Articoli di riviste: "Bauer Chemical Co"

1

Zhong, Pinyong, Yu-Chao Wang, Jin-Biao Liu, Linjun Zhang e Nianhua Luo. "K₂CO₃-promoted synthesis of amides from 1-aryl-2,2,2-trifluoroethanones and amines under mild conditions". RSC Advances 13, n. 26 (2023): 18160–64. http://dx.doi.org/10.1039/d3ra03329e.

Testo completo

Abstract (sommario):

A base-promoted amidation of 1-aryl-2,2,2-trifluoroethanones with amines via Haller–Bauer reaction has been developed. This reaction directly transforms aryl trifluoroethanone into amides without the use of stoichiometric chemical oxidants or transition-metal catalysts.

Gli stili APA, Harvard, Vancouver, ISO e altri

2

Engel, W., B. Rausenberger, W. Swiech, C. S. Rastomjee, A. M. Bradshaw e E. Zeitler. "In situ studies of heterogeneous reactions using surface electron microscopies LEEM, MEM, and PEEM". Proceedings, annual meeting, Electron Microscopy Society of America 51 (1 agosto 1993): 998–99. http://dx.doi.org/10.1017/s0424820100150824.

Testo completo

Abstract (sommario):

The preferred imaging techniques for the observation of physical and chemical processes at solid surfaces with high temporal and spatial resolution are low-energy electron microscopy (LEEM), mirror electron microscopy (MEM) and photoemission electron microscopy (PEEM). In these techniques the energy transfer to the surface during the imaging process itself is small so that surface processes such as adsorption, diffusion, chemical reactions etc. remain largely undisturbed.LEEM, MEM and PEEM, which all can be performed in an ultra-high-vacuum surface microscope of the Bauer/Telieps type, have been applied to the study of CO/O reaction-diffusion fronts on a Pt(100) surface saturated with CO. These fronts develop after admission of oxygen to the surface (10-6 mbar) at surface defects which provide adsorption sites for oxygen and thus initiate the autocatalytic oxidation process. The formed CO2 is instantaneously desorbed, freeing adsorption sites which are then occupied by oxygen from the gas phase. The front propagates over the whole surface, leaving behind an oxygen-covered region.

Gli stili APA, Harvard, Vancouver, ISO e altri

3

Vijayakumar, S., R. Arulkumaran, R. Sundararajan, S. P. Sakthinathan, R. Suresh, D. Kamalakkannan, K. Ranganathan et al. "Microwave Assisted Synthesis, Spectral Studies and Antimicrobial Activities of some 2′,4′-Difluorophenyl Chalcones". International Letters of Chemistry, Physics and Astronomy 14 (settembre 2013): 68–86. http://dx.doi.org/10.18052/www.scipress.com/ilcpa.14.68.

Testo completo

Abstract (sommario):

Some 2′,4′-difluorophenyl chalcones have been synthesized under microwave irradiation using aldol condensation between 2,4-difluoroacetophenone and substituted benzaldehydes using catalytic amount of hydroxyapatite. The yields of the chalcones are more than 85%. The purities of these synthesized chalcones were examined by their physical constants and spectroscopic data. The UV absorption maxima (λmax, nm), infrared stretches (ν, cm-1) of CO, fingerprint region of CHip/op, CH=CHop, C=Cop modes, NMR chemical shifts (δ, ppm) of vinyl proton, carbon and carbonyl carbons have been assigned and correlated with Hammett substituent constants, F and R parameters using single and multi-regression analysis. From the statistical analysis the effect of substituent on the above spectral frequencies can be discussed. The antimicrobial activities of these synthesized chalcones have been screened using Bauer-Kirby method.

Gli stili APA, Harvard, Vancouver, ISO e altri

4

Vijayakumar, S., R. Arulkumaran, R. Sundararajan, S. P. Sakthinathan, R. Suresh, D. Kamalakkannan, K. Ranganathan et al. "Microwave Assisted Synthesis, Spectral Studies and Antimicrobial Activities of some 2′,4′-Difluorophenyl Chalcones". International Letters of Chemistry, Physics and Astronomy 14 (19 maggio 2013): 68–86. http://dx.doi.org/10.56431/p-v23467.

Testo completo

Abstract (sommario):

Some 2′,4′-difluorophenyl chalcones have been synthesized under microwave irradiation using aldol condensation between 2,4-difluoroacetophenone and substituted benzaldehydes using catalytic amount of hydroxyapatite. The yields of the chalcones are more than 85%. The purities of these synthesized chalcones were examined by their physical constants and spectroscopic data. The UV absorption maxima (λmax, nm), infrared stretches (ν, cm-1) of CO, fingerprint region of CHip/op, CH=CHop, C=Cop modes, NMR chemical shifts (δ, ppm) of vinyl proton, carbon and carbonyl carbons have been assigned and correlated with Hammett substituent constants, F and R parameters using single and multi-regression analysis. From the statistical analysis the effect of substituent on the above spectral frequencies can be discussed. The antimicrobial activities of these synthesized chalcones have been screened using Bauer-Kirby method.

Gli stili APA, Harvard, Vancouver, ISO e altri

5

Patel, Falguni, e UV Shah. "A study of Isolation of Salmonella species from blood culture & it’s Antimicrobial Resistant Pattern." BJKines National Journal of Basic & Applied Sciences 15, n. 01 (18 giugno 2023): 10–15. http://dx.doi.org/10.56018/bjkines2023062.

Testo completo

Abstract (sommario):

Background: The main aim of this study was to monitor the antimicrobial resistant pattern of Salmonella isolates to select proper antibiotic & prevent drug resistance in Salmonella species. Material and Methods: Total 250 blood culture bottles were collected from patients clinically suspected enteric fever and loaded to BACTEC 9050. Out of them 200 signalled positive samples were inoculated on chocolate and Mac Conkey agar plates and incubated overnight at 370 C in the incubator and identified by colony characteristics, procedures like Gram staining, wet preparation for motility and bio-chemical reactions like oxidase test, catalase test, triple sugar iron agar, Citrate test, using Salmonella antisera like Poly O, O-9, and H-d. The clinical isolates were subjected to antibiotic sensitivity test on Mueller-Hinton agar, using modified Kirby Bauer disc diffusion method as per Clinical Laboratory Standard Institute (CLSI) guidelines. Results: Total 61 Salmonella were isolated. 49 were Salmonella typhi and 12 were Salmonella paratyphi. Overall rate of resistance of 49 S. typhi isolates was 2 % to ampicillin, 4 % to Azithromycin, 4 % to fluoroquinolones and 2 % to co-trimoxazole. S. paratyphi isolates were 100% sensitive to ampicillin, co-trimoxazole, chloramphenicol and 3rd generation cephalosporins. Conclusion: Enteric fever is one such infection which poses challenges in antimicrobial resistance. Continuous surveillance is important to track bacterial resistance and to treat infections in a cost-effective manner.

Gli stili APA, Harvard, Vancouver, ISO e altri

6

Ziegler, H. "Buchbesprechung: Common Fragrance ans Flavor Materials – Preparation, Properties ans Uses. Forth, completely revised edition. Von K. Bauer, D. Garbe, H. Surburg." Chemie Ingenieur Technik 74, n. 10 (15 ottobre 2002): 1472–73. http://dx.doi.org/10.1002/1522-2640(20021015)74:10<1472::aid-cite11111472>3.0.co;2-8.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

7

Gao, Yunfei, Tomoki Uchiyama, Kentaro Yamamoto, Toshiki Watanabe, Neha Thakur, Ryota Sato, Toshiharu Teranishi, Hideto Imai, Yoshiharu Sakurai e Yoshiharu Uchimoto. "Exploring the Degradation Mechanism on Pt_xCo_y Alloy Catalysts for Oxygen Reduction Reaction by Operando X-Ray Absorption Spectroscopy". ECS Meeting Abstracts MA2023-02, n. 40 (22 dicembre 2023): 1957. http://dx.doi.org/10.1149/ma2023-02401957mtgabs.

Testo completo

Abstract (sommario):

At present, alloying the Pt with 3d-transition metal, such as Co, has been demonstrated as an efficacious approach in enhancing the activity of the cathodic catalysts and diminishing the cost of Pt through ligand effect and strain effect. However, these catalysts were facing with a substantial challenge of the limited durability, primarily attributed to the leaching of the 3d-transition metal under the rigorous electrochemical conditions for the proton exchange membrane fuel cells (PEMFCs)[1]. Herein, we applied both operando conventional XAS and high energy resolution fluorescence detection (HERFD) XAS to identify the electro-chemical behaviors of subsize (about 2.5 nm) PtxCoy alloy catalysts with different Co content and associated with the Pt1Co3@Pt core-shell (CS) nanostructure catalysts obtained by simple displacement reaction. We find that the introduction of Co helps to modify the structure of PtCo alloy catalysts and benefit the activity, however, the increase content of Co brings to the heavier oxidation of Pt, which accelerate the degradation of the PtCo alloy catalysts. While the structure with Pt-rich shell suggested a high tolerance to the Pt oxidation which benefits both stability and activity. Based on these findings, we demonstrate the significance of designing PtCo CS nanostructure with high Co content to achieve optimal performance in PEMFCs. Our research provides valuable insights in designing the catalysts combined with operando XAS analysis and paves the way for the development for the large-scale application for PEMFCs. For the typical synthesis of PtCox alloy catalysts, the Pt(acac)2 and Co(acac)3 were used as Pt and Co precursors. 4mL ethanol was added to the pre-mixed Pt and Co precursors and heated up to 60 °C with magnetic stirring. After the precursors completely dissolved, certain amount of Vulcan 72 was added into the solution. Then repeat ultrasonication and magnetic stirring in 60 °C until the solution converted into slurry statement, dried the product in 30 °C over night. Next, the above well-milled products were treated at 700 °C for 2h in Ar atmosphere to transfer into alloy particles. According to the introduced ratio between Pt and Co, the catalysts were noted as Pt3Co1, Pt1Co1, and Pt1Co3. The contribution of CS nanostructure of Pt1Co3 was applied by simple displacement reaction using H2PtCl6 solution as Pt source. The production was annealed in H2 for 30 min. Operando conventional XAS (at BL36XU in Spring 8) was performed to investigate the electronic statement and structure changes during the operation. Operando HERFD XAS (at BL39XU in Spring 8) further identified the formation of metal Pt with chemisorbed O and Pt oxidation during the polarization varying different Co content and Pt-rich shell. The electronic performance of PtCo alloy catalysts was evaluated in rotating disk electrode, gas diffusion electrode, and membrane electrode assembly, which exhibited a higher performance (about 5 times higher than Pt/C) for Pt1Co3@Pt catalyst. Fig. 1a shows the STEM mapping results for Pt1Co3@Pt catalysts, the linear scanning profile is shown in the mix-image, and the signal intensity between the Pt L-edge and Co K-edge indicates the Pt-rich shell and Pt and Co core structure, which suggested the successful synthesis of Pt-rich shell with high Co content. To further analyze the electronic-behavior for the catalysts, the operando HERFD-XAS analysis was performed on Pt1Co3 and Pt1Co3@Pt catalysts, which provides a higher signal-to-noise ratio and detailed information about the electronic statement of Pt atom[2]. As shown in Figure 1b and c, the main Pt L3-edge white line intensity continuously increased and positively shifted, which suggested the increasing coverage of chemisorbed O or OH onto the Pt surface and the generation of oxidic component at high polarization potential for Pt1Co3 catalyst. While less changes were shown in Pt1Co3@Pt catalyst, which implied the formation of Pt-rich shell could help to suppress the oxidation of Pt in PtCo alloy catalysts and benefit the catalytic performance. References [1] Z.P. Wu, D.T. Caracciolo, Y. Maswadeh, et al. Nat. Commun. 12 (2021) 859. [2] M. Bauer, Phys.Chem.Chem.Phys. 16 (2014) 13827. Fig. 1 (a) STEM-mapping image for Pt1Co3@Pt catalysts and its linear-scanning mapping result for Pt L-edge (red) and Co K-edge (green), operando HERFD XAS analysis for (b) Pt1Co3 and (c) Pt1Co3@Pt catalysts varying different polarization potential (vs. RHE) in O2-satureated 0.1 M HClO4 solution. Figure 1

Gli stili APA, Harvard, Vancouver, ISO e altri

8

Barker, Jeremy. "(Europe Section Alessandro Volta Award) The Journey Towards the Large-Scale Commercialization of Low-Cost and High Energy Density Na-ion Batteries". ECS Meeting Abstracts MA2022-02, n. 6 (9 ottobre 2022): 2494. http://dx.doi.org/10.1149/ma2022-0262494mtgabs.

Testo completo

Abstract (sommario):

Na-ion batteries based on non-aqueous electrolytes represent an inexpensive and sustainable alternative to their Li-ion counterparts [1,2]. The cost advantage is particularly apparent at the present time as the prices of battery grade Li and Co precursor salts have spiraled upwards in the last 18 months. Faradion Limited is a UK-based company, founded in 2011 and from December 2021, part of Reliance Industries Limited of India*. It is commercializing its Na-ion battery technology in a number of large format applications. It has identified and developed a wide range of inexpensive and proprietary active materials and non-aqueous electrolyte systems which offer low manufacturing costs as well as outstanding electrochemical performance and intrinsic safety. Over the past 10 years the company has incorporated these materials into full-scale Na-ion cells to a point where battery performance characteristics such as energy density, rate capability and cycle life are competitive with commercial Li-ion technologies. The Faradion Na-ion prototype cells demonstrate low-capacity fade on cycling, coupled to low polarization and excellent columbic and energy (round-trip) efficiency and may be configured for both energy and power applications. The use of Al for both current collectors serves as an additional and significant cost and safety benefit and allows the cells to be stored and transported at 0 V (i.e. physically shorted) [3]. The Faradion Na-ion cells are manufactured on commercial Li-ion production lines using proven battery designs [4,5]. Pouch, cylindrical and prismatic cell designs have all been demonstrated successfully [6]. Faradion has worked with its commercial partners to scale-up its Na-ion cell chemistry to the 40 Wh and 90 Wh pouch cell level – see for example, figure 1. These cells deliver a cell level specific energy of over 150 Wh/kg and have been incorporated into a range of demonstrator energy storage applications, including E-bike, residential, renewables, telecoms and automotive [6]. Faradion’s technology roadmap indicates that a specific energy in excess of 190 Wh/kg will be accessible in the near future. Other key attributes such as low precursor costs, material sustainability and excellent temperature range, confirm that Faradion’s Na-ion battery technology will prove commercially successful in a range of large format applications [7]. Reference s: [1] J. Barker, M.Y. Saidi and J. Swoyer, Electrochem. Solid-State Chem. 6 (2003) A1 [2] K. Kubota and S. Komaba, J. Electrochem. Soc., 162 (2015) A2538. doi.org/10.1149/2.0151514jes [3] (a) A. Rudola, C.J. Wright and J. Barker, Energy Materials Advances, 2021 Article ID 9798460. doi.org/10.34133/2021/9798460 (b) J. Barker and C.J. Wright, Assignee: Faradion Limited. US Patent #11159027 [4] A. Bauer, J. Song, S. Vail, W. Pan, J. Barker and Y. Lu, Adv. Energy Materials, 1 2018, 1702869. doi.org/10.1002/aenm.201702869 [5] For example, J. Barker and R.J. Heap, Assignee: Faradion Limited, US Patent#9774035, US Patent #9917307, US Patent #1019628, US Patent #10115966, US Patent #10050271, US Patent #10399863 [6] (a) American Chemical Society, Chemical & Engineering News, July 20, 2015, Vol. 93, Issue 29. (b) American Chemical Society, Chemical & Engineering News, May 24, 2022, Vol. 100, Issue 19 [7] A. Rudola et al. J. Mater Chem A, 2021, 9, 8279-8302. doi.org/10.1039/D1TA00376C Footnote: [*] In late 2021, Faradion Limited was acquired by Reliance New Energy Systems Limited (RNESL), a wholly owned subsidiary of Reliance Industries Limited (RIL) of India. Figure 1

Gli stili APA, Harvard, Vancouver, ISO e altri

9

Svecova, Lenka. "(Invited) Why and How Should the PEMFCs be Recycled? – Focus on the MEA Case". ECS Meeting Abstracts MA2023-02, n. 38 (22 dicembre 2023): 1840. http://dx.doi.org/10.1149/ma2023-02381840mtgabs.

Testo completo

Abstract (sommario):

Proton-Exchange Membrane Fuel Cells (PEMFCs) are electrochemical devices with potential applications in mobility and stationary energy storage. Last decades have seen a growing interest in the research, the development and the small-scale industrialization of PEMFC. However, PEMFC requires Pt as catalyst for both electrochemical reactions. From the geological point of view, Pt is a scarce element, while between 7 to 12 t of mineral must be extracted to obtain 31.1 g of Pt. Moreover, Pt is considered as a critical raw material by the E.U. with a high supply shortage/breakdown risk.1 The recycling might be a feasible way how to face the current and future supply issues and to secure the access to resources. Although there are currently no legal obligation regarding the PEMFCs recycling, it is highly probable that regulations close to those already existing for batteries will be soon applied, implementing mandatory collection and recycling targets for spent PEMFCs. Finally, this might also be a way to decrease the costs and the environmental impacts of the PEMFCs’ sector as the use of Pt affects both its cost and is considered as a burden from the environmental point of view.2,3 Recycling it might be a feasible option to counteract these issues in a comparable manner to (i) an increase of the Pt catalyst durability, (ii) a decrease of its loading and (iii) its substitution by less noble metals. While the three latter pathways are already widely studied by different research teams, the recycling option has not attracted, up to now, significant attention and will be the scope of this presentation. Two different recycling approaches might be used to recover Pt. Pyrometallurgy is based on thermal treatment of metals, namely their reduction and smelting, while hydrometallurgy is a chemical approach consisting in metals dissolution and further purification. Each of them has its own pros and cons, whereas both approaches can be combined. Both have also been exploited for MEA recycling. Within our research group hydrometallurgical approach has been applied to MEA recycling. This approach is traditionally composed of several successive steps: pretreatment (including shredding and grinding), leaching, separation and purification followed by the final recovery. We have progressively exploited several manners to dissolve platinum. The Pt/C catalyst might be dissolved at room temperature by combining appropriate concentrations of oxidizing and complexing agents. We have namely achieved very high leaching yield when using either H2O2 (3%) and HNO3 (5%) as oxidizer diluted in concentrated HCl playing the role of the complexing agent.4 We have further demonstrated that electro-assisted leaching of Pt might also be feasible if an appropriate electrolyte is combined to the appropriate choice of oxidation and reduction potential that are applied alternatively. Once the Pt is dissolved its purification might be carried out via ion exchange or solvent extraction.4 These operations might also be feasible for its separation from Co in case of Pt3Co alloys presence in the spent MEAs.5,6 Finally, the recovery of Pt might be carried out by precipitation or Pt/C catalyst might be synthetized in a closed-loop manner.5 Two different approaches have been attempted within our research team and both of them have provided a catalyst which exhibited similar performance to a reference Pt/C catalyst in a single-cell PEMFC.5 Moreover, the environmental benefits of the recycling process have been assessed using the LCA methodology.5,7 The results show that primary platinum production remains the most impacting stage, even when MEA recycling is considered. Moreover, the assessment reveals that the MEA life-cycle impacts can be reduced significantly if electrodes recycling is carried out, while the main impact categories decrease is proportional to the platinum recycling rate. References 1 European Commission, Study on the Critical Raw Materials for the EU 2023 - Final Report, 2023. 2 M. Miotti, J. Hofer and C. Bauer, Int. J. Life Cycle Assess., 2017, 22, 94–110. 3 A. Simons and C. Bauer, Appl. Energy, 2015, 157, 884–896. 4 L. Duclos, L. Svecova, V. Laforest, G. Mandil and P.-X. Thivel, Hydrometallurgy, 2016, 160, 79–89. 5 L. Duclos, R. Chattot, L. Dubau, P. X. Thivel, G. Mandil, V. Laforest, M. Bolloli, R. Vincent and L. Svecova, Green Chem., 2020, 22, 1919–1933. 6 M. Gras, L. Duclos, N. Schaeffer, V. Mogilireddy, L. Svecova, Eric Chaînet, I. Billard and N. Papaiconomou, ACS Sustain. Chem. Eng., 2020, 8, 15865–15874. 7 L. Duclos, M. Lupsea, G. Mandil, L. Svecova, P.-X. Thivel and V. Laforest, J. Clean. Prod., 2017, 142, 2618–2628.

Gli stili APA, Harvard, Vancouver, ISO e altri

10

Schmelzle, Tobias, Emilie Chapeau, Daniel Bauer, Patrick Chene, Jason Faris, Cesar Fernandez, Pascal Furet et al. "Abstract LB319: IAG933, a selective and orally efficacious YAP1/WWTR1(TAZ)-panTEAD protein-protein interaction inhibitor with pre-clinical activity in monotherapy and combinations". Cancer Research 83, n. 8_Supplement (14 aprile 2023): LB319. http://dx.doi.org/10.1158/1538-7445.am2023-lb319.

