacial tensions at 1% concentration were 61.94% and 95.6% respectively; 81.71%of stability of emulsion, 62.5% of foam height and stable up to 315 minutes. Alkil Poliglikosida (APG) merupakan surfaktan nonionic yang telah mendapatkan beberapa greenlabel seperti Ecocert, EU Eco-flower Green Seal dan sebagainya sebagai surfaktan yang ramahlingkungan. Bahan dasar APG yaitu gula untuk membentuk gugus hidrofiliknya dan fatty alcoholuntuk membentuk gugus hidrofobiknya. Permasalahan dalam produksi APG adalah timbulnya warnagelap yang tidak dikehendaki yang menyebabkan penurunan mutu APG. Tujuan dari penelitian iniyaitu untuk meningkatkan mutu dan kinerja dari APG. Untuk meningkatkan kecerahan APG, makasebelum dilakukan proses destilasi dilakukan penambahan arang aktif 0-10% serta NaBH4 0-0,3%.Pada proses pemucatan ditambahkan 2% (b/b) H2O2 35% dan MgO 500 ppm. Hasil terbaik yaitupenambahan arang aktif 0% dan NaBH4 0,2% dengan karakteristik kecerahan 59,02(%T);kemampuan menurunkan tegangan permukaan dan antar muka pada konsentrasi 1% sebesar 61,94%dan 95,6%; kestabilan emulsi 81,71%, tinggi busa 62,5% dan umur busa 315 menit.
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Liu, Fa Hui, Chuan Hua Wang, Xiao Yan Liu, Xia Liang, and Chi Quan He. "Enhancing Aquatic Plant Uptake of PAHs Using Environment-Friendly Surfactant Alkyl Polyglucoside(APG)." Applied Mechanics and Materials 295-298 (February 2013): 255–58. http://dx.doi.org/10.4028/www.scientific.net/amm.295-298.255.
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Aquatic plant, Scirpus triqueter, uptake of PAHs was investigated with test time for periods of 336h. The effect of APG, an environment-friendly surfactant, on the plant uptake and distribution characteristics of PAHs in root and shoot of the plant were detected. Concentrations of phenanthrene and pyrene in the Scirpus triqueter root increased sharply at the early stage and reached the peak at 16 h, but in shoots elevated significantly and reached the peak at 48h. APG did not show any apparent phytotoxity toward the growth of Scirpus triqueter in the test concentration range. APG(≤30 mg L-1) can enhance the root uptake and root concentration factors (RCF) of phenanthrene in plant, whereas APG(>30 mg L-1) may inhibit the PAHs uptake by the plant. Results indicate that the APG would be a preferred selection for the application of surfactant-enhanced phytoremediation and optimal concentration should be determined before the application of APG.
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DIEFENBACH, MANFRED. "Das ‘Sehen des Herrn’ vor Damaskus: Semantischer Zugang zu Apg 9, 22 und 26." New Testament Studies 52, no. 3 (July 2006): 409–18. http://dx.doi.org/10.1017/s0028688506000221.
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Vom ‘Sehen des Herrn’ vor Damaskus durch Paulus ist sowohl in Apg 9.1–9; 22.4–11 und 26.9–18 als auch in Gal 1.13–15 und 1 Kor 9.1; 15.8–9 die Rede. Was bedeutet die Aussage: Jesus erschien Paulus? Das Resultat der Untersuchung der angeführten Textstellen unter Berücksichtigung der Wortfeldanalyse der drei Worte von Sehen – βλεπω = ‘Ansicht’ in Apg 9.8c, 9a; θεωρεω = ‘Durchsicht’ in Apg 9.7e oder οραω = ‘Einsicht’ in Apg 22.15; 26.16 – und die Notiz von der ‘Stimme’ aus dem Himmel lassen eine Steigerung der Darstellung des so genannten Damaskusereignisses in der Apg feststellen. Auf der Grundlage dieser Vision bzw. Erscheinung ist die Missionstätigkeit des ‘Zeugen’ respektive ‘Apostel’ Paulus aus der Sicht von Apg 26 und Gal 1.13–15 eine von Gott selbst gewollte.
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Rasco, Drew W., Yufeng Li, Yuefen Tang, Lichuang Men, Hengbang Wang, Jiao Ji, Zhiyan Liang, et al. "A phase I study of a novel IAP inhibitor APG-1387 as a monotherapy or in combination with pembrolizumab in treatments of patients with advanced solid tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 3125. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.3125.
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3125 Background: APG-1387 is a novel, bivalent small molecule IAP (inhibitor of apoptosis proteins) inhibitor. It has shown strong antitumor activities in multiple human xenograft cancer models. APG-1387 also acts as host immune modulator, supporting the notion that APG-1387 in combination with anti-PD1 antibody for cancer therapy. Methods: This study consists of two parts (NCT03386526). Part 1 is the dose escalation study of APG-1387 including a mPC (metastatic pancreatic cancer) cohort expansion. Part 2 is the dose escalation and cohort expansion study of APG-1387 in combination with pembrolizumab. APG-1387 is administrated IV for 30 minutes once weekly in a 21-day-cycle. Pembrolizumab is administrated at 200mg IV on day1 of a 21-day-cycle. The study objectives are to assess the safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed per RECIST v1.1 every 6 weeks). Results: Through Jan 4, 2019, total 23 patients had been treated in 4 cohorts of APG-1387 (20mg, 30mg, 45mg, 60mg). Two DLTs were observed at 60mg including lipase increase and Bell’s palsy, MTD was determined as 45mg. Nineteen of 23 patients experienced at least 1 TEAE. The most common TEAEs were nausea (21.7%), fatigue (17.4%), decreased appetite (13.0%), and abdominal pain (13.0%). Three grade 3 TEAEs including elevated bilirubin, lipase increase, and shortness of breath were documented at 45mg and 60mg. Three out of six mPC patients (one at 60mg, two at 45mg) achieved SD, one of them at 45mg has been treated > 5 cycles with confirmed SD (-18%). Two patients, who were treated with APG-1387 at 20mg in combination with pembrolizumab, had no DLT observed during the first cycle. Preliminary PK data of APG-1387 showed a dose proportionality in exposure (Cmax and AUC) over the dose range of 20-60 mg. Conclusions: APG-1387 was well tolerated and had manageable adverse events. The potential effects of APG-1387 alone or in combination with pembrolizumab deserve further exploration in patients with advanced solid tumors, especially in the mPC patients. Clinical trial information: NCT03386526.
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Rasco, Drew W., Nehal J. Lakhani, Yuefen Tang, Hengbang Wang, Jiao Ji, Jason Chen, ZHIYAN LIANG, Alex Amaya, Dajun Yang, and Yifan Zhai. "Phase Ib study of a novel bivalent IAP antagonist APG-1387 in combination of pembrolizumab for patients with advanced solid tumors." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3508. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3508.
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3508 Background: APG-1387 is an IAP (inhibitor of apoptosis proteins) antagonist that has strong antitumor activity in multiple xenograft cancer models and acts as a host immune modulator, supporting its exploration for use in combination with checkpoint inhibitors for cancer therapy. Methods: This “3+3” dose escalation and dose expansion study evaluated APG-1387 combined with pembrolizumab in patients with refractory or intolerant advanced solid tumors (NCT03386526). APG-1387 was administered IV once weekly with pembrolizumab 200 mg on day 1 of a 21-day cycle. Study aims were to assess safety/tolerability, recommended phase 2 dose (RP2D), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: As of December 25, 2019, total 28 patients had been treated in 3 dose cohorts of APG-1387: 20 mg (n = 4), 30 mg (n = 3), and 45 mg (n = 21, 18 in dose expansion). The median line of prior systemic cancer therapies was 3.0 (1-12). No dose-limiting toxicity was observed. The most common treatment-related adverse events (TRAEs; ≥10%) were fatigue (28.6%), arthralgia (14.3%), headache (14.3%), and tumor pain (10.7%). One patient in the 45-mg cohort had grade 2 Bell’s Palsy. G3+ TRAEs were autoimmune colitis, hypoxia, increased lipase, mucosal inflammation, pneumonitis, and tumor pain in 1 patient each (3.6%). Treatment-related SAEs were 1 G3 autoimmune colitis, 1 G2 myocarditis, and 1 G3 pneumonitis. The maximum tolerated dose (MTD)/RP2D for APG-1387 was 45 mg. Among 25 efficacy-evaluable patients, 1 with ER+, HER2‒ breast cancer receiving APG-1387 30 mg after failing 5 lines of therapy (PD-1 treatment-naïve, microsatellite stable) achieved confirmed PR (-79.2%) for 6 cycles but discontinued due to pneumonitis; another patient with PD-L1‒ non‒small-cell lung cancer treated at 45 mg had confirmed PR (-65.0%) for 6 cycles (ongoing). Other 11 patients had SD for 2-11 cycles. The disease control rate was 52%. Preliminary PK data showed a dose-proportional increase in APG-1387 exposure from 20 mg to 45 mg. Preliminary PD data showed that APG-1387 induced rapid degradation of cellular IAP1 and X-linked IAP in peripheral blood mononuclear cell samples; Increased serum release of interleukins (IL-12, IL-10) and monocyte chemotactic protein 4 was dose and time dependent. Conclusions: APG-1387 combined with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in patients with several tumor types. The ongoing study will further evaluate the efficacy of this combination. Clinical trial information: NCT03386526 .
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Reinsborough, Vincent C., and Vanessa C. Stephenson. "Inclusion complexation involving sugar-containing species: β-cyclodextrin and sugar surfactants." Canadian Journal of Chemistry 82, no. 1 (January 1, 2004): 45–49. http://dx.doi.org/10.1139/v03-180.
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Surface tension, proton NMR, and computer modeling studies were undertaken in nonionic alkylpolyglycoside (APG) solutions containing β-cyclodextrin (β-CD) with a view to characterize the inclusion complexes formed and to determine if the sugar entities of the host and guest molecules played a significant role in the process. The APGs investigated were four glucopyranosides (octyl G8, decyl G10, dodecyl G12, tetradecyl G14) and two maltosides (decyl M10, dodecyl M12). Critical micelle concentrations (CMC) were obtained in the surfactantβ-CD systems, which in all cases increased with increasing β-CD concentration. The 1:1 APGβ-CD inclusion complex was principally formed with binding constants of 425 (mol L1)1 for the G12 complex, 340 (mol L1)1 for the G10 complex, and 125 (mol L1)1 for the M12 complex. The preferred configuration of the G-12β-CD complex has the surfactant tail coiled in the CD cavity with the surfactant sugar moiety sealing off the narrower opening of the CD torus.Key words: alkylpolyglycoside, β-cyclodextrin, NMR, critical micelle concentration, surface tension.
