Oncorequisite role of an aldehyde dehydrogenase in the pathogenesis of T-cell acute lymphoblastic leukemia

Aldehyde dehydrogenases (ALDHs) are overexpressed in various types of cancers. One of the ALDH family genes, ALDH1A2, is aberrantly expressed in more than 50% of T-cell acute lymphoblastic leukemia (T-ALL) cases. However, its molecular function and role in T-ALL pathogenesis are largely unknown. ChIP-seq and RNA-seq analyses showed that the oncogenic transcription factor TAL1 and its regulatory partners bind to the intronic regulatory element of the ALDH1A2 gene, directly inducing a T-ALL-specific isoform with enzymatic activity. ALDH1A2 was preferentially expressed in the TAL1-positive T-ALL subgroup. In T-ALL cell lines, depletion of ALDH1A2 inhibited cell viability and induced apoptosis. Interestingly, gene expression and metabolomic profiling revealed that ALDH1A2 supported glycolysis and the TCA cycle, accompanied by NADH production, by affecting multiple metabolic enzymes to promote ATP production. Depletion of ALDH1A2 increased the levels of reactive oxygen species (ROS), while ROS levels were reduced by ALDH1A2 overexpression both in vitro and in vivo. Overexpression of ALDH1A2 accelerated tumor onset and increased tumor penetrance in a zebrafish T-ALL model. Taken together, our results indicate that ALDH1A2 protects against intracellular stress and promotes T-ALL cell metabolism and survival. ALDH1A2 overexpression enables leukemic clones to sustain a hyper-proliferative state driven by oncogenes

ONCOREQUISITE ROLES OF ALDEHYDE DEHYDROGENASE 1A2 IN THE MOLECULAR PATHOGENESIS OF T-CELL ACUTE LYMPHOBLASTIC LEUKEMIA

Ph.DDOCTOR OF PHILOSOPHY (SOM

Analysis of Propagation Characteristics along an Array of Silver Nanorods Using Dielectric Constants from Experimental Data and the Drude-Lorentz Model

In this study, the Fourier series expansion method (FSEM) was employed to calculate the complex propagation constants of plasma structures consisting of infinitely long, silver nanorod arrays in the range of 180–1900 nm, and the characteristics of the complex propagation constant were analyzed in depth. According to the results of FSEM using dielectric constants from Johnson experimental data, a multi-mode frequency band appears in the propagation stage, which can be adopted to achieve a multi-mode communication, multi-mode transceiver, integrated filter with single multi-mode combination. In the meantime, the comparison between the three sets of results with only single mode transmission of the generalized multipole technique (GMT) using dielectric constants from Johnson experimental data, FSEM using dielectric constants from Palik experimental data, and FSEM using dielectric function from Drude–Lorentz model suggested that the results of the four sets of complex propagation constants were well consistent with each other. Furthermore, a finite array of only 40 silver nanorods was studied, and the ability of guided waves when a finite array is excited by a plane wave at a specific wavelength was explored. According to different guiding abilities—propagation, attenuation, and cut off, it can be applied to waveguides, sensor, filters, etc

Oncogenic transcriptional program driven by TAL1 in T-cell acute lymphoblastic leukemia

10.1007/s12185-018-2518-zINTERNATIONAL JOURNAL OF HEMATOLOGY10915-1

Large-scale material extrusion-based additive manufacturing of short carbon fibre-reinforced silicon carbide ceramic matrix composite preforms

Large-scale short carbon fibre-reinforced silicon carbide (Csf/SiC) ceramic matrix composites (CMCs) have important applications in the field of aerospace engineering. This study proposed the use of material extrusion based additive manufacturing to fabricate large-scale Csf/SiC CMC preforms. In this paper, we determined how the key material extrusion parameters, including solid loading, nozzle diameter and layer height impact the stability of the additively manufactured Csf/SiC CMCs. The solid loading significantly influenced the stability of the Csf/SiC CMCs, and the slurry with 50 vol.% solid loading was better for additive manufacturing. The layer height played a significant role in the void formation in CMCs. It was appropriate for structure retention to set the layer height as 60–75% of the nozzle diameter. The effect of angle from vertical on the stability of out-of-plane structure was also investigated. When the angle was over 40o, the out-of-plane structure additively manufactured without supports tended to collapse. Large-scale Csf/SiC CMC preforms with out-of-plane structures were finally successfully fabricated. This study is believed to provide some fundamental understanding for the fabrication of large-scale fibre-reinforced ceramic matrix composites