Testo completo

Abstract (sommario):

Abstract The YAP-TEAD protein-protein interaction (PPI) is a critical event known to mediate YAP oncogenic functions downstream of the Hippo pathway. Current advanced pharmacological agents which aim at inhibiting YAP-TEAD oncogenic function do so by engaging into the lipid pocket of TEAD. Thereby the consequences of a direct pharmacological disruption of the interface of YAP and TEADs remain unexplored. Here we report the identification of IAG933, the first molecule able to potently and directly disrupt the YAP/TAZ-TEADs PPI with suitable properties to enter in clinical trial. The path to drug discovery was established by structure-based optimization of a truncated natural YAP peptide allowing the pharmacophore mapping of TEAD coil binding site. Based on in silico screening, validated hit was optimized using structure- and property-based lead optimization yielding IAG933, whose chemical structure will be for the first time disclosed here. Biochemical and cellular assays demonstrate that IAG933 specifically abrogates the interaction between YAP/TAZ coactivators and all four TEAD isoforms, thus selectively inhibiting TEAD-driven transcriptional activity and inducing anti-cancer effects. At the epigenome level, YAP eviction from chromatin was observed upon treatment with IAG933, while leaving TEADs genomic occupancy unaffected. Concomitantly, engagement of co-repressor VGLL4 translated to a decrease in enhancer activity with rapid and progressive changes in transcription of Hippo target genes. In preclinical experiments, IAG933 linear pharmacokinetics was consistent with dose proportional TEAD transcriptional inhibition and anti-tumor efficacy in xenograft and primary-tumor derived malignant pleural mesothelioma models. Daily treatment with IAG933 elicited complete tumor regression in the MSTO-211H xenograft model at well-tolerated doses. In line with the current clinical strategy for IAG933, robust anti-tumor efficacy in cancer models bearing NF2 loss of function or expressing TAZ-fusions was observed. Moreover, we provide evidence for combination benefits of IAG933 with several MAPK/KRAS inhibitors, both in vitro and in vivo, in non-Hippo altered models including lung, pancreatic and colorectal cancer. Overall, our results provide a rationale of progressing IAG933 as a monotherapy in patients with Hippo-mutated cancers, and as a combination partner in MAPK-dependent cancers, with the potential to treat patient populations of high unmet medical need. Citation Format: Tobias Schmelzle, Emilie Chapeau, Daniel Bauer, Patrick Chene, Jason Faris, Cesar Fernandez, Pascal Furet, Giorgio Galli, Jiachang Gong, Stephanie Harlfinger, Francesco Hofmann, Eloisa Jimenez Nunez, Joerg Kallen, Thanos Mourikis, Laurent Sansregret, Paulo Santos, Clemens Scheufler, Holger Sellner, Markus Voegtle, Markus Wartmann, Peter Wessels, Frederic Zecri, Nicolas Soldermann. IAG933, a selective and orally efficacious YAP1/WWTR1(TAZ)-panTEAD protein-protein interaction inhibitor with pre-clinical activity in monotherapy and combinations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB319.

Gli stili APA, Harvard, Vancouver, ISO e altri

11

Dittrich, Birger. "Is there a future for topological analysis in experimental charge-density research?" Acta Crystallographica Section B Structural Science, Crystal Engineering and Materials 73, n. 3 (1 giugno 2017): 325–29. http://dx.doi.org/10.1107/s2052520617006680.

Testo completo

Abstract (sommario):

Topological analysis using Bader and co-worker'sAtoms in Moleculestheory has seen many applications in theoretical chemistry and experimental charge-density research. A brief overview of successful early developments, establishing topological analysis as a research tool for characterizing intramolecular chemical bonding, is provided. A lack of vision in many `descriptive but not predictive' subsequent studies is discussed. Limitations of topology for providing accurate energetic estimates of intermolecular interaction energies are put into perspective. It is recommended that topological analyses of well understood bonding situations are phased out and are only reported for unusual bonding. Descriptive studies of intermolecular interactions should have a clear research focus.

Gli stili APA, Harvard, Vancouver, ISO e altri

12

Cen, Dongliang. "Adsorption of CO₂ on the Surface of Fe(111): A First-Principles Study". Science of Advanced Materials 15, n. 7 (1 luglio 2023): 894–904. http://dx.doi.org/10.1166/sam.2023.4464.

Testo completo

Abstract (sommario):

First-principle is used to study the structure parameters, adsorption energy, Bader charge, electronic density of states, charge-density transformation, and surface work function of CO2 molecule at various adsorption sites on the Fe(111) surface based on Density Function Theory (DFT). Results show that the CO2 molecule is absorbed on the Fe(111) surface by combining Fe–C and Fe–O multiple bonds. The type of adsorption of most configurations is chemisorption. The most stable structure is BS-Y, with an adsorption energy of −0.8115 eV. The order of stability of adsorption sites is bridge site > hcp site > fcc site > top site. Carbon dioxide mostly reacts with the uppermost two layers of Fe atoms and just partially with the lowermost two levels. In addition, the chemical bonds between CO2 molecule and Fe atoms are covalent, and the response mechanism is the hybridization of C-2s, C-2p, O-2s, and O-2p orbitals with Fe-3p, Fe-3d, Fe-4s orbitals, forming new chemical bonds. The BS-Y configuration has the smallest increment of work function, indicating that the lowest escape energy is required for the electron to escape from the surface.

Gli stili APA, Harvard, Vancouver, ISO e altri

13

Sree Devi, R. K., e S. SudhaKumari. "Synthesis, Characterization and Antimicrobial studies of Schiff base Ligand from amino acid L-arginine and its Cu(II), Ni(II),Co(II) complexesIJCTR.2019.130201". International Journal of ChemTech Research 13, n. 2 (2020): 1–8. http://dx.doi.org/10.20902/ijctr.2019.130201.

Testo completo

Abstract (sommario):

Transition metal complexes of Cu(II), Ni(II), Co(II) with a Schiff base Ligand (R,Z)-2-(2-hydroxy-3-methoxybenzylideneamino)-5-guanidinopentanoic acid (HMA-GPA) was synthesized by the condensation of 2-hydroxy-3-methoxybenzaldehyde and L- Arginine. These were characterized by elemental analysis IR, UV, magnetic susceptibility and molar conductivity measurements. The IR spectra of the Ligand HMA-GPA and the metal complexes suggest that the Ligand coordinates the metal ion through azomethine nitrogen, carboxylate Oxygen and Oxygen of the phenolic -OH group. The electronic absorption spectra and magnetic data indicate the Cu(II), Ni(II)complexes to be square planar and Co(II) complex to be octahedral. The metal complexes and the ligand were subjected to antimicrobial studies by Kirby Bayer Disc-diffusion method and found to have significant activity against the selected bacterial and fungal strains under study.

Gli stili APA, Harvard, Vancouver, ISO e altri

14

Farrugia, Louis J., Paul R. Mallinson e Brian Stewart. "Experimental charge density in the transition metal complex Mn2(CO)10: a comparative study". Acta Crystallographica Section B Structural Science 59, n. 2 (26 marzo 2003): 234–47. http://dx.doi.org/10.1107/s0108768103000892.

Testo completo

Abstract (sommario):

An accurate experimental charge density study at 100 K of Mn2(CO)10 [bis(pentacarbonylmanganese)(Mn—Mn)] has been undertaken. A comparison with previously reported structural determinations reveals no evidence for significant Mn—Mn bond lengthening between 100 and 296 K. The nature of the metal–metal and metal–ligand atom interactions has been studied by topological analysis using the Atoms in Molecules (AIM) approach of Bader [(1990), Atoms in Molecules: a Quantum Theory.Oxford: Clarendon Press]. An analysis of the density ρ(r), the Laplacian of the density ∇2ρ(r b ) and the total energy densities H(r b ) at the bond critical points is used to classify all the chemical bonds as covalent in nature. The results are compared qualitatively and quantitatively with previous charge density studies on this molecule and DFT calculations at the 6-311+G* B3LYP level. The topological properties of the theoretical and experimental densities are in close agreement.

Gli stili APA, Harvard, Vancouver, ISO e altri

15

Deng, Zun-Yi, e Jian-Min Zhang. "First-principles study of O2 and Cl2 molecule adsorption on pristine doped boron nitride nanotubes". Canadian Journal of Physics 94, n. 10 (ottobre 2016): 1071–79. http://dx.doi.org/10.1139/cjp-2016-0326.

Testo completo

Abstract (sommario):

The adsorption of oxygen (O2) and chlorine (Cl2) on pristine and impurity X atom (X = C, Al, Si, Ca, Mn, Fe, Co, Ni, Cu or Ge) doped (10,0) and (6,6) boron nitride nanotubes (BNNTs) has been theoretically studied using first-principles approach based on density functional theory. Comparing with the formation energy, the distance between gas molecule and X atoms, the Bader charge transfer, and the elevation of the dopant atom, we find that the O2 or Cl2 molecule undergoes weakly physical adsorption on the pristine (10,0) and (6,6) BNNTs, and the Al, Si, and Mn atoms are suitable dopants to modify BNNTs to enhance the reactivity of the tube to gas molecules. This work reveals that the sensitivity of BNNT-based chemical gas sensors for O2 and Cl2 can be drastically improved by introducing appropriate dopant, and Al-, Si-, and Mn-doped BNNTs can be used as O2 and Cl2 gas sensor manufacturing raw materials.

Gli stili APA, Harvard, Vancouver, ISO e altri

16

Sun, Chunwei, Jiannan Chen, Kuo Tian, Daoping Peng, Xin Liao e Xiyong Wu. "Geochemical Characteristics and Toxic Elements in Alumina Refining Wastes and Leachates from Management Facilities". International Journal of Environmental Research and Public Health 16, n. 7 (11 aprile 2019): 1297. http://dx.doi.org/10.3390/ijerph16071297.

Testo completo

Abstract (sommario):

A nationwide investigation was carried out to evaluate the geochemical characteristics and environmental impacts of red mud and leachates from the major alumina plants in China. The chemical and mineralogical compositions of red mud were investigated, and major, minor, and trace elements in the leachates were analyzed. The mineral and chemical compositions of red mud vary over refining processes (i.e., Bayer, sintering, and combined methods) and parental bauxites. The main minerals in the red mud are quartz, calcite, dolomite, hematite, hibschite, sodalite, anhydrite, cancrinite, and gibbsite. The major chemical compositions of red mud are Al, Fe, Si, Ca, Ti, and hydroxides. The associated red mud leachate is hyperalkaline (pH > 12), which can be toxic to aquatic life. The concentrations of Al, Cl−, F−, Na, NO32−, and SO42− in the leachate exceed the recommended groundwater quality standard of China by up to 6637 times. These ions are likely to increase the salinization of the soil and groundwater. The minor elements in red mud leachate include As, B, Ba, Cr, Cu, Fe, Ni, Mn, Mo, Ti, V, and Zn, and the trace elements in red mud leachate include Ag, Be, Cd, Co, Hg, Li, Pb, Sb, Se, Sr, and Tl. Some of these elements have the concentration up to 272 times higher than those of the groundwater quality standard and are toxic to the environment and human health. Therefore, scientific guidance is needed for red mud management, especially for the design of the containment system of the facilities.

Gli stili APA, Harvard, Vancouver, ISO e altri

17

Bustos-Gómez, Chrystyan Iván, Deisy Gasca-Martínez, Eunice Yáñez-Barrientos, Sergio Hidalgo-Figueroa, Maria L. Gonzalez-Rivera, Juan Carlos Barragan-Galvez, Juan Ramón Zapata-Morales, Mario Isiordia-Espinoza, Alma Rosa Corrales-Escobosa e Angel Josabad Alonso-Castro. "Neuropharmacological Activities of Ceiba aesculifolia (Kunth) Britten & Baker f (Malvaceae)". Pharmaceuticals 15, n. 12 (18 dicembre 2022): 1580. http://dx.doi.org/10.3390/ph15121580.

Testo completo

Abstract (sommario):

Ceiba aesculifolia (Kunth) Britten & Baker f (Malvaceae) is used for the folk treatment of mood disorders. C. aesculifolia bark was extracted in ethanol, and the extract (CAE) was chemically standardized using gas chromatography–mass spectrometry (GC-MS). This study evaluated the effects of CAE (10–100 mg/kg p.o.) on anxiolytic-like activity, sedation, locomotor activity, depression-like activity, and spatial working memory using in vivo rodent models. A possible mechanism for the anxiolytic-like and antidepressant-like actions induced by CAE was assessed using neurotransmission pathway inhibitors. Myristic acid was one of the compounds found in CAE using GC-MS. This study also evaluated the anxiolytic-like activity and the sedative actions of myristic acid and assessed a possible mechanism of action using neurotransmission pathway inhibitors and an in silico analysis. CAE elicited anxiolytic-like activity and antidepressant-like effects (ED50 = 57 mg/kg). CAE (10–100 mg/kg) did not affect locomotor coordination or induce sedation. The anxiolytic-like and antidepressant-like actions of CAE were reverted by prazosin, suggesting a possible participation of the noradrenergic system. The anxiolytic-like activity of myristic acid was reverted by the co-administration of prazosin and partially reverted by ketanserin. The docking study revealed that myristic acid can form favorable interactions within 5-HT2A and α1A-adrenoreceptor binding pockets.

Gli stili APA, Harvard, Vancouver, ISO e altri

18

Patil, Pallavi S., e Umesh B. Deshannavar. "Performance of Saccharomyces cerevisiae Strains to Ferment Sugarcane Juice". Asian Journal of Chemistry 31, n. 12 (16 novembre 2019): 2885–90. http://dx.doi.org/10.14233/ajchem.2019.22281.

Testo completo

Abstract (sommario):

In the present study, four Saccharomyces cerevisiae strains S. cerevisiae (NCIM 3200), S. cerevisiae (NCIM 3045), S. cerevisiae (baker′s yeast) and S. cerevisiae (EC1118) have been used and compared for their capability to ferment sugars from the juice of sugarcane (of variety CO 86032) for production of sugarcane wine. The growth pattern of each strain was studied followed by the fermentation at optimized conditions such as pH and temperature. The strains′ potential to produce sugarcane wine has been compared in terms of their sugar consumption, alcohol production, titrable acidity and volatile acidity production with respect to permissible amounts given by Indian Regulations. Saccharomyces cerevisiae (EC1118) performed better in fermentation among other compared Saccharomyces strains at the optimum temperature of 28 ºC, optimum pH 5, total soluble solids of 18 ºBrix and total sugar content of 185 g/L. Analysis of sugarcane wine fermented by Saccharomyces cerevisiae (EC1118) has pH, 3.57, total alcohol content, 13.55 ± 1.77 %, titrable acidity, 8.30 ± 0.01 g/L and volatile acidity, 0.84 ± 0.00 g/L. The overall acceptability from sensory analysis supports the above physico-chemical analysis results of sugarcane wine.

Gli stili APA, Harvard, Vancouver, ISO e altri

19

Zhang, Shuang, Xinxin Fan, Guojing Zhang, Weidong Wang e Lei Yan. "Preparation, characterization, and in vitro release kinetics of doxorubicin-loaded magnetosomes". Journal of Biomaterials Applications 36, n. 8 (30 novembre 2021): 1469–83. http://dx.doi.org/10.1177/08853282211060544.

Testo completo

Abstract (sommario):

The doxorubicin (DOX) was successfully coupled to the magnetosomes from Acidithiobacillus ferrooxidans ( At. ferrooxidans) by genipin bridging. The parameters (magnetosome concentration, DOX concentration, genipin concentration-, and cross-link time) expected for temperature significantly influenced the coupling rate. Bacterial magnetosome-doxorubicin complexes (BMDCs) were characterized by transmission electron microscope (TEM), particle size analyzer and Fourier transform infrared spectroscopy. Results indicated that BMDCs exhibited a mean particle size of 83.98 mm and displayed a negative charge. The chemical reaction occurring between CO and NH group and the physical adsorption predominated by electrostatic interaction were found to involve in coupling. BMDCs can release 40% of DOX in simulated gastrointestinal conditions within 38 h. Kinetic models including Higuchi, Korsmeyer–Peppas, Zero order, First order, Hixon-Crowell, Baker-Lonsdale, and Weibull and Gompertz were utilized to explore the release mechanism of DOX from BMDCs. All models were found to fit well (r2 ≥ 0.8144) with the release data and the Gompertz was the best fit model (r2 = 0.9742), implying that the complex mechanisms involving Fickian and Gompertz diffusion contributed to the release. These findings suggested that magnetosomes from At. ferrooxidans have great potential applications in biomedical and clinical fields as the carrier of target drug delivery systems in the future.

Gli stili APA, Harvard, Vancouver, ISO e altri

20

Haydon, Keith D., e R. Dean Boyd. "44 Amino acids in livestock: A historical perspective". Journal of Animal Science 97, Supplement_2 (luglio 2019): 22. http://dx.doi.org/10.1093/jas/skz122.041.

Testo completo

Abstract (sommario):

Abstract The advent of commercially viable synthetic amino acids (AA) and least cost formulation (LCF) have fundamentally changed swine and poultry diets over the past 40 years. Amino acids can be produced by chemical synthesis, hydrolysis of intact proteins and fermentation. Chemical synthesis of AA was first reported by Strecker (1850). Discovery of glutamate as the basis of Umami taste category (1907) spurred commercial AA production by hydrolysis. The discovery of commercially viable fermentative production of glutamate, by Kyowa Hakko Kogyo Co. (1957), revolutionized AA production. Their parallel discovery of lysine (Lys) production, using a natural C. glutmanicum mutant subsequently followed. This led to further screening for bacterial mutants for threonine (Thr, 1961), tryptophan (Trp, 1972), valine (Val, 1959) and isoleucine (Ile, 1972). The next milestone occurred with development of the first main-frame LCF programs (1960s). The first commercial application of dietary AA involved methionine (Met) for poultry, followed closely by Lys in swine. Use of other synthetic AA was cost-prohibitive, but they served as research tools. The next revolution involved recombinant DNA technology (1980s), which dramatically increased AA yield and reduced production cost. Simultaneously, development of PC based LCF enabled cost effective formulation. Subsequently, growth-derived AA ratio’s emerged from the labs of Fuller (1989) and Baker (1992). Patent expirations in the late 1980s led to new companies that produced rapid advances in fermentation methods, with new recombinant strains. Production cost declined further for Lys (1988), and production efficiencies allowed Thr (1995) and Trp (2000) to enter commercial diets. Advances in fermentation technology have enabled production of all ten essential AA. Extensive AA displacement of protein supplements has led to an ever-expanding global tonnage of AA for food and pet animals. With routine addition of 4–6 AA in swine diets, we question whether non-essential AA nitrogen may emerge as limiting (essential).

Gli stili APA, Harvard, Vancouver, ISO e altri

21

Qin, Xueping, Tejs Vegge e Heine Anton Hansen. "CO₂ Activation at Au(110)-Water Interfaces: An Ab Initio Molecular Dynamics Study". ECS Meeting Abstracts MA2022-01, n. 49 (7 luglio 2022): 2098. http://dx.doi.org/10.1149/ma2022-01492098mtgabs.

Testo completo

Abstract (sommario):

The electrochemical carbon dioxide reduction reaction (CO2RR) is a promising technology to establish a sustainable carbon cycle by minimizing the carbon footprint and producing useful chemicals.1-2 Gold is a highly active and selective electrocatalyst towards CO2RR to produce CO, being as one critical syngas component. Previous theoretical simulations are mainly focused on the key reaction intermediates (*COOH and *CO) using the computational hydrogen electrode (CHE) model, where the CO2 activation is usually neglected which is not accessed in the employed vacuum condition. Constructing the Au-water interface with explicit water layers is beneficial to evaluate the CO2 activation, which might be the rate-determining step (RDS) during CO2RR on Au surfaces.3 In this work, the multiple explicit water layers are introduced to simulate the Au(110)-water interface, and the role of applied potential is considered on Au surfaces with different surface charge densities where the K cations are artificially included into water solvents. Combining the standard ab initio molecular dynamics (AIMD) and state-of-the-art constrained AIMD (cAIMD) simulations, the CO2 activation is studied from both kinetic and thermodynamic aspects. Using the slow-growth sampling approach with thermodynamic integrations, we found that CO2 adsorption could be activated at Au-water interface with 2K+, and the free energy barrier is estimated to be 0.61 eV (Figure 1a, top). Additionally, 0.81 electrons are transferred to *CO2 during adsorption based on Bader charge analysis (Figure 1a, bottom). The key intermediates during CO2RR are shown in Figure 1b (including initial state, transition state, and final state), and the reversed CO2 desorption shows very similar free energy diagram, which validates both our sampling approach and interfacial models.4 Besides the CO2 activation, the full reaction pathway including the subsequent proton transfers during CO2RR will be explored in the further study, and the complete free-energy landscape will be constructed using this Au-water interfacial model. Such an AIMD simulation study from the atomic level can largely contribute to the complete understandings of catalytic reaction pathways on Au surfaces and the interfacial behaviors at solid-liquid interfaces. References (1) Nitopi, S.; Bertheussen, E.; Scott, S. B.; Liu, X.; Engstfeld, A. K.; Horch, S.; Seger, B.; Stephens, I. E. L.; Chan, K.; Hahn, C.; Nørskov, J. K.; Jaramillo, T. F.; Chorkendorff, I., Chem. Rev. 2019, 119, 7610-7672. (2) Seh, Z. W.; Kibsgaard, J.; Dickens, C. F.; Chorkendorff, I.; Nørskov, J. K.; Jaramillo, T. F., Science 2017, 355, eaad4998. (3) Wuttig, A.; Yaguchi, M.; Motobayashi, K.; Osawa, M.; Surendranath, Y., Proc. Natl. Acad. Sci. 2016, 113, E4585. (4) Qin, X.; Vegge, T.; Hansen, H. A., J. Chem. Phys. 2021, 155, 134703. Figure 1. (a) Free energy profile (top) and Bader charge analysis (bottom) for CO2 adsorption along SG-AIMD in Au(110)-42H2O-2K+. The dashed red lines represent the key intermediates with the CV of 2.74 (transition state, TS), and 2.12 Å (final state), respectively. (b) The key structures during CO2 adsorption, including the initial state (Initial), TS, and final state (Final). Color code: Au, golden; K, purple; C, blue; O, red; H, white. Figure 1

Gli stili APA, Harvard, Vancouver, ISO e altri

22

Qian, Yi, Kangjia Jiang e Long Li. "Improving the flame retardancy of ethylene vinyl acetate composites by incorporating layered double hydroxides based on Bayer red mud". e-Polymers 19, n. 1 (29 maggio 2019): 129–40. http://dx.doi.org/10.1515/epoly-2019-0015.

