Combination of eriocalyxin B and homoharringtonine exerts synergistic anti-tumor effects against t(8;21) AML.

Understanding the molecular pathogenesis of acute myeloid leukemia (AML) with well-defined genomic abnormalities has facilitated the development of targeted therapeutics. Patients with t(8;21) AML frequently harbor a fusion gene RUNX1-RUNX1T1 and KIT mutations as "secondary hit", making the disease one of the ideal models for exploring targeted treatment options in AML. In this study we investigated the combination therapy of agents targeting RUNX1-RUNX1T1 and KIT in the treatment of t(8;21) AML with KIT mutations. We showed that the combination of eriocalyxin B (EriB) and homoharringtonine (HHT) exerted synergistic therapeutic effects by dual inhibition of RUNX1-RUNX1T1 and KIT proteins in Kasumi-1 and SKNO-1 cells in vitro. In Kasumi-1 cells, the combination of EriB and HHT could perturb the RUNX1-RUNX1T1-responsible transcriptional network by destabilizing RUNX1-RUNX1T1 transcription factor complex (AETFC), forcing RUNX1-RUNX1T1 leaving from the chromatin, triggering cell cycle arrest and apoptosis. Meanwhile, EriB combined with HHT activated JNK signaling, resulting in the eventual degradation of RUNX1-RUNX1T1 by caspase-3. In addition, HHT and EriB inhibited NF-κB pathway through blocking p65 nuclear translocation in two different manners, to synergistically interfere with the transcription of KIT. In mice co-expressing RUNX1-RUNX1T1 and KITN822K, co-administration of EriB and HHT significantly prolonged survival of the mice by targeting CD34+CD38- leukemic cells. The synergistic effects of the two drugs were also observed in bone marrow mononuclear cells (BMMCs) of t(8;21) AML patients. Collectively, this study reveals the synergistic mechanism of the combination regimen of EriB and HHT in t(8;21) AML, providing new insight into optimizing targeted treatment of AML.

An AI-Aided Diagnostic Framework for Hematologic Neoplasms Based on Morphologic Features and Medical Expertise.

A morphologic examination is essential for the diagnosis of hematological diseases. However, its conventional manual operation is time-consuming and laborious. Herein, we attempt to establish an artificial intelligence (AI)-aided diagnostic framework integrating medical expertise. This framework acts as a virtual hematological morphologist (VHM) for diagnosing hematological neoplasms. Two datasets were established as follows: An image dataset was used to train the Faster Region-based Convolutional Neural Network to develop an image-based morphologic feature extraction model. A case dataset containing retrospective morphologic diagnostic data was used to train a support vector machine algorithm to develop a feature-based case identification model based on diagnostic criteria. Integrating these 2 models established a whole-process AI-aided diagnostic framework, namely, VHM, and a 2-stage strategy was applied to practice case diagnosis. The recall and precision of VHM in bone marrow cell classification were 94.65% and 93.95%, respectively. The balanced accuracy, sensitivity, and specificity of VHM were 97.16%, 99.09%, and 92%, respectively, in the differential diagnosis of normal and abnormal cases, and 99.23%, 97.96%, and 100%, respectively, in the precise diagnosis of chronic myelogenous leukemia in chronic phase. This work represents the first attempt, to our knowledge, to extract multimodal morphologic features and to integrate a feature-based case diagnosis model for designing a comprehensive AI-aided morphologic diagnostic framework. The performance of our knowledge-based framework was superior to that of the widely used end-to-end AI-based diagnostic framework in terms of testing accuracy (96.88% vs 68.75%) or generalization ability (97.11% vs 68.75%) in differentiating normal and abnormal cases. The remarkable advantage of VHM is that it follows the logic of clinical diagnostic procedures, making it a reliable and interpretable hematological diagnostic tool.

Realization of thousand-second improved confinement plasma with Super I-mode in Tokamak EAST.

Mastering nuclear fusion, which is an abundant, safe, and environmentally competitive energy, is a great challenge for humanity. Tokamak represents one of the most promising paths toward controlled fusion. Obtaining a high-performance, steady-state, and long-pulse plasma regime remains a critical issue. Recently, a big breakthrough in steady-state operation was made on the Experimental Advanced Superconducting Tokamak (EAST). A steady-state plasma with a world-record pulse length of 1056 s was obtained, where the density and the divertor peak heat flux were well controlled, with no core impurity accumulation, and a new high-confinement and self-organizing regime (Super I-mode = I-mode + e-ITB) was discovered and demonstrated. These achievements contribute to the integration of fusion plasma technology and physics, which is essential to operate next-step devices.

Nickel-Catalyzed Cross-Electrophile Coupling of 1,2,3-Benzotriazin-4(3H)-ones with Aryl Bromides.

The nickel-catalyzed cross-electrophile coupling of 1,2,3-benzotriazin-4(3H)-ones with aryl bromides to generate a diverse array of ortho-arylated benzamide derivatives has been developed. The reaction displayed good functional group tolerance with Zn as the reductant. The key to this transformation is the ring opening of benzotriazinones, which undergo a denitrogenative process to obtain various benzamide derivatives (29 examples, 42-93% yield). The scalability of this transformation was demonstrated.

4.6 GHz lower hybrid wave power control system for EAST.

In order to achieve steady state operation in experimental advanced superconducting tokamak (EAST), a 6 MW/4.6 GHz lower hybrid current drive system with twenty-four 250 kW/4.6 GHz high power klystron amplifiers (model VKC7849A) has been developed. A 4.6 GHz lower hybrid wave (LHW) power control system (4.6 GHz LPCS) with continuous wave mode has been set up, which was used to control the LHW power as needed. This paper introduces the architecture and software design of LPCS system, including microwave preamplifier subsystem, power measurement subsystem, power control computers, and so on. Proportional integral differential (PID) closed-loop control time is less than 100 µs due to the use of high-speed acquisition cards and user-programmable Field Programmable Gate Arrays. So far, high power CW operation and power control experiments with PID feedback mode by plasma parameters (beta, loop voltage, and so on) were performed in detail. Results show that 4.6 GHz LPCS is stable and reliable, suggesting that it meets the needs of EAST.