Zeitschriftenartikel: „ACE100“

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Shen, Chang-Hui, Benoit P. Leblanc, Jennifer A. Alfieri und David J. Clark. „Remodeling of Yeast CUP1 Chromatin Involves Activator-Dependent Repositioning of Nucleosomes over the Entire Gene and Flanking Sequences“. Molecular and Cellular Biology 21, Nr. 2 (15.01.2001): 534–47. http://dx.doi.org/10.1128/mcb.21.2.534-547.2001.

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ABSTRACT The yeast CUP1 gene is activated by the copper-dependent binding of the transcriptional activator, Ace1p. An episome containing transcriptionally active or inactiveCUP1 was purified in its native chromatin structure from yeast cells. The amount of RNA polymerase II on CUP1 in the purified episomes correlated with its transcriptional activity in vivo. Chromatin structures were examined by using the monomer extension technique to map translational positions of nucleosomes. The chromatin structure of an episome containing inactive CUP1 isolated from ace1Δ cells is organized into clusters of overlapping nucleosome positions separated by linkers. Novel nucleosome positions that include the linkers are occupied in the presence of Ace1p. Repositioning was observed over the entire CUP1 gene and its flanking regions, possibly over the entire episome. Mutation of the TATA boxes to prevent transcription did not prevent repositioning, implicating a chromatin remodeling activity recruited by Ace1p. These observations provide direct evidence in vivo for the nucleosome sliding mechanism proposed for remodeling complexes in vitro and indicate that remodeling is not restricted to the promoter but occurs over a chromatin domain including CUP1 and its flanking sequences.

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Koronyo-Hamaoui, Maya, Julia Sheyn, Eric Y. Hayden, Songlin Li, Dieu-Trang Fuchs, Giovanna C. Regis, Dahabada H. J. Lopes et al. „Peripherally derived angiotensin converting enzyme-enhanced macrophages alleviate Alzheimer-related disease“. Brain 143, Nr. 1 (03.12.2019): 336–58. http://dx.doi.org/10.1093/brain/awz364.

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Abstract Targeted overexpression of angiotensin-converting enzyme (ACE), an amyloid-β protein degrading enzyme, to brain resident microglia and peripheral myelomonocytes (ACE10 model) substantially diminished Alzheimer’s-like disease in double-transgenic APPSWE/PS1ΔE9 (AD+) mice. In this study, we explored the impact of selective and transient angiotensin-converting enzyme overexpression on macrophage behaviour and the relative contribution of bone marrow-derived ACE10 macrophages, but not microglia, in attenuating disease progression. To this end, two in vivo approaches were applied in AD+ mice: (i) ACE10/GFP+ bone marrow transplantation with head shielding; and (ii) adoptive transfer of CD115+-ACE10/GFP+ monocytes to the peripheral blood. Extensive in vitro studies were further undertaken to establish the unique ACE10-macrophage phenotype(s) in response to amyloid-β1-42 fibrils and oligomers. The combined in vivo approaches showed that increased cerebral infiltration of ACE10 as compared to wild-type monocytes (∼3-fold increase; P < 0.05) led to reductions in cerebral soluble amyloid-β1-42, vascular and parenchymal amyloid-β deposits, and astrocytosis (31%, 47–80%, and 33%, respectively; P < 0.05–0.0001). ACE10 macrophages surrounded brain and retinal amyloid-β plaques and expressed 3.2-fold higher insulin-like growth factor-1 (P < 0.01) and ∼60% lower tumour necrosis factor-α (P < 0.05). Importantly, blood enrichment with CD115+-ACE10 monocytes in symptomatic AD+ mice resulted in pronounced synaptic and cognitive preservation (P < 0.05–0.001). In vitro analysis of macrophage response to well-defined amyloid-β1-42 conformers (fibrils, prion rod-like structures, and stabilized soluble oligomers) revealed extensive resistance to amyloid-β1-42 species by ACE10 macrophages. They exhibited 2–5-fold increased surface binding to amyloid-β conformers as well as substantially more effective amyloid-β1-42 uptake, at least 8-fold higher than those of wild-type macrophages (P < 0.0001), which were associated with enhanced expression of surface scavenger receptors (i.e. CD36, scavenger receptor class A member 1, triggering receptor expressed on myeloid cells 2, CD163; P < 0.05–0.0001), endosomal processing (P < 0.05–0.0001), and ∼80% increased extracellular degradation of amyloid-β1-42 (P < 0.001). Beneficial ACE10 phenotype was reversed by the angiotensin-converting enzyme inhibitor (lisinopril) and thus was dependent on angiotensin-converting enzyme catalytic activity. Further, ACE10 macrophages presented distinct anti-inflammatory (low inducible nitric oxide synthase and lower tumour necrosis factor-α), pro-healing immune profiles (high insulin-like growth factor-1, elongated cell morphology), even following exposure to Alzheimer’s-related amyloid-β1-42 oligomers. Overall, we provide the first evidence for therapeutic roles of angiotensin-converting enzyme-overexpressing macrophages in preserving synapses and cognition, attenuating neuropathology and neuroinflammation, and enhancing resistance to defined pathognomonic amyloid-β forms.

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Li, Xiang, Junan Yang, Hui Liu und Pengjiang Hu. „HTLinker: A Head-to-Tail Linker for Nested Named Entity Recognition“. Symmetry 13, Nr. 9 (31.08.2021): 1596. http://dx.doi.org/10.3390/sym13091596.

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Named entity recognition (NER) aims to extract entities from unstructured text, and a nested structure often exists between entities. However, most previous studies paid more attention to flair named entity recognition while ignoring nested entities. The importance of words in the text should vary for different entity categories. In this paper, we propose a head-to-tail linker for nested NER. The proposed model exploits the extracted entity head as conditional information to locate the corresponding entity tails under different entity categories. This strategy takes part of the symmetric boundary information of the entity as a condition and effectively leverages the information from the text to improve the entity boundary recognition effectiveness. The proposed model considers the variability in the semantic correlation between tokens for different entity heads under different entity categories. To verify the effectiveness of the model, numerous experiments were implemented on three datasets: ACE2004, ACE2005, and GENIA, with F1-scores of 80.5%, 79.3%, and 76.4%, respectively. The experimental results show that our model is the most effective of all the methods used for comparison.

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Tan, Chuanqi, Wei Qiu, Mosha Chen, Rui Wang und Fei Huang. „Boundary Enhanced Neural Span Classification for Nested Named Entity Recognition“. Proceedings of the AAAI Conference on Artificial Intelligence 34, Nr. 05 (03.04.2020): 9016–23. http://dx.doi.org/10.1609/aaai.v34i05.6434.

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Named entity recognition (NER) is a well-studied task in natural language processing. However, the widely-used sequence labeling framework is usually difficult to detect entities with nested structures. The span-based method that can easily detect nested entities in different subsequences is naturally suitable for the nested NER problem. However, previous span-based methods have two main issues. First, classifying all subsequences is computationally expensive and very inefficient at inference. Second, the span-based methods mainly focus on learning span representations but lack of explicit boundary supervision. To tackle the above two issues, we propose a boundary enhanced neural span classification model. In addition to classifying the span, we propose incorporating an additional boundary detection task to predict those words that are boundaries of entities. The two tasks are jointly trained under a multitask learning framework, which enhances the span representation with additional boundary supervision. In addition, the boundary detection model has the ability to generate high-quality candidate spans, which greatly reduces the time complexity during inference. Experiments show that our approach outperforms all existing methods and achieves 85.3, 83.9, and 78.3 scores in terms of F1 on the ACE2004, ACE2005, and GENIA datasets, respectively.

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Hartmann, Rudolf, Tjerk Feenstra, Sabine Knappe, Michael Dockal und Friedrich Scheiflinger. „Elucidating the Excessive Pro-Coagulant Effect of a Sequence Identical Analogue to ACE910 in Combination with Bypassing Agents“. Blood 130, Suppl_1 (07.12.2017): 90. http://dx.doi.org/10.1182/blood.v130.suppl_1.90.90.

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Abstract Introduction: Emicizumab (ACE910), an antibody to FIX(a) and FX(a), is currently under investigation for treatment of hemophilia with inhibitors. In a phase III trial, two thromboembolic complications and three cases of microangiopathy were reported in patients on ACE910 prophylaxis [Oldenburg et al. NEJM 2017], whose breakthrough bleeding was treated with activated prothrombin complex concentrate aPCC (FEIBA) or aPCC and rFVIIa. We generated a sequence identical analogue (SIA) to ACE910 and analyzed its synergistic interplay with bypassing agents. Aims: To monitor in vitro the pro-coagulant activity of SIA ACE910 in the presence of FEIBA and rFVIIa, and detect the source of excessive coagulation induced by SIA ACE910 combined with FEIBA. Methods: A sequence identical analogue (SIA) to ACE910 was expressed in HEK293 cells, purified as previously described [Sampei et al. PLoS One 2013], and analyzed in several global hemostatic assays at different concentrations and test conditions using plasma and whole blood assays. In thrombin generation (TG) experiments, platelet-poor plasma (PPP) from hemophilia A inhibitor patients and hemophilia A plasma reconstituted with platelets from 3 healthy donors (PRP) was used. A normal TG range was established in healthy donor plasma. Therapeutic concentrations of SIA ACE910 (20-600 nM) were tested alone and with FEIBA (0.05-1 U/mL) or rFVIIa (0.88-5.25 µg/mL). To measure FEIBA components' contribution to the synergistic effect with SIA ACE910, PPP was spiked with select FEIBA components at concentrations corresponding to 0.5 U/mL FEIBA in combination with the antibody. Thrombus formation was analyzed in FVIII-inhibited blood using rotational thromboelastometry (ROTEM) and Total Thrombus-formation Analysis System (T-TAS). Results: Normal peak thrombin was 47-144 nM for PPP and 88-231 nM for PRP. rFVIIa and FEIBA had an additive effect on TG in combination with SIA ACE910 in both plasma types. Combined with rFVIIa (0.88 µg/mL) or FEIBA (0.5 U/mL), SIA ACE910 (600 nM) induced a ~2- and ~16-fold increase over SIA ACE910 alone. SIA ACE910+rFVIIa did not reach the normal range, while SIA ACE910+FEIBA far exceeded it. Adding individual FEIBA components to PPP showed that FIX was, with a half-maximal effect, the main driver for enhanced TG, followed by FIXa. formation in FVIII-inhibited whole blood using ROTEM and T-TAS confirmed the excessive effect of SIA ACE910+FEIBA. In ROTEM, FEIBA and rFVIIa reduced clotting time to shorter than normal, whereas SIA ACE910 had only little effect. Moreover, adding SIA ACE910 to rFVIIa exerted no effect over rFVIIa alone. Conclusion: Combining SIA ACE910 at plasma concentrations observed in patients [Oldenburg et al. NEJM 2017] with FEIBA induced excessive thrombin generation and faster clot formation. In vitro, this effect is mainly mediated by FEIBA component FIX. ACE910 binds to FIX and FIXa to the same extent, and displays its pro-coagulant effect via an unregulated mechanism. Therefore, careful judgement is needed in treating breakthrough bleeds with FEIBA. Disclosures Hartmann: Shire: Employment. Feenstra: Shire: Employment. Knappe: Shire: Employment. Dockal: Baxalta: Patents & Royalties; Shire: Employment, Equity Ownership; Baxter: Equity Ownership, Patents & Royalties. Scheiflinger: Baxter: Equity Ownership; Shire: Employment, Equity Ownership.

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Li, Hao-Kang, Ching-Wen Hsiao, Sen-Han Yang, Hsiu-Ping Yang, Tai-Sheng Wu, Zih-Fei Cheng, Chia-Yun Lee et al. „772 A potent and off-the-shelf oNK cell therapy product targets HER2+ cancer cells and resists suppressive tumor microenvironment“. Journal for ImmunoTherapy of Cancer 8, Suppl 3 (November 2020): A821. http://dx.doi.org/10.1136/jitc-2020-sitc2020.0772.

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BackgroundAutologous or allogeneic natural killer (NK) cells possess efficient cytotoxicity against tumor cells without severe side effects such as CRS or graft-versus-host disease (GvHD). In addition to chimeric antigen receptor (CAR) strategy, antibody-cell conjugates (ACC) platform provides more efficient way to arm NK cells with binding specificity and enhanced potency against target cells. In this work, we develop a NK cell therapy product ACE1702, a novel NK cell line oNK conjugated with trastuzumab, and assess its potency against HER2+ solid tumors.Methods oNK cells were covalently conjugated with monoclonal antibody Trastuzumab after sublethal irradiation by our patented antibody-cell conjugates (ACC) platform to become our cryopreserved final product ACE1702 compliant with current good manufacturing practice (cGMP). Function of ACE1702 was validated by real-time xCELLigence analyzer and MTT assay in vitro. Efficacy of intraperitoneally (ip.) delivered ACE1702 was evaluated in tumor-bearing female immune compromised NSG mice. Characterization of ACE1702 was analyzed by flow cytometry.ResultsWe demonstrated that the trastuzumab-armed oNK cells, ACE1702, exerted human epidermal growth factor 2 (HER2) binding specificity and enhanced cytotoxicity against various types of cancer cells with different grade of HER2 expressions compared to control oNK cells in vitro. In vivo results in human ovarian cancer cell line SK-OV-3-bearing xenograft mouse model further supported the in vitro observations. Of note, ACE1702 also displayed a better cytotoxicity against HER2+ cancer cells than trastuzumab and its derived antibody-drug conjugate. ACE1702 also remained cytotoxicity against cancer cells in the suppressive tumor microenvironment. Characterization revealed a preferential expression of NK activation receptors, and conjugation of trastuzumab with cell membrane proteins responsible for NK activity capacitated ACE1702 with enhanced cytotoxicity. These results underscore the potency of ACE1702 in eradication of cancer cells.ConclusionsHere we introduced a novel trastuzumab-modified oNK cell product with enhanced specificity against myriad types of HER2+ cancers. Selective conjugation of trastuzumab with membrane proteins contributing to NK activation conferred ACE1702 with enhanced cytotoxicity even in the suppressive tumor microenvironment.AcknowledgementsNoneTrial RegistrationNoneEthics ApprovalThe animal study was conducted according to protocols approved by the Institutional Animal Care and Use Committee of Muragenics.ConsentNone

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Minami, Hiroaki, Keiji Nogami, Takehisa Kitazawa, Kunihiro Hattori und Midori Shima. „FVIII Heavy Chain Enhances Tenase Activity Induced By FVIIIa Mimicking Bispesific Antibody, ACE910“. Blood 124, Nr. 21 (06.12.2014): 1481. http://dx.doi.org/10.1182/blood.v124.21.1481.1481.