Testo completo

Abstract (sommario):

AbstractNowadays, reducing the hazards of bayer red mud (BRM) is an important research direction in the fields of environmental and safety. In this article, Mg/Al/Fe ternary layered double hydroxides (Mg/Al/Fe-LDHs) were synthesized successfully by a co-precipitation method based on introducing Mg2+ into the BRM suspension. The thermogravimetric analysis (TGA) results showed that the decomposition rate of LDHs is higher than that of BRM, which indicates that LDHs can absorb more heat than BRM during the decomposition process. Subsequently, BRM and LDHs were added into the ethylene vinyl acetate (EVA) to investigate its effects on reducing flammability of the composites. The cone calorimeter test (CCT) results demonstrated that 50 wt% LDH-B can make the peak value of HRR (PHRR) decrease from 1694.8 kW/m2 (EVA) to 199.2 kW/m2 (ELDH2). The smoke density test (SDT) results showed that the luminous flux of ELDH2 is nearly 95% at the end of test with a pilot flame, which is much higher than that of EVA and EBRM. The thermogravimetry-Fourier transform infrared spectrometry (TG-FTIR) results confirmed that LDHs can improve the thermal stability of composites and reduce the production of some toxic gases. Compared with BRM, the improved flame retardancy of Mg/Al/Fe-LDHs is ascribed to the introduction of Mg2+, which offering an enhanced catalytic carbonization capability, as well as the physical barrier effect of char residue layer catalyzed by the lamellar LDHs

Gli stili APA, Harvard, Vancouver, ISO e altri

23

Ohmachi, Ken, Tomohiro Kinoshita, Kensei Tobinai, Gakuto Ogawa, Tomonori Mizutani, Nobuhiko Yamauchi, Noriko Fukuhara et al. "Randomized Phase II/III Study of Standard R-CHOP Versus CHOP Combined with Dose-Dense Weekly Rituximab (RW-CHOP) for Previously Untreated DLBCL: JCOG0601". Blood 132, Supplement 1 (29 novembre 2018): 4194. http://dx.doi.org/10.1182/blood-2018-99-110201.

Testo completo

Abstract (sommario):

Abstract Background: CHOP plus rituximab (R-CHOP) is the standard of care for previously untreated DLBCL. R-CHOP comprises CHOP and one-dose rituximab in each 21-day cycle; however, the schedule of rituximab administration has not been fully optimized. Dose-dense rituximab was expected to increase its peak concentration to enhance the synergistic effect with chemotherapy at early phase of treatment. To compare weekly administration of rituximab combined with CHOP (RW-CHOP) with standard R-CHOP in patients with previously untreated DLBCL, we conducted a multicenter, randomized phase II/III study (JCOG0601, UMIN000000929). Methods: Previously untreated patients with CD20+ DLBCL were eligible. Other major inclusion criteria were as follows: aged 20-79 years; ECOG performance status 0-2, at least 1 measurable lesion and preserved organ functions. At the beginning of the study, patients with advanced stage disease and the low or low-intermediate risk group by the International Prognostic Index (IPI) were eligible. These criteria were amended in September 2010 to allow enrollment of the patients with any IPI risk and any clinical stage because of slow accrual. Patients were randomly assigned to standard R-CHOP (rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [max 2 mg], all IV on day 1, and prednisone 100 mg/day PO [40mg/m2 for aged >65] on days 1-5, every 3 weeks) or RW-CHOP (standard CHOP with eight doses of weekly rituximab [375mg/m2 IV on days1, 8, 15, 22, 29, 36, 43 and 50]). Six cycles of CHOP were given in stage I non-bulky patients, 8 cycles were given in stage I bulky and II-IV patients, and rituximab was given 8 times regardless of cycles of CHOP. Randomization was stratified by institution, presence or absence of bulky mass and patient age. The primary endpoint of phase III part was progression-free survival (PFS). Secondary endpoints included overall survival (OS) and adverse events (AE). Assuming 3-year PFS in the R-CHOP arm to be 77% and expecting a 7% increase in 3-year PFS of the RW-CHOP arm, required sample size was 211 per arm with a one-sided alpha of 5%, power of 80%, an accrual period of 7 years, and a follow-up period of 3 years. Results: Between December 2007 and December 2014, a total of 422 patients were randomized to study treatments but primary analysis was performed in 421 patients: 213 to the R-CHOP arm and 208 to the RW-CHOP arm, because of one consent withdrawal. Baseline characteristics of 421 eligible patients were as follows (R-CHOP vs. RW-CHOP): median age, 61 vs. 62 years; male sex, 54.5% vs. 55.8%; Ann Arbor stage I/II/III/IV, 14.6/32.9/26.8/25.8% vs. 16.3/42.8/20.2/20.7%; and IPI score ≤2, 77.0% vs. 87.5%. With a median follow-up of 63.4 months (range: 3.2-119.2) among all patients, there was no significant difference in PFS between the arms (hazard ratio [HR], 0.95; 90.6% confidence interval [CI], 0.68 to 1.31; one-sided log-rank P = 0.39). The 3-year PFS and OS were 79.2% and 88.7% with the R-CHOP arm and 80.3% and 90.4% with the RW-CHOP arm, respectively. The complete response rate and overall response rate were 77.0% and 93.0% in the R-CHOP arm and 82.2% and 91.8% in the RW-CHOP arm, respectively. Major AEs were hematological toxicities and infections. Grade (G) 3/4 neutropenia and G 3/4 thrombocytopenia were observed in 97.7% and 8.0% in the R-CHOP arm and 97.1% and 5.3% in the RW-CHOP arm, respectively. G3 febrile neutropenia was occurred in 33.8% in the R-CHOP arm and in 22.1% in the RW-CHOP arm. The frequency of severe AE was 2.3% in the R-CHOP arm and 3.8% in the RW-CHOP arm. Safety profile was comparable. No unexpected AEs were experienced. Conclusion: In combination of standard CHOP and rituximab, dose-dense weekly rituximab at early phase of treatment did not improve the PFS in patients with untreated DLBCL. Figure. Figure. Disclosures Ohmachi: Celgene: Honoraria; Takeda Pharmaceutical Co., Ltd,: Honoraria; Pfizer: Honoraria; Chugai Pharma: Honoraria; Kyowa Hakko Kirin: Honoraria; Eisai: Honoraria; Janssen: Honoraria; Meiji Pharma: Honoraria. Kinoshita:Takeda: Honoraria; Takeda: Research Funding; Ono: Research Funding; MSD: Research Funding; Solasia: Research Funding; Janssen: Honoraria; Ono: Honoraria; Zenyaku: Research Funding; Eisai: Research Funding; Gilead: Research Funding. Tobinai:Kyowa Hakko Kirin: Honoraria, Research Funding; Zenyaku Kogyo: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA Bioscience International: Consultancy, Honoraria; SERVIER: Research Funding; Abbvie: Research Funding. Fukuhara:Sumitomo Dainippon: Research Funding; Solasia: Research Funding; Symbio: Research Funding; Sanofi: Research Funding; Pfizer: Research Funding; Otsuka Pharmaceutical: Research Funding; Ono: Honoraria, Research Funding; Novartis pharma: Research Funding; Nippon-shinyaku: Research Funding; MSD: Research Funding; Mundipharma: Honoraria, Research Funding; Mitsubishi Tanabe: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Japan Blood Products Organization: Research Funding; Janssen: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Eisai: Honoraria, Research Funding; Boehringer Ingelheim: Research Funding; Daiichi-Sankyo: Research Funding; Chugai: Research Funding; Celgene: Research Funding; Baxalta: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bayer Yakuhin: Research Funding; Alexionpharma: Research Funding; AbbVie: Research Funding; Astellas: Research Funding; Nihon Ultmarc: Research Funding; Taiho: Research Funding; Teijin Pharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Takeda: Honoraria. Uchida:Takeda Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa Hakko Kirin: Honoraria; Meiji Seika Pharma: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Teijin: Honoraria; Celgene: Honoraria; Mundipharma: Honoraria; Janssen Pharma: Honoraria; Otsuka Pharmaceutical: Honoraria; Eisai: Honoraria. Yamamoto:Solasia Pharma: Research Funding; Bristol-Myers Squibb: Honoraria; Novartis: Honoraria, Research Funding; ARIAD Pharmaceuticals: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Consultancy, Honoraria, Research Funding; AbbVie: Research Funding; Boehringer Ingelheim: Consultancy; Chugai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy; MSD: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku: Research Funding; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; Mundipharma: Consultancy, Honoraria; HUYA: Honoraria; SymBio: Research Funding; Gilead Sciences: Research Funding. Miyazaki:Kyowa Hakko Kirin,: Honoraria, Research Funding; Celgene: Honoraria; Chugai Pharma,: Honoraria, Research Funding; Sumitomo Group: Research Funding; Nippon Shinyaku: Research Funding; Takeda: Research Funding; Astellas Pharma: Research Funding; Shionogi Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eisai: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Teijin Pharma: Research Funding; Ono Pharmaceutical: Research Funding; Toyama Chemical Co: Research Funding; Mochida Pharmaceutical Co. Ltd.: Research Funding; Novo Nordisk: Research Funding. Tsukamoto:Kyowa-Kirin: Research Funding; Pfizer: Research Funding; Chugai: Research Funding; Eisai: Research Funding. Iida:Teijin Pharma: Research Funding; Toyama Chemical: Research Funding; Ono: Consultancy, Honoraria, Research Funding; Kyowa-Hakko Kirin: Research Funding; Chugai: Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Astellas: Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Gilead: Research Funding; MSD: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Sanofi: Consultancy. Yoshida:Taiho Pharma: Honoraria; Takeda Pharma: Honoraria; Celegene: Honoraria; Chugai Pharma: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding. Masaki:Ono: Research Funding; Kyowa Hakko Kirin: Research Funding; Phizer: Research Funding; Astellas: Research Funding; Eisai: Research Funding. Yakushijin:Mundipharma Co.,: Research Funding; Chugai Co.,: Research Funding; Kyowa-kirin Co.,: Research Funding; Merch Sharp & Dohme Corp.,,: Research Funding; Daiichi-Sankyo Inc.,: Research Funding; Eisai Co.: Research Funding. Suehiro:Kyowa Hakko Kirin: Research Funding; Ono Pharmaceutical: Research Funding; Chugai Pharmaceutical: Research Funding; Takeda Pharmaceutical: Research Funding. Nosaka:Bristol-Myers Squibb: Honoraria; Ono Pharmaceutical Co.LTD.: Honoraria; Eisai Co. Ltd.,: Honoraria; Kyowa Kirin Pharmaceutical Development, Inc.,: Honoraria; Chugai Pharmaceutical Co.LTD.,: Honoraria; Celgene Co. LTD.,: Honoraria. Dobashi:Celgene Co.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co. Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Inc.: Research Funding; Sysmex Co.: Research Funding. Kuroda:Chugai Pharma: Honoraria, Research Funding. Takamatsu:Taisho Toyama Pharmaceutical: Research Funding; TAIHO Pharmaceutical: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Kyowa Hakko Kirin: Research Funding; Chugai Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Celgene: Honoraria. Maruyama:Ono Pharmaceutical: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Asahi Kasei Pharma: Honoraria; AstraZeneca: Research Funding; Solasia Pharma: Research Funding; Pfizer: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Dai-Nippon-Sumitomo: Honoraria; Dai-ichi-Sankyo: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Novartis: Research Funding; Otsuka: Research Funding; Amgen Astellas BioPharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; Abbvie: Research Funding; Astellas Pharma: Research Funding; Mundipharma International: Honoraria, Research Funding. Ando:Eisai: Research Funding; Meiji Seika Pharma: Research Funding; Takeda Pharmaceutical: Research Funding; Kyowa Hakko Kirin: Research Funding; Japan Blood Products Organization: Research Funding. Ishizawa:Eisai: Honoraria; Janssen: Honoraria; Chugai: Honoraria; Celgene: Honoraria; Otsuka: Research Funding; Sanofi: Research Funding; Phizer: Research Funding. Ogura:Celltrion: Consultancy, Research Funding; Mundi Pharma: Consultancy; SymBio: Research Funding; Takeda: Honoraria; Cellgene: Honoraria; MeijiSeika Pharma: Consultancy. Hotta:SymBio: Consultancy; CellSeed Inc.: Membership on an entity's Board of Directors or advisory committees. Tsukasaki:Celgene: Honoraria; Eisai: Research Funding; Chugai Pharma: Honoraria, Research Funding; HUYA: Consultancy, Research Funding; Ono Pharma: Consultancy; Daiich-Sankyo: Consultancy; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Nagai:HUYA Bioscience International: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Gilead Sciences Inc.: Honoraria, Research Funding; Bayer Yakuhin Ltd.: Research Funding; Sanofi K. K.: Honoraria; Zenyaku Kogyo Co., Ltd.: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Roche Ltd.: Honoraria; Esai Co., Ltd.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; SymBio Pharmaceuticals Limited: Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Mundipharma K.K.: Honoraria, Research Funding; AstraZeneca plc.: Research Funding; Abbvie G. K.: Research Funding.

Gli stili APA, Harvard, Vancouver, ISO e altri

24

Bajdich, Michal, Karun K. Rao, Lan Zhou, Junko Yano e John M. Gregoire. "Photo-Electrochemical Oxygen Evolution Activity in Nickel and Cobalt Antimonates". ECS Meeting Abstracts MA2023-01, n. 37 (28 agosto 2023): 2125. http://dx.doi.org/10.1149/ma2023-01372125mtgabs.

Testo completo

Abstract (sommario):

Renewable generation of fuels via solar energy offers promising pathways towards sustainable energy future. Its deployment hinges on the discovery of electrochemically durable materials with good solar-to-chemical conversion efficiency. Necessary visible spectrum photoresponse from electrochemically stable materials is however quite rare. On the other hand, the oxygen evolution reaction (OER) requires electrodes that are not only catalytically active, but also stable under harsh electrochemical environments. In this talk, we report on and theoretical understanding of photo-electrochemical behavior an amorphous and crystaline versions of Ni-Sb-Ox and Co-Sb-Ox oxide photoanodes discovered via high-throughput experimental screening [1,2]. The newly discovered amorphous phases meet the requirements of operational stability, visible photoresponse, and appreciable photovoltage. Guided by experimental X-ray absorption characterization of these systems we use density functional theory calculations to perform a prototype phase search to identify a broad family of stable and metastable mixed rutile and hexagonal-like phases for other compositions [3]. Detailed Pourbaix analysis of the identified phases show excellent electrochemical stability, consistent with experimentally measured electrolyte concentrations of photoelectrochemical cells. We analyze when he identified phases form favorable oxygen vacancies formation energies under the reducing synthesis conditions which match measured Ni K-edge x-ray absorption spectra. The calculated OER overpotentials for the most active sites decreases with increasing Ni/Co content, which captures the experimentally observed trend. Stable amorphous metal-antimonates photoanodes are important systems for computational understanding of both the structural and catalytic behavior of these complex oxides and elucidating the co-optimization of photo-electrochemical activity and durability. This material is based on work performed by the Liquid Sunlight Alliance, which is supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, Fuels from Sunlight Hub under award DE-SC0021266. [1] Zhou, L., Peterson, E. A., Rao, K. K., Lu, Y., Li, X., Lai, Y., Bauers, S. R., Richter, M. H., Kan, K., Wang, Y., Newhouse, P. F., Yano, J., Neaton, J. B., Bajdich, M., & Gregoire, J. M. Addressing solar photochemistry durability with an amorphous nickel antimonate photoanode. Cell Reports Physical Science, 3(7), 100959. (2022). [2] Zhou, L., Wang, Y., Kan, K., Lucana, D. M., Guevarra, D., Lai, Y., & Gregoire, J. M. Surveying Metal Antimonate Photoanodes for Solar Fuel Generation. ACS Sustainable Chemistry and Engineering, 21, 33. (2022). [3] Rao, K. K., Zhou, L., Lai, Y., Richter, M. H., Li, X., Lu, Y., Yano, J., Gregoire, J. M. Bajdich, M., Resolving Atomistic Structure and Oxygen Evolution Activity in Nickel Antimonates, (under review).

Gli stili APA, Harvard, Vancouver, ISO e altri

25

Murata, Makoto, Yoshinobu Maeda, Masayoshi Masuko, Yasushi Onishi, Tomoyuki Endo, Seitaro Terakura, Yuichi Ishikawa et al. "Intrabone Transplantation of a Single Cord Blood Unit Using Non-Irradiated Reduced-Intensity Conditioning". Blood 128, n. 22 (2 dicembre 2016): 3390. http://dx.doi.org/10.1182/blood.v128.22.3390.3390.

Testo completo

Abstract (sommario):

Abstract Introduction: Cord blood transplantation (CBT) is a treatment option for patients with hematological disorder. Recent development of reduced-intensity conditioning (RIC) allows elderly patients and those with comorbidities to benefit from CBT. However, RIC-CBT has not been optimized in part due to graft failure or delayed engraftment. Intrabone infusion of cord blood cells has the potential to ensure engraftment and shorten the time of hematological recovery (Lancet Oncol 2008;9:831-9). The aim of this phase II study was to examine the efficacy and safety of intrabone transplantation of a single cord blood unit using non-irradiated RIC. Patients and Methods: Patients were eligible for the study if they had hematological malignancy, needed CBT, were ≥55 years or 16 to 54 years with hematopoietic stem cell transplantation-specific comorbidity index ≥1, and had an available cord blood unit with serological HLA-A, B, and DR ≥4/6 match and with cryopreserved total nucleated cells (TNCs) at least 2×107/kg. Cord blood units were thawed, washed with a saline solution plus dextran and human albumin, resuspended in approximately 10 ml of the solution, and aliquoted in two to four syringes. After local anesthesia, standard bone marrow aspiration needles were inserted into iliac bone. Approximately 5 ml of cord blood cell suspension was gently infused. This procedure was repeated for all the remaining aliquots across the iliac crest. All patients received tacrolimus and short-term methotrexate as graft-versus-host disease (GVHD) prophylaxis and granulocyte colony-stimulating factor after transplantation. The primary endpoint was the probability of survival with neutrophil engraftment on day 60 after transplantation. This study was approved by the ethical committee of each institute. Results: Of the 22 enrolled patients, one was not assessable because the patient did not receive intrabone CBT due to the worsening of general condition after the enrollment. The age of 21 evaluable patients ranged 38 to 66 years (median, 57 years). The diagnosis included leukemia (n = 14), lymphoma (n = 6), and myelodysplastic syndromes (n = 1). All patients received fludarabine 150 to 180 mg/m2 and cyclophosphamide 60 to 120 mg/kg with the exception of a patient who received fludarabine 125 mg/m2 and melphalan 140 mg/m2. The number of cryopreserved TNCs ranged 2.0 to 4.9×107/kg (median, 2.7×107/kg), and the number of cryopreserved CD34 positive cells ranged 0.44 to 3.14×105/kg (median, 0.92×105/kg). Mild swelling of skin at the injection site was observed in one patient, however it resolved spontaneously. No other complications occurred during or after the intrabone infusion of cells. The cumulative incidences of neutrophil (≥0.5×109/L), reticulocyte (≥1%), platelet (≥20×109/L) recoveries were 76.2%, 71.4%, and 76.2%, respectively. For those who achieved hematopoietic recovery, the median time to neutrophil, reticulocyte, and platelet recoveries were 17 days, 28 days, and 32 days, respectively. One patient died of veno-occlusive disease on day 42 with achievement of neutrophil recovery. Accordingly, the probability of survival with neutrophil engraftment on day 60 after transplantation (primary endpoint) was 71.4% (95%CI, 51.8 to 88.3%). Of evaluable 16 patients, seven (43.8%) and three (18.8%) developed grade II-IV and III-IV acute GVHD, respectively. No patients developed chronic GVHD. There was a significant difference in the incidence of neutrophil recovery between patients receiving ≤2.7×107/kg TNCs (n = 11) and those receiving >2.7×107/kg TNCs (n = 10) (55% vs. 100%, P = 0.035). Meanwhile, there was a significant difference in the time to neutrophil recovery between patients receiving ≤0.92×105/kg CD34 positive cells (n = 11) and those receiving >0.92×105/kg CD34 positive cells (n = 10) (median, 18 days vs. 16 days; range, 16 to 25 days vs. 14 to 19 days; P= 0.014). Overall survival at 1 year after transplantation was 52.4% (95%CI, 29.7 to 70.9%). Conclusion: The present data suggest that intrabone transplantation of a single cord blood unit using non-irradiated RIC provides an opportunity for patients who are unable to be exposed to irradiation at the time of pre-transplant conditioning for several reasons, including preservation of fertility, and exposure to the upper limit of irradiation before transplantation, to receive RIC-CBT. Further studies in a larger series of patients are required. Disclosures Maeda: Mundipharma KK: Research Funding. Onishi:SymBio Pharmaceuticals: Research Funding. Matsushita:KaketsuKen: Honoraria, Research Funding; Bayer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Biogen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novo Nordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Baxalta: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; CSL Behring: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; JB: Honoraria, Research Funding; Octapharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kiyoi:Yakult Honsha Co.,Ltd.: Research Funding; AlexionpharmaLLC.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Novartis Pharma K.K.: Research Funding; Phizer Japan Inc.: Research Funding; JCR Pharmaceutlcals Co.,Ltd.: Research Funding; Mochida Pharmaceutical Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Toyama Chemikal Co.,Ltd.: Research Funding; Alexion Pharmaceuticals: Research Funding; Zenyaku Kogyo Co.LTD.: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Celgene Corporation: Consultancy; Chugai Pharmaceutical Co. LTD.: Research Funding; Kyowa-Hakko Kirin Co.LTD.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Astellas Pharma Inc.: Consultancy, Research Funding; Eisai Co., Ltd.: Research Funding; MSD K.K.: Research Funding. Naoe:TOYAMA CHEMICAL CO.,LTD.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Pfizer Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Celgene K.K.: Honoraria, Research Funding; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; CMIC Co., Ltd.: Research Funding; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Astellas Pharma Inc.: Research Funding.