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Tolcher, Anthony W., Raghad Karim, Yuefen Tang, Hengbang Wang, Jiao Ji, Jason Chen, Angela Kaiser, et al. "Phase Ib study of a novel, small-molecule MDM2 inhibitor APG-115 combined with pembrolizumab in U.S. patients with metastatic solid tumors." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 3512. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.3512.
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3512 Background: APG-115 activates p53-mediated apoptosis in tumor cells retaining wild-type TP53. It also functions as a host immune modulator and enhances antitumor activities when combined with PD-1 blockade preclinically. MDM2 amplification is associated with hyperprogression in patients treated with checkpoint inhibitors. Methods: The Phase Ib / II study was designed to evaluate APG-115 combined with pembrolizumab in patients with metastatic solid tumors (NCT03611868). APG-115 was administered orally every other day for 2 weeks, at dose ranging from 50 mg – 200 mg, with pembrolizumab at 200 mg IV on Day 1 of a 21-day cycle. Study objectives were to assess safety including dose-limiting toxicity (DLT), serious adverse events (SAEs), treatment-related AEs (TRAEs), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy (assessed by RECIST v1.1), to determine recommended phase 2 dose (RP2D). Results: As of December 25, 2019, the enrollment of phase 1b study was completed. Total 19 patients had been treated in four APG-115 cohorts: 50 mg (n = 3), 100 mg (n = 3), 150 mg (n = 6), and 200 mg (n = 7). No DLT was observed, The TRAEs (≥15%) were nausea (47.4%), fatigue (36.8%), decreased platelet count (26.3%), and decreased appetite (21.1%), as well as diarrhea, vomiting, decreased neutrophil or white blood cell count, and hypothyroidism in 15.8% each. Grade > 3 TRAEs included decreased neutrophil and thrombocytopenia in 15.8% each. Two SAEs were treatment related: G3 febrile neutropenia and G3 adrenal insufficiency. No new safety finding from combination with Pembrolizumab. The RP2D of APG-115 was 150 mg. One patient with ovarian cancer has a CR lasting for 15 months, 2 patients had PR for 8-9 months: one NSCLC failed IO therapy, another with appendix cancer, and 7 had SD for 1.5-7 months. The objective response rate was 15.8%, and the disease control rate (DCR) was 52.6%. PK data indicated an approximately dose-proportional increase in APG-115 exposure over the range of 50-200 mg on Day 1. PD-PK analyses showed that serum macrophage inhibitory cytokine-1 (MIC-1) increase was time and dose dependent, the MIC-1 elevation correlated with APG-115 exposure, indicating p53 activation in these patients. Conclusions: APG-115 in combination with pembrolizumab is well tolerated. Encouraging antitumor effects were observed in several tumor types. The phase II study is ongoing in the cancer patients with specific bio-marker profiling. Clinical trial information: NCT03611868 .
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Makarova, Irina A. "The Role of Payments for Emissions of Pollutants From Associated Petroleum Gas Flaring as a Tool for Regulating the Rational Use of Natural Resources in the Oil-Producing Regions of the Russian Federation." Vestnik Tomskogo gosudarstvennogo universiteta. Ekonomika, no. 52 (2020): 198–214. http://dx.doi.org/10.17223/19988648/52/12.
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For a long time, Russia was the leader in associated petroleum gas (APG) flaring. This led to the destruction of useful raw materials and environmental pollution. Due to the tightening of the state policy in the field of the APG rational use and the introduction of fees for APG flaring in 2012, oil producing companies had an incentive to use APG efficiently. In addition, the level of air pollution began to decline. The budgets of the constituent entities of the Russian Federation in the oil-producing regions began to receive significant revenues. Some experts expected that the APG efficiency target would be achieved in 2014 or 2016. Unfortunately, some oil producers were unable to achieve the target. Moreover, at present, there is a reduction in payments for APG flaring in many regions. This causes concern for certain market participants. The object of this research is the impact of APG flaring fees on the level of rational APG use and on incomes of the oil-producing regions. The aim of the work is to study the role of these payments as a tool for regulating the rational use of APG. The analysis shows that the introduction of fees for emissions of pollutants generated by APG flaring plays an important role in ensuring the sustainable development of the regions. Firstly, this fee helps to improve the environmental situation in the region because the volume of gas flared has decreased significantly. Secondly, the application of fees for APG flaring contributes to an increase in the level of energy efficiency, the development and implementation of innovative technologies. Thirdly, the increase in APG deep processing makes it possible to obtain products required in the domestic industry. This improves the efficiency of the oil sector and accelerates import substitution. Fourthly, payments for emissions of pollutants generated during APG flaring form additional funds that can be spent on the development of the region. Fifthly, all oil-producing regions can be divided into two groups. The first group is a group that has practically reached or is very close to reaching the established limits for APG flaring. The second group of regions is a group for which reaching this target is still a difficult task. Experts point out the following reasons that prevent some oil-producing companies from achieving targets for APG flaring: (1) commissioning of new fields, which are characterized by an insufficient level of infrastructure development required for APG utilization; (2) closure of gas processing plants for repair work, which forces some companies to temporarily flare APG; (3) establishment of new benefits and exemptions; (4) geographic fragmentation of fields and limited reserves, which does not allow making the project for the rational use of APG profitable; (5) remoteness of some gas pipelines from the main oil-producing regions, difficult access to the gas transportation system.
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Xie, Yan, Chengcheng FU, Lingzhi Yan, Song Jin, Jingjing Shang, Xiaolan Shi, Jinlan Pan, et al. "Targeting 1q21 Amplification with APG2575 and Lenalidomide to Sensitize BCL-2 Inhibition with the Decrease of MCL-1 Protein in High Risk MM Models." Blood 136, Supplement 1 (November 5, 2020): 46–47. http://dx.doi.org/10.1182/blood-2020-139195.
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Background Multiple myeloma (MM) is a heterogenous plasma cell malignancy. About 30-40% of newly diagnosed and 20-60% of relapsed/refractory MM patients carry 1q21 amplification worldwide, a high-risk indicator for poor prognosis in RRMM. Different BCL-2 family anti-death proteins play important roles in MM survival and drug resistance. High expression of BCL-2 due to t (11;14) renders cell vulnerability to BCL-2 antagonist, however, patients carrying other genetic abnormality including 1q21 amplification have limited response to the newly emerged treatment choice. With MCL-1 upregulation accompanied with 1q21 amplification, we tested whether BCL-2 antagonist combined with IMiDs (immunomodulatory imide drugs), improves cell killing in high-risk MM patient models, including those resistant to bortezomib and lenalidomide. For that aim, we studied APG-2575, a novel and potent BCL-2 inhibitor developed by Ascentage Pharma Group and it is currently in clinical trials for hematologic malignances, including MM. Methods 1. Cells were treated with APG-2575 single agent or in combination with lenalidomide; 2. Cell line viability was assessed by CellTiter-Glo (CTG) assay; 3. Flow cytometry analysis was used to detect CD138+ cell surface marker in primary cells derived from MM patients; 4. Western blot analysis for BCL-2 family and IMiD signaling proteins. Results We first determined the cell sensitivity of APG-2575 as a single agent in a panel of MM cell lines, and as expected, those carrying t (11;14) were very sensitive to APG-2575, with low IC50 values ranging 7-23 nM. The IC50 values for cells carrying other genetic markers were greater than 5-10 μM. We then evaluated cell-death inducing activity of APG-2575 in MM patient-derived primary cells ex vivo, which were freshly prepared from patients' bone marrow aspirates. Primary cells were treated with APG-2575 or ABT-199 (venetoclax) for 18-24 hours, and the loss of CD138 surface marker was used to quantify cell death. As shown in Figure 1a, APG-2575 induced cell death (CD138+ loss) in a dose-dependent manner, and significant cell death was observed at 0.37-3.3 μM of APG-2575, indicating primary cells more sensitive than MM cell lines. Interestingly, the sensitivity to APG-2575 is similar in primary MM cells with or without 1q21 amplification. Since moderate cell death inducing activity was observed in MM cells when APG-2575 used as a single agent, we combined APG-2575 with lenalidomide. Cell death was increased in the combination groups compared with single agent, and it was dose-dependent (Figure 1b).Similar enhanced antiproliferative activity was confirmed in RPMI 8226 cell line, which carries 1q21 amplification (Figure 1c). We furthered to understand the mechanism of action (MoA) of this combination. In Figure 1d, Western blot analysis of RPMI 8226 cell line revealed that IKZF1 and IKZF3 proteins from the NF-KB pathway were downregulated by lenalidomide. And the decrease of MCL-1 protein and the strong induction of pro-death protein BAK were evident in the combination group of APG-2575 and lenalidomide, which helps to illustrate MoA underlying the synergistic effect of APG-2575 and lenalidomide in MM models. Conclusions In both cell lines and primary samples derived from MM patients, APG-2575 demonstrates cell death inducing activity as a single agent, and enhanced/synergistic effects when it combines with lenalidomide in RRMM resistant to lenalidomide and bortezomib. The combination decreases IKZF1, IKZF3 and MCL-1 proteins, and upregulates pro-death protein BAK, thus providing a strong rationale to combine BCL-2 inhibitor and lenalidomide to treat high-risk patient populations carrying 1q21 amplification. Disclosures FU: Ascentage Pharma (SuZhou) Co., Ltd: Other: research agreement contract . Yin:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Mao:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Deng:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Fang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.
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Zhang, Xing, Xizhi Wen, Guojuan Chen, Shan Zeng, Lichuang Men, Hengbang Wang, Shulan He, et al. "Phase I study results of APG-115, a MDM2-p53 antagonist in Chinese patients with advanced liposarcoma and other solid tumors." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): 11542. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.11542.