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Abstract Background: ACE910, asymmetric bispecific monoclonal antibodies to activated factor IX (IXa) and factor X, mimics the cofactor function of activated factor VIII (VIIIa) by modulating an optimal position on the tenase assembly. The estimated therapeutic range of ACE910 shows ~30% of thrombin generation in native tenase assembly, supporting that the structure on ACE910-mimicking tenase assembly is different from that on native tenase. Being close to physiological structure consisting from factor IXa, factor X, and factor VIIIa is important for potentiating the clotting function. We examined the effects of factor VIII subunits (light chain, heavy chain, A1 and A2, C2) on ACE910-tenase. Materials/Methods: The factor VIII light chain and heavy chain were isolated from EDTA-treated recombinant factor VIII following chromatography on SP- and Q- Sepharose columns. The A2 and A1 subunits were purified from thrombin-cleaved factor VIII heavy chain by Heparin-, SP- Sepharose columns. Purified factor Xa generation assays was examined with (i) factor VIII subunit (0-40 nM), ACE910 (10 µg/ml), phospholipid (PL) (40 µM), factor IXa (1 nM) and factor X (200 nM), (ii, iii) the A2 or heavy chain (40 nM), ACE910 (10 µg/ml), PL (40 µM), factor IXa and factor X (1 or 0-80 nM, and 0-300 or 200 nM, respectively). These mixtures were reacted for five minutes (i, ii) or one minute (iii). These assays were conducted at 37 °C. Results: (i) The factor Xa generation in ACE910-tenase complex in the absence of factor VIIIa was 10.1±2.2 nM. With the intact heavy chain and A2, amounts of factor Xa were increased dose-dependently, resulting in 1.3- and 1.2-fold increases, respectively. While, the light chain and A1 subunit failed to increase at all. (ii) Vmax for factor X in ACE910-tenase was 173.0±7.0 nM and Km was 31.2±3.9 nM. Vmax obtained with the heavy chain or A2 was 175.9±6.1 or 159.0±6.1 nM, whilst Km was 17.0±2.2 or 31.9±3.5 nM, respectively, indicating that the heavy chain enhanced the binding affinity for factor X in ACE910-tenase. (iii) Vmax for factor IXa in ACE910-tenase was 43.8±2.7 nM and Km was 36.9±4.8 nM. With the heavy chain or A2, Vmax was 46.8±3.0 or 45.0±3.1 nM, and Km was 36.4±3.0 or 32.1±4.9 nM, respectively, indicating that either the heavy chain or A2 did not enhance the catalytic activity and the binding affinity for factor IXa in ACE910-tenase. Conclusion: ACE910-tenase assembly seems to be close to physiological structure by the presence of intact heavy chain interacting with factor X. In addition, ACE910 may substitute the position such as the factor VIII(a) light chain associated with FIXa and FX on ACE910-tenase assembly defecting factor VIII. Disclosures Minami: Chugai Pharmaceutical Co., Ltd.: Research Funding. Nogami:Chugai Pharmaceutical Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kitazawa:Chugai Pharmaceutical Co., Ltd.: Employment, Equity Ownership, Patents & Royalties. Hattori:Chugai Pharmaceutical Co., Ltd.: Employment, Equity Ownership, Patents & Royalties. Shima:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Yada, Koji, Keiji Nogami, Tomoko Matsumoto, Takehisa Kitazawa, Kunihiro Hattori und Midori Shima. „Activated Protein C-Catalyzed Factor Va Inactivation Predominantly Contributes to the Downregulation of Coagulation Rather Than Factor VIIIa Inactivation“. Blood 124, Nr. 21 (06.12.2014): 4222. http://dx.doi.org/10.1182/blood.v124.21.4222.4222.

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Abstract Activated protein C (APC) directly inactivates factor (F)Va and FVIIIa dependently of protein S (PS), and furthermore inactivates FVIIIa through cofactor function of FV. Any impairment in these inactivation pathways may increase thrombotic risk. A previous report described that the APC resistance (APCR) associated with FV-Leiden was mainly due to the impaired cofactor activity of FV (Castoldi et al. Blood 2004;103, 4173). We have recently reported that FV-Nara carrying W1920R mutation exhibited APCR caused by a loss of FVa susceptibility to APC and APC cofactor activity resulting in more serious thrombotic potential than FV-Leiden (Nogami et al. Blood 2014;123, 2420). The contribution of each inactivation pathway associated with FVIII(a) and/or FV(a) for the hemostatic regulation remains unclear, however. An ACE910, bispecific antibody (Ab) to FIXa and FX mimicking the functions of FVIII, exerts tenase activities without FVIII(a) (Kitazawa et al. Nature Medicine. 2012;18, 1570). In this study, to elucidate the contribution of each pathway, we investigated the regulatory mechanism(s) by APC utilizing ACE910. FXa generation with ACE910 (10μg/ml) or with FVIIIa (0.3 nM) in FVIII-deficient plasma (ΔFVIII) was evaluated by the addition of APC (0-0.5 nM), PS (5 nM), and FV (1 nM). FXa generation with FVIIIa was reduced by ~60% maximally in an APC dose-dependent manner, whilst that with ACE910 was unaffected, indicating that ACE910 itself was not susceptible to inactivation by APC through the cofactor activity of FV. Thrombin generation in ΔFVIII with ACE910 (0-30μg/ml) was enhanced in an ACE910 dose-dependent fashion and ~10-fold of peak thrombin (PeakTh) (442 ± 7.0 nM), equivalent to 77.5% of PeakTh in pool normal plasma (PNP), was observed with ACE910 (30μg/ml) compared to that without ACE910 (44.6 ± 5.0 nM). To investigate the effect of APC upon the hemostatic enhancement by ACE910 in ΔFVIII, thrombin generation in ΔFVIII mixed with ACE910 (30μg/ml) and APC (0-16 nM) was examined. PeakTh showed the APC-dependent reduction to 156 ± 22nM and the %inhibition was 64.7%. Subsequently, we evaluated the effects of APC on thrombin generation in PNP or in PNP with an anti-FVIII Ab (FVIIIAb) (16BU/ml) supplemented by ACE910. Of note, the %inhibition of PeakTh by APC in latter with ACE910 and FVIIIAb (64%) was greater than that in PNP alone (35%) by ~1.9-fold. To elucidate the contribution of APC-catalyzed inactivation of FV(a) to the hemostatic regulation, we evaluated the thrombin generation in FV-diluted plasma (FV-dil) consisting of FV-deficient plasma and FV (8nM) corresponded to ~25% of its physiological concentration mixed with or without ACE910 and FVIIIAb in the presence or absence of APC. The %inhibition of PeakTh by APC in FV-dil with ACE910 and FVIIIAb (46.5%), being reduced in comparison with that of PNP with both Abs, was greater than that in FV-dil alone (18.3%) by ~2.5-fold, indicating that the inhibition of thrombin generation by APC-catalyzed FV(a) inactivation was FV(a) dose-dependent but enhanced in the absence of FVIII(a). Furthermore, the effects on thrombin generation with APC (0-16 nM) in plasmas carrying FV-Leiden without or with FVIIIAb and ACE910 (30μg/ml) were examined. It was of surprise that PeakTh in latter with FVIIIAb and ACE910 reduced exponentially by ~40% in an APC dose-dependent manner, whilst APC showed any little effects upon thrombin generation in FV-Leiden plasma alone indicating APCR. The susceptibility index to APC calculated by the rate of inhibition with FVIIIAb and ACE910 was 0.174, greater than that with FV-Leiden plasma alone (0.085) by ~2-fold. These results strongly suggested that APC could regulate the hemostatic enhancement by inactivation of FV(a) even FV-Leiden in the absence of another substrate, FVIII(a). We conclude that APC potentiates its catalytic activity to FVa more in the absence of FVIII(a) than in the presence of FVIII(a) and this mechanism would play significant roles in the downregulation of coagulation as one of the breaking systems. Disclosures Yada: Chugai Pharmaceutica Co., Ltd: Research Funding. Nogami:Chugai Pharmaceutical Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kitazawa:Chugai Pharmaceutical Co., Ltd.: Employment, Equity Ownership, Patents & Royalties. Hattori:Chugai Pharmaceutical Co., Ltd.: Employment, Equity Ownership, Patents & Royalties. Shima:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Takeyama, Masahiro, Keiji Nogami, Tomoko Matsumoto, Takehisa Kitazawa, Kunihiro Hattori und Midori Shima. „Anti-Factor IXa/Factor X Antibody (ACE910) Improves the Coagulation Function in Acquired Hemophilia A ex vivo“. Blood 126, Nr. 23 (03.12.2015): 3565. http://dx.doi.org/10.1182/blood.v126.23.3565.3565.

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Abstract <Introduction> Acquired hemophilia A (AHA) is a rare bleeding disorder in which autoantibodies (autoAbs) against coagulation factor (F)VIII impair the coagulation system. Anti-FVIII autoAbs developed in AHA are polyclonal and the majority of these autoAbs bind to the A2, A3, and/or C2 domains in FVIII. Different inhibitory actions of anti-FVIII autoAbs, depending on their epitopes, are well-known. We have recently developed a humanized anti-FIXa/X bispecific antibody, ACE910, which mimics the cofactor function of FVIIIa even in the presence of anti-FVIII alloantibodies. <Aim> In this study, we examined whether ACE910 improved the lower coagulation function in AHA patients using the comprehensive coagulation assays. <Methods> Two representative experiments were performed as follows; 1) In vitro effects of ACE910 on normal pooled plasmas (PNPs) mixed with various anti-FVIII monoclonal Abs (mAbs) as the reconstituted AHA-models. For this experiments, several anti-FVIII mAbs; VIII-9222 (epitope: anti-a1), VIII-2236 (anti-A2), VIII-3776 (anti-A3C1), ESH4 (anti-C2) were prepared. 2) Ex vivo effects of ACE910 on plasmas obtained from nine patients with AHA, whose regions of Abs were A1, A2 and light chain for four patients, A2 and light chain for three patients, A2 for one patient and light chain for one patient. The coagulation functions in obtained samples were evaluated using the comprehensive coagulation assays, clot waveform analysis (CWA) and thrombin generation assays (TGA). In CWA, the minimum value of the first derivative (min1) and the second derivative (min2) were calculated as an index of the maximum acceleration of the reaction and the maximum velocity of coagulation, respectively. In TGA, calibrated automated thrombin generation assays derived the standard parameters; peak thrombin, lagtime, and time to peak. Total thrombin generation at intervals from the beginning to peak level was quantified. These values (nmol/l) were divided by the sample times (min, time to peak - lagtime), and represented the mean velocity of thrombin generation until the reach to peak level, expressed as mean velocity to peak thrombin (MV-peak thrombin). We defined the attenuation of inhibitory effect (% of AIE) represented that ACE910 attenuated the parameters inhibited by mAbs in artificial AHA or by allo-Abs in AHA patients, respectively. Figure 1 represents the % of AIE on thrombin peak in TGA. <Results> PNPs were incubated with various anti-FVIII mAbs (100-500 mcg/ml) at 37 degrees Celsius for 2 hrs, and FVIII activities in these samples were decreased to 2.0-43%. These reactant mixtures were reacted with ACE910 (0-20 mcg/ml) for a further 2 hr-incubation. ACE910 improved the parameters of CWA (|min1|; 40-62%, and |min2|; 49-74% of AIE) and of TGA (thrombin peak; 46-72%, and MV-peak thrombin; 51-70% of AIE, respectively) in all PNPs with mAbs. These data indicated that ACE910 improved the coagulant activity in AHA patients. Therefore, we determined the efficacy of ACE910 for nine AHA patients ex vivo. FVIII activities and FVIII inhibitors were <1.0-7.5 % and 2.2-134 BU/ml, respectively. ACE910 improved the parameters for eight AHA patients in CWA (|min1|; 36-100 %, and |min2|; 52-100 % of AIE, respectively). For one AHA patient whose epitope was A2 and light chain, ACE910 showed the slight improvement in |min1| (12 % of AIE) and in |min2| (31 % of AIE). The reason was that the range of concentration of ACE910 was only from 0 to 5 mcg/dl. On the other hand, ACE910 improved the parameters for all AHA patients in TGA. ACE910 showed effect on thrombin peak (27-77 % of AIE). Furthermore, ACE910 improved MV-peak thrombin (17-73 % of AIE). Figure 2 shows representative TGA curve for the effect of ACE910 on one AHA patient whose allo-Ab was anti-light chain. <Conclusion> Our results indicated that ACE910 could improve the coagulant activities in AHA patients independent of the regions of antibodies and might be useful for the treatment of AHA patients. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Takeyama: Chugai Pharmaceutical Co., Ltd.: Research Funding. Nogami:Bayer, NovoNordisk, Baxalta, Chugai, Kaketsuken, Pfizer, Biogen: Honoraria; Chugai: Membership on an entity's Board of Directors or advisory committees; Bayer, Novo Nordisk, Baxalta. Biogen: Research Funding. Matsumoto:Chugai Pharmaceutical Co., Ltd: Research Funding. Kitazawa:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership, Patents & Royalties. Hattori:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership, Patents & Royalties. Shima:Chugai Pharmaceutical Co., Ltd. and F. Hoffmann-La Roche Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Muto, Atsushi, Takehisa Kitazawa, Kazutaka Yoshihasi, Minako Takeda, Tetsuhiro Soeda, Tomoyuki Igawa, Zenjiro Sampei et al. „Hemostatic Effect of a Novel Bispecific Antibody (ACE910) Against Activated Factor IX and Factor X in an Acquired Hemophilia A Model“. Blood 120, Nr. 21 (16.11.2012): 42. http://dx.doi.org/10.1182/blood.v120.21.42.42.