Gli stili APA, Harvard, Vancouver, ISO e altri

26

Leick, Mark B., Harrison Silva, Irene Scarfò, Rebecca Larson, Bryan D. Choi, Amanda A. Bouffard, Kathleen M. E. Gallagher et al. "Rational Chemical and Genetic Modifications Enhance Avidity and Function of CD70-Directed CAR-T-Cells for Myeloid Leukemia". Blood 138, Supplement 1 (5 novembre 2021): 405. http://dx.doi.org/10.1182/blood-2021-150596.

Testo completo

Abstract (sommario):

Abstract Chimeric Antigen Receptor T cells (CAR-T) have changed the therapeutic landscape for lymphoid malignancies, but not yet in myeloid malignancies like acute myeloid leukemia (AML). The TNF-alpha family member CD70 has emerged as a promising surface target antigen in AML after high complete response rates (CR) were seen in a Phase 1 trial of the CD70 antibody cusatuzumab (Riether et al, Nature Medicine 2020). Disappointingly, phase II results with cusatuzumab found CR rates less one-half those seen in the phase 1 (Trudel ASCO 2020). Because CAR-T cells may recognize lower antigen densities than monoclonal antibodies, we sought to develop a better CAR-T strategy for targeting the CD70 antigen in AML. A recent effort to improve on the 'first' generation natural-ligand based CD70 CAR (full length-CD27 fused to CD3zeta) compared a variety of CARs, including the single-chain variable-fragment as the binding moiety to CD70, found that the original 'first' generation CAR was superior (Shaffer Blood 2011, Sauer Blood 2021). Interestingly, a second generation natural-ligand based CAR that included the 4-1BB costimulatory domain was thought to be superior to first-generation (zeta-only) CARs with the same binder (Wang Clinical Cancer Research 2016). We first confirmed that the ligand-based 4-1BB (Native) CAR, had activity against multiple AML targets in standard CAR-T assays including activation, cytolysis, and demonstrated activity in a NOD-SCID IL2R γnull (NSG) Molm13 mouse model of AML. However, these models were not curative, even in combination with azacitidine, which we confirmed mediated increase CD70 expression on the AML cells. We hypothesized that surface cleavage of CD27, which is the natural ligand of CD70, attenuated the function of the Native CARs; we confirmed this hypothesis by measuring soluble CD27 in CAR T cells co-cultured with AML targets. To abrogate surface cleavage of ligand-based CARs, we generated and tested a panel of rationally designed, novel hinge CAR variants ('truncated', 'deleted', 'flexible', and 'CD8hinge&TM', Figure 1A). We found that the CD8hinge&TM variant had improved cytolysis against AML targets in vitro as well as higher binding avidity as measured by acoustic force microscopy (Figure 1B). Furthermore, there was no detectable soluble CD27 after co-culture with AML targets, suggesting successful abrogation of hinge cleavage. When all the CAR variants were compared in vivo to the Native CAR, CD8hinge&TM CARs mediated improved tumor control, had higher CAR expansion in blood and bone marrow, a persistent central memory phenotype beyond 30 days, and mediated improved survival (Figure 1C). The effect of the CD8hinge&TM CARs was further enhanced in combination with azacitidine. We also found that tumor control (maximum flux) correlated most strongly with relative binding avidity of the hinge variants (R 2 0.906) compared to other measures of in vitro function such as IFNg production (R 2 0.548) or in vitro cytolysis (R 2 0.5982). Finally, we tested the Native and CD8hinge&TM CARs in patient-derived xenograft (PDX) models and confirmed that the Native CAR T cells did not control AML tumor and resulted in uniform lethality, whereas the CD8hinge&TM CAR T cells had superior in vivo expansion and were able to mediate AML eradication in mice. Our findings demonstrate that natural-ligand binding domains of CARs targeting CD70 in AML can be effective but require mechanisms to overcome surface cleavage. CD70-targeted CARs comprised of a fusion of truncated CD27 to a CD8 hinge and transmembrane domain have promise in patients with AML, with and without combination with azacitidine. Figure 1 Figure 1. Disclosures Wehrli: Novartis: Current equity holder in publicly-traded company; Nestle: Current equity holder in publicly-traded company; CSL Behring: Patents & Royalties. Frigault: Editas: Consultancy; Takeda: Consultancy; Iovance: Consultancy; Arcellx: Consultancy; Kite: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy. Maus: Astellas: Consultancy; Arcellx: Consultancy; Agenus: Consultancy; Adaptimmune: Consultancy; tcr2: Consultancy, Divested equity in a private or publicly-traded company in the past 24 months; century: Current equity holder in publicly-traded company; ichnos biosciences: Consultancy, Current holder of stock options in a privately-held company; AstraZeneca: Consultancy; Atara: Consultancy; Bayer: Consultancy; BMS: Consultancy; Cabaletta Bio (SAB): Consultancy; CRISPR therapeutics: Consultancy; In8bio (SAB): Consultancy; Intellia: Consultancy; GSK: Consultancy; Kite Pharma: Consultancy, Research Funding; Micromedicine: Consultancy, Current holder of stock options in a privately-held company; Novartis: Consultancy; Tmunity: Consultancy; Torque: Consultancy, Current holder of stock options in a privately-held company; WindMIL: Consultancy.

Gli stili APA, Harvard, Vancouver, ISO e altri

27

Yasaka, Masahiro, Hiroshi Inoue, Yohko Kawai, Takenori Yamaguchi, Shinichiro Uchiyama, Masayasu Matsumoto, Satoshi Ogawa, Yukihiro Koretsune e Takeshi Yamashita. "Asymptomatic Intracranial Hemorrhage Among Japanese Patients Taking Edoxaban for Non-Valvular Atrial Fibrillation." Blood 114, n. 22 (20 novembre 2009): 1066. http://dx.doi.org/10.1182/blood.v114.22.1066.1066.

Testo completo

Abstract (sommario):

Abstract Abstract 1066 Poster Board I-88 Introduction: Edoxaban (the free base of DU-176b) is an oral, selective, reversible, direct factor Xa inhibitor in clinical development for the prevention of stroke in patients with non-valvular atrial fibrillation (AF). There is evidence that asymptomatic intracranial hemorrhage (ICH) may be a risk factor for symptomatic ICH in anticoagulated patients. A phase IIb study in Japanese AF patients compared the incidence of asymptomatic ICH with edoxaban and warfarin use. Patients and Methods: This was a multicenter, randomized, dose comparison study. Patients aged ≥20 years with CHADS2 score ≥1 were randomly assigned to receive 1 of 3 doses of edoxaban (30 mg, 45 mg, or 60 mg QD) or open-label warfarin dose-adjusted to a target international normalized ratio (INR) of 2.0 to 3.0 inclusive for patients aged <70 years and 1.6 to 2.6 inclusive for patients aged ≥70 years, for 12 weeks. The primary objective of the study was to assess the incidence of all bleeding events (major, clinically relevant non-major and minor bleeds) including asymptomatic ICH. Asymptomatic ICH was defined as newly detected hemorrhage on brain image (CT or MRI) by assessing pre- and post-treatment brain images and was obtained from all enrolled patients. All images were assessed by an Asymptomatic ICH Committee that was blinded to treatment assignment. Results: There were no clinically relevant differences in patient demographics and baseline characteristics between treatment groups. Overall, the time within the target INR range was 83% and 73% for patients aged ≥70 years and aged <70 years, respectively. The incidence of all bleeding events increased with increasing doses of edoxaban, but there were no statistically significant differences among the 3 edoxaban groups. The mean (95% confidence interval) incidences of all bleeding for edoxaban 30 mg, 45 mg, and 60 mg, and warfarin were 18.5% (12.7, 26.0), 22.4% (16.2, 30.2), 27.7% (20.7, 35.9), and 20.0% (13.9, 27.9), respectively. Of the total 536 patients enrolled, 17 patients did not fulfill the assessment criteria for asymptomatic ICH. Of the 17 patients, 1 patient in the edoxaban 60-mg group had symptomatic ICH. The remaining 519 (391 edoxaban, 128 warfarin) patients were evaluated for asymptomatic ICH. A total of 431 patients underwent CT (329 edoxaban, 102 warfarin), 81 patients underwent MRI (57 edoxaban, 24 warfarin), and 7 patients underwent CT/MRI (5 edoxaban, 2 warfarin). There were no asymptomatic ICH events in any treatment group. Conclusions: In this study of 3 fixed doses of edoxaban compared with well-controlled warfarin, edoxaban was safe and asymptomatic ICH was not detected. Disclosures: Yasaka: Nippon Boehringer lngelheim Co., Ltd.: Consultancy; Pfizer Japan Inc.: Consultancy; Daiichi Sankyo Co., LTD.: Consultancy. Kawai:Toyama Chemical: Consultancy; DaiichiSankyo: Consultancy. Yamaguchi:Mitsubishi Tanabe Pharma: Consultancy; Otsuka Pharmaceutical: Consultancy. Uchiyama:Bayer Yakuhin, LTD. : Consultancy; Nippon Boehringer lngelheim Co., Ltd.: Consultancy; Astellas Pharma Inc.: Consultancy. Ogawa:TEIJIN PHARMA LIMITED: Consultancy; Pfizer Japan Inc.: Consultancy; Bayer Yakuhin, LTD.: Consultancy; Astellas Pharma : Share Holder; Sanofi-aventis : Paid Instructor. Koretsune:Daiichi Sankyo: Consultancy, National Lead Investigator. Yamashita:Novartis: Consultancy; DaiichiSankyo: Consultancy, National Lead Investigator; Otsuka Pharmaceutical: Paid Instructor; Sanofi-aventis: Paid Instructor; TEIJIN PHARMA: Paid Instructor.

Gli stili APA, Harvard, Vancouver, ISO e altri

28

Crowley, P. J. "Book Review: Synthesis and chemistry of agrochemicals IV, ed. Don R. Baker, Joseph G. Fenyes & Gregory S. Basarab, American Chemical Society, Washington DC, 1995, xiv+490 pp., price US$129.95. ISBN 0 8412 3091 9". Pesticide Science 48, n. 1 (settembre 1996): 100. http://dx.doi.org/10.1002/(sici)1096-9063(199609)48:1<100::aid-ps439>3.0.co;2-n.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

29

Chaplin, M. F. "Book Review: Capillary electrophoresis. By Dale R. Baker, John Wiley & Sons, Inc., New York, 1995, 244 pp., price UK £40.00. ISBN 0 471 11763 3". Journal of Chemical Technology & Biotechnology 71, n. 4 (aprile 1998): 370. http://dx.doi.org/10.1002/(sici)1097-4660(199804)71:4<370::aid-jctb828>3.0.co;2-f.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

30

Mandato, Elisa, Qingsheng Yan, Jing Ouyang, Julia Paczkowska, Yan Qin, Yansheng Hao, Kamil Bojarczuk, Julia Hansen, Lee N. Lawton e Margaret A. Shipp. "MYD88 L265P Augments Proximal B-Cell Receptor Signaling in Large B-Cell Lymphomas Via an Interaction with DOCK8". Blood 138, Supplement 1 (5 novembre 2021): 1324. http://dx.doi.org/10.1182/blood-2021-153024.

Testo completo

Abstract (sommario):

Abstract Diffuse large B-cell lymphoma (DLBCL) is a genetically heterogeneous disease comprised of five subtypes including a subset of poor-prognosis activated B cell (ABC)-enriched tumors with frequent MYD88L265P mutations, often in association with CD79B alterations (Cluster 5 DLBCLs) (Nat. Med. 2018; 24:679-690). Primary central nervous system lymphomas (PCNSLs) and primary testicular lymphomas (PTLs) have similar genetic signatures including recurrent MYD88L265P mutations and concurrent CD79B alterations (Blood 2016; 127: 869-81). These findings prompted us to evaluate a potential role for MYD88L265P in proximal B-cell receptor (BCR) signaling, in addition to its defined function as an intermediary in the Toll-Like Receptor (TLR) pathway and downstream NF-kB activation. In previous studies by Jabara et al., wild-type (WT) MYD88 was found to be constitutively associated with the DOCK8 adapter and the PYK2 tyrosine kinase in normal B-cells (Nat. Immunol. 2012; 13:612-20). In this setting, physiologic ligation of TLR9 with CpG oligodeoxynucleotides (CpG) induced PYK2-mediated phosphorylation of DOCK8, recruitment of Src kinases, including LYN, and downstream activation of the proximal BCR pathway member, spleen tyrosine kinase (SYK) (Nat. Immunol. 2012; 13:612-20). We postulated that mutated MYD88L265P might similarly augment proximal BCR signaling in DLBCLs in the absence of physiologic (CpG-induced) TLR9 signaling. Using three DLBCL cell lines (OCI-Ly1, SU-DHL4 and OCI-Ly7) with intact BCR signaling and WT endogenous MYD88 and CD79B, we first established that physiologic CpG activation of TLR signaling induced the phosphorylation of PYK2 and the proximal BCR signaling components, SYK and Bruton's tyrosine kinase (BTK). Thereafter, we genetically engineered these three DLBCL cell lines to express MYD88 L265P or MYD88 WT, alone or in association with CD79B Y196F. In all three cell lines, the co-expression of MYD88 L265P and CD79B Y196F significantly increased magnitude and duration of SYK and BTK phosphorylation following BCR crosslinking. These findings highlight the likely role of MYD88L265P in CD79BY196F-associated proximal BCR signaling in DLBCL. To elucidate the potential role of the DOCK8 adapter in MYD88 L265P-augmented BCR signaling, we first assessed the colocalization of MYD88 WT or MYD88 L265P with DOCK8 in the same three genetically engineered DLBCL cell lines using proximity ligation assays (PLA), which detect protein-protein interactions at less than 40 nm in situ. In each of these cell lines, we detected significantly increased co-localized MYD88 L265P/DOCK8 signals in comparison to MYD88 WT/DOCK8 signals (p<.0001, all). Additionally, there were significantly increased co-localized DOCK8/LYN signals in DLBCL cell lines that expressed MYD88 L265P rather than MYD88 WT (p<.0001, all). These data provide the first direct evidence of an enhanced association between MYD88 L265P, DOCK8 and LYN in BCR-dependent DLBCLs and a basis for enhanced BCR signaling in primary tumors with concurrent MYD88L265P and CD79B genetic alterations. We next analyzed the consequences of MYD88 L265P-associated, DOCK8-dependent increased proximal BCR signaling by depleting DOCK8 in BCR-dependent DLBCL cells with endogenous MYD88L265P/CD79BY196F alterations (HBL1 and TMD8) or endogenous unmutated MYD88 WT/CD79B WT (OCI-Ly1 and SU-DHL4). ShRNA-mediated DOCK8 knockdown (KD) significantly decreased BCR-mediated phosphorylation of SYK and BTK in MYD88L265P/CD79BY196F DLBCL cell lines but not in lines with MYD88 WT/CD79B WT, highlighting the specific role of DOCK8 in MYD88 L265P-associated proximal BCR signaling. Of great interest, DOCK8 KD selectively decreased the proliferation of MYD88L265P/CD79BY196F, but not MYD88WT/CD79BWT, DLBCLs (p<.004, HBL1 and p<.009, TMD8; p = non sig., OCI-Ly1 and SU-DHL4). Additionally, DOCK8 KD significantly increased the efficacy of chemical PI3Kα/δ (copanlisib) and BTK (ibrutinib) inhibition in MYD88L265P/CD79BY196F DLBCLs (HBL1 and TMD8). Taken together, these data identify DOCK8 as an intermediary in MYD88L265P-driven proximal BCR signaling and a possible treatment target in LBCLs with co-occurring MYD88L265P/CD79BY196F mutations. Disclosures Shipp: AstraZeneca: Consultancy, Research Funding; Immunitas Therapeutics: Consultancy; Bristol Myers Squibb: Research Funding; Merck: Research Funding; Bayer: Other: Institution: Research Grant/Funding; Abbvie: Other: Institution: Research Grant/Funding.

Gli stili APA, Harvard, Vancouver, ISO e altri

31

Nicolaou, K. C., Markus Follmann, A. J. Roecker e Kevin W. Hunt. "Model Studies Towards Azadirachtin: Part 1. Construction of the Crowded C8bC14 Bond by Radical Chemistry We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), the Skaggs Institute for Chemical Biology, postdoctoral fellowships from Bayer AG (to M.F.) and the G. E. Hewitt Foundation (to K.W.H.), a predoctoral fellowship from the Division of Organic Chemistry of the American Chemical Society sponsored by Novartis (to A.J.R.), and grants from Abbott Laboratories, ArrayBiopharma, Bayer, Boehringer Ingelheim, DuPont, Glaxo, Hoffmann-LaRoche, Merck, Novartis, Pfizer, and Schering Plough." Angewandte Chemie 114, n. 12 (17 giugno 2002): 2207. http://dx.doi.org/10.1002/1521-3757(20020617)114:12<2207::aid-ange2207>3.0.co;2-z.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

32

Nicolaou, K. C., Markus Follmann, A. J. Roecker e Kevin W. Hunt. "Model Studies Towards Azadirachtin: Part 1. Construction of the Crowded C8bC14 Bond by Radical Chemistry We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), the Skaggs Institute for Chemical Biology, postdoctoral fellowships from Bayer AG (to M.F.) and the G. E. Hewitt Foundation (to K.W.H.), a predoctoral fellowship from the Division of Organic Chemistry of the American Chemical Society sponsored by Novartis (to A.J.R.), and grants from Abbott Laboratories, ArrayBiopharma, Bayer, Boehringer Ingelheim, DuPont, Glaxo, Hoffmann-LaRoche, Merck, Novartis, Pfizer, and Schering Plough." Angewandte Chemie International Edition 41, n. 12 (17 giugno 2002): 2103. http://dx.doi.org/10.1002/1521-3773(20020617)41:12<2103::aid-anie2103>3.0.co;2-s.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

33

Suzuki, Kenshi, Naohiro Sekiguchi, Shinya Rai, Wataru Munakata, Hiroshi Handa, Hirohiko Shibayama, Tomoyuki Endo et al. "Two -Year Follow-up Data of Phase II Study of Tirabrutinib, a Second-Generation Bruton's Tyrosine Kinase Inhibitor, in Patients with Treatment-Naïve or Relapsed/Refractory Waldenström's Macroglobulinemiatwo -Year Follow-up Data of Phase II Study of Tirabrutinib, a Second-Generation Bruton's Tyrosine Kinase Inhibitor, in Patients with Treatment-Naïve or Relapsed/Refractory Waldenström's Macroglobulinemia". Blood 138, Supplement 1 (5 novembre 2021): 1352. http://dx.doi.org/10.1182/blood-2021-146744.

