Selumetinib overcomes gefitinib primary and acquired resistance by regulating MIG6/STAT3 in NSCLC

Xiaoping Song,Lina Wang,Wei Tang,Luyao Yuan,Qingchao Liu,Jing Li,Daidi Fan 대한약학회 2023 Archives of Pharmacal Research Vol.46 No.12

Gefitinib, as the first-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has achieved great advances in the treatment of non-small cell lung cancer (NSCLC), but drug resistance will inevitably occur. Therefore, exploring the resistance mechanism of gefitinib and developing new combination treatment strategies are of great importance. In our study, the results showed that selumetinib (AZD6244) synergistically inhibited the proliferation of NSCLC with gefitinib. Selumetinib also enhanced gefitinib-induced apoptosis and migration inhibition ability in gefitinib-resistant lung cancer cell lines. Subsequently, the negative regulation between MIG6 and STAT3 was observed and verified through the STRING database and western blotting assays. Sustained activation of STAT3 was significantly downregulated when co-treatment with selumetinib in gefitinib-resistant cells. However, the downregulation of p-STAT3, resulting from the combination of selumetinib and gefitinib was counteracted by the deletion of MIG6, suggesting that selumetinib enhanced gefitinib sensitivity by regulating MIG6/STAT3 in NSCLC. In contrast, p-STAT3 was further inhibited after treatment with gefitinib and selumetinib when MIG6 was overexpressed. Furthermore, the combined administration of selumetinib and gefitinib effectively promoted the sensitivity of lung cancer xenografts to gefitinib in vivo, and the tumor inhibition rate reached 81.49%, while the tumor inhibition rate of the gefitinib monotherapy group was only 31.95%. Overall, MIG6/STAT3 negative regulation plays an important role in the sustained activation of STAT3 and the resistance to EGFR-TKIs. Our study also suggests that EGFR-TKIs combined with MEK1/2 inhibitors, such as selumetinib, may be beneficial to those NSCLC patients who develop a primary or acquired resistance to EGFR-TKIs, providing theoretical support for combining TKIs and selumetinib in clinical cancer treatment.

Compound heterozygous mutations of NDUFV1 identified in a child with mitochondrial complex I deficiency

Tang Xiaojun,Xu Wuhen,Song Xiaozhen,Ye Haiyun,Ren Xiang,Yang Yongchen,Zhang Hong,Wu Shengnan,Lan Xiaoping 한국유전학회 2022 Genes & Genomics Vol.44 No.6

Background: Mitochondrial complex I deficiency (MCID) is the most common biochemical defect identified in childhood with mitochondrial diseases, mainly including Leigh syndrome, encephalopathy, macrocephaly with progressive leukodystrophy, hypertrophic cardiomyopathy and myopathy. Objective: To identify genetic cause in a patient with early onset autosomal recessive MCID. Methods: Trio whole-exome sequencing was performed and phenotype-related data analyses were conducted. All candidate mutations were confirmed by Sanger sequencing. Results: Here we report a child of Leigh syndrome presented with global developmental delay, progressive muscular hypotonia and myocardial damage. A missense mutation c.118C > T (p.Arg40Trp) and a previously reported mutation c.1157G > A (p.Arg386His) in NDUFV1 have been identified as compound heterozygous in the patient. The mutation p.Arg386His is closely associated with the impairment of 4Fe-4S domain and this mutation has been reported pathogenic. The c.118C > T mutation has not been reported in ClinVar and HGMD database. In silico protein analyses showed that p.Arg40 is highly conserved in a wide range of species, and the amino acid substitution p.Trp40 largely decreases the stability of NDUFV1. In addition, the mutation has not been detected in the Asian populations and it was predicted to be deleterious by numerous prediction tools. Conclusion: This research expands the mutation spectrum of NDUFV1 and substantially provides an early and accurate diagnosis basis of MCID, which would benefit subsequently effective genetic counseling and prenatal diagnosis for future reproduction of the family.