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11542 Background: APG-115 is a potent, small-molecule MDM2 inhibitor and immune modulator with promising antitumor activities in various tumors, especially those wild-type TP53 with MDM2 amplification ( TP53wt+MDM2 amp). To better delineate safety, optimal dosage, and potential target population, we report updated results. Methods: Patients with advanced liposarcoma and other solid tumors received APG-115 (100-200 mg) orally every other day for 21 days of a 28-day cycle. The primary endpoints were safety and tolerability. Efficacy (assessed by RECIST v1.1), pharmacokinetics (PK) and pharmacodynamics (PD) have also been analyzed. Results: Enrollment of this Phase I study (CTR20170975) was completed. As of January 7, 2020, 21 patients (14 liposarcomas, 2 synovial sarcomas, 2 adenoid cystic carcinomas, 1 chondrosarcoma, 1 osteosarcoma, 1 rhabdomyosarcoma) were treated in 3 dose levels of APG-115: 100 mg (n = 11), 150 mg (n = 8) and 200 mg (n = 2). The median number of cycles of APG-115 was 2 (0; 6). Two DLTs were observed at 200 mg, thrombocytopenia and febrile neutropenia. The most common treatment-emergent adverse events (TEAEs) (≥20%) included leukopenia, thrombocytopenia, neutropenia, anemia, increased blood creatinine, hypercholesterolemia, hypertriglyceridemia, hypoalbuminemia, vomiting, and nausea. The incidence of TEAEs was much lower at 100 mg. Serious AEs occurred in 5 patients (23.8%) which were assessed as possibly drug related by investigators. In 20 efficacy-evaluable patients, there was 1 patient with a partial response, 12 patients with stable disease, and 7 patients with progressive disease, yielding a disease control rate (CR, PR, SD) of 61.9%. Among the 13 patients (9 liposarcomas) who benefited, 11 had TP53wt and 7 had TP53wt+MDM2 amp, including one liposarcoma patient (150 mg) who had a PR, she was kept-up over 10 months, even though the treatment was discontinued for over 5 months, indicating the host immune modulatory effects of APG-115. Another patient with liposarcoma (100 mg, TP53wt+MDM2 amp) had 28.5% tumor shrinkage at cycle 4 and remained on treatment. PK results showed an approximately dose-proportional increase in exposure on Day 1. PK-PD analyses showed the serum macrophage inhibitory cytokine-1 (MIC-1) increased with increased APG-115 exposure. Conclusions: The phase I data have demonstrated that APG-115 monotherapy was well tolerated, with minimal toxicity at 100mg (RP2D), and conferred encouraging anti-tumor activities in patients with liposarcomas. Clinical trial information: CTR20170975 .
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Campbell, Charles L. "Apg 9, 1-9 (10-20), 22.8.2010, 12. Sonntag nach Trinitatis." Göttinger Predigtmeditationen 64, no. 3 (April 2009): 357–63. http://dx.doi.org/10.13109/gpre.2009.64.3.357.
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Nonoguchi, Kohsuke, Katsuhiko Itoh, Jing-Hui Xue, Hiromu Tokuchi, Hiroyuki Nishiyama, Yoshiyuki Kaneko, Keiji Tatsumi, Hiroshi Okuno, Kiyotaka Tomiwa, and Jun Fujita. "Cloning of human cDNAs for Apg-1 and Apg-2, members of the Hsp110 family, and chromosomal assignment of their genes." Gene 237, no. 1 (September 1999): 21–28. http://dx.doi.org/10.1016/s0378-1119(99)00325-x.
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Rasco, Drew W., Nehal J. Lakhani, Yufeng Li, Lichuang Men, Hengbang Wang, Jiao Ji, Yuefen Tang, et al. "A phase I study of a novel MDM2 antagonist APG-115 in patients with advanced solid tumors." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 3126. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.3126.
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3126 Background: APG-115 is a potent and orally active small-molecule MDM2 protein inhibitor. Binding to MDM2 protein, APG-115 restores p53 tumor suppressive function via induction of apoptosis in tumor cells retaining wild-type p53. In addition, enhanced antitumor activity was demonstrated in the syngeneic tumor models after APG-115 combined with PD-1 blockade. Methods: This Phase I study (APG-115-US-001) was designed to enroll the patients with advanced solid tumors in US (NCT02935907). Study objectives included to assess safety, dose limited toxicity (DLT), pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity (assessed every 8 weeks per RECIST v1.1). The patients received APG-115 orally every other day (QOD) at the designated dose (ranging from 10 to 300 mg) for first 21 days of a 28-day cycle, until disease progression. Results: Up until Jan 4 2019, total 28 patients were treated with APG-115 at various doses (one patient at 10mg, 20mg and 50mg, respectively; 14 patients at 100mg, 6 patients at 200mg, and 5 patients at 300mg). The median number of prior systemic anticancer therapies was 4 (range 0-15). The DLTs were observed during cycle 1, including one grade 2 thrombocytopenia at 200mg, one grade 3 thrombocytopenia at 300mg, and one grade 3 fatigue at 100mg and 300mg respectively. The most common AEs (reported in ≥10% of pts) included: fatigue, nausea, vomiting, diarrhea, decreased appetite, dehydration, neutrophil count decreased, white blood cell count decreased, pain in extremity, thrombocytopenia. The most common Grade 3 or 4 treatment related AEs were fatigue (10.7%), and thrombocytopenia (10.7%). Six patients had stable disease (SD) after two cycle treatments, two of them are continuing in this study. PK analyses indicated that exposure (Cmax and AUC) generally increases with the increase of dose level from 20 mg to 300 mg. Conclusions: APG-115 was well tolerated and had manageable adverse events. The MTD/RP2D of APG-115 monotherapy with oral administration, QOD for 21 days of a 28-day cycle for treatment of patients with advanced solid tumors was determined as 100 mg. Further evaluation of APG-115 in combination with pembrolizumab in patients with advanced solid tumors is ongoing. Clinical trial information: NCT02935907.
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Nguyen, Nhat Minh, Eric Monier-Vinard, Najib Laraqi, Valentin Bissuel, and Olivier Daniel. "Practical analytical steady-state temperature solution for annealed pyrolytic graphite heat spreader." International Journal of Numerical Methods for Heat & Fluid Flow 27, no. 1 (January 3, 2017): 174–88. http://dx.doi.org/10.1108/hff-08-2015-0311.
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Purpose The purpose of this paper is to supply an analytical steady-state solution to the heat transfer equation permitting to fast design investigation. The capability to efficiently transfer the heat away from high-powered electronic devices is a ceaseless challenge. More than ever, the aluminium or copper heat spreaders seem less suitable for maintaining the component sensitive temperature below manufacturer operating limits. Emerging materials, such as annealed pyrolytic graphite (APG), have proposed a new alternative to conventional solid conduction without the gravity dependence of a heat-pipe solution. Design/methodology/approach An APG material is typically sandwiched between a pair of aluminium sheets to compose a robust graphite-based structure. The thermal behaviour of that stacked structure and the effect of the sensitivity of the design parameters on the effective thermal performances is not well known. The ultrahigh thermal conductivity of the APG core is restricted to in-plane conduction and can be 200 times higher than its through-the-thickness conductivity. So, a lower-than-anticipated cross-plane thermal conductivity or a higher-than-anticipated interlayer thermal resistance will compromise the component heat transfer to a cold structure. To analyse the sensitivity of these parameters, an analytical model for a multi-layered structure based on the Fourier series and the superposition principle was developed, which allows predicting the temperature distribution over an APG flat-plate depending on two interlayer thermal resistances. Findings The current work confirms that the in-plane thermal conductivity of APG is among the highest of any conduction material commonly used in electronic cooling. The analysed case reveals that an effective thermal conductivity twice as higher than copper can be expected for a thick APG sheet. The relevance of the developed analytical approach was compared to numerical simulations and experiments for a set of boundary conditions. The comparison shows a high agreement between both calculations to predict the centroid and average temperatures of the heating sources. Further, a method dedicated to the practical characterization of the effective thermal conductivity of an APG heat-spreader is promoted. Research limitations/implications The interlayer thermal resistances act as dissipation bottlenecks which magnify the performance discrepancy. The quantification of a realistic value is more than ever mandatory to assess the APG heat-spreader technology. Practical implications Conventional heat spreaders seem less suitable for maintaining the component-sensitive temperature below the manufacturer operating limits. Having an in-plane thermal conductivity of 1,600 W.m−1.K−1, the APG material seems to be the next paradigm for solving endless needs of a thermal designer. Originality/value This approach is a practical tool to tailor sensitive parameters early to select the right design concept by taking into account potential thermal issues, such as the critical interlayer thermal resistance.
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Pemmaraju, Naveen, Boyd Mudenda, Cunlin Wang, Jiao JI, Ming Lu, Tommy Fu, Eric Liang, et al. "Trial in Progress: Phase Ib/II Study of Bcl-2/Bcl-Xl Inhibitor Pelcitoclax (APG-1252) in Patients with Myelofibrosis (MF) That Progressed after Initial Therapy." Blood 136, Supplement 1 (November 5, 2020): 15–16. http://dx.doi.org/10.1182/blood-2020-137260.