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Abstract Abstract 42 Background: Hemophilia A is treated by intravenous replacement therapy with factor VIII (FVIII), either on demand to resolve bleeding or as a prophylactic to prevent bleeding. Recently, routine prophylactic treatment is recommended to effectively prevent bleeding and to reduce bleeding-related chronic joint damage. However, the need for frequent intravenous injections of FVIII negatively affects patients' quality of life and their adherence to the routine prophylactic regimen. More importantly, approximately 30% of severe hemophilia A patients develop inhibitory antibodies toward the injected FVIII, rendering the replacement therapy ineffective. To overcome these drawbacks, we generated a bispecific antibody (termed ACE910) against activated factor IX (FIXa) and factor X (FX), which mimics the cofactor function of FVIII. Objectives: The aims of the present study were to examine the FVIII-mimetic cofactor activity of ACE910 in vitro and its hemostatic activity in vivo. Methods: The FVIII-mimetic cofactor activity of ACE910 was evaluated by a thrombin generation assay in human FVIII-deficient plasma as well as by an enzymatic assay using purified coagulation factors. For in vivo studies, an acquired hemophilia A model was established in cynomolgus monkeys by a single intravenous injection of mouse monoclonal anti-FVIII neutralizing antibody, which was cross-reactive to cynomolgus monkey FVIII but not to porcine FVIII. After artificial bleeding had been induced, ACE910 or porcine FVIII was intravenously administered in a single dose or in twice-daily repeated doses, respectively. Bleeding symptoms, including anemia and skin bruising, were monitored for three days. A pharmacokinetic study of ACE910 was also performed with a single intravenous or subcutaneous administration to cynomolgus monkeys. Results: ACE910 concentration-dependently showed FVIII-mimetic cofactor activity in the enzymatic assay and improved thrombin generation parameters in human FVIII-deficient plasma. Intravenous administration of ACE910 (a single dose of 3 mg/kg) significantly reduced the bleeding symptoms in the acquired hemophilia A model of a non-human primate. This hemostatic effect was comparable to twice-daily intravenous administration of porcine FVIII (repeated doses of 10 U/kg). The half-life of ACE910 was approximately three weeks for both single intravenous and subcutaneous administrations. The subcutaneous bioavailability of ACE910 was nearly 100%. Conclusion: The bispecific antibody against FIXa and FX, ACE910, exerted FVIII-mimetic cofactor activity in vitro. Furthermore, a single dose of ACE910 demonstrated hemostatic activity comparable to twice-daily repeated doses of 10 U/kg porcine FVIII in vivo. Moreover, ACE910 exhibited high subcutaneous bioavailability and approximately three-week half-life in a non-human primate. Our bispecific antibody against FIXa and FX is a subcutaneously injectable, long-acting agent that removes the need to consider the induction or presence of FVIII inhibitors and may establish a novel principle for the prophylactic treatment of hemophilia A patients. Disclosures: Muto: Chugai Pharmaceutical Co., Ltd.: Employment. Kitazawa:Chugai Pharmaceutical Co., Ltd.: Employment. Yoshihasi:Chugai Pharmaceutical Co., Ltd.: Employment. Takeda:Chugai Pharmaceutical Co., Ltd.: Employment. Soeda:Chugai Pharmaceutical Co., Ltd.: Employment. Igawa:Chugai Pharmaceutical Co., Ltd.: Employment. Sampei:Chugai Pharmaceutical Co., Ltd.: Employment. Sakamoto:Chugai Pharmaceutical Co., Ltd.: Employment. Okuyama-Nishida:Chugai Pharmaceutical Co., Ltd.: Employment. Saito:Chugai Pharmaceutical Co., Ltd.: Employment. Kawabe:Chugai Pharmaceutical Co., Ltd.: Employment. Shima:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding. Hattori:Chugai Pharmaceutical Co., Ltd.: Employment.

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Yada, Koji, Keiji Nogami, Yasuaki Shida, Masahiro Takeyama, Ryu Kasai und Midori Shima. „Enhanced Global Hemostatic Potentials with a Bispecific Antibody to Factors IXa and X (ACE910) in the Whole Blood By Rotation Thromboelastometry (ROTEM)“. Blood 126, Nr. 23 (03.12.2015): 3503. http://dx.doi.org/10.1182/blood.v126.23.3503.3503.

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Abstract Background: ACE910, a humanized bispecific antibody to factor (F) IXa and FX mimicking the functions of FVIII, exerts tenase activities without FVIII (a) (Kitazawa et al. Nature Medicine. 2012;18, 1570). In primate hemophilia A (HA) models, the hemostatic enhancing effect of ACE910 has been reported and the clinical study investigating the effect and safety of ACE910 for human HA patients is on-going. However, the hemostatic effect of ACE910 remains unquantified and difficult to be evaluated. Objectives: In this study, we evaluated the viscoelastmetric parameters in the whole blood obtained from HA patients under long-term treatment of ACE910 in phase 1 and its extension studies, utilizing rotation thromboelastometry (ROTEM), in order to investigate global hemostatic function of HA patients under treatment with ACE910. Methods: Ca2+-triggered hemostatic functions were assessed by ROTEM in the citrated whole blood samples obtained and stabilized at the indicated points from five severe HA cases with inhibitors (Case 1 : 39 BU/ml, 2 : 41 BU/ml, 3 : 17 BU/ml, 4 : 11 BU/ml and 5 : 111 BU/ml ) and two severe cases without inhibitors (Case 6 and 7) under subcutaneous administration of ACE910, with the different types of dosing regimen (group A with 0.3 mg/kg/week subcutaneous injection (loading dose of 1 mg/kg) for Case 1, 2, group B with 1 mg/kg/week (loading dose of 3 mg/kg) for Case 3, 4, group C with 3 mg/kg/week for Case 6 and group D changing from group A to group C for Case 5, 7) in a course of clinical study. The samples from the subjects prior to administration of ACE910 were spiked ex vivo with ACE910 and the hemostatic functions of them were also evaluated by ROTEM. The parameters of clot time (CT), clot formation time (CFT), maximum clot formation (MCF) and alpha angle were evaluated. The hemostatic potentials in the samples from twenty healthy volunteers and other ten HA patients with the various FVIII:C were evaluated by ROTEM as controls and the correlation between FVIII:C and CT was obtained. Annualized bleeding rates (ABR) of each case were calculated. The studies were approved by local ethics committee and the informed consent was obtained from each patient. Results: Addition of ACE910 (f.c. 10 or 30 μg/ml) into the sample from each case prior to administration of ACE910 shortened CT from 5,562 ± 374 sec (median 5,924 sec) to 1,475 ± 138 or 1,131 ± 82 sec, equivalent to FVIII:C 3.3 or 12.2 IU/dL, respectively, in an ACE910 concentration dependent manner. In group A, the plasma concentration of ACE910 got to 12 ± 5 μg/ml at 12 week. CT was shortened to 1,443 ± 24 sec, equivalent to FVIII:C 3.7 IU/dL maximally at 47 week consistent with the result of the spiked result. ABR decreased from 38.6 ± 25.8 to 1.1 ± 0.8, showing 97% decrease. As for Case 3 in group B (ACE910: 31 μg/ml at 12 week), CT was shortened to 1,164 sec, equivalent to FVIII:C 11.9 IU/dL maximally at 47 week consistent with the spiked data. ABR apparently decreased from 38.6 to 3.6. In Case 4 who dropped out the clinical study at 4 week, CT was shortened to 977 sec, equivalent to FVIII:C 22 IU/dL, maximally at 3 week, and continued to be shortened till 29 week (1,758 sec, equivalent to FVIII:C 1.1 IU/dL). In group C, the shortening of CT from 1,594 ± 103 sec, equivalent to FVIII:C 2.0 ± 1.0 (median 3.6) IU/dL (before administration of ACE910), to 1,226 ± 71 sec (8.5 ± 2.5 (median 10.4) IU/dL) (at steady state) was observed in consistent with the decrease of ABR from 8.1 to 1.1. In group D, CT was shortened from 3,405 ± 386 sec to 1,409 ± 85 sec, equivalent to FVIII:C 4.2 IU/dL after middle to high dose escalation in consistent with decrease of ABR from 22.3 ± 9.6 to 3.8 ± 2.6. Among all cases except Case 4, CT and ABR were of clinically relevant difference between before and after administration of ACE910. Conclusions: The comprehensive hemostatic function evaluated by ROTEM in hemophilia A patients irrespective of presence of inhibitors was improved after administration of ACE910 in a dose dependent fashion, resulting in the reduction of ABR, which suggested the hemostatic effectiveness of ACE910 for HA patients. Disclosures Yada: Chugai Pharmaceutical Co., Ltd: Research Funding. Nogami:Bayer, Novo Nordisk, Baxalta. Biogen: Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees; Bayer, NovoNordisk, Baxalta, Chugai, Kaketsuken, Pfizer, Biogen: Honoraria. Shida:Chugai Pharmacoceutical Co. Ltd.: Research Funding. Takeyama:Chugai Pharmaceutical Co., Ltd.: Research Funding. Kasai:Chugai Pharmaceutical Co., Ltd.: Employment. Shima:Chugai Pharmaceutical Co., Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Baxalta: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Kaketsuken: Honoraria; Bayer: Honoraria, Research Funding.

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Shima, Midori, Hideji Hanabusa, Masashi Taki, Tadashi Matsushita, Tetsuji Sato, Katsuyuki Fukutake, Naoki Fukazawa, Shingo Maisawa, Koichiro Yoneyama und Keiji Nogami. „Safety and Prophylactic Efficacy Profiles of ACE910, a Humanized Bispecific Antibody Mimicking the FVIII Cofactor Function, in Japanese Hemophilia A Patients Both without and with FVIII Inhibitors: First-in-Patient Phase 1 Study“. Blood 124, Nr. 21 (06.12.2014): 691. http://dx.doi.org/10.1182/blood.v124.21.691.691.