Effects of Long-Term Fertilizer Practices on Rhizosphere Soil Autotrophic CO₂-Fixing Bacteria under Double Rice Ecosystem in Southern China

( Haiming Tang ),( Li Wen ),( Lihong Shi ),( Chao Li ),( Kaikai Cheng ),( Weiyan Li ),( Xiaoping Xiao ) 한국미생물생명공학회 2022 Journal of microbiology and biotechnology Vol.32 No.10

Soil autotrophic bacterial communities play a significant role in the soil carbon (C) cycle in paddy fields, but little is known about how rhizosphere soil microorganisms respond to different long-term (35 years) fertilization practices under double rice cropping ecosystems in southern China. Here, we investigated the variation characteristics of rhizosphere soil RubisCO gene cbbL in the double rice ecosystems of in southern China where such fertilization practices are used. For this experiment we set up the following fertilizer regime: without any fertilizer input as a control (CK), inorganic fertilizer (MF), straw returning (RF), and organic and inorganic fertilizer (OM). We found that abundances of cbbL, 16S rRNA genes and RubisCO activity in rhizosphere soil with OM, RF and MF treatments were significantly higher than that of CK treatment. The abundances of cbbL and 16S rRNA genes in rhizosphere soil with OM treatment were 5.46 and 3.64 times higher than that of CK treatment, respectively. Rhizosphere soil RubisCO activity with OM and RF treatments increased by 50.56 and 45.22%, compared to CK treatment. Shannon and Chao1 indices for rhizosphere soil cbbL libraries with RF and OM treatments increased by 44.28, 28.56, 29.60, and 23.13% compared to CK treatment. Rhizosphere soil cbbL sequences with MF, RF and OM treatments mainly belonged to Variovorax paradoxus, uncultured proteobacterium, Ralstonia pickettii, Thermononospora curvata, and Azoarcus sp.KH33C. Meanwhile, cbbL-carrying bacterial composition was obviously influenced by soil bulk density, rhizosphere soil dissolved organic C, soil organic C, and microbial biomass C contents. Fertilizer practices were the principal factor influencing rhizosphere soil cbbL-carrying bacterial communities. These results showed that rhizosphere soil autotrophic bacterial communities were significantly changed under conditions of different long-term fertilization practices Therefore, increasing rhizosphere soil autotrophic bacteria community with crop residue and organic manure practices was found to be beneficial for management of double rice ecosystems in southern China.

Effects of short-term soil tillage management on activity and community structure of denitrifiers under double-cropping rice field

Haiming Tang,Chao Li,Kaikai Cheng,Lihong Shi,Li Wen,Xiaoping Xiao,Yilan Xu,Weiyan Li,Ke Wang 한국미생물·생명공학회 2020 Journal of microbiology and biotechnology Vol.30 No.11

Soil physical and chemical characteristics, soil potential denitrification rates (PDR), community composition and nirK-, nirS- and nosZ-encoding denitrifiers were studied by using MiSeq sequencing, quantitative polymerase chain reaction (qPCR), and terminal restriction fragment polymorphism (T-RFLP) technologies base on short-term (5-year) tillage field experiment. The experiment included four tillage treatments: conventional tillage with crop residue incorporation (CT), rotary tillage with crop residue incorporation (RT), no-tillage with crop residue retention (NT), and rotary tillage with crop residue removed as control (RTO). The results indicated that soil organic carbon, total nitrogen and NH4 +-N contents were increased with CT, RT and NT treatments. Compared with RTO treatment, the copies number of nirK, nirS and nosZ in paddy soil with CT, RT and NT treatments were significantly increased. The principal coordinate analysis indicated that tillage management and crop residue returning management were the most and the second important factors for the change of denitrifying bacteria community, respectively. Meanwhile, this study indicated that activity and community composition of denitrifiers with CT, RT and NT treatments were increased, compared with RTO treatment. This result showed that nirK, nirS and nosZ-type denitrifiers communities in crop residue applied soil had higher species diversity compared with crop residue removed soil, and denitrifying bacteria community composition were dominated by Gammaproteobacteria, Deltaproteobacteria, and Betaproteobacteria. Therefore, it is a beneficial practice to increase soil PDR level, abundance and community composition of nitrogen-functional soil microorganism by combined application of tillage with crop residue management.

Engineering Realization of Full Attitude System Based On GPS Carrier Phase and MEMS IMU

Kanghua Tang,Meiping Wu,Xiaoping Hu 한국항해항만학회 2006 한국항해항만학회 학술대회논문집 Vol.1 No.-

This paper describes the design and realization of full attitude system based on MEMS IMU and GPS carrier phase. The work can be divided into two parts: First, initial heading is determined by using two GPS receivers. And this paper discusses the usage of space geometry conditions to reduce the range of ambiguity search. The method presented in this paper was tested on the static. On the static condition, an accuracy better than 0.06 degrees for heading for 3.48m long baseline has been achieved. Integration of GPS and low cost MEMS IMU are used to realize the real-time heading attitude system. Second, level attitude (pitch and roll) is determined using the method of frequency-velocity for the feedback control. At the same time, the method using the attitude based on MEMS IMU to help determination of the range of ambiguity search is proposed. The results done on the sea show that an alternative means to provide real-time, cost-effective, accurate and reliable attitude information for attitude surveys. Though motivated by a big ships application, the design can be applied to other vehicles.