Testo completo

Abstract (sommario):

Abstract Background: Tirabrutinib (TIR) is a second-generation oral Bruton's tyrosine kinase (Btk) inhibitor that is more selective for Btk than first-generation Btk inhibitors such as ibrutinib. TIR has been designed to improve the safety and efficacy of ibrutinib, and has been suggested to have a more favorable toxicity profile, including in atrial fibrillation (Af) and bleeding events. In 2020, TIR was approved in Japan for use in treatment-naïve (TN) or relapsed/refractory (R/R) Waldenström's macroglobulinemia (WM) based on the results of a phase II study (trial registration: Japic CTI-184057). In the phase II study, 18 TN (cohort A) and 9 R/R (cohort B) WM patients were enrolled. We previously reported the results of this study with data cutoff on August 28, 2019 (Sekiguchi et al., Cancer Sci. 2020 Sep; 111 (9): 3327-3337). In the report, major response rate (MRR, ≥ partial response [PR]) was 88.9% in cohort A and 88.9% in cohort B. Overall response rate (ORR, ≥ minor response [MR]) was 94.4% in cohort A and 100% in cohort B, with median follow-up period of 6.5 months (cohort A) and 8.3 months (cohort B). We herein report two-year follow-up data of this study (data cutoff on February 1, 2021). Methods: Phase II study was an open-label, prospective, single-arm study conducted at 19 facilities in Japan. TN or R/R WM patients with serum IgM ≥ 500 mg/dL were treated with TIR 480 mg under fasting conditions once daily until disease progression or clinically unacceptable toxicity. The primary endpoint was MRR assessed by an independent review committee (IRC) according to the VI th International Workshop on WM (IWWM) criteria. Secondary endpoints included ORR, time to major response (TTMR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Results: The median follow-up period was 23.8 months in cohort A and 25.4 months in cohort B. Of the 27 patients, 5 patients discontinued treatment due to adverse events (1 patient with atypical mycobacterial infection), progressive disease (1 patient), physician's discretion (1 patient), or withdrawal by subject (2 patients). IRC-assessed MRR was 94.4% (95% CI: 72.7-99.9) in cohort A and 88.9% (95% CI: 51.8-99.7) in cohort B. IRC-assessed ORR was 94.4% (95% CI: 72.7-99.9) in cohort A and 100.0% (95%CI: 66.4-100.0) in cohort B. The rate of ≥ very good PR was 33.3% in both cohorts. Median TTMR was 1.9 months (range 1.0-20.3) in cohort A and 2.1 months (range 1.0-3.7) in cohort B. Median PFS, OS and DOR were not achieved in either cohort. Two-year PFS rate was 94.4% in cohort A and 88.9% in cohort B. Two-year OS rate was 100% in both cohorts. Continued reductions in IgM were observed in patients who remained on treatment. In contrast, 3 patients who discontinued treatment for reasons other than withdrawal by subject had an increase in IgM after discontinuation. In the overall study population, the most common adverse events (AEs) were rash (44.4%), neutropenia (33.3%), and nasopharyngitis (25.9%). Two patients experienced Af and 9 patients experienced bleeding AE. All events of rash, nasopharyngitis, Af and bleeding AE were < grade 3. The most frequently reported ≥ grade 3 AEs were neutropenia (22.2%), lymphopenia (18.5%), and leukopenia (11.1%). During this extended follow-up period, no new ≥ grade 3 treatment-related AEs were observed except for hypertriglyceridemia observed in 1 patient. Conclusion: TIR demonstrated sustained efficacy in TN and R/R WM patients during the two-year follow-up period. Additionally, no new safety signals for TIR were identified compared to previous reports. TIR is a useful treatment option for WM. Figure 1 Figure 1. Disclosures Suzuki: Abie: Honoraria; Sanofi: Honoraria; Novartis: Honoraria; ONO: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Sekiguchi: Ono: Research Funding; A2 Healthcare: Research Funding; Astellas: Research Funding; Janssen: Research Funding; Merck Sharp & Dohme: Research Funding; Otsuka: Research Funding; Pfizer: Research Funding; PPD-SNBL: Research Funding; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding; Bristol Myers Squibb: Research Funding. Rai: Janssen Pharmaceutical: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau. Munakata: CHUGAI PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria, Research Funding; Novartis Pharma K.K.: Honoraria, Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Research Funding; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Sanofi K.K.: Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Amgen inc.: Research Funding; MSD K.K.: Research Funding; Astellas Pharma Inc.: Research Funding; AbbVie GK: Research Funding; Kyowa Kirin Co., Ltd.: Research Funding; Celgene K.K.: Honoraria; SymBio Pharmaceuticals Limited: Honoraria; Eisai Co., Ltd.: Honoraria; AstraZeneca K.K.: Honoraria. Handa: Ono: Honoraria; BMS: Honoraria; Janssen: Honoraria; Daiichi Sankyo: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding; Takeda: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Abbvie: Honoraria; Shionogi: Research Funding; MSD: Research Funding. Shibayama: Otsuka: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Nippon Shinyaku: Honoraria; Fujimoto: Honoraria; Daiichi Sankyo: Speakers Bureau; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding, Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Celgene: Research Funding; Mundi Pharma: Honoraria; Essentia Pharma Japan: Research Funding. Terui: AbbVie: Speakers Bureau; Celgene: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Esai: Speakers Bureau; Janssen: Speakers Bureau; MSD: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Fukuhara: AbbVie: Honoraria; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria; HUYA Bioscience International: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria. Tatetsu: Ono Pharmaceutical: Honoraria; Chugai: Honoraria; Eisai: Honoraria; Novartis: Honoraria; Mesoblast: Patents & Royalties. Iida: Chugai: Research Funding; Celgene: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Glaxo SmithKlein: Research Funding; Amgen: Research Funding; Abbvie: Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Iguchi: Ono Pharma USA, Inc.: Current Employment. Izutsu: Allergan Japan: Honoraria; Symbio: Honoraria, Research Funding; Pfizer: Research Funding; Ono: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Genmab: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Yakult: Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; FUJI FILM Toyama Chemical: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for WM/LPL.

Gli stili APA, Harvard, Vancouver, ISO e altri

34

Xu, X. Steven, Sam Liao, Meletios A. Dimopoulos, Pieter Sonneveld, P. Joy Ho, Andrew Belch, Merav Leiba et al. "Population Pharmacokinetic and Exposure-Response Analyses for Daratumumab in Combination Therapies for Patients with Multiple Myeloma Who Have Received 1 or More Prior Lines of Therapy". Blood 128, n. 22 (2 dicembre 2016): 3340. http://dx.doi.org/10.1182/blood.v128.22.3340.3340.

Testo completo

Abstract (sommario):

Abstract Introduction: Daratumumab (DARA) is a first-in-class human CD38 IgG1κ monoclonal antibody that has demonstrated activity as monotherapy and in combination with standard of care regimens for multiple myeloma (MM). Population pharmacokinetics (PPK) analyses were conducted to describe the PK characteristics of DARA following its administration in combination therapies, to evaluate the influence of covariates on its disposition in patients with MM who had received ≥1 prior therapy, and to compare its PK in combination therapies with that of monotherapy. Exposure-efficacy/safety analyses were performed to investigate the relationship between DARA exposure and selected efficacy and safety endpoints. Methods: The PPK analysis primarily included data from two phase 3 studies in which DARA was combined with background regimens: MMY3003 (POLLUX; lenalidomide [R]/dexamethasone [d]) and MMY3004 (CASTOR; bortezomib [V]/d). Data from two phase 1/2 studies (GEN503 [Rd] and MMY1001 [pomalidomide/d; Vd; V-thalidomide-d; V-melphalan-d]) were also used. Most patients included in the analysis (684 of 694) received 16 mg/kg DARA intravenously. A PPK model based on previous monotherapy studies was used to fit the concentration-time data from combination studies. Subgroup analyses were conducted to evaluate the influence of patient and disease characteristics on exposure to DARA. Based on data from MMY3003 and MMY3004, the exposure-efficacy analyses investigated the relationship between maximal trough concentrations (Cpre-infusion,max) and progression-free survival (PFS), duration of response (DOR), and overall response rate (ORR), while the exposure-safety relationship was explored for infusion-related reactions (IRRs), thrombocytopenia, anemia, neutropenia, lymphopenia, and infections. Results: Exposure to DARA was similar between the monotherapy and combination therapies. Based on combination therapy data, the effects of the intrinsic and extrinsic factors (age, sex, race, renal and hepatic impairment, baseline albumin, type of MM, region, type of combination therapy, ECOG, refractory status, and number of prior lines of therapy) were similar to or smaller than those in the monotherapy studies. Consistent with the monotherapy studies, none of the investigated intrinsic and extrinsic factors had clinically important effects on the exposure to DARA as all the covariate effects were within 25%. Although the clearance and volume of distribution of DARA increased with increasing body weight, the exposure to DARA was relatively consistent across the range of body weights after administration on a mg/kg-basis. Despite the decreasing concentration of DARA over time due to less frequent dosing, the current dosing schedule was adequate to produce concentration levels that maintained target saturation during the Q4W dosing period in the dosing schedules for MMY3003 (QW for 8 weeks, Q2W for 16 weeks, and Q4W, thereafter) and MMY3004 (QW for 9 weeks, Q3W for 15 weeks, and Q4W, thereafter). The exposure-efficacy analyses on the data from combination therapies suggest that maximum clinical benefit to PFS, DOR, and ORR was attained for the majority of the patients with an acceptable safety profile at the recommended dose of 16 mg/kg. No apparent relationships between drug exposure and IRRs, thrombocytopenia, anemia, neutropenia, and lymphopenia were identified within the studied concentration range. Although the overall rate of infection (any grade) appeared to increase with drug exposure, this trend was not observed for grade ≥3 infections. These findings were consistent with results from the monotherapy studies. Conclusion: The PK of DARA was similar between monotherapy and combination studies. No clinically relevant demographic or clinical characteristics were identified. Therefore, no dose adjustment based on these factors is recommended. Population PK and exposure-response analyses for combination therapies support the recommended body weight-based 16 mg/kg dose and the dosing schedules for the MMY3003 and MMY3004 studies. Disclosures Xu: Janssen: Employment, Equity Ownership. Liao:Pharmax: Employment; Janssen Research & Development: Consultancy; Johnson & Johnson: Equity Ownership. Dimopoulos:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Amgen, Celgene, Janssen, Karyopharm, Takeda: Consultancy, Honoraria; Amgen, Celgene, Janssen, Karyopharm: Research Funding. Ho:Janssen, Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Belch:Amgen, Celgene, Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Capra:Janssen: Speakers Bureau. Gomez:Janssen, Bristol Myers Squibb, Celgene, Amgen: Consultancy. Medvedova:Oregon Health & Science University: Employment. Iida:Janssen Pharmaceuticals, Takeda Pharmaceuticals Co, Celgene, Bristol-Myers Squibb, Ono Pharmaceuticals Co: Honoraria; Janssen Pharmaceuticals, Takeda Pharmaceuticals Co, Celgene, Bristol-Myers Squibb, Chugai Pharmaceuticals, Kyowa Hakko Kirin Co, Eli Lilli Japan, Novartis Pharma, Sanofi, Bayer Yakuhin, Toyama Chemical Co, Teijin Pharma, Astellas Pharma: Research Funding. Qi:Janssen: Employment. Schecter:Janssen: Employment, Equity Ownership. Khokhar:Janssen: Employment. Yan:Janssen: Employment; Johnson & Johnson: Equity Ownership. Zhang:Janssen: Employment, Equity Ownership. Clemens:Johnson & Johnson: Equity Ownership; Janssen: Employment.

Gli stili APA, Harvard, Vancouver, ISO e altri

35

Katagiri, Seiichiro, Daigo Akahane, Akihiko Gotoh, SungGi Chi, Kentaro Fukushima, Hirohiko Shibayama, Naoko Hosono et al. "Genomic Analysis Focusing on RUNX1-RUNX1T1 in Japanese Patients with AML: HM-Screen-Japan 01". Blood 138, Supplement 1 (5 novembre 2021): 4464. http://dx.doi.org/10.1182/blood-2021-148492.

Testo completo

Abstract (sommario):

Abstract Background and Methods: Acute myeloid leukemia (AML) bearing the RUNX1-RUNX1T1 fusion gene is known to be one of the core-binding factor AML (CBF-AML) which exerts relatively good prognosis. The RUNX1-RUNX1T1 fusion gene are present in approximately 3.5% of patients with AML (data from cBioPortal). However, the real-world epidemiology of this mutation and co-existing gene alterations have not been fully investigated in Japan. We launched an actionable mutation profiling multicenter study named Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233), in which a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel for patients with relapsed/refractory (R/R) AML as well as patients with newly-diagnosed (ND) AML who were ineligible for standard chemotherapy. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. Results: We found 12 patients (6.8%) with the RUNX1-RUNX1T1 fusion gene out of 177 patients who joined this study and the F1H report was successfully retuned. Eight of these patients were enrolled as R/R AML and four were enrolled as ND AML who are ineligible for standard chemotherapy. Four (50%) of R/R patients were received allogeneic hematopoietic stem cell transplantation. Among the 12 patients with the RUNX1-RUNX1T1 fusion gene, eight (66.7%) had KIT mutation. The major amino acid alteration of KIT was D816V/Y and two patients had two different point-mutations of KIT (one with D816Y plus D816V and the other with D816V plus N822K). No particular mutations, other than KIT, were predominantly co-occurred with RUNX1-RUNX1T1 fusion gene. Especially in R/R patients, 75 % of them had the KIT mutation. Two R/R patients without the KITmutation had JAK2 V617F and FLT3 D835Y respectively. Conclusions: AML with RUNX1-RUNX1T1 fusion gene is currently not indicated for transplantation in the first remission. Previous studies have demonstrated that approximately 30% of patients with CBF-AML harbored the KIT mutations at diagnosis, which might be an indicator of poor prognosis. In our study, the KIT mutations were detected much more frequently than in previously studies of newly-diagnosed CBF-AML. This result may suggest that patients with the KIT mutations were concentrated because our study targeted AML patients who were R/R to prior therapy or ineligible for standard chemotherapy. In addition, no specific mutations highly related to the RUNX1-RUNX1T1 fusion gene were detected other than the KIT mutation, suggesting the KIT mutation might be a suitable molecular marker to predict poor prognosis in AML with the RUNX1-RUNX1T1 fusion gene. Our study revealed the importance of KIT mutations in patients with R/R AML with RUNX1-RUNX1T1 fusion gene, and that the KITmutations may be a promising therapeutic target for this population. Furthermore, it is interesting that driver mutations such as JAK2 and FLT3 mutation were detected in R/R patients without KIT mutation, although further investigation is needed. This suggests that comprehensive genomic assays are highly useful in establishing precision medicine, even in this type of AML, which is generally considered to have a good prognosis. Since most of R/R patients need allo-SCT, precision medicine targeting KIT may be considered for post-recurrence treatment in AML with RUNX1-RUNX1T1 fusion gene, such as bridge therapy to transplantation, in the future. Figure 1 Figure 1. Disclosures Shibayama: Janssen Pharmaceutical K.K.: Research Funding, Speakers Bureau; Nippon Shinyaku Co., Ltd.: Speakers Bureau; Fujimoto Pharmaceutical Corp.: Speakers Bureau; Daiichi Sankyo Co., Ltd.: Speakers Bureau; Chugai Pharmaceutical Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AstraZeneca K.K.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PharmaEssentia Japan KK: Research Funding; Eisai Co., Ltd.: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; AbbVie GK: Research Funding, Speakers Bureau; Celgene K.K.: Research Funding; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Bristol-Myers Squibb K.K.: Speakers Bureau. Yamauchi: Daiichi Sankyo: Research Funding; Astellas: Research Funding; Abbie: Research Funding; Chugai: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Otsuka: Research Funding; Solasia Pharma: Research Funding. Kondo: Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy. Yamamoto: IQIVA/Incyte: Research Funding; AstraZeneca: Honoraria, Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Chugai: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Kuroda: Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; Gilead Sciences, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Yoshimitsu: Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Ishitsuka: BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; MSD: Research Funding; Teijin Pharma: Research Funding; Otsuka Pharmaceutical: Other: Personal fees; Shire: Other; Mochida: Other: Personal fees, Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Ono: Novartis Pharma KK: Honoraria; Merck Sharp & Dohme: Honoraria, Research Funding; Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Takahashi: Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Toyamakagaku: Research Funding; Eizai: Research Funding; Chugai: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Iyama: Novartis: Honoraria; Nippon Shinyaku: Honoraria; MSD: Research Funding; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Daiichi Sankyo: Honoraria; CSL Behring: Honoraria; Astellas: Honoraria; Alexion Pharmaceuticals: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Celgene: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Yakult: Research Funding; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; Beigene: Research Funding; Chugai: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Pfizer: Research Funding; Symbio: Honoraria, Research Funding; Allergan Japan: Honoraria; FUJI FILM Toyama Chemical: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Novartis Pharma KK: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.

Gli stili APA, Harvard, Vancouver, ISO e altri

36

Fukushima, Kentaro, Hirohiko Shibayama, SungGi Chi, Naoko Hosono, Takahiro Yamauchi, Seiichiro Katagiri, Akihiko Gotoh et al. "Clinical Significance of FLT3 Mutations in a Comprehensive NGS Multicenter Study of AML: HM-Screen-Japan 01". Blood 138, Supplement 1 (5 novembre 2021): 2313. http://dx.doi.org/10.1182/blood-2021-146796.

Testo completo

Abstract (sommario):

Abstract Background and Methods: FMS-like tyrosine kinase 3 (FLT3) internal tandem duplication (FLT3-ITD) and tyrosine kinase domain mutation (FLT3-TKD) are types of mutations present in approximately 30% of patients with acute myeloid leukemia (AML). Currently, FLT3 inhibitors (FLT3i) are available in clinical practice, and the second-generation FLT3i, gilteritinib and quizartinib, are being used in Japan. However, the actual epidemiology of FLT3 mutations and co-existing gene alterations, particularly resistance mechanisms after FLT3i treatment, have not been thoroughly investigated in a Japanese population. Therefore, we conducted an actionable mutation profiling multicenter study, Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233), in which a comprehensive genomic assay was performed using the FoundationOne Heme (F1H) panel for patients with relapsed/refractory (R/R) AML and patients with newly diagnosed AML who were ineligible for standard chemotherapy (ND unfit). Paraffin-embedded bone marrow samples were used for next-generation sequencing (NGS) examination using the F1H panel. We analyzed the relationships between FLT3 gene mutations and other mutations and then chronologically evaluated the variant allele frequency (VAF) of gene mutations in the genomic profiles of patients with AML receiving FLT3i. Results: Of the 171 patients who participated in this study, 49 (28.7%) had FLT3 mutations. FLT3-ITD and FLT3-TKD accounted for 59% and 43% of all cases of FLT3 mutations, respectively. Two patients (4%) were found to have dual mutations: one with FLT3-ITD plus FLT3-TKD and another with FLT3-ITD plus FLT3-F691L. Eight patients (4.5%) were found to have the FLT3-N676K mutation, which is sensitive to gilteritinib but undetectable by currently available PCR-based companion diagnostic tools in Japan. Frequently co-occurring mutations included those of NPM1 (37%), DNMT3A (33%), IDH1/IDH2 (27%), WT1 (24%), and RUNX1 (22%). Mutations in RAS pathway-related genes (e.g., KRAS, NRAS, and PTPN11) were observed in 15 patients (31%). No gene alteration showed statistically significant co-occurrence with the FLT3mutation. However, the median number of mutations that co-exist with FLT3-TKD was slightly higher than that of FLT3-ITD (four genes [3-5] vs. three genes [2-5]). Sequential changes in the VAF of each gene alteration were investigated in nine patients with FLT3 mutations who eventually gained resistance to FLT3i. It was suggested that there were various patterns in clone evolution. Some showed the acquisition of not only CBL or NRAS as RAS pathways, but also other driver mutations: one showed a persistent FLT3mutation, one showed FLT3-ITD plus FLT3-TKD, and one showed a newly acquired FLT3 mutation substituting an existing FLT3 mutation. We also found that founder mutations, such as the DNMT3Amutation, remain even after eradication of FLT3 mutation during treatment with FLT3i, which could be the cause of the outcome of complete remission with incomplete hematologic recovery. Conclusions: This is the first report to analyze R/R and ND unfit AML cases in a Japanese cohort using F1H NGS, revealing a higher incidence of FLT3-ITD/TKD mutations than previously reported. Therefore, F1H mutational analyses for R/R and ND unfit AML patients harboring FLT3-ITD/TKD mutations may reveal novel therapeutic targets that are sensitive to FLT3i. Samples from these patients showed non-canonical gain-of-function mutations, such as N676K, S451F, V592D, and F691L, which could guide the selection of optimal anti-FLT3 therapies. In addition, longitudinal NGS analysis revealed clonal evolution in cases in which resistance to the FLT3i, gilteritinib and quizartinib were observed. Time-dependent analysis of allele frequencies can help evaluate the details of leukemia clonal evolution and provide optimal treatment options. Figure Legends Fig.1 Overview of gene mutations using F1H NGS analyses. The color of each column indicates the type of genetic mutation. Blue column; point mutation/insertion/deletion, green column; fusion gene, purple column; dual mutations. Fig.2 The chronological changes of leukemic cells fractions bearing each gene mutations during treatment with FLT3 inhibitors, gilteritinib and quizartinib. Figure 1 Figure 1. Disclosures Shibayama: Otsuka: Honoraria; Pfizer: Honoraria; Bristol-Myers Squibb: Honoraria; Sanofi: Honoraria; Nippon Shinyaku: Honoraria; Fujimoto: Honoraria; Daiichi Sankyo: Speakers Bureau; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Research Funding, Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; AbbVie: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Celgene: Research Funding; Mundi Pharma: Honoraria; Essentia Pharma Japan: Research Funding. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Sumitomo Dainippon Pharma Co., Ltd.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Astellas Pharma Inc.: Consultancy, Honoraria; SANWA KAGAKU KENKYUSHO CO.,LTD.: Consultancy. Yamamoto: IQIVA/Genmab: Research Funding; Micron: Honoraria; Zenyaku: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SymBio: Honoraria, Research Funding; Solasia Pharma: Research Funding; Sanofi: Honoraria; Otsuka: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Mundipharma: Research Funding; MSD: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria; Janssen: Honoraria; HUYA: Consultancy; IQIVA/HUYA: Honoraria; IQIVA/Incyte: Research Funding; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Chugai: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; ADC Therapeutics: Honoraria. Kuroda: Kyowa Kirin: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shionogi: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Otsuka Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Novartis Pharma K.K.: Research Funding, Speakers Bureau; Ono Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K.: Research Funding; Celgene K.K.: Research Funding, Speakers Bureau; Takeda Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Nippon-Boehringer-Ingelheim Co., Ltd.: Research Funding; Mundipharma K.K.: Research Funding; Amgen-Astellas Biopharma K.K.: Research Funding; Nippon-Shinyaku Co., Ltd.: Research Funding, Speakers Bureau; Kyowa-Kirin Co., Ltd.: Research Funding, Speakers Bureau; Pfizer Japan Inc.: Research Funding, Speakers Bureau; Alexion Pharmaceuticals, Inc.: Research Funding, Speakers Bureau; Eisai Co., Ltd.: Speakers Bureau; MSD K.K.: Research Funding, Speakers Bureau; PharmaEssentia Japan KK: Research Funding, Speakers Bureau; Yakult Honsha Co., Ltd.: Research Funding, Speakers Bureau; Daiichi Sankyo Co., Ltd.: Research Funding, Speakers Bureau; Sumitomo-Dainippon Pharma Co., Ltd.: Research Funding; SymBio Pharmaceuticals Ltd.: Research Funding, Speakers Bureau; Gilead Sciences, Inc.: Research Funding; Bristol-Myers-Squibb K.K.: Research Funding, Speakers Bureau; Apellis Pharmaceuticals, Inc.: Research Funding; AbbVie GK: Research Funding, Speakers Bureau; Astellas Pharma Inc.: Research Funding, Speakers Bureau; Incyte Biosciences Japan G.K.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding, Speakers Bureau; Sanofi K.K.: Speakers Bureau; Amgen K.K.: Research Funding. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Eisai: Other: Personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Pfizer: Other: Personal fees; Novartis: Other: Personal fees; Janssen Pharmaceuticals: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Takeda: Other: Personal fees, Research Funding; BMS: Other; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; MSD: Research Funding; Teijin Pharma: Research Funding; Otsuka Pharmaceutical: Other: Personal fees; Shire: Other; Mochida: Other: Personal fees, Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Ono: Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Takahashi: Kyowahakko-Kirin: Research Funding; Toyamakagaku: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Ono: Research Funding. Iyama: SymBio Pharmaceuticals: Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Alexion Pharmaceuticals: Honoraria, Research Funding. Izutsu: Allergan Japan: Honoraria; Symbio: Honoraria, Research Funding; Pfizer: Research Funding; Ono: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Genmab: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Yakult: Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; FUJI FILM Toyama Chemical: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Novartis Pharma KK: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.