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Abstract Background: Although routine supplementation of exogenous factor VIII (FVIII) effectively prevents bleeding complications in hemophilia A patients, the development of FVIII inhibitors and the need for frequent venous access are still problematic. To overcome these medical problems, a humanized bispecific antibody to factors IXa and X (ACE910) mimicking the FVIII cofactor function has been created. Objectives: To investigate the safety, pharmacokinetic and pharmacodynamic profiles of ACE910 as well as its prophylactic efficacy on bleeding, a first-in-patient open-label phase I study was conducted with once-weekly subcutaneous (SC) administration of ACE910 in Japanese hemophilia A patients both without and with FVIII inhibitors. Methods: In the present study, Japanese patients with severe hemophilia A (FVIII:C <1%, ages 12 to 59 years) were treated with once-weekly SC ACE910 at one of the following dose levels for 12 successive weeks: 0.3 (C-1), 1 (C-2) and 3 mg/kg (C-3). Loading doses of 1 and 3 mg/kg were administered as initial doses to the C-1 and C-2 cohorts, respectively. Prior to the study enrollment, the patients without FVIII inhibitors had received FVIII prophylactic replacement therapy while the patients with FVIII inhibitors had received on-demand therapy and/or prophylactic therapy with bypassing agents. Each cohort included 6 patients (18 patients in total). At least 2 patients without and with FVIII inhibitors were enrolled in each cohort. The annualized bleeding rate (ABR) during 12 weeks receiving ACE910 was calculated, and compared to those demonstrated during 6 months period prior to the study enrollment. In case bleeding event occurred during the course of ACE910 administrations, the patient was treated with on-demand use of FVIII or bypassing agents. Results: The results of the C-1 and C-2 cohorts during 12 weeks receiving ACE910 are shown in this abstract since C-3 cohort is under evaluation. The results from the C-3 cohort will be presented at the time of the meeting. (1) Safety Data In total, 30 adverse events (AEs) were reported in 10 out of the 12 patients. All AEs were of mild intensity, except for 1 moderate AE in a patient on the C-2 cohort (upper respiratory tract infection). Neither serious adverse events nor laboratory abnormalities to indicate a hypercoagulable state were observed in either cohort. In addition, no AEs related to hypercoagulation were observed including when concomitant on-demand therapy (FVIII or bypassing agents) was given for bleeding. One patient in the C-2 cohort discontinued ACE910 administration due to erythema at the injection site of mild intensity. No anti-ACE910 antibodies were developed during the course of ACE910 administrations. (2) Efficacy Data Four out of 6 patients had FVIII inhibitors in both cohorts. The inhibitor titers of these patients were 3-111 BU/mL. All the patients in both groups had target joints. The ABR prior to the study enrollment in the patients without and with FVIII inhibitors ranged 8.1-77.1 and 18.3-56.8, respectively. During the course of ACE910 administrations the ABR decreased in all patients compared to the ABR prior to the study enrollment. In the C-1 cohort, the ABR decreased by 22.8%-100% and 64.7%-100% in the patients without and with FVIII inhibitors, respectively. In the C-2 cohort, the ABR decreased by 100% and 88.9%-100% in the patients without and with FVIII inhibitors, respectively. (3) Pharmacokinetic and Pharmacodynamic Data The plasma ACE910 concentration increased in a dose-dependent manner. In all the patients in both cohorts, shortening of APTT and promotion of thrombin generation were observed after the start of ACE910 dosing. Conclusion: The present study is the first to demonstrate that once-weekly SC ACE910 prophylaxis possesses a favorable safety and a promising efficacy profiles in severe hemophilia A patients irrespective of the presence of FVIII inhibitors. Collectively, ACE910 is expected to offer an effective and convenient prophylactic treatment option for hemophilia A, including patients with FVIII inhibitors and/or with venous access difficulty. Disclosures Shima: Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: ACE910 clinical phase1 study. Hanabusa:Chugai Pharmaceutical Co., Ltd.: Research Funding. Taki:Chugai Pharmaceutical Co., Ltd.: Research Funding. Matsushita:Chugai Pharmaceutical Co., Ltd.: Research Funding. Sato:Chugai Pharmaceutical Co., Ltd.: Research Funding. Fukutake:Chugai Pharmaceutical Co., Ltd.: Research Funding. Fukazawa:Chugai Pharmaceutical Co., Ltd.: Employment. Maisawa:Chugai Pharmaceutical Co., Ltd.: Employment. Yoneyama:Chugai Pharmaceutical Co., Ltd.: Employment. Nogami:Chugai Pharmaceutical Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Uchida, Naoki, Takehiko Sambe, Koichiro Yoneyama, Naoki Fukazawa, Takehiko Kawanishi, Shinichi Kobayashi und Midori Shima. „A first-in-human phase 1 study of ACE910, a novel factor VIII–mimetic bispecific antibody, in healthy subjects“. Blood 127, Nr. 13 (31.03.2016): 1633–41. http://dx.doi.org/10.1182/blood-2015-06-650226.

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Key Points Single subcutaneous dosing of ACE910 has a linear PK profile, a half-life of 4 to 5 weeks, and FVIII-mimetic procoagulant activity in humans. ACE910 at doses up to 1 mg/kg is well tolerated and has no notable adverse hypercoagulable effect in healthy Japanese and white adults.

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Shida, Yasuaki, Keiji Nogami, Hiroaki Minami, Hiroaki Yaoi, Tomoko Matsumoto, Takehisa Kitazawa, Kunihiro Hattori und Midori Shima. „Distinct Localization of Coagulation Factor VIII, Von Willebrand Factor and Factor VIIIa-Mimetic Bispecific Antibody Contributing to Thrombus Formation Under Whole Blood Flow Conditions“. Blood 124, Nr. 21 (06.12.2014): 1483. http://dx.doi.org/10.1182/blood.v124.21.1483.1483.

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Abstract Background Factor VIII (FVIII) is an essential factor for coagulation system in the intrinsic pathway. Due to the short survival of FVIII in the plasma circulation, it requires von Willebrand factor (VWF) as a carrier protein to maintain the optimal level for hemostasis. VWF also plays an important role in primary hemostasis by bridging platelets to exposed subendothelial collagens, especially under high shear flow environment. Since VWF carries FVIII, it is conceivable that VWF takes FVIII to the sites of vascular injury. However, the role of FVIII at the local sites under flow conditions is not fully understood despite of the fact that increased level of FVIII is associated with the risk of venous thrombosis and the deficiency of FVIII is the pathology of the bleeding disorder, hemophilia A. The treatment of hemophilia A largely depends on the infusion of FVIII concentrates, which is often complicated by the development of the inhibitor. Recently, bispecific antibody（ACE910）that mimics the role of FVIIIa by recognizing FIXa and FX has been developed and is currently under clinical trial. This antibody theoretically works regardless of the presence of devastating inhibitors against FVIII. Furthermore, it could also improve the clinical outcome of the other bleeding disorders, such as von Willebrand disease (VWD). Aim To analyze the role of FVIII and VWF, and impact of ACE910 at the sites of vascular injury under various shear conditions, we have developed the flow-mediated thrombosis model using flow chamber system. Method Whole blood obtained from healthy donors, hemophilia A and VWD patients were perfused into the collagen coated flow chamber under high (2,500s-1) or low shear (50s-1) flow conditions with/without FVIII concentrate, FVIII/VWF concentrate and ACE910. Formed thrombus was fixed and immunostaining was performed with phalloidin (Platelet), anti-FVIII antibody (FVIII) and anti-thrombin antibody (Thrombin). For the detection of ACE910, anti-human IgG or anti-ACE antibody (rAQ8 or rAJ540) were used. Size of thrombi and distribution of platelet, FVIII, thrombin and ACE910 were analyzed. Result 1) Under high shear flow, thrombus formation of VWD blood was significantly impaired while blood from Hemophilia A demonstrated nearly normal thrombus formation. Addition of FVIII/VWF but not FVIII concentrate to the blood of these patients rescued the impaired thrombus formation. ACE910 enhanced the thrombus formation of blood from both VWD and hemophilia A. Under low shear flow, blood from both hemophilia A and VWD demonstrated decreased thrombus formation. FVIII, FVIII/VWF concentrates and ACE910 improved the size of thrombus. 2) Localization of FVIII was evaluated with thrombin as a marker for the activation of coagulation. Platelets and thrombin demonstrated complete co-localization and intensity of thrombin staining was associated with thrombus size. VWF localized mainly outer layer of thrombus and FVIII localized in and around thrombus. At high shear condition, FVIII and VWF mostly existed with platelets. By contrast, FVIII and VWF demonstrated less co-localization with platelets under low shear condition. ACE910 demonstrated similar tendency to FVIII localization although ACE910 did not appear around thrombus. Conclusion We have developed the flow chamber system to evaluate the extent of thrombogenesis under various shear environment. VWF showed dominant role under high shear conditions while FVIII plays a key role under low shear conditions. FVIII, VWF and ACE910 demonstrated distinct localization. Interestingly, the distribution of FVIII was broader than VWF and platelet. FVIII localized to platelets presumably prior to its activation and contributed for the subsequent thrombin generation at local sites. Finally, ACE910 demonstrated consistent enhancement of thrombus formation of blood from both hemophilia A and VWD and, therefore, is prompted for the treatment of these bleeding disorders. Disclosures Shida: Chugai Pharmaceutical Co., Ltd.: Research Funding. Nogami:Chugai Pharmaceutical Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding. Minami:Chugai Pharmaceutical Co., Ltd.: Research Funding. Yaoi:Chugai Pharmaceutical Co., Ltd.: Research Funding. Matsumoto:Chugai Pharmaceutical Co., Ltd.: Research Funding. Kitazawa:Chugai Pharmaceutical Co., Ltd.: Employment, Equity Ownership, Patents & Royalties. Hattori:Chugai Pharmaceutical Co., Ltd.: Employment, Equity Ownership, Patents & Royalties. Shima:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Zhang, L. J., J. L. Chen, B. L. Yang, X. G. Kong, D. Bourguet und G. Wu. „Thermotolerance, oxidative stress, apoptosis, heat-shock proteins and damages to reproductive cells of insecticide-susceptible and -resistant strains of the diamondback moth Plutella xylostella“. Bulletin of Entomological Research 107, Nr. 4 (31.01.2017): 513–26. http://dx.doi.org/10.1017/s0007485317000049.

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AbstractIn this study, we investigated thermotolerance, several physiological responses and damage to reproductive cells in chlorpyrifos-resistant (Rc) and -susceptible (Sm) strains of the diamondback moth, Plutella xylostella subjected to heat stress. The chlorpyrifos resistance of these strains was mediated by a modified acetylcholinesterase encoded by an allele, ace1R, of the ace1 gene. Adults of the Rc strain were less heat resistant than those of the Sm strain; they also had lower levels of enzymatic activity against oxidative damage, higher reactive oxygen species contents, weaker upregulation of two heat shock protein (hsp) genes (hsp69s and hsp20), and stronger upregulation of two apoptotic genes (caspase-7 and -9). The damage to sperm and ovary cells was greater in Rc adults than in Sm adults and was temperature sensitive. The lower fitness of the resistant strain, compared with the susceptible strain, is probably due to higher levels of oxidative stress and apoptosis, which also have deleterious effects on several life history traits. The greater injury observed in conditions of heat stress may be due to both the stronger upregulation of caspase genes and weaker upregulation of hsp genes in resistant than in susceptible individuals.

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Kanematsu, Takeshi, Nobuaki Suzuki, Naomi Sanda, Mika Ogawa, Mayuko Kishimoto, Atsuo Suzuki, Hitoshi Kiyoi, Ryu Kasai und Tadashi Matsushita. „Clinical Course and Management of Surgical Emergency in a Severe Hemophilia a Patient Under Weekly Subcutaneous Administration of a Bispecific Antibody to Factors IXa and X (ACE910)“. Blood 126, Nr. 23 (03.12.2015): 1099. http://dx.doi.org/10.1182/blood.v126.23.1099.1099.

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Abstract Background FVIIIa acts as a cofactor in the intrinsic pathway in which FIXa activates FX. ACE910 is a FIXa/FX-recognizing bispecific antibody that was designed to be a replacement for FVIIIa. Because of its nature, ACE910 is not affected by FVIII inhibitor. A clinical trial is now being conducted for the potential effect in the prophylactic treatment for bleeding hemophilia A patients. Here we present the perioperative care of a patient who had incidentally suffered from appendicitis and underwent an emergency surgery during the clinical trial. Methods Plasma ACE910 concentration and FXIa-triggered thrombin generation assay (TGA) was obtained in the central measurement of the trial. An activated partial thromboplastin time (APTT), and the tissue factor (TF)-triggered TGA were conducted at our laboratory. TF-triggered TGA was performed by means of calibrated automated thrombogram (Thrombinoscope BV), in accordance with the manufacturer's instructions. We used PPP-reagent LOWTM and FluCa-KitTM in Fluoroscan Ascent FLTM (Thermo Fisher Scientific Inc.) and monitored the thrombin generation for 2 hours, set at an excitation wavelength of 390 nm and an emission wavelength of 460 nm, and ThrombinoscopeTM software (Thrombinoscope BV). ROTEM® was performed as manufactured (Tem Innovations GmbH). Case The patient is a 60-year-old man suffering from hemophilia A without inhibitors and had severe hemophilic arthropathy in the number of target joints. Even after biweekly prophylaxis had been introduced by 2000 units of rFVIII concentrates, the annualized bleeding rate remained to be 10.1 In November 2013, ACE910 was introduced by way of subcutaneous administration and the initial dose was 3 mg/kg, followed by weekly administration of 1 mg/kg. After that, he had not had any of joint or soft tissue bleeding. In the 63rd week after the initial administration, he had severe abdominal pain and diagnosed as acute appendicitis that required emergency surgery. His APTT was consistently normal since ACE910 administration, we selected to undergo the surgery without any additional FVIII replacement, although his previous product was set up to be administrated any time on demand. ACE910 had been administered as scheduled earlier on the day of the diagnosis of acute appendicitis, followed by the emergency appendectomy. Results The appendectomy was performed by pararectal incision. Although the patient's appendix was necrosed and perforated, it was easy to stop bleeding during surgery and the total amount of bleeding was only 45 mL. On postoperative day 11, a small amount of bleeding was found after the removal of drainage catheter placed subfascially, however, the bleeding stopped immediately after the bleeding site was sutured. No other issues on bleeding were found. Trough levels of plasma ACE910 concentration were maintained at 27-41 µg/mL during the period between the 12th week after the initiation of ACE910 and the time of preoperative stage. In FXIa-triggered TGA, lag time was remarkably improved after the initiation of ACE910 and remained stable throughout the course of emergency surgery (Table 1). Although peak thrombin levels were slightly decreased a week after surgery, APTT and several In-TEM values by ROTEM® remained at almost normal levels (Table 2). Discussion and Conclusion We successfully conducted the hemostatic management for appendicitis in the perioperative period without any additional administration of FVIII concentrate. The patient showed less bleeding under ACE910 prophylaxis. To date there are little information on appropriate use of FVIII concentrate in patients with acute bleeding or major surgery who are under ACE910 prophylaxis. Generally in bleeding hemophilic patients with major surgery, the loss of clotting factors due to hemodilution by fluid replacement should also be carefully monitored. In such condition, the optimum ACE910 concentration could not be well interpreted, however, the careful monitoring might be required especially in highly invasive surgeries. In our experience, TF-triggered TGA demonstrated a marginal change only between postoperative days 7 and 13, although it is not totally known whether these changes were affected by ACE910 pharmacodynamics. Further researches are needed to explore the suitable biomarkers to indicate hemostasis of hemophilic patients under the administration of ACE910. Disclosures Suzuki: Baxalta: Honoraria; Bayer Healthcare: Honoraria; Novo Nordisk Pharma: Honoraria. Kiyoi:Novartis Pharma K.K.: Research Funding; MSD K.K.: Research Funding; Pfizer Inc.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Yakult Honsha Co.,Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; Teijin Ltd.: Research Funding; Taisho Toyama Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Japan Blood Products Organization: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; FUJIFILM RI Pharma Co.,Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding. Kasai:Chugai Pharmaceutical Co., Ltd.: Employment. Matsushita:Asahi Kasei Pharma: Honoraria, Research Funding, Speakers Bureau; Sysmex: Speakers Bureau; Octapharma AG: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; CLS-Behling: Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bayer Healthcare: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Seamens: Speakers Bureau; Nihon Pharmaceutical: Honoraria, Research Funding, Speakers Bureau; Kaketsuken: Honoraria, Research Funding, Speakers Bureau; Eisai: Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Japan Blood Products Organization: Honoraria, Research Funding; Novartis Pharma: Honoraria, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novo Nordisk Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Research Funding.