Grain Morphology and Orientation Effect on the High‑Temperature Tensile Behavior of Directionally Solidified Magnesium Alloy

Qin Tang,Xiaoping Lin,Shengshi Zhao,Yi Niu,Heng Sun,Yun Dong 대한금속·재료학회 2020 METALS AND MATERIALS International Vol.26 No.4

Columnar-structured Mg97.27Zn2.54Y0.19alloy with the preferred growth direction of ⟨22̄45⟩ and ⟨12̄33⟩, andMg98.01Zn1.84Y0.13Zr0.03alloy with the preferred growth direction of ⟨11̄20⟩ were prepared using the directional solidificationtechnique and then tensile tested at 250–300 °C. The results showed that the Mg97.27Zn2.54Y0.19alloy with columnar dendriticstructure experienced a significant deformation strengthening period when stretched at 250 °C, and a typical dynamicrecrystallization stage at 300 °C, which were mainly accounted for its well-developed secondary dendrites, a large numberof branch-shaped second phases distributed in the longitudinal grain boundary, and less granular second phases existingin the crystal. While in the whole test temperature range (250–300 °C), the stress–strain curves of Mg98.01Zn1.84Y0.13Zr0.03alloys with cellular dendritic crystals showed a steady deformation state because of the second phases with strip distributingin the longitudinal grain boundary, which was induced by a balance between the deformation strengthening and the dynamicrecrystallization. Especially at 300 °C, this steady deformation state existed in the strain of 5.6%–36%. The good uniformplastic deformation was closely related to the small misorientations between columnar grains, the associated movement ofgrains by grain boundary slipping, and the less percentage of dynamically recrystallized grains which could do harm to theorientation continuity of the columnar crystals.

Attrition behavior of fine particles in a fluidized bed with bimodal particles: Influence of particle density and size ratio

Zeeshan Nawaz,Tang Xiaoping,Xiaobo Wei,Fei Wei 한국화학공학회 2010 Korean Journal of Chemical Engineering Vol.27 No.5

To process the solid particulates in fluidized bed and slurry phase reactors, attrition is an inevitable consequence and is therefore one of the preliminary parameters for the catalyst design. In this paper, the mechanical degradation propensity of the zeolite catalysts (particles) was investigated in a bimodal distribution environment using a Gas Jet Attrition - ASTM standard fluidized bed test (D-5757). The experimentation was conducted in order to explore parameters affecting attrition phenomena in a bimodal fluidization. In a bimodal fluidization system, two different types of particles are co-fluidized isothermally. The air jet attrition index (AJI) showed distinct increases in the attrition rate of small particles in a bimodal fluidization environment under standard operating conditions, in comparison with single particle. A series of experiments were conducted using particles of various sizes, with large particles of different densities and sizes. Experimental results suggest that the relative density and particle size ratio have a significant influence on attrition behavior during co-fluidization. Therefore a generalized relationship has been drawn using Gwyn constants;those defined material properties of small particles. Moreover, distinct attrition incremental phenomenon was observed during co-fluidization owing to the change in collision pattern and impact, which was associated with relative particle density and size ratios.

Influence of operating conditions, Si/Al ratio and doping of zinc on Pt-Sn/ZSM-5 catalyst for propane dehydrogenation to propene

Zeeshan Nawaz,Tang Xiaoping,Fei Wei 한국화학공학회 2009 Korean Journal of Chemical Engineering Vol.26 No.6

The direct catalytic dehydrogenation of propane to propene is an important route to enhance propene production. In the present experimentation the focus was to investigate the influence of incipient operating conditions, Si/Al ratio of zeolite support and effect of zinc doping on Pt-Sn/ZSM-5 catalyst performance. The catalysts were extensively investigated by reaction tests in a continuous plug-flow quartz micro-reactor. The experimental data shows that the manipulation of operating parameters significantly improves the reaction performance, while huge dynamicity is observed in product distribution. Reaction temperature, 600℃ is found to be most suitable, while increasing the weight hourly space velocity (WHSV), propene selectivity improves at the expense of lower conversion. The OPE was drawn to observe overall reaction network. It was found that the acidity of zeolitic support plays a more important role in achieving desired product selectivity than additional metallic content. Accordingly, the Si/Al ratio of the ZSM-5 zeolite the pro- pene selectivity was enhanced, leading to remarkable improvement in the total olefins selectivity which was remarkably improved owing to a suppression of secondary reactions. At Si/Al ratio 300, the selectivity of propene and total olefins becomes stable at 73% and 90% respectively. The doping of Zn on Pt-Sn/ZSM-5 improves only propene selectivity, but is severely affected by quick deactivation.