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Background: Pelcitoclax (APG-1252), a novel dual inhibitor of Bcl-2/Bcl-xL, is active as monotherapy in patients with advanced solid tumors and well tolerated up to 240 mg twice weekly (NCT03387332). Preclinical data suggest that cells with Janus-associated kinase-2 (JAK2) mutations, including those associated with bone marrow fibrosis, are dependent on Bcl-2/Bcl-xL for survival and that addition of BH3 mimetics targeting Bcl-2/Bcl-xL induces apoptosis. Furthermore, in JAK2‒mutated cell models, apoptotic synergy is demonstrated when a JAK2 inhibitor and Bcl-2/Bcl-xL inhibitor are combined, as inhibition of Bcl-xL overcomes resistance to JAK2 inhibitors. Taken together, APG-1252 could overcome resistance to JAK2 inhibitors, and the combination could augment clinical benefit in patients with suboptimal responses to JAK2 inhibitor‒based therapy. Study Objectives: The primary objective of this open-label trial is to evaluate the safety and efficacy of APG-1252, as monotherapy and when combined with ruxolitinib, in adults with histologically or cytologically confirmed MF who require therapy and are ineligible for JAK2 inhibitors (and can receive single-agent APG-1252) or have had inadequate responses to ruxolitinib-based therapy (and can receive this treatment plus APG-1252). Secondary objectives include APG-1252 pharmacokinetics, time to response, and duration of response. Exploratory objectives include changes in cytogenetics and molecular mutations, bone marrow fibrosis, and cytokines on treatment. Study Design: The study is divided into Part 1 (APG-1252 monotherapy) and Part 2 (APG-1252 plus ruxolitinib). For Part 1, the key inclusion criterion is ineligibility for JAK2 inhibitors and for Part 2, inadequate responses to prior ruxolitinib-based therapy. A standard 3+3 dose-escalation design is being implemented to determine the maximum tolerated dose (MTD) of APG-1252 monotherapy in Part 1 and APG-1252 combined with ruxolitinib in Part 2. APG-1252 will initially be administered at 160 mg intravenously by 30-minute injection once weekly in a 28-day cycle. The dose can be escalated to a maximum of 240 mg or reduced to a minimum of 80 mg, depending on tolerability. Part 2 will begin once the MTD and recommended phase 2 dose (RP2D) of APG-1252 monotherapy have been determined. In Part 2, ruxolitinib will be administered orally twice daily per the package insert. After the MTD for APG-1252 monotherapy has been determined, no additional patients will be enrolled in Part 1; however, up to 15 to 30 additional patients can be enrolled in Part 2, to further evaluate the safety and anticancer activity of the combination at MTD or RP2D. Patients will continue treatment until disease progression or unacceptable toxicity. Clinical responses are being assessed every 12 weeks according to criteria from the International Working Group‒Myeloproliferative Neoplasms Research and Treatment and European LeukemiaNet panels, while optimal clinical benefit will be evaluated at 24 weeks. Enrollment will be from September 2020 and preliminary results estimated in October 2022. For further information, contact: yzhai@ascentage.com. Registration: ClinicalTrials.gov Identifier NCT04354727. Disclosures Pemmaraju: Pacylex Pharmaceuticals: Consultancy; Roche Diagnostics: Honoraria; LFB Biotechnologies: Honoraria; Stemline Therapeutics: Honoraria, Research Funding; Celgene: Honoraria; AbbVie: Honoraria, Research Funding; MustangBio: Honoraria; Affymetrix: Other: Grant Support, Research Funding; Cellectis: Research Funding; Daiichi Sankyo: Research Funding; Plexxikon: Research Funding; Samus Therapeutics: Research Funding; DAVA Oncology: Honoraria; Blueprint Medicines: Honoraria; Novartis: Honoraria, Research Funding; Incyte Corporation: Honoraria; SagerStrong Foundation: Other: Grant Support. Mudenda:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Wang:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. JI:Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Lu:Ascentage Pharma Group: Current Employment, Current equity holder in publicly-traded company. Fu:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Liang:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. McClain:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Sheladia:Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Novartis: Consultancy, Research Funding; Sierra Oncology: Consultancy, Research Funding; Blueprint Medicines Corp: Research Funding; PharmaEssentia: Research Funding; ItalPharma: Research Funding; AstraZeneca: Research Funding; Protagonist Therapeutics: Research Funding; Promedior: Research Funding; Celgene: Consultancy, Research Funding; NS Pharma: Research Funding; Genentech: Research Funding; CTI Biopharma Corp: Research Funding; Incyte Corporation: Consultancy, Research Funding; Roche: Research Funding; Gilead: Research Funding. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.
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Kern, Florian, Ruslan I. Stanika, Bettina Sarg, Martin Offterdinger, Daniel Hess, Gerald J. Obermair, Herbert Lindner, Christine E. Bandtlow, Ludger Hengst, and Rüdiger Schweigreiter. "Nogo-A couples with Apg-1 through interaction and co-ordinate expression under hypoxic and oxidative stress." Biochemical Journal 455, no. 2 (September 27, 2013): 217–27. http://dx.doi.org/10.1042/bj20130579.
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Zhu, Mengyuan, Yuejiao Huang, Jie Tang, Shan Shao, Linlin Zhang, Yu Zhou, Song He, and Yuchan Wang. "Role of Apg-1 in HSF1 activation and bortezomib sensitivity in myeloma cells." Experimental Hematology 81 (January 2020): 50–59. http://dx.doi.org/10.1016/j.exphem.2019.12.007.
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Luo, Qiuyun, Wentao Pan, Suna Zhou, Guangfeng Wang, Hanjie Yi, Lin Zhang, Xianglei Yan, et al. "A Novel BCL-2 Inhibitor APG-2575 Exerts Synthetic Lethality With BTK or MDM2-p53 Inhibitor in Diffuse Large B-Cell Lymphoma." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 28, no. 4 (September 1, 2020): 331–44. http://dx.doi.org/10.3727/096504020x15825405463920.
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Despite therapeutic advances, the effective treatment for relapsed or refractory diffuse large B-cell lymphoma (DLBCL) remains a major clinical challenge. Evasion of apoptosis through upregulating antiapoptotic B-cell lymphoma-2 (BCL-2) family members and p53 inactivation, and abnormal activation of B-cell receptor signaling pathway are two important pathogenic factors for DLBCL. In this study, our aim is to explore a rational combination of BCL-2 inhibitor plus Brutons tyrosine kinase (BTK) blockade or p53 activation for treating DLBCL with the above characteristics. We demonstrated that a novel BCL-2 selective inhibitor APG-2575 effectively suppressed DLBCL with BCL-2 high expression via activating the mitochondrial apoptosis pathway. BTK inhibitor ibrutinib combined with BCL-2 inhibitors showed synergistic antitumor effect in DLBCL with mean expression of BCL-2 and myeloid cell leukemia-1 (MCL-1) through upregulating the expression level of BIM and modulating MCL-1 and p-Akt expression. For p53 wild-type DLBCL with high expression of BCL-2, APG-2575 showed strong synergic effect with mouse double minute 2 (MDM2)p53 inhibitor APG-115 that can achieve potent antitumor effect and markedly prolong survival in animal models. Collectively, our data provide an effective and precise therapeutic strategy through rational combination of BCL-2 and BTK or MDM2p53 inhibitors for DLBCL, which deserves further clinical investigation.
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Jeon, Kyung-Won, and John F. Feldhunsen. "Teachers' and parents' perceptions of social-psychological factors of underachievement among the gifted in Korea and the United States." Gifted Education International 9, no. 2 (September 1993): 115–19. http://dx.doi.org/10.1177/026142949300900212.
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A survey was designed to compare perceptions of American teachers of the gifted (ATG), American parents of the gifted (APG), Korean teachers of the gifted (KTG), and Korean parents of the gifted (KPG) concerning social-psychological factors of underachievement in the gifted. There were four subsections: (1) familyparental factors, (2) psychological factors, (3) sociological factors, and (4) peer-relationship factors. Two hundred-eighty eight teachers and parents, 60 ATG, 77 APG, 28 KTG, and 50 KPG served as respondents. American teachers and parents, as compared to Korean teachers and parents, tended to overemphasize the importance of peer relationship, psychological environment, and social environment as causes of underachievement.
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Zhang, Xing, Xizhi Wen, Chen Yang, Shan Zeng, Lichuang Men, Hengbang Wang, Yuxiang Ma, et al. "A phase I study of a novel MDM2-P53 antagonist APG-115 in Chinese patients with advanced soft tissue sarcomas." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 3124. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.3124.
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3124 Background: APG-115 is a novel and orally active small-molecule MDM2 inhibitor. APG-115 alone or in combination with chemotherapeutic, targeted or IO agents have shown potent antitumor activities in multiple human xenograft tumor models and human cancer patient derived xenograft (PDX) models. Methods: The patients with advanced solid tumors were enrolled in this study in China (CTR20170975). The study objectives were to assess safety, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of APG-115. The patients received APG-115 (ranging 100–200 mg) orally QOD for first 21 days of a 28-day-cycle, until disease progression. Antitumor response assessment was performed every 8 weeks per RECIST v1.1. Archived tumor tissues were collected for analyses of MDM2 and TP53 before treatment. Results: As cut-off on Jan 4 2019, total 13 patients (9 soft tissue sarcomas (STSs), 2 adenoid cystic carcinomas (ACCs) and 2 osteosarcomas) were treated in 3 cohorts of APG-115 (100mg, 150mg, 200mg). The median number of prior systemic anticancer therapies was 2 (range 0-4). Two DLTs were observed in one patient at 200mg including thrombocytopenia and febrile neutropenia. The most common TEAEs (≥50% of pts) included: anemia, thrombocytopenia, vomiting, hypercholesterolaemia, and leukopenia. SAEs occurred in 7 patients (54%), four of which were treatment related. The most common Grade 3 or 4 TRAEs were anemia (38.5%), thrombocytopenia (38.5%), leukopenia (30.8%), and neutropenia (23.1%). One partial response was observed in a liposarcoma patient with MDM2-amplification and TP53-wild type at the 150mg cohort, 5 patients (3 STSs, 2 ACCs) had SD as the best overall response. PK analyses indicated an approximately dose proportional increase in Cmax and AUC0-t following a single or multiple oral administration across dose levels. Preliminary PD data showed that serum MIC-1 increase was exposure dependent within the dose range tested. Conclusions: Preliminary data suggested that APG-115 had promising anti-tumor activity in treatment of patients with MDM2-amplification and TP53-WT liposarcoma. Safety profile and PD effect were consistent with other MDM2 inhibitors. Dosing regimen optimization are ongoing. Clinical trial information: CTR20170975.
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Vo, Thuy-Vi, Ya-Yen Chou, and Bing-Hung Chen. "Preparation of Microemulsion from an Alkyl Polyglycoside Surfactant and Tea Tree Oil." Molecules 26, no. 7 (March 31, 2021): 1971. http://dx.doi.org/10.3390/molecules26071971.
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Preparation and characterization of microemulsions consisting of a plant-derived alkyl polyglycoside (APG) surfactant and the essential oil of Melaleuca alternifolia (tea tree) was studied. This nonionic APG surfactant used was Triton CG-110 with a CMC at 1748 ppm at 25 °C. Tea tree oil (TTO) was extracted from tea tree leaves by Triton CG-110-assisted hydrodistillation method. The preparation of the microemulsion was aided by the construction of pseudo-ternary phase diagrams, which were investigated at the different weight ratios of surfactant mixtures (Smix = Triton CG-110/PPG) as 0.6:1, 1.8:1, 1:0 with hydrodistilled and commercial TTO by water titration method at room temperature. Particularly, structure of microemulsion was identified by electrical conductivity and viscosity. Moreover, shelf stability of some microemulsion made of 1% TTO with various concentration of Triton CG-110/PPG (1.8:1 w/w) were monitored for over a two-month period with dynamic light scattering. These results showed that microemulsion made of 1% TTO, 9% Triton CG-110/PPG (1.8:1 w/w) was insensitive with time and temperature of storage.