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Garcia, Martin. „Diversity Events at ACE12“. Journal - American Water Works Association 104, Nr. 5 (Mai 2012): 106–7. http://dx.doi.org/10.5942/jawwa.2012.104.0081.

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Yada, Koji, Keiji Nogami, Takehisa Kitazawa, Kunihiro Hattori und Midori Shima. „ACE910 Facilitates Its Hemostatic Effect with the Lower Concentration of Factor X Than That Required for Factor VIIa-Driven Coagulation“. Blood 126, Nr. 23 (03.12.2015): 1077. http://dx.doi.org/10.1182/blood.v126.23.1077.1077.

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Abstract The hemostatic effect of bypassing agents such as recombinant (r) factor (F)VIIa and activated prothrombin complex concentrates (aPCC) for hemophilia A with inhibitors (HA-inh) is not always stable (Berntope, Haemophilia 2009). The mechanism(s) of its instability remain unclear, however. We have recently reported the HA-inh case showing the attenuated responsiveness to aPCC (Ogiwara, Int J Hematol. 2014). Some groups reported the hemostatic effects of the complex concentrates of FVIIa and FX (Shirahata, Haemophilia 2012) in HA-inh, suggesting that FX would play the key role in the hemostatic effect by FVIIa. ACE910, a humanized bispecific antibody to FIXa and FX mimicking the functions of FVIIIa, exerting FXase activities without FVIII(a) (Kitazawa, Nature Medicine 2012). In this study, we attempted to elucidate the dependency on FX of the FVIIa- and/or ACE910-driven coagulation. Firstly, the global hemostatic potentials in the whole blood samples obtained from the four HA-inh cases (Case 1, 2, 3 and 4) under perioperative hemostatic treatment with the intermittent administration of rFVIIa every 2-3hr were evaluated by Ca2+-triggered viscoelastometric assay with ROTEM. The first infusion of rFVIIa shortened CT (from 5,087 ± 1,261 to 1,157 ± 208 sec) and increased MCF (from 17 ± 8.7 to 58.8 ± 1.3 mm) in each case. Additional rFVIIa after the 7th administration in Case 1, the 13th in Case 2 and the 12th in Case 3 little affected CT and MCF as well as clinical symptom, indicative of poor responsiveness, while Case 4 showed the improvement of the parameters even after the frequent infusion of rFVIIa, identified as a responsive case. Thrombin generation (TG) triggered by TF (1pM) or TF (1pM) together with ellagic acid (0.3μM) was evaluated in the plasma from the cases with poor response. Peak thrombin (PeakTh) was little changed between pre- and post-additional infusion of rFVIIa in the cases with poor response, similar to the pattern of ROTEM. The level of FX antigen measured by an ELISA in the plasma was 90.5 ± 9.6 nM, showing 67% of normal control (~140 nM), of little difference among the four cases at the first administration of rFVIIa, while that in Case 1, 2 or 3 at the 7th, 13th or 12th administration, respectively, decreased to 39.1 ± 7.0 nM, equivalent to ~45% of that (86.8 ± 12.9 nM) kept in the responsive Case 4. Addition of FX (300nM) in the plasma of poor response to rFVIIa ex vivo increased PeakTh to ~80% of normal control, suggesting that FVIIa-driven hemostatic effect would be dependent upon FX. Furthermore, to investigate the FX-dependency of FVIIa- and ACE910-driven coagulation, TG in the reconstituted HA-inh model plasmas consisting of FX-deficient plasma in which FVIII was inactivated by an anti-FVIII polyclonal antibody (10BU/ml) with/without rFVIIa (50 and 150 nM) or ACE910 (10, 30 and 60 μg/ml) was evaluated in the presence of various concentrations of FX (f.c. 0 - 300 nM). The control experiment without rFVIIa or ACE910 showed the FX dose-dependent increase of PeakTh. In the plasmas with FX ranged from 50 to 300nM, PeakTh improved to almost normal level by rFVIIa as well as ACE910. Of note, with the lower concentration of FX (10-20 nM), PeakTh improved to almost normal level in the presence of ACE910, increased by 38 ± 2.4%, 45 ± 1.7% and 48 ± 0.8% compared to those in its absence, respectively, in an ACE910 dose-dependent manner, whilst the presence of rFVIIa little affected TG compared to those in its absence. Taken together, ACE910 could exert its hemostatic effect with the lower amount of FX than that required for the rFVIIa-driven coagulation. Disclosures Yada: Chugai Pharmaceutical Co., ltd: Research Funding. Nogami:Bayer, NovoNordisk, Baxalta, Chugai, Kaketsuken, Pfizer, Biogen: Honoraria; Bayer, Novo Nordisk, Baxalta. Biogen: Research Funding; Chugai: Membership on an entity's Board of Directors or advisory committees. Kitazawa:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership, Patents & Royalties. Hattori:Chugai Pharmaceutical Co., Ltd: Employment, Equity Ownership, Patents & Royalties. Shima:Biogen: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Research Funding; Novo Nordisk: Honoraria, Research Funding; Kaketsuken: Honoraria.

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Igawa, Tomoyuki, Zenjiro Sampei, Tetsuhiro Soeda, Yukiko Okuyama-Nishida, Chifumi Moriyama, Tetsuya Wakabayashi, Eriko Tanaka et al. „Generation of a Novel Bispecific Antibody (ACE910) Against Activated Factor IX and Factor X Mimicking the Function of Factor VIII Cofactor Activity“. Blood 120, Nr. 21 (16.11.2012): 1126. http://dx.doi.org/10.1182/blood.v120.21.1126.1126.

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Abstract Abstract 1126 Exogenous factor VIII (FVIII) is used to reduce bleeding complications in patients with severe hemophilia A. However, there are two drawbacks of current routine prophylaxis by FVIII. One is the requirement of frequent intravenous administration due to its short half-life and low subcutaneous bioavailability of FVIII. Second is the development of anti-FVIII antibodies (inhibitors) in approximately 30% of the severe patients which deprives the patients from routine prophylaxis by FVIII. To overcome these drawbacks, bispecific IgG antibody against activated factor IX (FIXa) and factor X (FX), which mimics the cofactor function of FVIII by placing these two factors into spatially appropriate positions, was screened from approximately 40,000 bispecific antibodies recognizing FIXa by the one arm and FX by the other arm. The therapeutic potential of the bispecific antibody identified from the screening was marginal due to insufficient FVIII-mimetic activity and poor pharmacokinetics, and moreover, large scale purification of recombinant bispecific IgG antibody was challenging. Therefore, the lead bispecific antibody, after humanization, was subjected to multidimensional optimization process in order to improve both the therapeutic potential and the manufacturability of the bispecific antibody. FVIII-mimetic activity was improved by modifying its binding properties to FIXa and FX, and the pharmacokinetics was improved by engineering the charge properties of the variable region. Difficulty of manufacturing bispecific antibody was overcome by identifying common light chain for anti-FIXa and FX heavy chain through framework/complementarity determining region shuffling, and by isoelectric point engineering of the two heavy chain variable regions to facilitate ion exchange chromatography purification of the bispecific antibody. Engineering to overcome low solubility and deamidation was also performed to enable stable high concentration liquid formulation for clinical use. ACE910, multidimensionally optimized bispecific antibody, exhibited potent FVIII-mimetic activity in human FVIII deficient plasma (more than 10% of FVIII activity at 300 nM in thrombin generation assay), and half-life of approximately 3 weeks with high subcutaneous bioavailability in cynomolgus monkey, enabling effective prophylaxis by subcutaneous administration with long dosing interval. In silico immunogenicity prediction analysis suggested that ACE910 was minimally immunogenic in human, in contrast to high immunogenicity of FVIII in human. Importantly, the activity of ACE910 was not affected by the presence of inhibitors, while polyclonal anti-ACE910 antibody did not inhibit FVIII activity, allowing the use of ACE910 without considering the development or presence of inhibitors. Furthermore, ACE910 could be purified in a large scale manufacturing, and formulated into patient-friendly subcutaneously injectable liquid formulation for clinical use. We believe that ACE910, with its multidimensionally optimized profile, would significantly improve the quality of life of hemophilia A patients by reducing not only bleeding but also the burden on the patients themselves, their parents, and all medical staff. Disclosures: Igawa: Chugai Pharmaceutical Co.,Ltd: Employment. Sampei:Chugai Pharmaceutical Co., Ltd.: Employment. Soeda:Chugai Pharmaceutical Co.,Ltd: Employment. Okuyama-Nishida:Chugai Pharmaceutical Co., Ltd.: Employment. Moriyama:Chugai Pharmaceutical Co.,Ltd: Employment. Wakabayashi:Chugai Pharmaceutical Co.,Ltd: Employment. Tanaka:Chugai Pharmaceutical Co.,Ltd: Employment. Muto:Chugai Pharmaceutical Co., Ltd.: Employment. Kojima:Chugai Pharmaceutical Co.,Ltd: Employment. Kitazawa:Chugai Pharmaceutical Co., Ltd.: Employment. Yoshihashi:Chugai Pharmaceutical Co.,Ltd: Employment. Harada:Chugai Pharmaceutical Co.,Ltd: Employment. Funaki:Chugai Pharmaceutical Co.,Ltd: Employment. Haraya:Chugai Pharmaceutical Co.,Ltd: Employment. Tatsuhiko:Chugai Pharmaceutical Co.,Ltd: Employment. Suzuki:Chugai Pharmaceutical Co.,Ltd: Employment. Esaki:Chugai Pharmaceutical Co.,Ltd: Employment. Nabuchi:Chugai Pharmaceutical Co.,Ltd: Employment. Hattori:Chugai Pharmaceutical Co., Ltd.: Employment.

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Peña, Maria Marjorette O., Keith A. Koch und Dennis J. Thiele. „Dynamic Regulation of Copper Uptake and Detoxification Genes in Saccharomyces cerevisiae“. Molecular and Cellular Biology 18, Nr. 5 (01.05.1998): 2514–23. http://dx.doi.org/10.1128/mcb.18.5.2514.

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ABSTRACT The essential yet toxic nature of copper demands tight regulation of the copper homeostatic machinery to ensure that sufficient copper is present in the cell to drive essential biochemical processes yet prevent the accumulation to toxic levels. In Saccharomyces cerevisiae, the nutritional copper sensor Mac1p regulates the copper-dependent expression of the high affinity Cu(I) uptake genesCTR1, CTR3, and FRE1, while the toxic copper sensor Ace1p regulates the transcriptional activation of the detoxification genes CUP1, CRS5, andSOD1 in response to copper. In this study, we characterized the tandem regulation of the copper uptake and detoxification pathways in response to the chronic presence of elevated concentrations of copper ions in the growth medium. Upon addition of CuSO4, mRNA levels of CTR3 were rapidly reduced to eightfold the original basal level whereas the Ace1p-mediated transcriptional activation of CUP1 was rapid and potent but transient.CUP1 expression driven by an Ace1p DNA binding domain-herpes simplex virus VP16 transactivation domain fusion was also transient, demonstrating that this mode of regulation occurs via modulation of the Ace1p copper-activated DNA binding domain. In vivo dimethyl sulfate footprinting analysis of the CUP1 promoter demonstrated transient occupation of the metal response elements by Ace1p which paralleled CUP1 mRNA expression. Analysis of a Mac1p mutant, refractile for copper-dependent repression of the Cu(I) transport genes, showed an aberrant pattern of CUP1expression and copper sensitivity. These studies (i) demonstrate that the nutritional and toxic copper metalloregulatory transcription factors Mac1p and Ace1p must sense and respond to copper ions in a dynamic fashion to appropriately regulate copper ion homeostasis and (ii) establish the requirement for a wild-type Mac1p for survival in the presence of toxic copper levels.