Gli stili APA, Harvard, Vancouver, ISO e altri

37

Nicolaou, K. C., A. J. Roecker, Markus Follmann e Rachid Baati. "Model Studies Towards Azadirachtin: Part 2. Construction of the Crowded C8bC14 Bond by Transition Metal Chemistry We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), the Skaggs Institute for Chemical Biology, a predoctoral fellowship from the Division of Organic Chemistry of the American Chemical Society sponsored by Novartis (to A.J.R.), postdoctoral fellowships from Bayer AG (to M.F.), and Association pour la Recherche sur le Cancer (to R.B.), and grants from Abbott Laboratories, ArrayBiopharma, Bayer, Boehringer Ingelheim, DuPont, Glaxo, Hoffmann-LaRoche, Merck, Novartis, Pfizer, and Schering Plough." Angewandte Chemie 114, n. 12 (17 giugno 2002): 2211. http://dx.doi.org/10.1002/1521-3757(20020617)114:12<2211::aid-ange2211>3.0.co;2-w.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

38

Nicolaou, K. C., A. J. Roecker, Markus Follmann e Rachid Baati. "Model Studies Towards Azadirachtin: Part 2. Construction of the Crowded C8bC14 Bond by Transition Metal Chemistry We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), the Skaggs Institute for Chemical Biology, a predoctoral fellowship from the Division of Organic Chemistry of the American Chemical Society sponsored by Novartis (to A.J.R.), postdoctoral fellowships from Bayer AG (to M.F.), and Association pour la Recherche sur le Cancer (to R.B.), and grants from Abbott Laboratories, ArrayBiopharma, Bayer, Boehringer Ingelheim, DuPont, Glaxo, Hoffmann-LaRoche, Merck, Novartis, Pfizer, and Schering Plough." Angewandte Chemie International Edition 41, n. 12 (17 giugno 2002): 2107. http://dx.doi.org/10.1002/1521-3773(20020617)41:12<2107::aid-anie2107>3.0.co;2-4.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

39

Husain, Munavvar. "(Digital Presentation) Designing New Complex Hydrides Based on Transition Metals for Hydrogen Storage Applications". ECS Meeting Abstracts MA2023-02, n. 8 (22 dicembre 2023): 3290. http://dx.doi.org/10.1149/ma2023-0283290mtgabs.

Testo completo

Abstract (sommario):

The widespread implementation of the hydrogen economy demands access to materials with a high weight percentage of hydrogen. Mg-based hydrogen storage alloys have become a research hot-spot in recent years owing to their high hydrogen storage capacity, good reversibility of hydrogen absorption/desorption, low cost, and abundant resources. However, high decomposition temperature of Mg-based hydrides limits their practical usage. Hydrogen is lightest of all elements, typically it need large volumes or high pressures to store appreciable amount of hydrogen. To overcome these challenges research activities are currently going on metal hydrides and complex hydrides based on transition metal. The main challenges come when endothermic decomposition enthalpy is considered. It becomes difficult to release the hydrogen at ambient thermodynamic conditions. On the other hand, the meta-stable hydrides are characterized by a low reaction enthalpy and a decomposition reaction that is thermodynamically favourable under the ambient conditions. The good kinetics along with evolution of hydrogen around the room temperature possessed by these materials offer much promise for underground storage and it can be used as a grid energy. The present research specifically focus on transition metal based complex hydrides such as NaMgMnH6 and NaMgFeH6 for hydrogen storage and especially predicted the crystal structure of the same using VASP simulation package. ABCX6 and AB2X6 were taken as reference composition A,B,C and X were substituted with Na, Mg, transition metals(Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu) and H, respectively. From the ICSD database search the corresponding structural variants were considered as trial structure to predict the ground state structure of these newly designed compounds. using the predicted ground state structure for these compounds, important properties like formation energy, hydrogen site energy, partial density of states(pDOS), electron density(ED), Mulliken effective charge(MEC), Bader electron charge(BEC), Born effective charge, ELF and COHP were calculated. the calculated properties of these compounds were compared with the well known reference compounds. We found that both NaMgMnH6 and NaMgFeH6 are stable with negative formation energy and als othey are semiconductors with the band gap value of 0.51 eV and 1.01 eV, respectively. from the calculated electronic structure we found that both these materials are having indirect band behaviour. Analysing the electronic density of states, charge density and various charges mentioned above the chemical bonding behaviour was established as iono-covalent in nature. from the force as well as stress minimisation considering 53 structural variants as input the ground state structure, its space group, equilibrium lattice parameters and atom positions are listed. Also from the energy vs. volume curve for the ground state structure, the equilibrium volume, bulk modulus and pressure derivatives were found out. Among NaMgMnH6 and NaMgFeH6 our spin polarised calculation show that NaMgMnH6 is possesing spontaneous magnetic polarisation with substantial magnetic moment at the Mn site. Among the considered paramagnetic, ferromagnetic, as well as A-, C-,and G- antiferromagnetic configurations the G type antiferromagnetic configuration is found to be the ground state for NaMgMnH6.

Gli stili APA, Harvard, Vancouver, ISO e altri

40

Yoshimitsu, Makoto, Koji Izutsu, Shinichi Makita, Kisato Nosaka, Atae Utsunomiya, Shigeru Kusumoto, Satoko Morishima et al. "Pivotal Phase 2 Study of the EZH1 and EZH2 Inhibitor Valemetostat Tosylate (DS-3201b) in Patients with Relapsed or Refractory Adult T-Cell Leukemia/Lymphoma". Blood 138, Supplement 1 (5 novembre 2021): 303. http://dx.doi.org/10.1182/blood-2021-146657.

Testo completo

Abstract (sommario):

Abstract Background: Enhancer of zeste homolog 2 (EZH2) and its close homolog, EZH1, catalyze the attachment of 3 methyl groups to histone H3 at lysine 27 (H3K27me3). H3K27me3 is an epigenetic mark involved in downregulating gene expression associated with tumor suppression and cell differentiation. Recent evidence suggests that adult T-cell leukemia/lymphoma (ATL) can be driven by epigenetic dysregulation (Blood. 2016;127:1790-1802). Specifically, altered EZH2 expression has been implicated in the development and progression of ATL. Valemetostat tosylate (DS-3201b; valemetostat) is a novel, potent, and selective dual inhibitor of EZH2 and EZH1 that has demonstrated antitumor activity against hematologic malignancies, especially T-cell lymphoma, including relapsed or refractory (R/R) ATL in a phase 1 study (EHA 2021. Abstract S218). Here, we report the results from the primary analysis of a pivotal phase 2 study of valemetostat in Japanese patients (pts) with R/R ATL. Aims: This multicenter, single-arm, open-label, phase 2 study (NCT04102150) evaluated the efficacy and safety of single-agent valemetostat in pts with R/R ATL. The primary objective was to evaluate efficacy by central efficacy assessment committee (EAC)-assessed overall response rate (ORR), defined as the proportion of pts whose best response was complete remission (CR), uncertified CR, or partial remission using international consensus criteria (J Clin Oncol. 2009;27:453-59). The null hypothesis was an ORR of ≤5% (binomial test with a 1-sided significance level of 5%). Secondary outcome measures included CR rate, duration of response (DOR) per EAC, efficacy per investigator (INV) assessment, and the safety and pharmacokinetics of valemetostat. Methods: Pts ≥20 years of age with R/R ATL (acute, lymphomatous, or unfavorable chronic type) were enrolled from 24 sites in Japan. Pts must have had a positive antihuman T-cell leukemia virus type 1 antibody serum test and received prior therapy with mogamulizumab or ≥1 prior systemic therapy in the case of intolerance of, or contraindication for, mogamulizumab. Pts with prior allogeneic hematopoietic stem cell transplant were excluded. Valemetostat 200 mg was orally administered once daily in continuous 28-day cycles until disease progression or intolerance. The EAC-determined efficacy assessment was based on central evaluation of radiographic images and clinical data, including peripheral blood, skin, and bone marrow lesions (J Clin Oncol. 2009;27:453-59). Results: At the time of data cutoff (April 24, 2021), the study enrolled the planned 25 pts which included 16, 6, and 3 pts with acute, lymphomatous, or unfavorable chronic ATL subtypes, respectively. The median age was 69 years (range, 59-84 years). The median number of prior lines of therapy was 3 (range, 1-8). 24 pts (96.0%) had prior treatment with mogamulizumab. The study met its primary endpoint: with a median follow-up of 28 weeks (range, 14-71 weeks), valemetostat resulted in a 48% (12/25) ORR per EAC assessment (P<.0001; 95% CI, 27.8%-68.7%), including a 20% CR rate. Primary efficacy data are summarized in the Table. The median DOR (n=12) was not reached (95% CI, 8.14 weeks-not reached). EAC- and INV-assessed results were similar. 8 of 25 pts (32%) remained on treatment. 25 pts (100%) experienced ≥1 treatment-emergent adverse event (TEAE). Grade ≥3 TEAEs occurred in 15 pts (60%), and grade ≥3 serious TEAEs occurred in 6 pts (24%); valemetostat was not associated with any deaths. Dose interruption or reduction due to TEAEs occurred in 5 (20%) and 2 (8%) pts, respectively. Two pts (8%) discontinued due to TEAEs. The most common TEAEs (≥30% of pts) were platelet count decreased (80%), dysgeusia (36%), anemia (48%), and alopecia (40%); grade ≥4 platelet count decreased occurred in 3 pts (12%). Summary/Conclusions: Valemetostat resulted in a high response rate and durable antitumor effect in Japanese pts with R/R ATL, the majority of whom were pretreated with mogamulizumab. Valemetostat's safety profile was manageable. These results are consistent with those observed in the phase 1 study conducted in Japan and the US, suggesting that valemetostat could be a new treatment option for pts with R/R ATL. Valemetostat is also being evaluated in a global phase 2 study in pts with R/R ATL and R/R peripheral T-cell lymphoma (NCT04703192). Figure 1 Figure 1. Disclosures Yoshimitsu: Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Izutsu: Kyowa Kirin: Honoraria, Research Funding; Incyte: Research Funding; Chugai: Honoraria, Research Funding; Bayer: Research Funding; Beigene: Research Funding; AstraZeneca: Honoraria, Research Funding; Yakult: Research Funding; AbbVie: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Eisai: Honoraria, Research Funding; MSD: Research Funding; Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Pfizer: Research Funding; Symbio: Honoraria, Research Funding; Allergan Japan: Honoraria; FUJI FILM Toyama Chemical: Honoraria. Makita: Takeda: Consultancy, Honoraria; SymBio: Honoraria; Novartis: Honoraria; Eisai: Honoraria; Daiichi-Sankyo: Consultancy; CSL Behring: Honoraria; Chugai: Honoraria; BMS: Consultancy, Honoraria. Nosaka: Eisai Co., Ltd: Honoraria; Celgene K.K.: Honoraria; Kyowa Kirin Co., Ltd: Consultancy, Honoraria, Research Funding; Meiji Seika Parma Co., Ltd: Honoraria; Chugai Pharmaceutical Co., Ltd.: Research Funding; Janssen Pharmaceutical K.K.: Honoraria; Bristol Myers Squibb: Honoraria. Utsunomiya: Novartis Pharma: Honoraria; Kyowa Kirin: Honoraria; Daiichi Sankyo: Honoraria; Celgene: Honoraria; Pfizer: Honoraria; Janssen Pharmaceutical: Honoraria; JIMRO: Honoraria; Meiji Seika Pharma: Honoraria; Otsuka Medical Devices: Honoraria. Kusumoto: Daiichi Sankyo: Research Funding; Chugai: Honoraria, Research Funding; Kyowa Kirin: Honoraria. Tsukasaki: Solasia Pharma: Consultancy; Meiji Seika Pharma: Consultancy; Yakuruto: Consultancy; HUYABIO: Consultancy, Research Funding; Ono Pharma: Consultancy; Daiichi Sankyo: Consultancy, Research Funding; Takeda: Honoraria; Kyowa-hakko/Kirin: Honoraria, Research Funding; Eizai: Honoraria, Research Funding; Byer: Research Funding; Chugai Pharma: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Ono: Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding; Astellas Pharma Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Rai: Chugai Pharmaceutical: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau. Yamada: Daiichi Sankyo: Current Employment. Kato: Bristol Myers Squibb: Current equity holder in publicly-traded company; Daiichi Sankyo: Current Employment. Tachibana: Daiichi Sankyo: Current Employment. Kakurai: Daiichi Sankyo: Current Employment. Adachi: Daiichi Sankyo: Current Employment. Tobinai: Celgene: Consultancy, Honoraria; Chugai Pharmaceutical: Honoraria; Eisai: Honoraria; Daiichi Sankyo: Consultancy, Honoraria; HUYA Bioscience International: Consultancy, Honoraria; Kyowa Kirin: Honoraria; Mundipharma: Consultancy, Honoraria; Ono Pharmaceutical: Consultancy, Honoraria; Solasia Pharma: Honoraria; Takeda Pharmaceutical: Consultancy, Honoraria; Yakult: Honoraria; Zenyaku Kogyo: Consultancy, Honoraria. Yonekura: AbbVie: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Daiichi Sankyo: Honoraria; Eisai: Honoraria; Eli Lilly Japan: Honoraria; Janssen Pharmaceuticals: Honoraria; Kaken Pharmaceutical: Honoraria; Kyowa Kirin: Honoraria; Maruho: Honoraria; Minophagen Pharmaceutical: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Taiho Pharmaceutical: Honoraria; Torii Pharmaceutical: Honoraria; UCB Japan: Honoraria. Ishitsuka: Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Novartis: Other: Personal fees; Janssen Pharmaceuticals: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Takeda: Other: Personal fees, Research Funding; BMS: Other; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees.

Gli stili APA, Harvard, Vancouver, ISO e altri

41

Chi, SungGi, Kentaro Fukushima, Hirohiko Shibayama, Naoko Hosono, Takahiro Yamauchi, Seiichiro Katagiri, Akihiko Gotoh et al. "Genomic Analysis of NPM1 Mutation and KMT2A(MLL)-Rearrangement/Amplification in Japanese Patients with Acute Myeloid Leukemia: Hematologic Malignancies (HM)-Screen-Japan 01". Blood 138, Supplement 1 (5 novembre 2021): 4460. http://dx.doi.org/10.1182/blood-2021-149425.

Testo completo

Abstract (sommario):

Abstract Background and Methods: NPM1 mutation and KMT2A(MLL)-rearrangement/amplification are present in approximately 27% and 8.5% patients with acute myeloid leukemia (AML), respectively (data from cBioPortal). Although they have different clinical features and prognostic impact, recent studies suggest that the MLL co-factor, menin, plays a key role in maintaining self-renewal of immature leukemic cells by upregulating transcription of HOXA and MEIS (Gundry et al.). However, the real-world epidemiology of these mutations and co-existing gene alterations have not been thoroughly investigated in Japan. We launched an actionable mutation profiling multicenter study entitled Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233). In this study, a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel for patients with relapsed/refractory (R/R) AML as well as patients with newly-diagnosed (ND) AML who are ineligible for standard chemotherapy. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. Results: One-hundred-eighty-two patients were recruited in this study and the F1H report was successfully returned in 177 patients (97.3%). Median age of 68 patients with ND-AML was 73 [63-79] years and those of 109 patients with R/R-AML was 50 [40-68.5] years. Median turn-around time was 13 days (minimum 8 days).We found 32 patients (18.1%) with NPM1 mutation and 23 patients (13.0%) of KMT2A(MLL)-rearrangement/amplification out of the 177 patients. These two alterations were mutually exclusive in this study. The median age of patients with NPM1 mutation (NPM1 mt.) and KMT2A-rearrangement (KMT2A-r) were 56.5 [43.5-73.8] and 62 [45-71] years, respectively. Three quarters or more patients were R/R-AML in both groups. WT1 expression levels were much higher in patients with NPM1 mt. than the other group (6,000 [77-110,000] vs. 93 [34-5,800] copies/mcgRNA). The major amino acid alteration of NPM1 was a frameshift mutation at the 288 th histidine (W288fs*12). Patterns of KMT2A(MLL)-rearrangement included MLL fusion (e.g., MLL-MLLT3) and partial tandem duplication (PTD) in ten patients each. MLL amplification was observed in three patients. Frequently co-occurring mutations with NPM1 mt. included FLT3 (56.3%), DNMT3A (46.9%), TET2 (34.4%), WT1 (18.8%), IDH1 (18.8%), and IDH2 (15.6%). Those with KMT2A-r included FLT3 (39.1%), TP53 (26.1%), PTPN11 (21.7%), DNMT3A (17.4%), and IDH2 (17.4%). Mutations of RAS pathway-related genes (e.g., KRAS, NRAS, PTPN11, and NF1) were observed in five patients with NPM1 mt. (15.6%) and 11 patients (47.8%) with KMT2A-r. None of the six patients with TP53 mutation had NPM1 mutation. The prognostic impact of each genes is currently being analyzed. Conclusions: Approximately three in ten patients with AML had NPM1 mutation and/or KMT2A(MLL)-rearrangement/amplification. No single patient had both the alterations. FLT3 and DNA methylation-associated genes (e.g., DNMT3A and TET2) were frequently seen in patients with NPM1 mt. In contrast, TP53 and RAS pathway-related gene alterations (e.g., NRAS, KRAS, PTPT11 and NF1) were relatively dominant in patients with KMT2A-r. TP53 mutation seemed unlikely to occur along with NPM1 mutation. Figure 1 Figure 1. Disclosures Shibayama: Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Avvie: Honoraria, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Essentia Pharma Japan: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Fujimoto: Honoraria; Nippon Shinyaku: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Otsuka: Honoraria; Mundi Pharma: Honoraria. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Pfizer: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Astellas Pharma Inc.: Consultancy, Honoraria; Abbvie: Honoraria. Yamamoto: Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; AbbVie: Honoraria, Research Funding. Kuroda: Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Taiho Pharmaceutical: Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Astellas: Research Funding, Speakers Bureau; Abbvie: Research Funding; Gilead: Research Funding; Symbio: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau; Takeda: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Mundipharma: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Eli Lilly: Research Funding; Huya Japan: Other: Personal fees. Ono: DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Mundipharma K.K.: Honoraria; Celgene: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Fujishima: Pfizer: Speakers Bureau. Takahashi: Toyamakagaku: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Eizai: Research Funding; Asahikasei: Research Funding; Kyowahakko-Kirin: Research Funding; Ono: Research Funding. Iyama: Alexion Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Symbio: Honoraria; Takeda: Honoraria, Research Funding; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Genmab: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Yakult: Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.

Gli stili APA, Harvard, Vancouver, ISO e altri

42

Uchiyama, Satoshi, Nakamura Hirotaka, SungGi Chi, Kentaro Fukushima, Hirohiko Shibayama, Naoko Hosono, Takahiro Yamauchi et al. "Properties and Distribution of IDH-1/2 Mutations in Acute Myeloid Leukemia By the Comprehensive Genomic Analysis". Blood 138, Supplement 1 (5 novembre 2021): 4447. http://dx.doi.org/10.1182/blood-2021-149801.