Tuber borchii Shapes the Ectomycorrhizosphere Microbial Communities of Corylus avellana

( Xiaolin Li ),( Xiaoping Zhang ),( Mei Yang ),( Lijuan Yan ),( Zongjing Kang ),( Yujun Xiao ),( Ping Tang ),( Lei Ye ),( Bo Zhang ),( Jie Zou ),( Chengyi Liu ) 한국균학회 2019 Mycobiology Vol.47 No.2

In this study, eight-month-old ectomycorrhizae of Tuber borchii with Corylus avellana were synthesized to explore the influence of T. borchii colonization on the soil properties and the microbial communities associated with C. avellana during the early symbiotic stage. The results showed that the bacterial richness and diversity in the ectomycorrhizae were significantly higher than those in the control roots, whereas the fungal diversity was not changed in response to T. borchii colonization. Tuber was the dominant taxon (82.97%) in ectomycorrhizae. Some pathogenic fungi, including Ilyonectria and Podospora, and other competitive mycorrhizal fungi, such as Hymenochaete, had significantly lower abundance in the T. borchii inoculation treatment. It was found that the ectomycorrhizae of C. avellana contained some more abundant bacterial genera (e.g., Rhizobium, Pedomicrobium, Ilumatobacter, Streptomyces, and Geobacillus) and fungal genera (e.g., Trechispora and Humicola) than the control roots. The properties of rhizosphere soils were also changed by T. borchii colonization, like available nitrogen, available phosphorus and exchangeable magnesium, which indicated a feedback effect of mycorrhizal synthesis on soil properties. Overall, this work highlighted the interactions between the symbionts and the microbes present in the host, which shed light on our understanding of the ecological functions of T. borchii and facilitate its commercial cultivation.

Metallogenesis and hydrothermal evolution of the Saibo copper deposit in the western Tianshan: evidence from fluid inclusions, H-O-S isotopes, and Re-Os geochronology

Bowen Zhang,Xiaofei Tang,Chuan Chen,Xiaoping Gong,Chunmei Su 한국지질과학협의회 2023 Geosciences Journal Vol.27 No.1

The Saibo copper polymetallic deposit, located in the West Tianshan Sailimu-Sitaihaiquan copper lead and zinc ore belt, is a new breakthrough in medium-large copper mine. Through the thin section authentication and the thermometric analysis of fluid inclusion, it is concluded that skarnization was developed in this deposit, the mineralization stage can be divided into retrograde skarn stage (S1), quartz-sulfide stage (S2) and quartz-carbonate stage (S3). Fluid inclusions (FIs) were distinguished as liquid-rich aqueous FIs (LV-type), vapor-rich aqueous FIs (VL-type), and NaCl daughter mineral-bearing three phase FIs (S-type). The mineralization fluids indicate that the initial stage (S1 stage) is of high temperature and high salinity, with a handful of metallicmatters. During the main metallogenic stage (S2 stage), the meteoric water is mixed, the temperature and salinity gradually decrease, the fluid is distinctly boiling, and a large amount of metallic matters are precipitated, and then to the S3 stage, when the temperature and salinity decrease along with the carbonation. Chalcopyrite Re-Os dating yielded a mineralization age of 379.2 ± 7.7 Ma, which corresponds well with the zircon U-Pb age (385.9 ± 1.3 Ma) of the granite porphyry. The C-H-O isotopes indicate that the ore-forming fluid was dominated by initial mixed magmatic water in the early stage and by meteoric water in the late stage, and C is derived from limestone strata metasomatized by magmatic fluids. The S and Pb isotopes indicate that the ore-forming materials are derived from the mixed crust-mantle source, of which S is almost entirely derived from the mantle, while Pb is mainly derived from the crustal material of the orogenic belt. On the whole, the Saibo copper deposit is a typical calcium skarn type deposit, which formed in the shallower setting at active continental margin in the Late Devonian period.