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Delgado Almandoz, Josser E., Yasha Kayan, Adam N. Wallace, Ronald M. Tarrel, Jennifer L. Fease, Jill Marie Scholz, Anna M. Milner, Pezhman Roohani, Maximilian Mulder und Mark L. Young. „Larger ACE 68 aspiration catheter increases first-pass efficacy of ADAPT technique“. Journal of NeuroInterventional Surgery 11, Nr. 2 (03.07.2018): 141–46. http://dx.doi.org/10.1136/neurintsurg-2018-013957.

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PurposeTo report the efficacy of A Direct Aspiration first-Pass Thrombectomy (ADAPT) technique with larger-bore ACE aspiration catheters as first-line treatment for anterior circulation emergent large vessel occlusions (ELVOs), and assess for the presence of a first-pass effect with ADAPT.MethodsWe retrospectively reviewed 152 consecutive patients with anterior circulation ELVOs treated with the ADAPT technique as first-line treatment using ACE60, 64, or 68 at our institution. Baseline characteristics, procedural variables, and modified Rankin Scale (mRS) at 90 days were recorded.ResultsFifty-seven patients were treated with ACE60 (37.5%), 35 with ACE64 (23%), and 60 with ACE68 (39.5%). Median groin puncture to reperfusion time was 30 min with ACE60, 26 min with ACE64, and 19.5 min with ACE68. Successful reperfusion after the first ADAPT pass was 33% with ACE60 and 53% with ACE68 (P=0.04). The stent-retriever rescue rate was 26% with ACE60, 3% with ACE64, and 10% with ACE68 (P=0.004). In multivariate logistic regression analysis, use of the ACE68 aspiration catheter was an independent predictor of successful reperfusion after the first ADAPT pass (P=0.016, OR1.67, 95% CI 1.1 to 2.54), and successful reperfusion after the first ADAPT pass was an independent predictor of good clinical outcome at 90 days (P=0.0004, OR6.2, 95% CI 2.27 to 16.8).ConclusionUse of the larger-bore ACE 68 aspiration catheter was associated with shorter groin puncture to reperfusion time, higher rate of successful reperfusion after the first ADAPT pass, and lower rate of stent-retriever rescue. Further, a first-pass effect was demonstrated in our ADAPT patient cohort.

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YALÇIN, M. E., und J. A. K. SUYKENS. „SPATIOTEMPORAL PATTERN FORMATION ON THE ACE16k CNN CHIP“. International Journal of Bifurcation and Chaos 16, Nr. 05 (Mai 2006): 1537–46. http://dx.doi.org/10.1142/s0218127406015489.

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In this paper, we report on pattern formation occurring on the ACE16k CNN chip. The CNN chip can be programmed with a cloning template in order to generate spiral waves and autowaves. The waves diffract from internal sources which cannot be relocated on the network. However, by using initial and/or input images, sources (external sources) can be located at any place on the network. Furthermore a competition between autowaves generated by external and internal sources is observed. Propagation of autowaves on the inhomogeneous CNN array, formed by the fixed-state map, is presented.

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Moore, Randy. „Innovation Discussions to Continue at ACE17“. Opflow 43, Nr. 5 (Mai 2017): 10. http://dx.doi.org/10.5991/opf.2017.43.0034.

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Samelson-Jones, Benjamin J., John D. Finn, Rodney M. Camire und Valder R. Arruda. „The Complete Dependence of Factor IX Padua (R338L) Hyperactivity on Factor VIIIa Cofactor Activity Supports Its Safety As a Transgene for Hemophilia B Gene Therapy“. Blood 132, Supplement 1 (29.11.2018): 3486. http://dx.doi.org/10.1182/blood-2018-99-119270.

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Abstract Factor IX (FIX) Padua (R338L) has been described as a game changer for hemophilia B (HB) gene therapy. The ~8-fold increased specific activity compared to wild-type FIX (FIX WT) in aPTT-based clotting assay has recently allowed for a lowering of adeno-associated virus (AAV) vector dose compared to earlier gene therapy trials using FIX WT, while still achieving sustained near-curative FIX activity levels. The lowered AAV vector dose mitigated the vector dose-dependent hepatotoxicity, which had remained a major safety and efficacy limitation for AAV gene therapy. To date, at least 2 pivotal phase III gene therapy trials for HB using AAV FIX Padua are planned. Despite this enthusiasm, the underlying molecular mechanism of the hyperactivity of FIX Padua is undefined. As such, the safety concerns of unregulated FIX activity and the potential for ensuing thrombotic complications have not been fully addressed. Indeed, recent thrombotic complications in non-gene therapy hemophilia clinical trials evaluating non-factor therapies that promote hemostasis by circumventing regulatory interactions should engender caution. Activated FVIII (FVIIIa) is essential for the biological activity of activated FIX (FIXa), which provides an important regulatory requirement. To determine the role of FVIIIa in the hyperactivity of FIX Padua, we measured the relative specific activity of FIX Padua compared to WT in HB plasma using a unique reagent, ACE910. ACE910 is a bispecific antibody that sufficiently brings together FIXa and its substrate, FX, to efficiently promote hemostasis, even in the absence of FVIIIa molecules. It has been described as a "FVIII-mimetic" and is currently approved as a bypassing agent for hemophilia A patients with FVIII inhibitors. In our assays, plasma FVIII activity is inhibited to <1% normal activity with a cocktail of monoclonal anti-FVIII antibodies. In unadulterated HB plasma, recombinant zymogen FIX Padua has a ~8-fold higher clotting activity compared to FIX WT (Fig). However, when FVIIIa is replaced by ACE910, FIX Padua and WT have comparable clotting activities (Fig). Similarly, we observe that the hyperactivity of activated FIX Padua compared to WT in a clotting assay is completely abrogated by replacing FVIIIa with ACE910. These results suggest that the enhanced clotting activity of FIX(a) Padua compared to FIX(a) WT is wholly dependent on FVIIIa cofactor activity. We also measured the ability of recombinant FIX(a) Padua and WT to restore thrombin production to HB plasma in a thrombin generation assay (TGA). We observe that the EC50 of thrombin generation in HB plasma of zymogen and activated FIX Padua is ~8-fold lower than for FIX(a) WT. However, when FVIIIa is replaced with ACE910, FIX(a) Padua and WT demonstrate comparable EC50s of thrombin generation. Importantly, we observe no difference in the binding of FIXa Padua and FIXa WT with ACE910 in enzyme kinetic studies; this was expected because FIXa Padua and WT have an identical ACE910 binding site in their EGF-domain. Combined, these results demonstrate that the ~8 fold hyperactivity of FIX(a) Padua compared to FIX(a) WT in plasma assays requires FVIIIa cofactor activity. Consistent with this mechanism, we have previously observed in reconstituted systems that FIX(a) Padua and WT have comparable rates of activation by FXIa and inactivation by antithrombin. This result suggests that FIX Padua and WT are regulated similarly, supporting the safety of FIX Padua as a transgene. Enzyme kinetic studies of FIXa Padua and WT without FVIIIa demonstrate similar rates of FX activation, while FIXa Padua demonstrates increased rates of FX activation with FVIIIa compared to FIXa WT. We conclude, therefore, the mechanism of the increased specific activity of FIX(a) Padua is wholly dependent on its enhanced interaction with its cofactor FVIIIa. This enhancement is essential for the increased activity observed in both reconstituted and plasma-based assays. Moreover, the augmented interaction of FIX(a) Padua with FVIIIa is sufficient to account for the ~8-fold pro-hemostatic enhancement compared to FIX(a) WT observed in plasma assays. Combined, these results definitively address previously unanswered safety concerns regarding the potential risk of thrombotic complications with the use of FIX Padua transgene. They strongly support the ongoing use of FIX Padua in HB gene therapy. Disclosures Camire: Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Consultancy; Spark Therapeutics: Membership on an entity's Board of Directors or advisory committees.

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Muto, Atsushi, Kazutaka Yoshihashi, Minako Takeda, Takehisa Kitazawa, Tetsuhiro Soeda, Tomoyuki Igawa, Zenjiro Sampei et al. „Anti-factor IXa/X bispecific antibody ACE910 prevents joint bleeds in a long-term primate model of acquired hemophilia A“. Blood 124, Nr. 20 (13.11.2014): 3165–71. http://dx.doi.org/10.1182/blood-2014-07-585737.

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Key Points A long-term acquired hemophilia A model expressing spontaneous joint bleeds and other bleeds was newly established in nonhuman primates. Weekly SC dose of the anti-FIXa/X bispecific antibody ACE910 prevented joint bleeds and other bleeds in the primate hemophilia A model.

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Fudal, Isabelle, Jérôme Collemare, Heidi U. Böhnert, Delphine Melayah und Marc-Henri Lebrun. „Expression of Magnaporthe grisea Avirulence Gene ACE1 Is Connected to the Initiation of Appressorium-Mediated Penetration“. Eukaryotic Cell 6, Nr. 3 (März 2007): 546–54. http://dx.doi.org/10.1128/ec.00330-05.

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ABSTRACT Magnaporthe grisea is responsible for a devastating fungal disease of rice called blast. Current control of this disease relies on resistant rice cultivars that recognize M. grisea signals corresponding to specific secreted proteins encoded by avirulence genes. The M. grisea ACE1 avirulence gene differs from others, since it controls the biosynthesis of a secondary metabolite likely recognized by rice cultivars carrying the Pi33 resistance gene. Using a transcriptional fusion between ACE1 promoter and eGFP, we showed that ACE1 is only expressed in appressoria during fungal penetration into rice and barley leaves, onion skin, and cellophane membranes. ACE1 is almost not expressed in appressoria differentiated on Teflon and Mylar artificial membranes. ACE1 expression is not induced by cellophane and plant cell wall components, demonstrating that it does not require typical host plant compounds. Cyclic AMP (cAMP) signaling mutants ΔcpkA and Δmac1 sum1-99 and tetraspanin mutant Δpls1::hph differentiate melanized appressoria with normal turgor but are unable to penetrate host plant leaves. ACE1 is normally expressed in these mutants, suggesting that it does not require cAMP signaling or a successful penetration event. ACE1 is not expressed in appressoria of the buf1::hph mutant defective for melanin biosynthesis and appressorial turgor. The addition of hyperosmotic solutes to buf1::hph appressoria restores appressorial development and ACE1 expression. Treatments of young wild-type appressoria with actin and tubulin inhibitors reduce both fungal penetration and ACE1 expression. These experiments suggest that ACE1 appressorium-specific expression does not depend on host plant signals but is connected to the onset of appressorium-mediated penetration.

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Torres-Torres, G., I. Cuauhtémoc-López, A. Espinosa de los Monteros, Dora Ma Frías-Márquez, J. C. Arévalo Pérez und G. del Angel. „Water remediation contaminated with MTBE using a catalytic oxidation process in batch reactor: influence of the cerium loading on the activity and CO2 selectivity“. Water Science and Technology 78, Nr. 7 (09.10.2018): 1509–16. http://dx.doi.org/10.2166/wst.2018.430.

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Abstract Destruction of methyl tert-butyl ether (MTBE) in liquid phase and in a batch reactor was studied using ruthenium catalysts over alumina support, modified with different cerium loadings. Ce loading increment causes an increase in the particle size from 1.26 nm to 2.3 nm, enhancing the MTBE oxidation (at 150 °C), and the selectivity toward CO2. The high catalytic activity of Ru/ACe10 is attributed to the species Ce4+-O2−-M that could favor the oxygen transfer between the catalyst surface and the adsorbed species by a redox mechanism. Thus, CeOx plays an important role in both enhancing the affinity between MTBE and catalyst during MTBE adsorption and promoting the catalytic activity for MTBE oxidation.

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Whittle, James R. R., und Thomas U. Schwartz. „Structure of the Sec13–Sec16 edge element, a template for assembly of the COPII vesicle coat“. Journal of Cell Biology 190, Nr. 3 (09.08.2010): 347–61. http://dx.doi.org/10.1083/jcb.201003092.

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Ancestral coatomer element 1 (ACE1) proteins assemble latticework coats for COPII vesicles and the nuclear pore complex. The ACE1 protein Sec31 and Sec13 make a 2:2 tetramer that forms the edge element of the COPII outer coat. In this study, we report that the COPII accessory protein Sec16 also contains an ACE1. The 165-kD crystal structure of the central domain of Sec16 in complex with Sec13 was solved at 2.7-Å resolution. Sec16 and Sec13 also make a 2:2 tetramer, another edge element for the COPII system. Domain swapping at the ACE1–ACE1 interface is observed both in the prior structure of Sec13–Sec31 and in Sec13–Sec16. A Sec31 mutant in which domain swapping is prevented adopts an unprecedented laminated structure, solved at 2.8-Å resolution. Our in vivo data suggest that the ACE1 element of Sec31 can functionally replace the ACE1 element of Sec16. Our data support Sec16 as a scaffold for the COPII system and a template for the Sec13–Sec31 coat.

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Thiele, D. J. „ACE1 regulates expression of the Saccharomyces cerevisiae metallothionein gene.“ Molecular and Cellular Biology 8, Nr. 7 (Juli 1988): 2745–52. http://dx.doi.org/10.1128/mcb.8.7.2745.