Testo completo

Abstract (sommario):

Abstract Background: Isocitrate dehydrogenase (IDH)-1 and -2 are TCA cycle-involved enzymes which convert isocitrate to alpha-ketoglutarate. Mutations that alter the enzymatic activity causes accumulation of a mal-metabolite D-2-hydroxyglutarate, which results in inhibition of DNA methylation and tumorigenesis. IDH-1 and IDH-2 mutation are present in approximately 7-10% and 10% of patients with acute myeloid leukemia (AML), respectively. Recently, whole exome sequencing has been used for the next-generation sequencing of AML, and certain gene mutations have been identified in patients with AML. The treatment strategies for leukemia have undergone drastic changes with the rapid development of new drugs. However, the proper use of newly developed agents poses a major challenge in AML treatment. Genome profiling analysis can be used to select the optimal treatment for patients with newly diagnosed AML. IDH mutant-specific inhibitors such as ivosidenib and enasidenib were already approved in the US, and combination treatment with venetoclax and Azacitidine was recently approved in Japan. Methods and Results: We lunched an actionable mutation profiling multicenter study named Hematologic Malignancies (HM)-SCREEN-Japan 01 (UMIN000035233), in which a comprehensive genomic assay was performed by Foundation One Heme (F1H) panel. The primary outcome was the frequency of each genomic alteration, as determined using F1H, which is a comprehensive genome profiling test based on next-generation sequencing, in the AML specimens. The secondary outcome was the association between each genomic alteration and the clinicopathological characteristics, prognosis, and quality of specimens used in the genetic analysis. The eligibility criteria were as follows: 1) histological diagnosis of AML through bone marrow aspiration; 2) fulfillment of either of the following conditions: i) newly diagnosed AML unfit for standard treatment (ND-unfit AML) or ii) R/R-AML; 3) sufficient sample collection via bone marrow aspiration; 4) Age of participants 20 years or above during registration; 5) provision of written informed consent by participants. Paraffin-embedded bone marrow samples were gathered from 17 Japanese faculties and the F1H reports were returned to the patients. The median turnaround time was 13 days (minimum 8 days). We found 13 patients (7.3%) with IDH1 mutation and 17 patients (9.6%) with IDH2 mutation out of 177 patients who joined this study and the F1H report was successfully returned. Only one patient had both mutations, and each mutation was mutually exclusive in all the other patients (Figure 1). The major amino acid alteration of IDH1 and IDH2 were R132C/G/H/L and R140Q/W, respectively. Frequently co-occurring mutations include FLT3 (44.8%), NPM1 (34.5%), DNMT3A (31.0%) and RUNX1 mutation (20.7%). Mutations of RAS pathway-related genes (e.g., KRAS, NRAS and PTPN11) were seen in 6 patients (20.7%). Any gene alterations didn't show statistically significant co-occurrence with IDH1 and IDH2 mutation. Serial genome profiling analyses were performed to evaluate the time-dependent changes in the genome profiles of patients administered FLT3 inhibitors, gilteritinib, and quizartinib for treating FLT3-mutated AML. Also in this cohort, we are examining the properties and distribution of IDH1/2 mutations during treatment with FLT3 inhibitors. In the several patients, expansion and persistence of IDH mutated clones seemed to be cause of resistance (Figure 2 as the representative result). The detailed clinical outcomes of AML patients with IDH1/2 mutations are under investigation. Conclusions: In our evaluation of the suitability of F1H for HM-SCREEN-Japan 01, we successfully identified IDH-1/2 mutation that can be used as therapeutic targets in AML, which have rarely been identified thus far. Figure 1 Figure 1. Disclosures Shibayama: Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Nippon Shinyaku: Honoraria; Daiichi Sankyo: Honoraria; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Fujimoto: Honoraria; AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria; Mundi Pharma: Honoraria; Essentia Pharma Japan: Research Funding. Yamauchi: Otsuka: Research Funding; Ono Pharmaceutical: Honoraria; Pfizer: Honoraria, Research Funding; Chugai: Honoraria; Abbie: Research Funding; Astellas: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Kondo: Otsuka Pharmaceutical: Consultancy, Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho CO.,LTD: Consultancy; Pfizer: Honoraria; Astellas Pharma Inc.: Consultancy, Honoraria; Abbvie: Honoraria. Yamamoto: AbbVie: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria; Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria. Kuroda: Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Asahi Kasei: Research Funding; Shionogi: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Sysmex: Research Funding; Eisai: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; MSD: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Astellas: Research Funding, Speakers Bureau; Abbvie: Research Funding; Gilead: Research Funding; Symbio: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Ono: Research Funding, Speakers Bureau; Janssen: Research Funding; Celgene: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; Nippon Boehringer Ingelheim: Research Funding; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau; Mundipharma: Research Funding. Yoshimitsu: Novartis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria. Ishitsuka: Asahi kasei: Research Funding; Eli Lilly: Research Funding; MSD: Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Kyowa Kirin: Other: Personal fees, Research Funding; Ono Pharmaceutical: Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; BMS: Other; Takeda: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Janssen Pharmaceuticals: Other: Personal fees; Huya Japan: Other: Personal fees; Novartis: Other: Personal fees; Pfizer: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Mochida: Other: Personal fees, Research Funding; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding. Ono: Pfizer Japan Inc.: Honoraria; Bristol-Myers Squibb Company: Honoraria; Celgene: Honoraria, Research Funding; Otsuka Pharmaceutical Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Eisai Co., Ltd.: Honoraria; Astellas Pharma Inc.: Honoraria; Takeda Pharmaceutical Company Limited.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Novartis Pharma KK: Honoraria; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Takahashi: Toyamakagaku: Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Research Funding; Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Eizai: Research Funding. Iyama: Alexion Pharmaceuticals: Honoraria, Research Funding; Astellas: Honoraria; CSL Behring: Honoraria; Daiichi Sankyo: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; MSD: Research Funding; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Genmab: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Eisai: Honoraria, Research Funding; Incyte: Research Funding; Huya Biosciences: Research Funding; Chugai: Honoraria, Research Funding; Symbio: Honoraria; Solasia: Research Funding; Pfizer: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; MSD: Research Funding; Kyowa Kirin: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Minami: Novartis Pharma KK: Honoraria; Ono: Research Funding; Pfizer Japan Inc.: Honoraria; Astellas: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb Company: Honoraria; CMIC: Research Funding.

Gli stili APA, Harvard, Vancouver, ISO e altri

43

Takahashi, Naoto, Masahiro Kizaki, Masatomo Miura, Tatsuya Kawaguchi, Ritsuro Suzuki, Kazuhito Yamamoto, Kazunori Ohnishi, Itaru Matsumura, Tomoki Naoe e Koichi Akashi. "Efficacy and Safety of Tyrosine Kinase Inhibitors for Treatment of Newly Diagnosed Chronic Myeloid Leukemia: Results Using Data Obtained with the New Target System from the Japanese Registry". Blood 132, Supplement 1 (29 novembre 2018): 1751. http://dx.doi.org/10.1182/blood-2018-99-111680.

Testo completo

Abstract (sommario):

Abstract A multicenter observational study, conducted by the Japanese Society of Hematology (JSH), evaluated the effectiveness and safety of tyrosine kinase inhibitors (TKIs) in newly diagnosed patients with chronic myeloid leukemia -chronic phase (CML-CP). The clinical data of this study were collected using the New Target system, which is an online database that can be easily accessed by physicians. A total of 506 patients were enrolled from 102 institutions between April 2010 and March 2013; data for 444 patients (median age: 56 [range 18-92] years; 65% male) were analyzed. According to the Sokal score, 201 (45.3%), 178 (40.1%), and 64 patients (14.4%) were classified into the low, intermediate, and high-risk groups. As the first-line therapy, 148 (29.8%) patients received imatinib (IM), 173 (34.8%) received nilotinib (NIL), and 146 (29.4%) received dasatinib (DAS). BCR-ABL1 % was regularly monitored every 3 months in the first year and every 6 months thereafter. TKI plasma trough concentrations were determined with LC-MS/MS at 3, 6, and 12 months. At 60 months of follow up, 5-year progression-free survival (PFS) and overall survival (OS) were 94.5% (95%CI, 91.2-96.5) and 94.8% (95%CI, 91.6-96.9), respectively. The 5-year OS curve was significantly better in patients treated with NIL or DAS than that in patients with IM (IM, 90.9% [95%CI, 83.7-95.0]; NIL, 98.0% [95%CI, 92.2-99.5]; DAS, 96.0% [95%CI, 89.4-98.5]; log-rank test: P =0.0345). An early molecular response (EMR; BCR-ABL1 <10%) was found in 328 patients at 3 months (IM, n=84; NIL, n=127; and DAS, n=117). The 5-year PFS curve was significantly better in patients with EMR than without (EMR, 95.9% [95%CI, 92.6-97.7]; no-EMR, 77.5% [95%CI, 59.8-88.1]; log-rank test: P =0.0002). Additionally, 49 patients (IM, n=9; NIL, n=24; DAS, n=16) achieved deep molecular response (DMR; BCR-ABL1≤0.0032%) by 36 months. The DMR was observed in a higher proportion of patients with EMR (BCR-ABL1<10% at 3 months or BCR-ABL1<1% at 6 months) after TKI treatment (<10%, P =0.0367; <1%, P =0.0068). Testing for BCR-ABL1mutation was performed in 101 patients. Various BCR-ABL1mutations were identified in 23 patients (IM, n=13; NIL, n=8; and DAS, n=2). T315I mutation was not identified. Exon 8/9 35bp insertion was identified in 14 patients (IM, n=8; NIL, n=5; DAS, n=1). Seven out of these 14 patients achieved DMR; and all patients with exon 8/9 35bp insertion did not progress to accelerated or blast phase . The achievement of major molecular response (MMR, BCR-ABL1<0.1%) was associated with a higher trough concentration (C0) (DAS mean C02.65 ng/mL in MMR at 6 months vs. 1.98 ng/mL in no-MMR, P=0.0165; NIL mean C0 1,285.3 ng/mL in MMR at 3 months vs. 1,049.8 ng/mL in no-MMR,P=0.0746). No new safety issues occurred. Among 444 analyzed patients in the safety data set, only 2 patients with NIL had peripheral arterial occlusive disease [grade 1] or acute coronary disease [grade 3]. No patients developed pulmonary arterial hypertension in this study. We measured pleural effusion (PE) in patients with DAS and liver/pancreas dysfunction in patients with NIL, which were the common adverse events. In the DAS arm, 28 patients revealed pleural effusion (grade 1, 3 patients; grade2, 22 patients; grade3, 3 patients). It occurred not only in the first year of treatment but also in the second or third year (median 10.5 [range 1-60] months). However, no statistically significant association was found between pleural effusion and trough concentration of DAS in this study (2.71 ng/mL in patients with PE vs. 2.27 ng/mL in patients without, P =0.1339). In the NIL arm, 17 patients revealed severe liver dysfunction (grade 3-4, n=6), increased bilirubin values (grade 3, n=4), or increased lipase values (grade 3-4, n=7). The adverse events occurred in 3 months in these patients with NIL, except for 4 patients. In summary, this 5-year Japanese registry using the New Target system demonstrated that TKI treatments in newly diagnosed patients with CML-CP achieved satisfying and trustworthy outcomes. Figure. Figure. Disclosures Takahashi: Bristol-Myers Squibb: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Kizaki:Nippon Shinyaku,: Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau. Kawaguchi:Novartis Pharma K.K.: Honoraria, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau; Alexion: Honoraria, Speakers Bureau. Suzuki:Celgene: Honoraria; Sawai Pharmaceutical: Honoraria; Ohtsuka: Honoraria; MSD: Research Funding; Meiji Seika Pharma: Honoraria; Takeda Pharmaceuticals: Honoraria; Shionogi: Honoraria; Novartis: Honoraria; Mochida Pharmaceutical: Honoraria; Chugai Pharmaceutical: Honoraria; Kyowa-Hakko Kirin: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Gilead Sciences: Consultancy; MundiPharma: Consultancy; Jazz Pharmaceuticals: Consultancy. Yamamoto:Chugai: Consultancy, Honoraria, Research Funding; Meiji Seika Pharma: Consultancy; Mundipharma: Consultancy, Honoraria; Ono: Consultancy, Honoraria, Research Funding; ARIAD Pharmaceuticals: Research Funding; Bayer: Research Funding; Celgene: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Gilead Sciences: Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Solasia Pharma: Research Funding; SymBio: Research Funding; Takeda: Honoraria, Research Funding; AbbVie: Research Funding; Boehringer Ingelheim: Consultancy; Zenyaku: Research Funding; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Otsuka: Honoraria; Pfizer: Honoraria; Sumitomo Dainippon: Honoraria; HUYA: Honoraria. Naoe:Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding; Pfizer Japan Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding. Akashi:MSD: Research Funding; Ono Pharmaceutical: Research Funding; Novartis pharma: Research Funding; Otsuka Pharmaceutical: Research Funding; Chugai Pharma: Research Funding; Astellas Pharma: Research Funding; Eisai: Research Funding; Taiho Pharmaceutical: Research Funding; sanofi: Research Funding; Asahi-kasei: Research Funding; Pfizer: Research Funding; Kyowa Hakko Kirin: Research Funding, Speakers Bureau; Eli Lilly Japan: Research Funding; Celgene: Research Funding, Speakers Bureau; Bristol-Myers Squibb: Research Funding, Speakers Bureau.

Gli stili APA, Harvard, Vancouver, ISO e altri

44

Nicolaou, K. C., Marta Nevalainen, Brian S. Safina, Mark Zak e Stephan Bulat. "A Biomimetically Inspired Synthesis of the Dehydropiperidine Domain of Thiostrepton We thank Drs. D. H. Huang and L. Pasternack, G. Suizdak, and R. Chadja for NMR spectroscopic, mass spectrometric, and X-ray crystallographic assistance, respectively. Financial support for this work was provided by The Skaggs Institute for Chemical Biology, the National Institutes of Health (USA), fellowships from The Academy of Finland (M.N.), The Skaggs Institute for Research (M.Z.), and Bayer AG (S.B.), and grants from Abbott, Amgen, Array Biopharma, Boehringer-Ingelheim, Glaxo, Hoffmann-LaRoche, DuPont, Merck, Novartis, Pfizer, and Schering Plough." Angewandte Chemie 114, n. 11 (3 giugno 2002): 2021. http://dx.doi.org/10.1002/1521-3757(20020603)114:11<2021::aid-ange2021>3.0.co;2-j.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

45

Nicolaou, K. C., Marta Nevalainen, Brian S. Safina, Mark Zak e Stephan Bulat. "A Biomimetically Inspired Synthesis of the Dehydropiperidine Domain of Thiostrepton We thank Drs. D. H. Huang and L. Pasternack, G. Suizdak, and R. Chadja for NMR spectroscopic, mass spectrometric, and X-ray crystallographic assistance, respectively. Financial support for this work was provided by The Skaggs Institute for Chemical Biology, the National Institutes of Health (USA), fellowships from The Academy of Finland (M.N.), The Skaggs Institute for Research (M.Z.), and Bayer AG (S.B.), and grants from Abbott, Amgen, Array Biopharma, Boehringer-Ingelheim, Glaxo, Hoffmann-LaRoche, DuPont, Merck, Novartis, Pfizer, and Schering Plough." Angewandte Chemie International Edition 41, n. 11 (3 giugno 2002): 1941. http://dx.doi.org/10.1002/1521-3773(20020603)41:11<1941::aid-anie1941>3.0.co;2-v.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

46

Tilly, Hervé, Franck Morschhauser, Laurie H. Sehn, Jonathan W. Friedberg, Marek Trněný, Jeff P. Sharman, Charles Herbaux et al. "The POLARIX Study: Polatuzumab Vedotin with Rituximab, Cyclophosphamide, Doxorubicin, and Prednisone (pola-R-CHP) Versus Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisone (R-CHOP) Therapy in Patients with Previously Untreated Diffuse Large B-Cell Lymphoma". Blood 138, Supplement 2 (4 dicembre 2021): LBA—1—LBA—1. http://dx.doi.org/10.1182/blood-2021-154729.

Testo completo

Abstract (sommario):

Abstract Background: The current standard of care for patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL) is R CHOP; however, approximately 40% of patients are not cured. The CD79b-targeting antibody-drug conjugate, polatuzumab vedotin, is approved in relapsed/refractory DLBCL in combination with bendamustine and rituximab, and has also demonstrated promising first line activity and safety when combined with rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) in a Phase Ib/II study (Tilly, et al. Lancet Oncol 2019). Thus, in the Phase III POLARIX study (NCT03274492) we compared pola-R-CHP with R-CHOP in patients with previously untreated DLBCL. Methods: In this double-blind, placebo-controlled, international study, patients with previously untreated DLBCL and an International Prognostic Index (IPI) of 2-5 were randomized 1:1 to receive six cycles of pola-R-CHP (with a vincristine placebo) or R-CHOP (with a polatuzumab vedotin placebo); all patients also received two additional cycles of rituximab. Patients received polatuzumab vedotin 1.8mg/kg or vincristine 1.4mg/m² administered on Day 1, plus intravenous rituximab 375mg/m2, cyclophosphamide 750mg/m², doxorubicin 50mg/m², and placebo on Day 1, and oral prednisone 100mg once daily on Days 1-5. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included investigator-assessed event-free survival (EFS), independent review committee-assessed complete response (CR) rate at the end of treatment by positron emission tomography-computed tomography (PET-CT), disease-free survival (DFS), overall survival (OS), and safety. Results: Overall, 879 patients were randomized, 440 to pola-R-CHP and 439 to R-CHOP. Median age was 65 (range 19-80) years, and the majority of patients had IPI 3-5 (62.0%). At the data cut-off of June 28, 2021, and after a median follow-up of 28.2 months, PFS was superior with pola-R-CHP vs R CHOP (hazard ratio [HR] 0.73; 95% confidence interval [CI]: 0.57-0.95; P<0.02). The 2-year PFS rate was 76.7% (95% CI: 72.7-80.8) with pola-R-CHP vs 70.2% (95% CI: 65.8-74.6) with R-CHOP. EFS favored pola-R-CHP compared with R-CHOP (HR 0.75; 95% CI: 0.58-0.96; P=0.02). The end-of-treatment PET-CT CR rate was not significantly different with pola-R-CHP vs R-CHOP (78.0% vs 74.0%; P=0.16); however, DFS suggested responses were more durable with pola-R-CHP than with R-CHOP (HR 0.70; 95% CI: 0.50-0.98). There was no difference in OS between treatment arms (HR 0.94; 95% CI: 0.65-1.37; P=0.75). At the time of data cut-off, 99 (23%) and 133 (30%) patients in the pola-R-CHP and R-CHOP arms, respectively, had received at least one subsequent anti-lymphoma therapy. Fewer patients in the pola-R-CHP than the R-CHOP arm received subsequent anti-lymphoma treatments (radiotherapy, 9.3% vs 13.0%; stem cell transplantation, 3.9% vs 7.1%; chimeric antigen receptor T-cell therapy, 2.0% vs 3.6%). The safety profile was comparable for pola-R-CHP vs R-CHOP, including rates of grade 3-4 adverse events (AEs; 57.7% vs 57.5%), serious AEs (34.0% vs 30.6%), grade 5 AEs (3.0% vs 2.3%), and AEs leading to dose reduction (9.2% vs 13.0%), respectively. The frequency and severity of peripheral neuropathy were similar for pola-R-CHP vs R-CHOP (any grade, 52.9% vs 53.9%; grade 3-4, 1.6% vs 1.1%). Conclusion: The pola-R-CHP combination demonstrated a 27% reduction in the relative risk of disease progression, relapse, or death compared with R-CHOP, with a similar safety profile in the first-line treatment of patients with DLBCL. Disclosures Tilly: Karyopharm: Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Meeting attendance and travel, Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Morschhauser: AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZenenca: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria; Genentech, Inc.: Consultancy; Janssen: Honoraria; Genmab: Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy; Incyte: Membership on an entity's Board of Directors or advisory committees. Sehn: Novartis: Consultancy; Genmab: Consultancy; Debiopharm: Consultancy; Teva: Consultancy, Research Funding; Roche/Genentech: Consultancy, Research Funding; AbbVie: Consultancy; Acerta: Consultancy; Amgen: Consultancy; Apobiologix: Consultancy; AstraZeneca: Consultancy; Celgene: Consultancy; Gilead: Consultancy; Incyte: Consultancy; Janssen: Consultancy; Kite: Consultancy; Karyopharm: Consultancy; Lundbeck: Consultancy; Merck: Consultancy; Morphosys: Consultancy; Sandoz: Consultancy; Seattle Genetics: Consultancy; Takeda: Consultancy; TG Therapeutics: Consultancy; Verastem: Consultancy. Friedberg: Bayer: Membership on an entity's Board of Directors or advisory committees; Acerta: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Trněný: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Portola: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria. Sharman: AbbVie: Consultancy; AstraZeneca: Consultancy; BeiGene: Consultancy; Bristol-Myers Squibb: Consultancy; Lilly: Consultancy; Pharmacyclics LLC, an AbbVie Company: Consultancy; TG Therapeutics: Consultancy; Centessa: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy; Velos: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees. Herbaux: Takeda: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Honoraria; Janssen: Honoraria. Burke: Verastem: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; Adaptive Biotechnologies: Consultancy; Epizyme: Consultancy; Kura: Consultancy; AbbVie: Consultancy; BeiGene: Consultancy, Speakers Bureau; Kymera: Consultancy; Bristol-Myers Squibb: Consultancy; X4 Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Gilead: Consultancy; Genentech, Inc.: Consultancy. Matasar: Memorial Sloan Kettering Cancer Center: Current Employment; Merck Sharp & Dohme: Consultancy, Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; GlaxoSmithKline: Honoraria, Research Funding; Bayer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; IGM Biosciences: Research Funding; Pharmacyclics: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Rocket Medical: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding; ImmunoVaccine Technologies: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Juno Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy, Honoraria. Rai: Chugai Pharmaceutical Co., Ltd: Speakers Bureau; ONO Pharmaceutical Co., Ltd: Speakers Bureau; Janssen Pharmaceutical: Speakers Bureau; Eisai Co., Ltd: Speakers Bureau. Izutsu: AbbVie: Honoraria; Allergan Japan: Honoraria; AstraZeneca: Honoraria, Research Funding; Bayer: Research Funding; BeiGene: Research Funding; Celgene: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Genmab: Honoraria, Research Funding; Huya Biosciences: Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Takeda: Honoraria, Research Funding; Yakult: Research Funding. Mehta-Shah: C4 Therapeutics: Consultancy; Kiowa Hakko Kirin: Consultancy; Karyopharm: Consultancy; Ono Pharmaceuticals: Consultancy; Secura Bio: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Research Funding; Bristol-Myers Squibb: Research Funding; Celgene: Research Funding; Innate Pharmaceuticals: Research Funding; Roche/Genentech: Research Funding; Corvus Pharmaceuticals: Research Funding; Verastem: Research Funding. Oberic: Celgene: Honoraria; F. Hoffmann-La Roche Ltd: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Janssen: Honoraria, Other: Support for attending meetings and/or travel; Gilead: Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; AbbVie: Other: Support for attending meetings and/or travel; Incyte: Membership on an entity's Board of Directors or advisory committees. Jurczak: Maria Sklodowska-Curie National Research Institute of Oncology: Current Employment; Jagiellonian University: Ended employment in the past 24 months. Greil: Sandoz: Honoraria, Research Funding; Amgen: Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses, Research Funding. Pinto: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; Gilead Sciences: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel; MSD: Honoraria; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Other: Support for attending meetings and/or travel; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau. Abrisqueta Costa: Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche Ltd: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees. Hirata: Genentech, Inc.: Current Employment; Genentech/Roche: Current holder of stock options in a privately-held company. Jiang: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Yan: F. Hoffmann-La Roche Ltd: Current Employment, Current equity holder in publicly-traded company. Lee: Genentech, Inc.: Current Employment; F. Hoffmann-La Roche Ltd: Current equity holder in publicly-traded company. Flowers: AbbVie: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; BeiGene: Consultancy; Celgene: Consultancy, Research Funding; Denovo Biopharma: Consultancy; Epizyme: Consultancy; Roche/Genentech: Consultancy, Research Funding; Genmab: Consultancy; Gilead: Consultancy, Research Funding; Karyopharm: Consultancy; Pharmacyclics/Janssen: Consultancy; Seattle Genetics: Consultancy; Spectrum: Consultancy; 4D: Research Funding; Acerta: Research Funding; Adaptimmune: Research Funding; Allogene: Research Funding; Amgen: Research Funding; Cellectis: Research Funding; EMD: Research Funding; Guardant: Research Funding; Iovance: Research Funding; Janssen: Research Funding; Kite: Research Funding; Morphosys: Research Funding; Nektar: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; Xencor: Research Funding; Ziopharm: Research Funding; Burroughs Wellcome Fund: Research Funding; Eastern Cooperative Oncology Group: Research Funding; National Cancer Institute: Research Funding; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding. Salles: Bayer: Honoraria; AbbVie: Consultancy, Honoraria; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Debiopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genmab: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Ipsen: Consultancy; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Kite/Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Loxo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Miltenyi: Consultancy; Morphosys: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rapt: Consultancy, Membership on an entity's Board of Directors or advisory committees; Regeneron: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Velosbio: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allogene: Consultancy. OffLabel Disclosure: Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b on malignant B-cells. Polatuzumab vedotin in combination with bendamustine and rituximab (pola-BR) improved complete response rate and overall survival compared with BR alone in patients with relapsed/refractory diffuse large B-cell lymphoma. Pola-BR is approved for the treatment of adult patients with relapsed or refractory diffuse large B-cell lymphoma, not otherwise specified, after at least two prior therapies.