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Kitsios, V., A. Sekimoto, C. Atkinson, J. A. Sillero, G. Borrell, A. G. Gungor, J. Jiménez, and J. Soria. "Direct numerical simulation of a self-similar adverse pressure gradient turbulent boundary layer at the verge of separation." Journal of Fluid Mechanics 829 (September 20, 2017): 392–419. http://dx.doi.org/10.1017/jfm.2017.549.
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The statistical properties are presented for the direct numerical simulation of a self-similar adverse pressure gradient (APG) turbulent boundary layer (TBL) at the verge of separation. The APG TBL has a momentum thickness-based Reynolds number range from $Re_{\unicode[STIX]{x1D6FF}_{2}}=570$ to 13 800, with a self-similar region from $Re_{\unicode[STIX]{x1D6FF}_{2}}=10\,000$ to 12 300. Within this domain the average non-dimensional pressure gradient parameter $\unicode[STIX]{x1D6FD}=39$, where for a unit density $\unicode[STIX]{x1D6FD}=\unicode[STIX]{x1D6FF}_{1}P_{\!e}^{\prime }/\unicode[STIX]{x1D70F}_{w}$, with $\unicode[STIX]{x1D6FF}_{1}$ the displacement thickness, $\unicode[STIX]{x1D70F}_{w}$ the mean shear stress at the wall and $P_{\!e}^{\prime }$ the far-field pressure gradient. This flow is compared with previous zero pressure gradient and mild APG TBL ($\unicode[STIX]{x1D6FD}=1$) results of similar Reynolds number. All flows are generated via the direct numerical simulation of a TBL on a flat surface with far-field boundary conditions tailored to apply the desired pressure gradient. The conditions for self-similarity, and the appropriate length and velocity scales, are derived. The mean and Reynolds stress profiles are shown to collapse when non-dimensionalised on the basis of these length and velocity scales. As the pressure gradient increases, the extent of the wake region in the mean streamwise velocity profiles increases, whilst the extent of the log-layer and viscous sublayer decreases. The Reynolds stress, production and dissipation profiles of the APG TBL cases exhibit a second outer peak, which becomes more pronounced and more spatially localised with increasing pressure gradient. This outer peak is located at the point of inflection of the mean velocity profiles, and is suggestive of the presence of a shear flow instability. The maximum streamwise velocity variance is located at a wall normal position of $\unicode[STIX]{x1D6FF}_{1}$ of spanwise wavelength of $2\unicode[STIX]{x1D6FF}_{1}$. In summary as the pressure gradient increases the flow has properties less like a zero pressure gradient TBL and more akin to a free shear layer.
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Walad Wirawan, Rap Leanon, and Zuhrina Masyithah. "PENGARUH SUHU ADSORPSI DAN JUMLAH PENAMBAHAN KARBON AKTIF TERHADAP KECERAHAN SURFAKTAN DECYL POLIGLIKOSIDA DARI D-GLUKOSA DAN DEKANOL." Jurnal Teknik Kimia USU 4, no. 3 (September 29, 2015): 12–16. http://dx.doi.org/10.32734/jtk.v4i3.1475.
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Alkyl plyglycosides (APG) is a nonionic surfactant which is environmentally friendly. Carbohidrate source as APG’s raw material supplied the hydrophilic group, and fatty alcohol acted as hydrophobic group. Some undesirable compounds formed during the APG synthesis and caused dark color. In direct synthesis, D-glucose reacts directly with decanol in molar ratio of D-glucose:decanol is 1:5 and 0,5 % of HCl as catalist based on weight of D-glucose for 1 hour at reaction temperature about 95 oC. And then the solution is neutralized with NaOH 50 % on pH 8-10. Added activated carbon with variation 1, 3, 5, 7, and 9 % based on weight of solution at adsorption temperature with variation 30, 40, dan 50 oC, then filtrate and distilate the solution at vacuum condition. Product is analized using spectroscopy fourier transform infrared (FT-IR) and spectroscopy UV-Vis. The highest percent of transmittance is about 44,90 % obtained at adsorption temperature 50 oC and amount of activated carbon 3 %.
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Chen, Lijun, Xin Zhang, Cuifeng Zhang, Zhongbin Bao, and Tingting Xu. "Synthesis and characterisation of fluorine-silicon acrylate latex emulsified by novel green surfactants." Pigment & Resin Technology 47, no. 3 (May 8, 2018): 255–60. http://dx.doi.org/10.1108/prt-03-2017-0025.
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Purpose Motivated by the globally increasing concern over environmental protection, the interest of a large part of the scientific community focuses on the development of green surfactants aiming to replace traditional toxic surfactants-based alternatives. The purpose of this paper is to prepare acrylate copolymer latex modified with fluorine and silicone monomer, which is emulsified with the green surfactants of sodium rosinate and alkyl polyglycoside (APG). Design/methodology/approach A series of acrylic copolymer latexes containing fluorine–silicon have been prepared by semi-continuous seed emulsion polymerisation of mixed monomers of methyl methacrylate (MMA), butyl acrylate (BA), hexafluorobutylmethacrylate (HFMA) and vinyltriethoxysilane (VTES) and emulsified by green mixed surfactants of sodium rosinate and APG. Findings The optimum recipe of preparing the emulsion is as follows: the amount of emulsifiers is 6 per cent and the mass ratio of sodium rosinate to APG is 1:3. The amount of initiator is 0.4 per cent, and the amounts of the silicon monomer and fluorine monomer are 5 and 7 per cent, respectively. In comparison with the acrylate latex prepared without fluorine monomer and silicon monomer, the thermal stability and the water resistance of the film of the resultant latex clearly improved. Practical implications The acrylic copolymer latexes containing fluorine–silicon emulsified with green surfactants can be used in the coatings, adhesives, finishing agents and so on. Originality/value The acrylic copolymer latexes containing fluorine–silicon have been prepared by semi-continuous seed emulsion polymerisation. The green mixed surfactants of sodium rosinate and APG have been used as the emulsifiers to replace traditional toxic surfactants-based alternatives.
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Korotkikh, S. A., G. V. Zhiborkin, E. S. Knyazeva, and L. V. Rusakova. "The efficiency of monotherapy of patients with primary open-angle glaucoma with Bimatoprost 0.03 % (Bimoptic)." Russian Ophthalmological Journal 11, no. 4 (December 11, 2018): 75–79. http://dx.doi.org/10.21516/2072-0076-2018-11-4-75-79.
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Purpose: to evaluate the hypotensive effect and adverse reactions occurrence in patients with primary open angle glaucoma (POAG) who received Bimatoprost (Bimoptic Rompharm) monotherapy.Materials and methods. 46 patients (75 eyes) with stage I–III POAG were prescribed bimatoprost therapy. Of these, 16 patients (20 eyes) had newly diagnosed glaucoma, 15 patients (27 eyes) previously received treatment with prostaglandin analogs (APG — Latanoprost), and 15 patients (28 eyes) previously received treatment with a fixed combination (FC) composed of timolol B-blocker and brinzolamide carbonic anhydrase inhibitor. The reason for transferring the patient from therapy with APG and FC to monotherapy with Bimatoprost was insufficient hypotensive effect of APG/FC therapy, and the presence of dry eye syndrome of varying severity in most patients. The results were evaluated after 1, 4 and 12 weeks of Bimatoprost therapy. Results. A hypotensive effect of monotherapy with Bimatoprost was confirmed in patients with newly diagnosed POAG. An additional hypotensive effect was revealed when patients with POAG were transferred from APG and FC therapy to monotherapy with Bimatoprost. Adverse reactions: mild and moderate hyperaemia, periorbital manifestations such as skin pigmentation, deepening of upper eyelid folds, narrowing of the palpebral fissure (ptosis) were noted, respectively, in 8, 6.7, 1.3, 2.7, 2.7 % of cases respectively, but did not require a discontinuation of the therapy in any patient. Eyelash growth was noted by 3 patients (4 %). This effect was not considered to be a side effect, since none of the patients bothered. In 47 % of patients who had previously received APG and FC therapy and had dry eye syndrome of varying severity, objective and subjective positive changes relating to dry eye syndrome was noted. A positive dynamic of morphometric parameters of the optic nerve and cells of the retinal ganglion complex was revealed in patients of all groups of study.Conclusion. Monotherapy with Bimatoprost can be recommended as therapy of choice for patients with newly diagnosed glaucoma, and those previously receiving antihypertensive therapy with PGAs or fixed combinations (-blocker + carbonic anhydrase inhibitor) including those having dry eye syndrome of varying severity.
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Shin, Daniel Sanghoon, Eri Srivatsan, Hassan Nasser, Anela Tosevska, Jonathan Jacobs, Matteo Pellegrini, and Marilene Wang. "Potential role of botanical drug APG-157 as immune adjuvant in patients with oral squamous cell carcinoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): e17572-e17572. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.e17572.
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e17572 Background: Natural botanical drugs, such as curcumin, resveratrol and related flavonoids, are under clinical studies. Previous pilot study of curcumin, a polyphenol, for normal and patients with oral squamous cell carcinoma (OSCC) showed significant inhibition of inflammatory cytokines in saliva. Phase I investigation was performed on APG-157 to evaluate the potential utility an as oral drug for the treatment of OSCC. Methods: A double-blind, randomized, placebo-controlled phase I clinical trial was conducted with a botanical preparation containing a combination of curcumin related polyphenol molecules (pharmaceutical name APG-157). 12 Subjects with oral cancer and 13 normal control subjects were recruited. Two doses of the drug, 3x100 mg and 3x200 mg, were tested. The drug was administered orally each hour for 3 consecutive hours. Blood and saliva were collected pre-treatment and 1, 2, 3, and 24 hours post-treatment. Salivary cells and supernatants were analyzed for the expression of cytokines by multiplex ELISA and microbial content by 16S RNA sequence. Pre- and post-treatment tumor biopsies of one subject were studied for expression using the RNA seq and immunofluorescence (IF). Results: This study did not reveal any toxicity and there was a dose dependent inhibition of inflammatory cytokines, IL-1β, TNF-alpha and IL-8 in the salivary supernatant of cancer subjects treated with the drug. Tumor RNA-seq revealed down regulation of gene ontologies of cell adhesion, cell cycle and cell division and up regulation of generation of precursor metabolite/energy in the post-treatment tumor sample. Microbiome study showed significant decrease in Bacterioides after 24 hours of treatment. There was also a trend of decreasing Bacteroides among other cancer subjects treated with APG-157. IF showed a marked increase in the number of CD4, CD8 T cells in post-treatment tumor. PD-L1 expression was up-regulated in the post-treatment tumor sample. Conclusions: APG-157 is found to be safe and toxicity was not observed. The drug has shown a decrease in inflammatory cytokines. Moreover, there was a markedly increased CD4, CD8 T cells infiltration on a subject and decreased Bacteriodes microbial population after APG-157 treatment suggesting that it might have potential synergistic effect with immune checkpoint blockade immunotherapy. Decreased expression of cell growth related genes and increased expression of growth inhibitory genes pointed to a potential anti-tumor activity of APG-157.