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Copper resistance in Saccharomyces cerevisiae is mediated, in large part, by the CUP1 locus, which encodes a low-molecular-weight, cysteine-rich metal-binding protein. Expression of the CUP1 gene is regulated at the level of transcriptional induction in response to high environmental copper levels. This report describes the isolation of a yeast mutant, ace1-1, which is defective in the activation of CUP1 expression upon exposure to exogenous copper. The ace1-1 mutation is recessive and lies in a genetic element that encodes a trans-acting CUP1 regulatory factor. The wild-type ACE1 gene was isolated by in vivo complementation and restores copper inducibility of CUP1 expression and copper resistance to the otherwise copper-sensitive ace1-1 mutant. Linkage analysis and gene deletion experiments verified that this gene represents the authentic ACE1 locus. ACE1 maps to the left arm of chromosome VII, 9 centimorgans centromere distal to lys5. The ACE1 gene appears to play a direct or indirect positive role in activation of CUP1 expression in response to elevated copper concentrations.

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Thiele, D. J. „ACE1 regulates expression of the Saccharomyces cerevisiae metallothionein gene“. Molecular and Cellular Biology 8, Nr. 7 (Juli 1988): 2745–52. http://dx.doi.org/10.1128/mcb.8.7.2745-2752.1988.

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Copper resistance in Saccharomyces cerevisiae is mediated, in large part, by the CUP1 locus, which encodes a low-molecular-weight, cysteine-rich metal-binding protein. Expression of the CUP1 gene is regulated at the level of transcriptional induction in response to high environmental copper levels. This report describes the isolation of a yeast mutant, ace1-1, which is defective in the activation of CUP1 expression upon exposure to exogenous copper. The ace1-1 mutation is recessive and lies in a genetic element that encodes a trans-acting CUP1 regulatory factor. The wild-type ACE1 gene was isolated by in vivo complementation and restores copper inducibility of CUP1 expression and copper resistance to the otherwise copper-sensitive ace1-1 mutant. Linkage analysis and gene deletion experiments verified that this gene represents the authentic ACE1 locus. ACE1 maps to the left arm of chromosome VII, 9 centimorgans centromere distal to lys5. The ACE1 gene appears to play a direct or indirect positive role in activation of CUP1 expression in response to elevated copper concentrations.

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Szczypka, M. S., und D. J. Thiele. „A cysteine-rich nuclear protein activates yeast metallothionein gene transcription.“ Molecular and Cellular Biology 9, Nr. 2 (Februar 1989): 421–29. http://dx.doi.org/10.1128/mcb.9.2.421.

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The ACE1 gene of the yeast Saccharomyces cerevisiae is required for copper-inducible transcription of the metallothionein gene (CUP1). The sequence of the cloned ACE1 gene predicted an open reading frame for translation of a 225-amino-acid polypeptide. This polypeptide was characterized by an amino-terminal half rich in cysteine residues and positively charged amino acids. The arrangement of many of the 12 cysteines in the configuration Cys-X-Cys or Cys-X-X-Cys suggested that the ACE1 protein may bind metal ions. The carboxyl-terminal half of the ACE1 protein was devoid of cysteines but was highly acidic in nature. The ability of a bifunctional ACE1-beta-galactosidase fusion protein to accumulate in yeast cell nuclei was consistent with the possibility that ACE1 plays a direct role in the regulation of copper-inducible transcription of the yeast metallothionein gene.

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Szczypka, M. S., und D. J. Thiele. „A cysteine-rich nuclear protein activates yeast metallothionein gene transcription“. Molecular and Cellular Biology 9, Nr. 2 (Februar 1989): 421–29. http://dx.doi.org/10.1128/mcb.9.2.421-429.1989.

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The ACE1 gene of the yeast Saccharomyces cerevisiae is required for copper-inducible transcription of the metallothionein gene (CUP1). The sequence of the cloned ACE1 gene predicted an open reading frame for translation of a 225-amino-acid polypeptide. This polypeptide was characterized by an amino-terminal half rich in cysteine residues and positively charged amino acids. The arrangement of many of the 12 cysteines in the configuration Cys-X-Cys or Cys-X-X-Cys suggested that the ACE1 protein may bind metal ions. The carboxyl-terminal half of the ACE1 protein was devoid of cysteines but was highly acidic in nature. The ability of a bifunctional ACE1-beta-galactosidase fusion protein to accumulate in yeast cell nuclei was consistent with the possibility that ACE1 plays a direct role in the regulation of copper-inducible transcription of the yeast metallothionein gene.

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Lafrance, David. „ACE13: Where Water Professionals Shop for Value“. Journal - American Water Works Association 105, Nr. 5 (Mai 2013): 6. http://dx.doi.org/10.1002/j.1551-8833.2013.tb08881.x.

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Moore, Randy. „Innovating the Future of Water at ACE19“. Opflow 45, Nr. 5 (Mai 2019): 26–27. http://dx.doi.org/10.1002/opfl.1190.

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Li, Hao-Kang, Ching-Wen Hsiao, Sen-Han Yang, Hsiu-Ping Yang, Tai-Sheng Wu, Chia-Yun Lee, Yan-Liang Lin et al. „A Novel off-the-Shelf Trastuzumab-Armed NK Cell Therapy (ACE1702) Using Antibody-Cell-Conjugation Technology“. Cancers 13, Nr. 11 (31.05.2021): 2724. http://dx.doi.org/10.3390/cancers13112724.

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Natural killer (NK) cells harbor efficient cytotoxicity against tumor cells without causing life-threatening cytokine release syndrome (CRS) or graft-versus-host disease (GvHD). When compared to chimeric antigen receptor (CAR) technology, Antibody-Cell Conjugation (ACC) technology has been developed to provide an efficient platform to arm immune cells with cancer-targeting antibodies to recognize and attack cancer cells. Recently, we established an endogenous CD16-expressing oNK cell line (oNK) with a favorable expression pattern of NK activation/inhibitory receptors. In this study, we applied ACC platform to conjugate oNK with trastuzumab and an anti-human epidermal growth factor receptor 2 (HER2) antibody. Trastuzumab-conjugated oNK, ACE-oNK-HER2, executed in vitro and in vivo cytotoxicity against HER2-expressing cancer cells and secretion of IFNγ. The irradiated and cryopreserved ACE-oNK-HER2, designated as ACE1702, retained superior HER2-specific in vitro and in vivo potency with no tumorigenic potential. In conclusion, this study provides the evidence to support the potential clinical application of ACE1702 as a novel off-the-shelf NK cell therapy against HER2-expressing solid tumors.

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Li, Bing, Yan Hong Wang, Ju Mei Wang und Wei De Shen. „Full Length cDNA Cloning and Expression Characteristics of Ace Gene from Wild Silkworm, Bombyx mandarina“. Advanced Materials Research 175-176 (Januar 2011): 51–55. http://dx.doi.org/10.4028/www.scientific.net/amr.175-176.51.

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Acetylcholinesterase (AChE), which contains two subfamilies, ace1 and ace2 in insects, was identified to be the target of organophosphorous and carbamate insecticides. To research the sequences and tissues expressions of two aces, full length cDNAs encoding two ace genes were cloned, designated as Bmm-ace1 and Bmm-ace2 from larvae of the Bombyx mandarina. The amino acid sequence of Bmm-ace1 shared 99.71 % homology with its homolog, Bm-ace1, in silkworm, Bombyx mori, with two mutations (G664S and S307P), and the amino acid sequence of Bmm-ace2 shared 99.37 % homology with Bm-ace2, in B. mori , with four mutations (M18I, N233S, I310V and G621S). Tissue expression analysis showed that ace1 gene expressed only in the brains and fat bodies of B. mandarina, while ace2 genes expressed in all the tissues tested. ace1 and ace2 expressed highly in brains and fat bodies. The present results are significant to the study of resistance evolution of Lepidorptera as well as the understanding of the mechanism of pesticide resistance of insects.

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Evans, C. F., D. R. Engelke und D. J. Thiele. „ACE1 transcription factor produced in Escherichia coli binds multiple regions within yeast metallothionein upstream activation sequences.“ Molecular and Cellular Biology 10, Nr. 1 (Januar 1990): 426–29. http://dx.doi.org/10.1128/mcb.10.1.426.

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The ACE1 protein of Saccharomyces cerevisiae was expressed as a trpE-ACE1 fusion protein in Escherichia coli and shown to bind CUP1 upstream activation sequences at multiple regions in a copper-inducible manner. These binding sites contain within them the sequence 5'-TC(T)4-6GCTG-3', which we propose constitutes an important part of the ACE1 consensus recognition sequence.

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Evans, C. F., D. R. Engelke und D. J. Thiele. „ACE1 transcription factor produced in Escherichia coli binds multiple regions within yeast metallothionein upstream activation sequences“. Molecular and Cellular Biology 10, Nr. 1 (Januar 1990): 426–29. http://dx.doi.org/10.1128/mcb.10.1.426-429.1990.

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The ACE1 protein of Saccharomyces cerevisiae was expressed as a trpE-ACE1 fusion protein in Escherichia coli and shown to bind CUP1 upstream activation sequences at multiple regions in a copper-inducible manner. These binding sites contain within them the sequence 5'-TC(T)4-6GCTG-3', which we propose constitutes an important part of the ACE1 consensus recognition sequence.

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Faulk, Katelynn, Brent Shell, T. Prashant Nedungadi und J. Thomas Cunningham. „Role of angiotensin-converting enzyme 1 within the median preoptic nucleus following chronic intermittent hypoxia“. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 312, Nr. 2 (01.02.2017): R245—R252. http://dx.doi.org/10.1152/ajpregu.00472.2016.

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Sustained hypertension is an important consequence of obstructive sleep apnea. An animal model of the hypoxemia associated with sleep apnea, chronic intermittent hypoxia (CIH), produces increased sympathetic nerve activity (SNA) and sustained increases in blood pressure. Many mechanisms have been implicated in the hypertension associated with CIH, including the role of ΔFosB within the median preoptic nucleus (MnPO). Also, the renin-angiotensin system (RAS) has been associated with CIH hypertension. We conducted experiments to determine the possible association of FosB/ΔFosB with a RAS component, angiotensin-converting enzyme 1 (ACE1), within the MnPO following 7 days of CIH. Retrograde tract tracing from the paraventricular nucleus (PVN), a downstream region of the MnPO, was used to establish a potential pathway for FosB/ΔFosB activation of MnPO ACE1 neurons. After CIH, ACE1 cells with FosB/ΔFosB expression increased colocalization with a retrograde tracer that was injected unilaterally within the PVN. Also, Western blot examination showed ACE1 protein expression increasing within the MnPO following CIH. Chromatin immunoprecipitation (ChIP) assays demonstrated an increase in FosB/ΔFosB association with the ACE1 gene within the MnPO following CIH. FosB/ΔFosB may transcriptionally target ACE1 within the MnPO following CIH to affect the downstream PVN region, which may influence SNA and blood pressure.

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Biro, Attila, Arnold Markovich, Judit Rita Homoki, Erzsébet Szőllősi, Csaba Hegedűs, Szabolcs Tarapcsák, János Lukács, László Stündl und Judit Remenyik. „Anthocyanin-Rich Sour Cherry Extract Attenuates the Lipopolysaccharide-Induced Endothelial Inflammatory Response“. Molecules 24, Nr. 19 (21.09.2019): 3427. http://dx.doi.org/10.3390/molecules24193427.

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The anthocyanin content of Hungarian sour cherry is remarkable based on our preliminary investigations. Nutraceutical and pharmaceutical effects of anthocyanins have been extensively studied. The objective of this work was to investigate the the effect of purified sour cherry extract using human umbilical cord vein endothelial cells (HUVECs) as the inflammatory model. HUVECs were isolated by enzymatic digestion and characterized by flow cytometry. The optimal concentration range of sour cherry extract was selected based on MTT, apoptosis, and necrosis assays. Cells were divided into three groups, incubating with M199 medium as control, or with lipopolysaccharide (LPS) or with LPS plus anthocyanin extract (ACE). The effect of sour cherry extract on oxidative stress, pro-inflammatory factors, and arachidonic pathway was investigated. An amount of 50 μg/mL ACE (ACE50) was able to increase the level of glutathione and decrease the ROS, thereby improving the unbalanced redox status in inflammation. ACE50 lowered pro-inflammatory cytokine levels including Interleukin-6 (IL-6), regulated on activation, normal T cell expressed and secreted (RANTES), granulocyte-macrophage colony-stimulating factor (GM-CSF), and tumor necrosis factor alpha (TNF-α). ACE50 affected the arachidonic acid pathway by reducing the LPS-induced enzyme expression (cyclooxygenase-1, cyclooxygenase-2, and prostacyclin synthase). The extract under investigation seems to have a pleiotropic effect including anti-oxidative, anti-inflammatory, hemostatic, and vasoactive effects. Our results indicate that purified sour cherry extract could reduce the LPS-induced inflammatory response, thereby improving endothelial dysfunction.

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Li, Bing, Yan Hong Wang, Ju Mei Wang und Wei De Shen. „Cloning and Expression Analysis of Acetylcholinesterase Gene (Bm-ace1, Bm-ace2) from Domesticated Silkworm, Bombyx mori“. Advanced Materials Research 175-176 (Januar 2011): 13–18. http://dx.doi.org/10.4028/www.scientific.net/amr.175-176.13.