Gli stili APA, Harvard, Vancouver, ISO e altri

47

Hosono, Naoko, Takahiro Yamauchi, SungGi Chi, Kentaro Fukushima, Hirohiko Shibayama, Seiichiro Katagiri, Akihiko Gotoh et al. "Hematologic Malignancies (HM)-Screen-Japan 01: A Mutation Profiling Multicenter Study on Patients with Acute Myeloid Leukemia". Blood 138, Supplement 1 (5 novembre 2021): 4457. http://dx.doi.org/10.1182/blood-2021-149960.

Testo completo

Abstract (sommario):

Abstract Background: Recently, whole exome sequencing has been used for the next-generation sequencing of acute myeloid leukemia (AML), and certain gene mutations have been identified in patients with AML. The treatment strategies for leukemia have undergone drastic changes with the rapid development of new drugs. However, the proper use of newly developed agents poses a major challenge in AML treatment. Genome profiling analysis can be used to select the optimal treatment for patients with newly diagnosed AML. Methods and Results: Hematologic malignancies (HM)-SCREEN-Japan 01 is an actionable mutation profiling multicenter study of patients with newly diagnosed AML who cannot be treated with first standard treatment or patients who have relapsed/refractory AML (R/R-AML). The objective of this study was to evaluate the frequency and characteristics of cancer-related genomic alterations in patients with AML using a comprehensive genome profiling assay (FoundationOne®Heme (F1H)) and determine the quality of specimens used in gene analysis. Before participant recruitment, approval was obtained from the institutional review board at each participating institution. The trial was registered in the UMIN Clinical Trials Registry (UMIN000035233). This study was conducted at 17 participating institutions and had a sample size of 200. The eligibility criteria were as follows: 1) histological diagnosis of AML through bone marrow aspiration; 2) fulfillment of either of the following conditions: i) newly diagnosed AML unfit for standard treatment (ND-unfit AML) or ii) R/R-AML; 3) sufficient sample collection via bone marrow aspiration; 4) Age of participants 20 years or above during registration; 5) provision of written informed consent by participants. The primary outcome was the frequency of each genomic alteration, as determined using F1H, which is a comprehensive genome profiling test based on next-generation sequencing, in the AML specimens. The secondary outcome was the association between each genomic alteration and the clinicopathological characteristics, prognosis, and quality of specimens used in the genetic analysis. Serial genome profiling analyses were performed to evaluate the time-dependent changes in the genome profiles of patients administered FLT3 inhibitors, gilteritinib, and quizartinib for treating AML. One hundred and eighty-two patients were recruited, and the F1H report was successfully obtained for 177 patients (97.3%). The median age of the 66 patients with ND-unfit AML was 73 years (63-79 years), and that of the 105 patients with R/R-AML was 50 years (41-68 years). The median turnaround time was 13 days (minimum 8 days). Recurrent alterations were observed in FLT3 (28.7%), TP53 (21.6%), RUNX1 (20.5%), DNMT3A (18.7%), NPM1 (18.7%), ASXL1 (15.2%), TET2 (14.0%), KMT2A-rearrangement (13.5%), and NRAS (13.5%). IDH1 and/or IDH2 mutations were identified in specimens collected from 30 patients (17.5%). Compared with the prevalence in 2247 patients with AML in the US and Europe who underwent F1H analysis, the frequencies of mutations in FLT3 (28.7% vs. 20.5%) and TP53 (21.6% vs. 17.0%) were higher in this Japanese cohort. Mutations in IDH2, PTPN11, and SF3B1 were observed along with KMT2A rearrangement. Mutations in TP53 tended to be exclusive to the FLT3 mutation. In comparison between the ND-unfit AML and R/R-AML, mutations in TET2 and ASXL1 tended to be more frequnt in ND-unfit AML (17.9% vs. 7.0%, p=0.038, 18.9% vs. 8.5%, p=0.055, respectively). The median expression level of WT1 mRNA at the time of sample collection was 4,490 copies/μgRNA (n=158), and WT1 mutation was frequently found in the WT1-high expression group (13.9% vs. 3.8%, p=0.03), suggesting that the mutation of WT1 may cause overexpression of WT1 as an oncogene. Conclusions: In our evaluation of the suitability of F1H for HM-SCREEN-Japan 01, we successfully identified leukemia-associated genes that can be used as therapeutic targets in AML, which have rarely been identified thus far. Figure 1 Figure 1. Disclosures Yamauchi: Astellas: Research Funding; Abbie: Research Funding; Chugai: Honoraria; Pfizer: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Otsuka: Research Funding; Daiichi Sankyo: Research Funding; Solasia Pharma: Research Funding. Shibayama: Celgene: Research Funding; Ono: Honoraria, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Avvie: Honoraria, Research Funding; Eisai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Chugai: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Essentia Pharma Japan: Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Honoraria; Fujimoto: Honoraria; Nippon Shinyaku: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Otsuka: Honoraria; Mundi Pharma: Honoraria. Kondo: Astellas Pharma Inc.: Consultancy, Honoraria; Otsuka Pharmaceutical: Honoraria, Research Funding; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb: Honoraria; Sumitomo Dainippon Pharma: Honoraria; Sanwa Kagaku Kenkyusho: Consultancy. Yamamoto: Eisai: Honoraria, Research Funding; IQIVA/Incyte: Research Funding; IQIVA/HUYA: Honoraria; HUYA: Consultancy; Janssen: Honoraria; Kyowa Kirin: Honoraria; Meiji Seika Pharma: Consultancy, Honoraria, Research Funding; MSD: Honoraria; Mundipharma: Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Ono: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Sanofi: Honoraria; Solasia Pharma: Research Funding; SymBio: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Yakult: Honoraria, Research Funding; Zenyaku: Honoraria, Research Funding; Micron: Honoraria; IQIVA/Genmab: Research Funding; ADC Therapeutics: Honoraria; Daiichi Sankyo: Honoraria; Chugai: Honoraria, Research Funding; Bristol-Myers Squibb/Celgene: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding. Kuroda: Sanofi: Consultancy, Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; Otsuka Pharmaceutical: Honoraria, Research Funding; Astellas Pharma: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; MSD: Research Funding; Abbvie: Consultancy, Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Sysmex: Research Funding; Pfizer: Honoraria, Research Funding; Nippon Shinyaku: Honoraria, Research Funding; Shionogi: Research Funding; Asahi Kasei: Research Funding; Taiho Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Current Employment, Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Dainippon Sumitomo Pharma: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Bristol-MyersSquibb: Consultancy, Honoraria, Research Funding; Janssen Pharmaceutical K.K: Consultancy. Usuki: Nippon Boehringer Ingelheim: Research Funding; Takeda: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Janssen: Research Funding; Ono: Research Funding, Speakers Bureau; Brisol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Otsuka: Research Funding, Speakers Bureau; Sumitomo Dainippon: Research Funding; Daiichi Sankyo: Research Funding, Speakers Bureau; Symbio: Research Funding, Speakers Bureau; Gilead: Research Funding; Abbvie: Research Funding; Astellas: Research Funding, Speakers Bureau; Astellas-Amgen-Biopharma: Research Funding; Nippon shinyaku: Research Funding, Speakers Bureau; Kyowa Kirin: Research Funding, Speakers Bureau; Pfizer: Research Funding; Alexion: Speakers Bureau; Eisai: Speakers Bureau; MSD: Speakers Bureau; PharmaEssentia: Speakers Bureau; Yakult: Speakers Bureau; Mundipharma: Research Funding. Yoshimitsu: Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Ishitsuka: Eli Lilly: Research Funding; Mochida: Other: Personal fees, Research Funding; Eisai: Other: Personal fees, Research Funding; Sumitomo Dainippon Pharma: Other: Personal fees, Research Funding; Genzyme: Other: Personal fees; Astellas Pharma: Other: Personal fees, Research Funding; Pfizer: Other: Personal fees; Novartis: Other: Personal fees; Janssen Pharmaceuticals: Other: Personal fees; Taiho Pharmaceuticals: Other: Personal fees, Research Funding; Mundipharma: Other: Personal fees; Takeda: Other: Personal fees, Research Funding; BMS: Other; Chugai Pharmaceutical: Honoraria, Other: Personal fees, Research Funding; Celgene: Honoraria, Other: Personal fees; Ono Pharmaceutical: Other: Personal fees, Research Funding; Kyowa Kirin: Other: Personal fees, Research Funding; Daiichi Sankyo: Consultancy, Other: Personal fees; Shire: Other; Otsuka Pharmaceutical: Other: Personal fees; Teijin Pharma: Research Funding; MSD: Research Funding; Asahi kasei: Research Funding; Huya Japan: Other: Personal fees. Ono: DAIICHI SANKYO COMPANY, LIMITED.: Honoraria; Novartis Pharma KK: Honoraria; Bristol-Myers Squibb Company: Honoraria; Pfizer Japan Inc.: Honoraria; Otsuka Pharmaceutical Co., Ltd.: Honoraria; ONO PHARMACEUTICAL CO., LTD.: Honoraria, Research Funding; Takeda Pharmaceutical Company Limited.: Honoraria; Astellas Pharma Inc.: Honoraria; Eisai Co., Ltd.: Honoraria; Janssen Pharmaceutical K.K: Honoraria; Mundipharma K.K.: Honoraria; TAIHO PHARMACEUTICAL CO., LTD.: Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Merck Sharp & Dohme: Honoraria, Research Funding. Takahashi: Kyowahakko-Kirin: Research Funding; Ono: Research Funding; Asahikasei: Research Funding; Toyamakagaku: Research Funding; Eizai: Research Funding; Chugai: Research Funding; Otsuka Pharmaceutical: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Iyama: Otsuka: Honoraria, Research Funding; Novartis: Honoraria; Nippon Shinyaku: Honoraria; MSD: Research Funding; Otsuka Pharmaceuticals Factory: Honoraria; Otsuka Pharmaceuticals Factory: Honoraria; Daiichi Sankyo: Honoraria; CSL Behring: Honoraria; Astellas: Honoraria; Alexion Pharmaceuticals: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; SymBio Pharmaceuticals: Research Funding. Izutsu: Yakult: Research Funding; Takeda: Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Fuji Film Toyama Chemical: Honoraria; Genmab: Honoraria, Research Funding; Huya Biosciences: Research Funding; Incyte: Research Funding; Janssen: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; MSD: Research Funding; Novartis: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Pfizer: Research Funding; Solasia: Research Funding; Symbio: Honoraria; Celgene: Honoraria, Research Funding; Beigene: Research Funding; Bayer: Research Funding; AstraZeneca: Honoraria, Research Funding; Allergan Japan: Honoraria; AbbVie: Honoraria. Minami: Bristol-Myers Squibb Company: Honoraria; Novartis Pharma KK: Honoraria; Pfizer Japan Inc.: Honoraria; Takeda: Honoraria; Astellas: Honoraria; Ono: Research Funding; CMIC: Research Funding.

Gli stili APA, Harvard, Vancouver, ISO e altri

48

Nicolaou, K. C., Wenyuan Qian, Federico Bernal, Noriaki Uesaka, Petri M. Pihko e Jürgen Hinrichs. "Synthesis of the ABCD Ring System of Azaspiracid We thank Drs. D. H. Huang and G. Siuzdak for NMR spectroscopic and mass spectrometric assistance, respectively. This work was financially supported by the National Institutes of Health (USA), The Skaggs Institute for Chemical Biology, a predoctoral fellowship from Bristol-Myers Squibb (to F.B.), postdoctoral fellowships from The Skaggs Institute for Research (to W.Q.), the Academy of Finland, the Ella and Georg Ehrnrooth Foundation and the Tauno Tönning Foundation (all to P.M.P.), and Bayer AG (to J.H.), as well as grants from Abbott, Amgen, ArrayBiopharma, Boehringer-Ingelheim, Glaxo, Hoffmann-La Roche, DuPont, Merck, Novartis, Pfizer, and Schering Plough." Angewandte Chemie International Edition 40, n. 21 (5 novembre 2001): 4068. http://dx.doi.org/10.1002/1521-3773(20011105)40:21<4068::aid-anie4068>3.0.co;2-y.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

49

Tavakkoli, Montreh, Justin D. Kaner, Sharma Sahil, Tony Taldone, Swathi Merugu, Gabriela Chiosis, Gail J. Roboz e Monica L. Guzman. "Epichaperome Abundance Predicts Response to the Epichaperome Inhibitor, Puh-71, in Acute Myeloid Leukemia". Blood 134, Supplement_1 (13 novembre 2019): 5145. http://dx.doi.org/10.1182/blood-2019-125175.

Testo completo

Abstract (sommario):

The epichaperome, which was previously described by our team (Rodina et al. Nature 2016, Joshi et al. Nature Reviews Cancer 2018), is a complex hyper-connected network of chaperones and co-chaperones that are present in a subset of tumors, and its role is to facilitate the survival of malignant cells. We have previously shown abundant epichaperome networks in different tumor types, including AML. PU-H71 is a novel epichaperome inhibitor that selectively targets cells expressing the epichaperome. We hypothesize that personalizing PU-H71 in AML based on epichaperome abundance will significantly improve the clinical efficacy of PU-H71. To investigate this, we assessed the frequency of epichaperome abundance in primary AML samples and sought to develop a method with clinical application to predict response to PU-H71. We screened 55 de novo and relapsed/refractory primary AML bone marrow and peripheral blood samples for epichaperome abundance and cytotoxicity. Epichaperome abundance was assessed by incubating cells with FITC-bound PU-H71 (labeled F2) for 4 hours followed by analysis by multi-parameter flow cytometry. A chemically similar FITC-bound PU-H71, which does not bind the epichaperome, termed F9, was used as a control (Taldone et al. Bioorg Med Chem Lett 2011). MV411 cell lines were also used as positive controls (given known epichaperome abundance and high sensitivity to PU-H71), and intra-sample T-cells were used as negative controls. Furthermore, we assessed cell survival by incubating cells with 0.5uM PU-H71 for 48-hours followed by evaluation by multi-parameter flow cytometry. All analyses were performed in duplicates or triplicates. The ratio of blast F2 to F9 was combined with the F2-F9 blast to T cell ratio to calculate epichaperome abundance. Data on epichaperome abundance was available in 50 patient samples. Cytotoxicity data was available in 41 patients. 22/41 (54%) of patient samples underwent ≥60% cell death, respectively, and 7/41 (17%) were resistant to PU-H71, as defined by < 5% cytotoxicity. An ROC curve using epichaperome cut-offs of 1, 2.5, 4.5, 6, 8 and 15 provided an AUC of 0.97 (95% CI 0.889-1.056, p=0.006). Using a cut-off of 4.5 for epichaperome abundance, 22/50 (44%) of samples expressed high levels of the epichaperome, and sensitivity and specificity for predicting >60% in vitro cytotoxicity to PU-H71 were 81.8% (95% CI 59.7-94.8%) and 94.7% (95% CI 74-100%) (Figure 1). This method's diagnostic accuracy was 87.8%, with positive and negative likelihood ratios of 15.5 and 0.19. Collectively, our data suggests that this flow cytometry-based evaluation of epichaperome abundance is a promising tool for detecting epichaperome abundance and personalizing the treatment of PU-H71 in patients with AML. Disclosures Chiosis: Samus Therapeutics: Equity Ownership, Patents & Royalties: Intellectual rights to the PU-FITC assay. Roboz:Trovagene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Otsuka: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orsenix: Consultancy, Membership on an entity's Board of Directors or advisory committees; MEI Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Actinium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amphivena: Consultancy, Membership on an entity's Board of Directors or advisory committees; Argenx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astex: Consultancy, Membership on an entity's Board of Directors or advisory committees; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Eisai: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees. Guzman:Samus Therapeutics: Patents & Royalties: intellectual rights to the PU-FITC assay; Cellectis: Research Funding; SeqRx: Consultancy.

Gli stili APA, Harvard, Vancouver, ISO e altri

50

Huynh, My Hang V., Jennifer Smyth, Modi Wetzler, Brendan Mort, Paul K. Gong, Laura M. Witham, Donald L. Jameson et al. "Remarkable Rate Enhancement of Ligand Substitution Promoted by Geometrical Arrangement of Tridentate “Spectator” Ligands K.J.T. acknowledges Arco Chemical and the National Science Foundation for support of this research. M.H.V.H. gratefully acknowledges postdoctoral fellowship support from the Director's Office of Los Alamos National Laboratory. Los Alamos National Laboratory is operated by the University of California for the U.S. Department of Energy under Contract W-7405-ENG-36. M.H.V.H. also thanks Dr. Beverly K. Hartline (Deputy Laboratory Director, Argonne National Laboratory), Dr. Donald G. Lee (Chemistry Professor, University of Regina, Saskatchewan, Canada, S4S0A2), Dr. R. Thomas Baker (Los Alamos National Laboratory), and Dr. David E. Morris (Los Alamos National Laboratory) for their suggestions and discussions." Angewandte Chemie International Edition 40, n. 23 (3 dicembre 2001): 4469. http://dx.doi.org/10.1002/1521-3773(20011203)40:23<4469::aid-anie4469>3.0.co;2-3.

Testo completo

Gli stili APA, Harvard, Vancouver, ISO e altri

Articoli di riviste sul tema "Bauer Chemical Co"

Cita una fonte nei formati APA, MLA, Chicago, Harvard e in molti altri stili