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Xu, Guo Mei, and Tie Jun Shi. "Synthesis of Alkyl Polyglycoside and its Application in the Glyphosate." Applied Mechanics and Materials 716-717 (December 2014): 126–29. http://dx.doi.org/10.4028/www.scientific.net/amm.716-717.126.
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Using sweet potato starch, butanol, and dodecyl alcohol as raw materials, the alkyl indican surfactant was synthesized by two-step reactions with composite catalysts of p-toluene sulfonic acid and citric acid, the synthesis conditions were investigated through orthogonal method and the structure of the product was characterized by IR and mass spectroscopy. The weeding test was also studied by adding the appropriate proportion of alkyl indican surfactant. The results showed that the best technological conditions was: reaction took place under 120 C and last for 4 h, msweet potato starch:mn-butanol: mn-dodecanol=msp:mnb:mnd=1:2:5, the content of composite catalysts was 1.6 wt% p-toluene sulfonic acid and 10.0 wt% citric acid. The weeding test demonstrated that added 1% APG into the glyphosate could killed almost all weeds in five days and had an excellent weeding efficiency. Compared with spraying glyphosate with no APG, which could decrease the amount of glyphosate used and protect the environment.
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Reinmuth, Eckart. "Beobachtungen zur Rezeption der Genesis bei Pseudo–philo (LAB 1–8) und Lukas (Apg 7.2–17)." New Testament Studies 43, no. 4 (October 1997): 552–69. http://dx.doi.org/10.1017/s0028688500023389.
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Mit dem vorliegenden Beitrag sollen einige Beobachtungen zur Rezeption der Genesis durch Pseudo–Philo (Liber Antiquitatum Biblicarum)1 und Lukas vorgeführt werden. Beide Autoren arbei–ten im ungefähr gleichen Zeitraum, dem letzten Drittel des ersten Jahrhunderts.2 Auf Berührungen zwischen ihren Erzählwerken wurde bereits früher hingewiesen.3 Der vorliegende Beitrag fragt nach der Bedeutung der Genesis in der Textwelt beider Autoren; er beschränkt sich nicht auf deren explizite Schriftzitate.4 Bezug–nahmen auf die Genesis sind vielmehr in beiden Werken auf vielfältige Weise realisiert. Sie zeigen zugleich lediglich einen Ausschnitt der biblisch bestimmten Intertextualität, die für beide Werke kennzeichnend ist.
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Nonoguchi, Kohsuke, Hiromu Tokuchi, Hiroshi Okuno, Hirohiko Watanabe, Haruto Egawa, Kaoru Saito, Osamu Ogawa, and Jun Fujita. "Expression of Apg-1, a member of the Hsp110 family, in the human testis and sperm." International Journal of Urology 8, no. 6 (June 2001): 308–14. http://dx.doi.org/10.1046/j.1442-2042.2001.00304.x.
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Rap Leanon, Walad Wirawan, and Zuhrina Masyithah. "PENGARUH RASIO MOLAR SUBSTRAT DAN KONSENTRASI KATALIS PADA PEMBUATAN DECYL POLIGLIKOSIDA DARI D-GLUKOSA DAN DEKANOL." Jurnal Teknik Kimia USU 4, no. 2 (June 8, 2015): 7–12. http://dx.doi.org/10.32734/jtk.v4i2.1464.
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There are two methods to produce alkyl polyglucoside (APG) which are direct method and indirect method. In this research, APG synthesize with direct method that involves by directly reacting d-glucose with decanol with molar ratio variation of d-glucose:decanol are 1:10; 2:10; 4:10 and 6:10 (mol GL/mol C10) and HCl concentration as catalyst variation are 0,5; 1; 1,5 dan 2 (% based on weight of d-glucose) in 3 hours with temperature reaction is 95 0C. Next process is neutralizing with strong base (NaOH) until pH value is about 8-10 then the aqueous solutions are distillated with vacuum distillation. This research analyze density, yield and wavelength. Decyl polyglycoside synthetic optimum results best density value is 1,05 gr/mL in molar ratio of d-glucose:decanol 2:10 (mol GL/mol C10) and catalyst concentration 0,5%. Best yield in molar ratio of d-glucose:decanol 2:10 (mol GL/mol C10) and catalyst consentration 1,5% (% based on weight of d-glucose) with yield value is 84,09 %. Wavelength analysis of ether and OH linkage with Fourier Transform Infrared (FT-IR) spectroscopy detected ether (COC) linkage at wavenumber 1032,33 cm-1 and OH groups detected at wavenumber 3365,21 cm-1.
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Deng, Jing, Yan Yin, Tingting Mao, Guoqin Zhai, Dongmei Yang, Douglas Fang, Shaomeng Wang, Yifan Zhai, and Dajun Yang. "Probing Distinct Oncogene Addiction By Novel BCL-2 Inhibitors." Blood 132, Supplement 1 (November 29, 2018): 2616. http://dx.doi.org/10.1182/blood-2018-99-119816.
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Abstract Introduction Evading apoptosis is one of the key mechanisms that cells become cancerous. Oncogenic proteins in the family, including BCL-2, BCL-xL, and MCL-1, which counteract the pro-death function of tumor suppressor like proteins, have been shown in many models of tumorigenesis. Thus how to reprogram the apoptosis regulatory machinery to tilt towards pro-death activity has been the focus of modern cancer therapy, regardless of conventional or targeted therapy. Inhibiting BCL-2, BCL-xL and/or MCL-1 anti-death proteins has also become the hot pursuit for drug development. To effectively kill cancers with heterogeneity, it is necessary to understand which oncogene is the underlying mechanism. Applying novel BCL-2 inhibitors, a selective or dual inhibitor for BCL-2/BCL-xL, which have been developed by Ascentage Pharma Group and currently under phase I/II clinical trials, we probed the oncogene addiction patterns in a panel of hematologic malignancy cell lines, including ALL, AML and MM. Methods Cell sensitivity to BCL-2 inhibitors was assessed by Cell-titer-glow assays. 2. Protein expression levels by Western blotting, or protein complexing detected by MSD method were used to dissect the mechanism of sensitivity or resistance. 3. Mice xenograft models were carried out to confirm the tumor growth inhibition (efficacy model) and regression (survival model) through combination treatments. 4. RNAseq was performed to reveal the transcriptome alteration by APG-115, a novel MDM2 inhibitor also developed by Ascentage, to re-sensitize cells to BCL-2 inhibitors. Results A panel of hematologic malignancy cell lines were first assessed cells' sensitivity to novel BCL-2/ BCL-xL inhibitors, and revealed a distinct pattern of dependence on BCL-2, BCL-xL or MCL-1, from the most sensitive ALL line RS4;11 to BCL-2, to the most resistant one like MM line H929. In between there is a mix pattern of dependence on these three anti-death proteins. To dissect the mechanism of action, we established and validated BCL-2:BIM complex using MSD method. In BCL-2 dependent cell lines, BCL-2:BIM complex correlates with cells sensitivity to BCL-2 selective inhibitor. While in the mix pattern, high BCL-2:BIM complex alone does not predict drug sensitivity. Pretreating cells with BCL-2 inhibitors, either selective or dual inhibitors, can disrupt the BCL-2:BIM complex and reduce signals detected by MSD methods (Figure 1). Such reduction is consistent with co-immunoprecipitation results using Ascentage selective BCL-2 inhibitor or reference compound ABT-199, suggesting BCL-2 protecting cells through sequestering pro-death protein BIM. To overcome resistance to BCL-2 inhibitor, we combined it with our novel MDM2 inhibitor APG-115. Both in vitro cell viability assay and mice xenograft models demonstrated that MDM2 and BCL-2 inhibitor combination can re-sensitize cells and effectively inhibit tumor growth or lead to tumor regression. To obtain a full transcriptome profile changed by APG-115, we further performed RNAseq on OCI-AML3, which is intrinsically resistant to BCL-2 inhibitor. RNAseq results revealed that APG-115 reprogramed cell cycle and apoptosis pathway, increasing its known targets for cell cycle regulation (p21, p15 protein) and pro-death proteins (BAX, PUMA and NOXA). Furthermore, APG-115 also increased significantly some target genes involved in immune or inflammatory response pathway, including MIC-1 (macrophage inhibitory cytokine-1, GDF15), IL-24 (also known as mda-7, melanoma differentiation-associated protein 7, tumor suppressing protein), and PADI4 (peptidyl arginine deiminase, type IV, regulating granulocyte and macrophage via histone remodeling), which may alter tumor microenvironment and manifest cell death signals (Figure 2). Conclusions Using novel selective or dual BCL-2/BCL-xL inhibitor, we probed the oncogene addiction patterns in a panel of hematologic malignancy cell lines, and revealed a mix pattern of dependence on BCL-2, BCL-xL or MCL-1. The BCL-2 addiction relies on the sequestration of pro-death proteins like BIM. Disrupting BCL-2:BIM complex by BCL-2 inhibitors can trigger cell death. MDM2 inhibitor APG-115 reprograms cell cycle, apoptosis and immune/inflammatory pathways to re-sensitize cells to BCL-2 inhibitor. Disclosures Deng: Ascentage Pharma Group: Employment. Yin:Ascentage Pharma Group: Employment. Mao:Ascentage Pharma Group: Employment. Zhai:Ascentage Pharma Group: Employment. Yang:Ascentage Pharma Group: Employment. Fang:Ascentage Pharma Group: Employment. Wang:Ascentage Pharma Group: Employment. Zhai:Ascentage Pharma Group Inc.: Employment. Yang:Ascentage Pharma Group Inc.: Employment.