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Acetylcholinesterase (AChE, 2 EC 3.1.1.7), encoded by the ace gene, catalyzes the hydrolysis of the neurotransmitter acetylcholine to terminate nerve impulses at the postsynaptic membrane. In this study, AChE genes (Bm-ace1, Bm-ace2) were cloned from domesticated silkworm Bombyx mori (Dazao strain) through RT-PCR. Sequence analysis showed that the ORF of Bm-ace1 gene contained 2 025 bp nucleotides, encoding 683 amino acid residues. The predicted protein has a molecular weight (MW) of 76.96 kD and an isoelectric point (pI) of 6.36; The ORF of Bm-ace2 gene contained 1 917 bp nucleotides, encoding 638 AA’s. The predicted protein has a MW of 71.68 kD and a pI of 5.49. These two acetylcholinesterase genes both contain conserved motifs including a catalytic triad, a choline-binding site and an acyl picket. A clustering analysis showed that Bm-ace1 (ABY50088)shared highest similarity with Bmm-ace1 (ABM66370) from Chinese wild silkworm (B. mandarina), Bm-ace2 (ABY50089) shared highest similarity with Bm-ace2 (NP_001037366) from B. mori. Using semi-quantitative RT-PCR, expression analyses in insect tissues and in development period demonstrated that Bm-ace1and Bm-ace2 were expressed highly in head and fat bodies; Bm-ace1 and Bm-ace2 were expressed firstly higher, then lower and higher again from 1st instar to 5th instar stages. Bm-ace1 was expressed higher than that of Bm-ace2 in all the stages. This result will help understanding of the resistance mechanism of B. mori to organophosphosphorous insecticides.

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Holappa, Mervi, Jarkko Valjakka und Anu Vaajanen. „Angiotensin(1-7) and ACE2, “The Hot Spots” of Renin-Angiotensin System, Detected in the Human Aqueous Humor“. Open Ophthalmology Journal 9, Nr. 1 (31.03.2015): 28–32. http://dx.doi.org/10.2174/1874364101509010028.

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Background: The main purpose of the study was to establish whether essential components of the renin-angiotensin system (RAS) exist in the human aqueous humor. Methods: Forty-five patients ≥ 60 (74±7) years of age undergoing cataract surgery at Tampere University Hospital were randomly selected for the prospective study. The exclusion criterion was the use of oral antihypertensive medicine acting via renin-angiotensin system. Aqueous humor samples were taken at the beginning of normal cataract extraction. The samples were frozen and stored at -80 °C. The concentrations of intraocular endogenous RAS components Ang(1-7), ACE2, and ACE1 were measured using ELISA. Results: Concentration medians of Ang(1-7), ACE2, and ACE1 in the aqueous humor were: Ang(1-7) 4.08 ng/ml, ACE2 2.32 ng/ml and ACE1 0.35 ng/ml. The concentrations were significantly higher in glaucomatous than in non-glaucomatous eyes, ACE1 (p=0.014) and Ang(1-7) (p=0.026) vs non-glaucomatous eyes. Conclusions: Ang(1-7), ACE2 and ACE1 are found in the human aqueous humor. The observations are consistent with the conception that local tissue-RAS exists in the human eye and it might have a role in the control of intraocular pressure.

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Keller, Greg, Amanda Bird und Dennis R. Winge. „Independent Metalloregulation of Ace1 and Mac1 in Saccharomyces cerevisiae“. Eukaryotic Cell 4, Nr. 11 (November 2005): 1863–71. http://dx.doi.org/10.1128/ec.4.11.1863-1871.2005.

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ABSTRACT Ace1 and Mac1 undergo reciprocal copper metalloregulation in yeast cells. Mac1 is functional as a transcriptional activator in copper-deficient cells, whereas Ace1 is a transcriptional activator in copper-replete cells. Cells undergoing a transition from copper-deficient to copper-sufficient conditions through a switch in the growth medium show a rapid inactivation of Mac1 and a corresponding rise in Ace1 activation. Cells analyzed after the transition show a massive accumulation of cellular copper. Under these copper shock conditions we show, using two epitope-tagged variants of Mac1, that copper-mediated inhibition of Mac function is independent of induced protein turnover. The transcription activity of Mac1 is rapidly inhibited in the copper-replete cells, whereas chromatin immunoprecipitation studies showed only partial copper-induced loss of DNA binding. Thus, the initial event in copper inhibition of Mac1 function is likely copper inhibition of the transactivation activity. Copper inhibition of Mac1 in transition experiments is largely unaffected in cells overexpressing copper-binding proteins within the nucleus. Likewise, high expression of a copper-binding, non-DNA-binding Mac1 mutant is without effect on the copper activation of Ace1. Thus, metalloregulation of Ace1 and Mac1 occurs independently.

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Aro, Nina, Marja Ilmén, Anu Saloheimo und Merja Penttilä. „ACEI of Trichoderma reesei Is a Repressor of Cellulase and Xylanase Expression“. Applied and Environmental Microbiology 69, Nr. 1 (Januar 2003): 56–65. http://dx.doi.org/10.1128/aem.69.1.56-65.2003.

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ABSTRACT We characterized the effect of deletion of the Trichoderma reesei (Hypocrea jecorina) ace1 gene encoding the novel cellulase regulator ACEI that was isolated based on its ability to bind to and activate in vivo in Saccharomyces cerevisiae the promoter of the main cellulase gene, cbh1. Deletion of ace1 resulted in an increase in the expression of all the main cellulase genes and two xylanase genes in sophorose- and cellulose-induced cultures, indicating that ACEI acts as a repressor of cellulase and xylanase expression. Growth of the strain with a deletion of the ace1 gene on different carbon sources was analyzed. On cellulose-based medium, on which cellulases are needed for growth, the Δace1 strain grew better than the host strain due to the increased cellulase production. On culture media containing sorbitol as the sole carbon source, the growth of the strain with a deletion of the ace1 gene was severely impaired, suggesting that ACEI regulates expression of other genes in addition to cellulase and xylanase genes. A strain with a deletion of the ace1 gene and with a deletion of the ace2 gene coding for the cellulase and xylanase activator ACEII expressed cellulases and xylanases similar to the Δace1 strain, indicating that yet another activator regulating cellulase and xylanase promoters was present.

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Knight, S. A., K. T. Tamai, D. J. Kosman und D. J. Thiele. „Identification and analysis of a Saccharomyces cerevisiae copper homeostasis gene encoding a homeodomain protein.“ Molecular and Cellular Biology 14, Nr. 12 (Dezember 1994): 7792–804. http://dx.doi.org/10.1128/mcb.14.12.7792.

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Yeast metallothionein, encoded by the CUP1 gene, and its copper-dependent transcriptional activator ACE1 play a key role in mediating copper resistance in Saccharomyces cerevisiae. Using an ethyl methanesulfonate mutant of a yeast strain in which CUP1 and ACE1 were deleted, we isolated a gene, designated CUP9, which permits yeast cells to grow at high concentrations of environmental copper, most notably when lactate is the sole carbon source. Disruption of CUP9, which is located on chromosome XVI, caused a loss of copper resistance in strains which possessed CUP1 and ACE1, as well as in the cup1 ace1 deletion strain. Measurement of intracellular copper levels of the wild-type and cup9-1 mutant demonstrated that total intracellular copper concentrations were unaffected by CUP9. CUP9 mRNA levels were, however, down regulated by copper when yeast cells were grown with glucose but not with lactate or glycerol-ethanol as the sole carbon source. This down regulation was independent of the copper metalloregulatory transcription factor ACE1. The DNA sequence of CUP9 predicts an open reading frame of 306 amino acids in which a 55-amino-acid sequence showed 47% identity with the homeobox domain of the human proto-oncogene PBX1, suggesting that CUP9 is a DNA-binding protein which regulates the expression of important copper homeostatic genes.

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Knight, S. A., K. T. Tamai, D. J. Kosman und D. J. Thiele. „Identification and analysis of a Saccharomyces cerevisiae copper homeostasis gene encoding a homeodomain protein“. Molecular and Cellular Biology 14, Nr. 12 (Dezember 1994): 7792–804. http://dx.doi.org/10.1128/mcb.14.12.7792-7804.1994.

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Yeast metallothionein, encoded by the CUP1 gene, and its copper-dependent transcriptional activator ACE1 play a key role in mediating copper resistance in Saccharomyces cerevisiae. Using an ethyl methanesulfonate mutant of a yeast strain in which CUP1 and ACE1 were deleted, we isolated a gene, designated CUP9, which permits yeast cells to grow at high concentrations of environmental copper, most notably when lactate is the sole carbon source. Disruption of CUP9, which is located on chromosome XVI, caused a loss of copper resistance in strains which possessed CUP1 and ACE1, as well as in the cup1 ace1 deletion strain. Measurement of intracellular copper levels of the wild-type and cup9-1 mutant demonstrated that total intracellular copper concentrations were unaffected by CUP9. CUP9 mRNA levels were, however, down regulated by copper when yeast cells were grown with glucose but not with lactate or glycerol-ethanol as the sole carbon source. This down regulation was independent of the copper metalloregulatory transcription factor ACE1. The DNA sequence of CUP9 predicts an open reading frame of 306 amino acids in which a 55-amino-acid sequence showed 47% identity with the homeobox domain of the human proto-oncogene PBX1, suggesting that CUP9 is a DNA-binding protein which regulates the expression of important copper homeostatic genes.

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Moore, Randy. „Innovating the Future of Water at ACE18 and Beyond“. Opflow 44, Nr. 11 (31.10.2018): 8. http://dx.doi.org/10.1002/opfl.1095.

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CEMBRANO, GUSTAVO LIÑAN, ANGEL RODRÍGUEZ-VÁZQUEZ, SERVANDO ESPEJO MEANA und RAFAEL DOMÍNGUEZ-CASTRO. „ACE16k: A 128×128 FOCAL PLANE ANALOG PROCESSOR WITH DIGITAL I/O“. International Journal of Neural Systems 13, Nr. 06 (Dezember 2003): 427–34. http://dx.doi.org/10.1142/s0129065703001765.

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This paper presents a new generation 128×128 Focal-Plane Analog Programmable Array Processor -FPAPAP, from a system level perspective. It has been manufactured in a 0.35μm standard digital 1P-5M CMOS technology. It has been designed to achieve the high-speed and moderate-accuracy -8b- requirements of most real time -early-vision applications. External data interchange and control are completely digital. The chip contains close to four million transistors, 90% of them working in analog mode. It achieves peak computing values of 0.33TeraOPS while keeping power consumption at reasonable limits -82.5GOPS/W. Preliminary experimental results are also provided in the paper.

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Andraka, B., C. S. Jee und G. R. Stewart. „Ground state inCeAl3: ACe1−xLaxAl3study“. Physical Review B 52, Nr. 13 (01.10.1995): 9462–65. http://dx.doi.org/10.1103/physrevb.52.9462.

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Knappe, Sabine, Rudolf Hartmann, Brahm Goldstein, Bruce M. Ewenstein, Leonard Valentino und Friedrich Scheiflinger. „Synergistic Effects of a Procoagulant Bispecific Antibody and Rescue Therapies on Thrombin Generation- a Potential Safety Risk“. Blood 128, Nr. 22 (02.12.2016): 4952. http://dx.doi.org/10.1182/blood.v128.22.4952.4952.

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Abstract Background: Investigational non-factor products, such as ACE 910 (Emicizumab), offer potential new treatment options for hemophilia patients with inhibitors. However, their uncertain and unregulated mechanisms of action raise multiple concerns around safety and efficacy in specific clinical contexts. As an antibody to FIXa and FX, ACE 910 lacks the inherent regulatory characteristics that are present in replacement factor and bypassing agents in the context of hemostasis. FEIBA is a plasma-derived, activated prothrombin complex concentrate developed to prevent and treat bleeding episodes in hemophilia A and B patients with inhibitors. There are more than 40 years of clinical experience with FEIBA. Extensive prospective clinical study data, as well as post-approval pharmacovigilance data demonstrated the product to be safe and highly effective. In an ongoing phase III study (NCT02622321), hemophilia A patients with inhibitors are treated with Emicizumab. To evaluate the treatment options for ACE910-treated patients experiencing breakthrough bleeding, we studied, in-vitro, the thrombin generation profile of various combinations of FEIBA with a biosimilar version of ACE910. Methods: A biosimilar antibody to Emicizumab (BS-Em) was expressed in mammalian cells, purified and extensively biochemically characterized. Therapeutic doses of BS-Em (200-600nM) in combination with several concentrations of FEIBA (0.1-1IU/ml) were analyzed in standard in-vitro thrombin generation (TG) experiments (1pM TF trigger) using 3 inhibitor patient plasma. A normal range of TG for the experimental conditions used was established using plasma from 34 healthy individuals. Results: The combination of FEIBA and BS-Em resulted in peak thrombin values of >500nM (600nM BS-Em/1IU/ml FEIBA) while the normal range was established to span peak thrombin levels of ~50-120nM thrombin. Titration experiments established that at 600nM BS-Em, FEIBA concentrations of >0.2IU/ml led to peak thrombin values 4- 10-fold higher than the normal range. Conclusions: Our in-vitro experiments demonstrate an excessive thrombin generation potential for the combination of BS-Em and FEIBA at concentrations expected to be generated in patients participating in this study. Caution and clinical judgement will be required when considering the use of ACE910 in hemophilia A patients with inhibitors as options to treat breakthrough bleeds if they occur might be reduced or lead to potential AE. Disclosures Knappe: Shire: Employment. Hartmann:Shire: Employment. Goldstein:Shire: Employment. Ewenstein:Shire: Employment. Valentino:Shire: Employment. Scheiflinger:Shire: Employment.

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