作者: Natani, Sirisha ; Oudejans, Lieve ; Gallipoli, Paolo ; Cutillas, Pedro ; Copland Iii, John A ; Durko, Jozef ; Boet, Emeline ; Rio-Machin, Ana ; von Kriegsheim, Alex ; Yuneva, Mariia ; Austin, Michael J ; Magee, Aoife M S ; Hazlehurst, Lori ; Fitzgibbon, Jude ; Finch, Andrew J ; Burt, Richard ; Lawson, Hannah ; Tamburini, Jerome ; Woodley, Keith ; Bewicke-Copley, Findlay ; Dembitz, Vilma ; Peck, Barrie ; James, Sophie C ; Kranc, Kamil ; Rouault-Pierre, Kevin ; Rodriguez Blanco, Giovanny ; Sarry, Jean-Emmanuel ; Casado, Pedro ; Wang, Lydia M ; Schwaller, Juerg ; Atkinson, Samantha ; Patel, Bela ; Philippe, Céline ; Campos, Joana ; Pereira-Martins, Diego ; Schuringa, Jan Jacob

AbstractIdentification of specific and therapeutically actionable vulnerabilities, ideally present across multiple mutational backgrounds, is needed to improve acute myeloid leukemia (AML) patients’ outcomes. We identify stearoyl-CoA desaturase (SCD), the key enzyme in fatty acid (FA) desaturation, as prognostic of patients' outcomes and, using the clinical-grade inhibitor SSI-4, show that SCD inhibition (SCDi) is a therapeutic vulnerability across multiple AML models in vitro and in vivo. Multiomic analysis demonstrates that SCDi causes lipotoxicity, which induces AML cell death via pleiotropic effects. Sensitivity to SCDi correlates with AML dependency on FA desaturation regardless of mutational profile and is modulated by FA biosynthesis activity. Finally, we show that lipotoxicity increases chemotherapy-induced DNA damage and standard chemotherapy further sensitizes AML cells to SCDi. Our work supports developing FA desaturase inhibitors in AML while stressing the importance of identifying predictive biomarkers of response and biologically validated combination therapies to realize their full therapeutic potential.

2023-08-07·Molecular pharmaceutics

Radiosynthesis and Preliminary Evaluation of [¹¹C]SSI-4 for the Positron Emission Tomography Imaging of Stearoyl CoA Desaturase 1.

Article

作者: Li, Kang-Po ; Cai, Hancheng ; Parent, Ephraim E ; Knight, Joshua A ; Copland, John A ; Gleba, Justyna J

Stearoyl CoA desaturase 1 (SCD1) is the rate-limiting enzyme for converting saturated fatty acids (SFAs) into monounsaturated fatty acids (MUFAs) and plays a key role in endogenous (de novo) fatty acid metabolism. Given that this pathway is broadly upregulated across many tumor types with an aggressive phenotype, SCD1 has emerged as a compelling target for cancer imaging and therapy. The ligand 2-(4-(2-chlorophenoxy)piperidine-1-carboxamido)-N-methylisonicotinamide (SSI-4) was identified as a potent and highly specific SCD1 inhibitor with a strong binding affinity for SCD1 at our laboratory. We herein report the radiosynthesis of [¹¹C]SSI-4 and the preliminary biological evaluation including in vivo PET imaging of SCD1 in a human tumor xenograft model. Radiotracer [¹¹C]SSI-4 was labeled at the carbamide position via the direct [¹¹C]CO₂ fixation on the Synthra MeIplus module in high molar activity and good radiochemical yield. In vitro cell uptake assays were performed with three hepatocellular carcinoma (HCC) cell lines and three renal cell carcinoma (RCC) cell lines. Additionally, in vivo small animal PET/CT imaging with [¹¹C]SSI-4 and the biodistribution were carried out in a mouse model bearing HCC xenografts. Radiotracer [¹¹C]SSI-4 afforded a 4.14 ± 0.44% (decay uncorrected, n = 10) radiochemical yield based on starting [¹¹]CO₂ radioactivity. The [¹¹C]SSI-4 radiosynthesis time including HPLC purification and SPE formulation was 25 min from the end of bombardment to the end of synthesis (EOS). The radiochemical purity of [¹¹C]SSI-4 was 98.45 ± 1.43% (n = 10) with a molar activity of 225.82 ± 33.54 GBq/μmol (6.10 ± 0.91 Ci/μmol) at the EOS. In vitro cell uptake study indicated all SSI-4 responsive HCC and RCC cell line uptakes demonstrate specific uptake and are blocked by standard compound SSI-4. Preliminary small animal PET/CT imaging study showed high specific uptake and block of [¹¹C]SSI-4 uptake with co-injection of cold SSI-4 in high SCD1-expressing organs including lacrimal gland, brown fat, liver, and tumor. In summary, novel radiotracer [¹¹C]SSI-4 was rapidly and automatedly radiosynthesized by direct [¹¹C]CO₂ fixation. Our preliminary biological evaluation results suggest [¹¹C]SSI-4 could be a promising radiotracer for PET imaging of SCD1 overexpressing tumor tissues.

2022-01-02·Expert Review of Medical Devices3区 · 工程技术

Evaluating adaptation effect in real versus virtual reality environments with people who stutter

3区 · 工程技术

Article

作者: Almudhi, Abdulaziz

INTRODUCTIONThe adaptation effect refers to the gradual reduction of dysfluencies with repeated exposure to a substance. The concept of adaptation was originally defined in light of the reading task. Yet, limited studies have also confirmed the adaptation effect in spontaneous-speech. The reduction in the dysfluencies can be attributed to the reduction in the anxiety, or getting habituated to the content of reading material or due to motor learning.METHODSThis research aimed at measuring the adaptation effect in real and virtual reality (VR) environments for spontaneous-speech and reading. The objectives were divided into two categories. The first objective aimed at comparing the adaption effect for the real and VR environments on the reading task, while the second objective addressed the same objective, but for the spontaneous-speech task. The study involved 24 participants in the age range of 19-33 years. SSI-4 was administered on the participants.CONCLUSIONThe reduction in dysfluencies was seen for both real and VR testing environments. The reduction in the dysfluency was more marked for reading-task compared to spontaneous-speech task. The results shed light on the relationship between adaptation effect and the test environment.

100 项与 SSI-4 相关的药物交易

登录后查看更多信息

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
成人急性髓性白血病	临床前	英国	Queen Mary University of London	2022-12-09
成人急性髓性白血病	临床前	美国	Modulation Therapeutics, Inc.	2022-12-09