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Peitz, Camila, and Claudia Regina Xavier. "Evaluation of aerated lagoon modified with spongy support medium treating Kraft pulp mill effluent." Revista Facultad de Ingeniería Universidad de Antioquia, no. 92 (June 7, 2019): 60–69. http://dx.doi.org/10.17533/udea.redin.20190725.
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The pulp industry generates high effluent flows, which contain high chemical oxygen demand (COD), biochemical oxygen demand (BOD5), colour and ecotoxicity. This study aimed to evaluate the treatment of Kraft pulp effluent by aerated lagoon modified with sponge support media (APG). It was assessed the arrangement of the support media in the aerated lagoons in the organic load rate (OLR) of 0.2 kgCOD m-3 d-1, and after that, with OLR variation from 0.2 to 1.2 kgCOD m-3 d-1. The parameters evaluated were BOD5, COD, colour, lignin derivatives, total phenolic compounds and acute ecotoxicity in D. magna. COD and BOD5 removals were 32% and 88%, respectively, for free and confined support media in 0.2 kgCOD m-3 d-1. There was no colour or total phenolic compounds removal under these conditions. Considering the treatment in which there was a variation of the organic load rate, 1.2 kgCOD m-3 d-1 had the best performance. In this case, 50% and 75% of COD and BOD5 were removed, respectively. Removal of colour, total phenolic compounds and lignin derivatives were around 20%, 18% and 10%, respectively. The acute ecotoxicity was reduced to toxicity factor equal to 1 in all treatments. Comparing the aerated lagoon modified systems with those without the APG, it was suggested to apply spongy support in higher organic load rate than these typically used in aerated lagoons.
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Seemann, Gunnar, Christine Höper, Frank B. Sachse, Olaf Dössel, Arun V. Holden, and Henggui Zhang. "Heterogeneous three-dimensional anatomical and electrophysiological model of human atria." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 364, no. 1843 (April 12, 2006): 1465–81. http://dx.doi.org/10.1098/rsta.2006.1781.
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Investigating the mechanisms underlying the genesis and conduction of electrical excitation in the atria at physiological and pathological states is of great importance. To provide knowledge concerning the mechanisms of excitation, we constructed a biophysical detailed and anatomically accurate computer model of human atria that incorporates both structural and electrophysiological heterogeneities. The three-dimensional geometry was extracted from the visible female dataset. The sinoatrial node (SAN) and atrium, including crista terminalis (CT), pectinate muscles (PM), appendages (APG) and Bachmann's bundle (BB) were segmented in this work. Fibre orientation in CT, PM and BB was set to local longitudinal direction. Descriptions for all used cell types were based on modifications of the Courtemanche et al . model of a human atrial cell. Maximum conductances of , and were modified for PM, CT, APG and atrioventricular ring to reproduce measured action potentials (AP). Pacemaker activity in the human SAN was reproduced by removing , but including , , and gradients of channel conductances as described in previous studies for heterogeneous rabbit SAN. Anisotropic conduction was computed with a monodomain model using the finite element method. The transversal to longitudinal ratio of conductivity for PM, CT and BB was 1 : 9. Atrial working myocardium (AWM) was set to be isotropic. Simulation of atrial electrophysiology showed initiation of APs in the SAN centre. The excitation spread afterwards to the periphery near to the region of the CT and preferentially towards the atrioventricular region. The excitation extends over the right atrium along PM. Both CT and PM activated the right AWM. Earliest activation of the left atrium was through BB and excitation spread over to the APG. The conduction velocities were 0.6 m s −1 for AWM, 1.2 m s −1 for CT, 1.6 m s −1 for PM and 1.1 m s −1 for BB at a rate of 63 bpm. The simulations revealed that bundles form dominant pathways for atrial conduction. The preferential conduction towards CT and along PM is comparable with clinical mapping. Repolarization is more homogeneous than excitation due to the heterogeneous distribution of electrophysiological properties and hence the action potential duration.
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Truksa, Jaroslav, Jonathan Flanagan, Pauline Lee, and Ernest Beutler. "Characterization of IL-6 Responsive Elements in Hepcidin Promoters at the Molecular Level: Lessons from the Two Closely Related Promoter Sequences, Murine Hepc1 and Hepc2." Blood 108, no. 11 (November 16, 2006): 1555. http://dx.doi.org/10.1182/blood.v108.11.1555.1555.
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Abstract Hepcidin is an antimicrobial peptide that plays an important role in regulation of iron metabolism. There is one hepcidin peptide in humans and two hepcidin peptides in mice, hepcidin 1 and hepcidin 2, the murine mature peptides sharing 68% homology at the amino-acid level. The promoter region of these two genes is highly conserved (92% homology of 500 bp promoter sequence from the start of translation). However, regulation of transcription of these two genes is different. Human hepcidin and murine hepcidin 1 mRNA levels become elevated in response to iron excess and inflammation, while murine hepcidin 2 responds only to iron. Wrighting and Andrews (Blood Ahead of Print July 2006) demonstrated that the inflammatory pathway is mediated by STAT3 and that the binding site includes nucleotides −145 to −143 from start of translation in the human hepcidin promoter. Moreover, mutation of these nucleotides led to loss of IL-6 responsiveness. Alignment of the nucleotide sequences of hepcidin promoters revealed that there are two major differences between the murine hepcidin 2 (mHepc2) and the human hepcidin (hHEPC) and the murine hepcidin 1 (mHepc1) sequence in the proximal 140 bp promoter region. There is a substitution of T for A at −136 in the STAT3/AP1 site and an inversion of ApG to GpA at position −127–8 in the AP1 site. We cloned mHepc1 and mHepc2 promoters into a pGL3 basic luciferase reporter vector and mutated the two different sites in order to determine if creating the mHepc2 sequence in the mHepc1 promoter eliminated IL-6 responsiveness and if creating the mHepc1 sequence in the mHepc2 promoter restored IL-6 responsiveness of that promoter. We also created the equivalent A→T mutation in the STAT3/AP1 site in the hHEPC construct and the TpTpC→GpGpA mutation at −143–5, the same mutant as made by Wrighting and Andrews. Plasmids were transfected into human hepatoma HepG2 cells and human kidney HEK293T cells. As expected, the wildtype hHEPC reporter construct was induced 10 fold or more by IL-6. The T→A and TpTpC→GpGpA hHEPC mutants both displayed significantly reduced, but not absent, IL-6 responsiveness. The basal level of the native mHepc1-driven reporter was at least 10-fold higher than that of the native mHepc2. Furthermore, the mHepc1 promoter was similarly responsive to IL-6 as the hHEPC while the response of mHepc2 promoter was negligible. Interestingly, although the mHepc1 promoter-driven reporter manifests baseline expression even in cells of non-hepatic origin (kidney HEK293T cells), the ability to respond to IL-6 is restricted to cells of hepatic origin. We observed a significantly lower basal level of luciferase reporter activity in the mHepc1 promoter mutated to mHepc2 (A→ T and GpA→ApG), however, it was still IL-6 responsive. In contrast, complementary mutagenesis of mHepc2 to mHepc1 (T→ A and ApG→GpA) increased the basal level of reporter expression and significantly increased the mHepc2 promoter responsiveness to IL-6 although not to the extent seen with mHepc1 promoter. We conclude that the promoter region at nt −126 to −145 from the start of translation is important for the basal level of expression of hepcidin and is important for IL-6 responsiveness in the hHEPC promoter but there are probably additional regions responsible for IL-6 responsiveness in the mHepc1 promoter.
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Chao, Wen-Wan, Yueh-Hsiung Kuo, Shie-Liang Hsieh, and Bi-Fong Lin. "Inhibitory Effects of Ethyl Acetate Extract ofAndrographis paniculataon NF-κB Trans-Activation Activity and LPS-Induced Acute Inflammation in Mice." Evidence-Based Complementary and Alternative Medicine 2011 (2011): 1–9. http://dx.doi.org/10.1093/ecam/nep120.
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This study was to investigate anti-inflammatory effect ofAndrographis paniculata(Burm. f.) Nees (Acanthaceae) (AP). The effects of ethyl acetate (EtOAc) extract from AP on the level of inflammatory mediators were examined first using nuclear factor kappa B (NF-κB) driven luciferase assay. The results showed that AP significantly inhibited NF-κB luciferase activity and tumor necrosis factorα(TNF-α), interleukin 6 (IL-6), macrophage inflammatory protein-2 (MIP-2) and nitric oxide (NO) secretions from lipopolysaccharide (LPS)/interferon-γstimulated Raw264.7 cells. To further evaluate the anti-inflammatory effects of APin vivo, BALB/c mice were tube-fed with 0.78 (AP1), 1.56 (AP2), 3.12 (AP3) and 6.25 (AP4) mg kg−1body weight (BW)/day in soybean oil, while the control and PDTC (pyrrolidine dithiocarbamate, an anti-inflammatory agent) groups were tube-fed with soybean oil only. After 1 week of tube-feeding, the PDTC group was injected with 50 mg kg−1BW PDTC and 1 h later, all of the mice were injected with 15 mg kg−1BW LPS. The results showed that the AP1, AP2, AP3 and PDTC groups, but not AP4, had significantly higher survival rate than the control group. Thus, the control, AP1, AP2, AP3 and PDTC groups were repeated forin vivoparameters. The results showed that the AP and PDTC groups had significantly lower TNF-α, IL-12p40, MIP-2 or NO in serum or peritoneal macrophages and infiltration of inflammatory cells into the lung of mice. The AP1 group also had significantly lower MIP-2 mRNA expression in brain. This study suggests that AP can inhibit the production of inflammatory mediators and alleviate acute hazards at its optimal dosages.
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Yagüe, Genoveva, Manuel Segovia, and Pedro L. Valero-Guillén. "Phospholipid composition of several clinically relevant Corynebacterium species as determined by mass spectrometry: an unusual fatty acyl moiety is present in inositol-containing phospholipids of Corynebacterium urealyticum." Microbiology 149, no. 7 (July 1, 2003): 1675–85. http://dx.doi.org/10.1099/mic.0.26206-0.