Results of Lung Cancer Screening with Low-dose Computed Tomography and Exploration of Risk Factors in Guangzhou

Background and objective Both of lung cancer incidence and mortality rank first among all cancers in China. Previous lung cancer screening trials were mostly selective screening for high-risk groups such as smokers. Non-smoking women accounted for a considerable proportion of lung cancer cases in Asia. This study aimed to evaluate the outcome of community-based mass screening in Guangzhou and identify the high-risk factors for lung cancer. Methods Residents aged 40-74 years in Guangzhou were screened with low-dose computed tomography (LDCT) for lung cancer and the pulmonary nodules were classified and managed according to China National Lung Cancer Screening Guideline with Low-dose Computed Tomography (2018 version). The detection rate of positive nodules was calculated. Before the LDCT examination, residents were required to complete a "lung cancer risk factors questionnaire". The risk factors of the questionnaire were analyzed by least absolute shrinkage and selection operator (LASSO) penalized Logistic regression analysis. Results A total of 6256 residents were included in this study. 1228 positive nodules (19.63%) and 117 lung cancers were confirmed, including 6 cases of Tis, 103 cases of stage I (accounting for 88.03% of lung cancer). The results of LASSO penalized Logistic regression analysis indicated that age ≥50 yr (OR=1.07, 95%CI: 1.06-1.07), history of cancer (OR=3.29, 95%CI: 3.22-3.37), textile industry (OR=1.10, 95%CI: 1.08-1.13), use coal for cooking in childhood (OR=1.14, 95%CI: 1.13-1.16) and food allergy (OR=1.10, 95%CI: 1.07-1.13) were risk factors of lung cancer for female in this district. Conclusion This study highlighted that numerous early stages of lung cancer cases were detected by LDCT, which could be applied to screening of lung cancer in women. Besides, age ≥50 yr, personal history of cancer, textile industry and use coal for cooking in childhood are risk factors for women in this district, which suggested that it’s high time to raise the awareness of early lung cancer screening in this group

Inhibition of BTK and PI3Kδ impairs the development of human JMML stem and progenitor cells

Juvenile myelomonocytic leukemia (JMML) is an aggressive myeloproliferative neoplasia that lacks effective targeted chemotherapies. Clinically, JMML manifests as monocytic leukocytosis, splenomegaly with consequential thrombocytopenia. Most commonly, patients have gain-of-function (GOF) oncogenic mutations in PTPN11 (SHP2), leading to Erk and Akt hyperactivation. Mechanism(s) involved in co-regulation of Erk and Akt in the context of GOF SHP2 are poorly understood. Here, we show that Bruton's tyrosine kinase (BTK) is hyperphosphorylated in GOF Shp2-bearing cells and utilizes B cell adaptor for PI3K to cooperate with p110δ, the catalytic subunit of PI3K. Dual inhibition of BTK and p110δ reduces the activation of both Erk and Akt. In vivo, individual targeting of BTK or p110δ in a mouse model of human JMML equally reduces monocytosis and splenomegaly; however, the combined treatment results in a more robust inhibition and uniquely rescues anemia and thrombocytopenia. RNA-seq analysis of drug-treated mice showed a profound reduction in the expression of genes associated with leukemic cell migration and inflammation, leading to correction in the infiltration of leukemic cells in the lung, liver, and spleen. Remarkably, in a patient derived xenograft model of JMML, leukemia-initiating stem and progenitor cells were potently inhibited in response to the dual drug treatment