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A comparative study on phospholipids of Corynebacterium amycolatum, Corynebacterium jeikeium and Corynebacterium urealyticum was carried out using fast-atom bombardment (FAB) and electrospray ionization (ESI) mass spectrometry. Data obtained indicate the presence of acylphosphatidylglycerol (APG), diphosphatidylglycerol, phosphatidylglycerol (PG), phosphatidylinositol (PI) and triacylphosphatidylinositol dimannosides (Ac3PIM2) in these bacteria. In general, octadecenoyl and hexadecanoyl fatty acyl moieties predominated in phospholipids of C. amycolatum, whereas high levels of hexadecenoyl were found in C. jeikeium and C. urealyticum. Mass spectra from purified APG and PG indicated that the sn-1 position of the glycerol was occupied by octadecenoyl in the three species studied. Notably, several major molecular species of PI and Ac3PIM2 from C. urealyticum contained significant amounts of a moiety identified as 10-methyleneoctadecanoyl, located at the sn-1 position of these molecules. On the other hand, multiantibiotic resistant and susceptible strains of C. amycolatum differed in several minor phospholipid fatty acids of 19 carbon atoms, identified as 10-methyloctadecenoic, 10-methyloctadecanoic (tuberculostearic acid) and 10-methyleneoctadecanoic. The results demonstrate an overall similarity among the phospholipids of the different species studied but also significant differences related to the acyl chains of the glycerol moiety of these compounds, notably the high levels of an unusual fatty acyl moiety in inositol-containing phospholipids of C. urealyticum.
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Deng, Jing, Tingting Mao, Xiaojing Huang, Li Rui, Guangfeng Wang, Douglas D. Fang, Dajun Yang, and Yifan Zhai. "A Novel BCL-2/BCL-Xl Dual Inhibitor Overcomes Ibrutinib-Resistance Conferred By the Upregulation of Integrin Pathway and BCL-Xl." Blood 134, Supplement_1 (November 13, 2019): 2573. http://dx.doi.org/10.1182/blood-2019-128708.
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Introduction Ibrutinib, a first-in-class oral covalent inhibitor of Bruton's tyrosine kinase (BTK), has been FDA-approved for the treatment of mantle cell lymphoma, chronic lymphocytic leukemia (CLL) and Waldenström's macroglobulinemia. In CLL, 80% overall response rate (OR) as a monotherapy or 96% OR in the combination with BCL-2 selective inhibitor venetoclax demonstrates a promising regimen for CLL patients. However, ibrutinib only yields to a modest (38%) OR in follicular lymphoma (FL) trial, especially doing poorly in patients with NF-kB constitutive activation via CARD11 mutation. To better understand ibrutinib resistance mechanism, we established a resistance model using sensitive follicular lymphoma cell line DOHH2, and characterized the gene expression profile and signaling pathway alteration, and tested potential approach to overcome the resistance. Methods 1. DOHH2-IR (ibrutinib resistant) cells were established by exposing to the increasing concentrations of the drug over 3 months and confirmed by cell viability assays. 2. RNA-seq was performed to reveal the transcriptome alteration between DOHH2 and DOHH2-IR cells. 3. Cell sensitivity to BCL-2/BCL-xL inhibitors was assessed by CTG assays. Results Parental DOHH2 and resistant DOHH2-IR cells were first confirmed ibrutinib sensitivity/resistance by CTG assay, which showed an IC50 of 0.074 uM for DOHH2, but 160 fold greater for DOHH2-IR at 12.19 uM. To decipher the mechanisms underlying the induced ibrutinib resistance, whole-transcriptome RNA-seq was performed on parental and resistant cells. Unsupervised hierarchical clustering showed significant alterations in gene expression signatures. Among them, 4,925 genes were significantly up-regulated and 3,727 genes were down-regulated. Kyoto Encyclopedia of Genes and Genome (KEGG) analysis showed that the components of BCR signaling pathway had been significantly downregulated in the resistant cells, so were those in pro-survival NF-kB and mTOR pathways, anti-apoptotic BCL-2 and BFL-1 genes, and TP53 pathway; in contrast, BCL-xL, MAP kinase and extracellular matrix (ECM)-receptor interaction genes, especially those integrin family genes, were increased (Figure 1). The upregulation of BCL-xL gene expression prompted us to investigate if inhibiting BCL-xL would resume cell sensitivity to killing. We thus treated cells with APG-1252-M1 (ester hydrolyzed active metabolite of APG-1252 for in vitro study), a novel BCL-2/BCL-xL dual inhibitor developed by Ascentage. In comparison, we also treated cells with BCL-2 selective inhibitor APG-2575, which is also a proprietary compound by Ascentage, and its reference compound ABT-199. APG-2575 and ABT-199 partially restored cell death in the resistant cells, with IC50s of 0.65 uM and 1.19 uM, respectively, which were greater than parental cells with IC50s of approximate 0.05 uM. However, the dual inhibitor APG-1252-M1 effectively killed DOHH2-IR cells with an IC50 of 0.017 uM, and cell death was potently elicited within 24 hours (Figure 2). This finding is consistent with RNA-seq data, that BCL-2 is downregulated, while BCL-xL is induced during ibrutinib resistant selection. Conclusions In an ibrutinib-resistant DOHH2 model, we show that reprogram of BTK and apoptosis pathway is associated with ibrutinib resistance. Instead of mutating BTK or its downstream PLCg2 gene in CLL, resistant cells have selected to bypass the pathway; and unexpectedly, NF-kB pathway is also downregulated in DOHH2-IR, which is contrast to previously report that it is one of resistant mechanisms for ibrutinib. Evading apoptosis is one of the key mechanisms in which cancer cells can survive or become resistant to therapies. Integrin family proteins or ECM - receptor interactions also play important roles in drug resistance. Further studies are needed to understand how the components of integrin pathway cross-talk with BCL-2 family proteins. However, the potent killing activity conferred by APG-1252 confirms that BCL-xL upregulation is key in this FL ibrutinib resistance model. Collectively, the results suggest that the combination of ibrutinib and BCL-2/BCL-xL dual inhibitor may produce deeper and longer duration response in follicular lymphoma patients. Disclosures Deng: Ascentage Pharma Group: Employment. Mao:Ascentage Pharma Group: Employment. Huang:Ascentage Pharma Group: Employment. Rui:Ascentage Pharma Group: Employment. Wang:Ascentage Pharma Group: Employment. Fang:Ascentage Pharma Group: Employment. Yang:Ascentage Pharma Group: Employment. Zhai:Ascentage Pharma Group: Employment.
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Kaneko, Yoshiyuki, Toshio Kimura, Hiroyuki Nishiyama, Yoichi Noda, and Jun Fujita. "Developmentally Regulated Expression of APG-1, a Member of Heat Shock Protein 110 Family in Murine Male Germ Cells." Biochemical and Biophysical Research Communications 233, no. 1 (April 1997): 113–16. http://dx.doi.org/10.1006/bbrc.1997.6410.
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Shao, Wen-Ze, Qi Ge, Zong-Liang Gan, Hai-Song Deng, and Hai-Bo Li. "A Generalized Robust Minimization Framework for Low-Rank Matrix Recovery." Mathematical Problems in Engineering 2014 (2014): 1–8. http://dx.doi.org/10.1155/2014/656074.
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This paper considers the problem of recovering low-rank matrices which are heavily corrupted by outliers or large errors. To improve the robustness of existing recovery methods, the problem is solved by formulating it as a generalized nonsmooth nonconvex minimization functional via exploiting the Schattenp-norm(0 < p ≤1)andLq(0 < q ≤1)seminorm. Two numerical algorithms are provided based on the augmented Lagrange multiplier (ALM) and accelerated proximal gradient (APG) methods as well as efficient root-finder strategies. Experimental results demonstrate that the proposed generalized approach is more inclusive and effective compared with state-of-the-art methods, either convex or nonconvex.
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Cesare, Sabrina, Irina Uscatescu, Jonathan di Tomasso, Lorella Ciutto, Kevin Yu-Chueh, Henry Olders, Nathalie Aubin, et al. "Developing pathways for cancer rehabilitation in tertiary oncology centers: Initial observations at the McGill University Health Centre." Journal of Clinical Oncology 32, no. 31_suppl (November 1, 2014): 17. http://dx.doi.org/10.1200/jco.2014.32.31_suppl.17.
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17 Background: No definitive rehabilitation pathways exist for cancer patients. To address this gap, the Cancer Rehabilitation interdisciplinary team at the McGill University Health Centre has developed three program paths (e.g., Restorative, Supportive, and Cachexia) to meet the various specialized and personalized needs of cancer patients. Methods: A consecutive cohort of patients referred to the Cancer Rehabilitation Clinic between January 1st and June 30th, 2014 was considered. We examined the following baseline characteristics: handgrip strength (HGS), the abridged Patient Generated-Subjective Global Assessment (aPG-SGA) and Edmonton Symptom Assessment System (ESAS) self-reported questionnaires. Results: Of the 54 patients evaluated (57.4% male), 20 (mean age: 47.4 yrs), 8 (59.9 yrs) and 26 (64.6 yrs) were assigned to the restorative, supportive and cachexia streams, respectively. The most common cancer diagnoses were gastrointestinal (15%), gynecological (13%), breast (12%) and lung (12%). Table 1 contains baseline aPG-SGA, ESAS and HGS scores. Conclusions: Our preliminary data confirm clinically significant differences in muscle strength across the 3 streams for both males and females, as well as significant differences in nutritional, appetite and well-being scores between the patients in the restorative and cachexia pathways. Our data confirm the need of personalized and targeted interventions to achieve or maintain optimal performance and quality of life in cancer survivors with different disease and treatment characteristics. [Table: see text]
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Xue, Jing-Hui, Hidenao Fukuyama, Kohsuke Nonoguchi, Yoshiyuki Kaneko, Tsuneo Kido, Manabu Fukumoto, Yasuhisa Fujibayashi, Katsuhiko Itoh, and Jun Fujita. "Induction of Apg-1, a Member of the Heat Shock Protein 110 Family, Following Transient Forebrain Ischemia in the Rat Brain." Biochemical and Biophysical Research Communications 247, no. 3 (June 1998): 796–801. http://dx.doi.org/10.1006/bbrc.1998.8894.
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