To explore the synergistic effect of vitamin D deficiency and sarcopenia on vertebral osteoporostic fracture (VF) in patients with rheumatoid arthritis (RA). A total of 188 patients with RA and 158 control subjects were enrolled. Bone mineral density (BMD) at the total hip, neck of femur, lumbar vertebra 1–4, and skeletal muscle mass was measured by dual energy X-ray absorptiometry (DXA) and biological electrical impedance, respectively. Serum 25(OH)D was tested by electrochemiluminescence. The prevalence of VF and osteoporosis (OP) were compared between RA and controls. The synergism of sarcopenia and vitamin D deficiency on VF in patients with RA was tested by χ2 test and logistic regression. The prevalence of OP at all measured sites and VF in RA patients were all higher than those in controls (P < 0.0001). The incidence of VF in RA either with sarcopenia or with vitamin D deficiency was higher than for those without sarcopenia or without vitamin D deficiency (χ2 = 5.069, P = 0.027, χ2 = 8.822, P = 0.001). Age, disease duration, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), DAS28, health assessment questionnaire (HAQ), Sharp score, and body mass index (BMI) were significantly different between RA with sarcopenia or not (P < 0.05). Logistic regression analysis found that age (OR = 1.095, 95%, CI: 1.044–1.150, P < 0.0001) was a significant risk factor for VF in patients with RA, while high skeletal muscle mass (SMI) (OR = 0.513, 95% CI: 0.327–0.804, P = 0.004) was a protective factor for VF in RA patients. VF, sarcopenia, and vitamin D deficiency are common in patients with RA. Sarcopenia and vitamin D deficiency may be risk factors for the incidence of VF in RA patients. • RA patients had a higher incidence of OP and VF, also a high prevalence of sarcopenia and vitamin D deficiency. • Vitamin D deficiency and sarcopenia may might have a synergistic effect on VF in RA. • Aging and sarcopenia are risk factors for VF in RA patients, and sarcopenia were associated with disease activity and structural damage.

Purpose:Non-steroidal anti-inflammatory drugs (NSAIDs) have generally been viewed as first-line therapy for axial spondyloarthritis (axSpA). Imrecoxib is a selective COX-2 inhibitor developed independently in China. At present, only one single-center RCT trial has shown that imrecoxib is equally effective as celecoxib in treating axSpA. Based on real-world data, our study aims to explore the efficiency of imrecoxib and TNF inhibitor (TNFi) combined with imrecoxib in treating axSpA. Patients and Methods:A total of 163 patients with axSpA who had more than two follow-up records in 6 months and treated with imrecoxib/celecoxib/TNFi combined with imrecoxib/TNFi combined with celecoxib from the First Affiliated Hospital of Anhui Medical University SpA Real World Database (AHSpA) were selected for analysis of our study. The linear mixed model was used to compare efficacy indexes before and after treatment and between different groups, adjust baseline measurement value and follow-up time. The Kaplan-Meier survival analysis was used to identify the differences in cumulative clinical remission rates between groups with different treatment at the follow-up period. Results:Results showed that after treatment ASDAScrp was slightly improved in imrecoxib group and celecoxib group within 6 months (p < 0.05). CRP, ESR, BASDAI, ASDAScrp, BASFI, occiput to wall distance and finger floor distance all significantly improved in TNFi combined with imrecoxib group and TNFi combined with celecoxib group within 6 months (all p < 0.05). According to the Kaplan-Meier survival curve and Log rank test analysis, the clinical remission rate was not significantly different between different treatment during 24-month follow-up (all p > 0.05). Conclusion:ASDAScrp improved slightly within 6 months after treatment with imrecoxib, and TNFi combined with imrecoxib significantly improved multiple effect indexes in axSpA patients. The efficacy of imrecoxib and celecoxib in the treatment of axSpA is equivalent. Also, they have the same efficacy after being combined with TNFi.

To investigate the rate of subclinical inflammation in patients with axial spondyloarthritis (axSpA) with nonsteroidal anti-inflammatory drug (NSAID)/anti-tumor necrosis factor (TNF)-α drug-induced clinical remission and to explore factors influencing clinical and imaging remission. One hundred twenty-five patients with axSpA followed up for at least 6 months were enrolled in this prospective study and randomly divided into two groups. Ninety patients were treated with anti-tumor necrosis factor (TNF)-α or anti-TNF-α combined with nonsteroidal anti-inflammatory drugs (NSAIDs) (anti-TNF-α treatment group), and thirty-five patients were treated with only NSAIDs (non anti-TNF-α treatment group). The improvements in the clinical remission rate, imaging remission rate, and disease parameters before and after the different treatments were compared. Risk factors for clinical and imaging remission were analyzed by multivariate logistic regression analysis. The clinical and imaging remission rate was increased after treatment especially in the anti-TNF-α group (P < 0.001). The remission rate of imaging in the group with clinical remission was higher than that in the group with clinical non-remission (P < 0.05). After treatment, the remission rates of imaging in the clinical remission and non-remission group were significantly higher than those before treatment (P < 0.0001). The results of multivariate logistic regression analysis showed that higher CRP was a risk factor for failure of clinical remission in axSpA (OR = 2.034, 95% CI:1.595 ~ 2.617, P < 0.001), while higher ASDAScrp was a risk factor for failure of imaging remission (OR = 1.306, 95% CI:1.026 ~ 1.688, P < 0.05). Anti-TNF-α treatment was a protective factor for both clinical (OR = 0.234, 95% CI:0.091 ~ 0.605, P < 0.05) and imaging remission (OR = 0.511, 95% CI:0.286 ~ 0.914, P < 0.05). Even after regular treatment, some clinical remission patients continued to have evidence of subclinical inflammation. Higher CRP and ASDAScrp are risk factors for clinical and imaging non-remission in axSpA respectively, Continuous NSAID treatment (more than 1 year) can effectively improve clinical and MRI inflammation in patients, but anti-TNF-α treatment is more beneficial for clinical and imaging remission.

This work aims to analyze and construct a novel competing endogenous RNA (ceRNA) network in ankylosing spondylitis (AS) with bone bridge formation, lncRNA. Using RNA sequencing and bioinformatics, we analyzed expression profiles of long noncoding RNAs (lncRNAs), microRNAs (miRNAs), and mRNAs in whole blood cells from 5 AS patients and 3 healthy individuals. Next, we verified the expression levels of candidate lncRNAs in 97 samples using the ΔΔCt value of real-time quantitative polymerase chain reaction (qRT-PCR). We used multivariate logistic regression analysis to screen lncRNAs and clinical indicators for use in the prediction model. Both SPSS 24.0 and R software were used for data analysis and prediction model construction. The results showed that compared with the normal controls, 205 long noncoding RNAs (lncRNAs), 961 microRNAs (miRNAs), and 200 mRNAs (DEmRNAs) were differentially expressed in the AS patients. We identified lncRNA 122K13.12 and lncRNA 326C3.7 among 205 lncRNAs differentially expressed between AS patients and healthy humans. Then, we noted that 30 miRNAs and five mRNAs formed a ceRNA network together with these two lncRNAs. These ceRNA networks might regulate the tumor necrosis factor (TNF) signaling pathway in AS development. In addition, the expression level of lncRNA 122K13.12 and lncRNA 326C3.7 correlated with various structural damage indicators in AS. Specifically, the lncRNA 326C3.7 expression level was an independent risk factor in bone bridge formation [area under the ROC curve (AUC) = 0.739 (0.609–0.870) and p = 0.003], and the best Youden Index was 0.405 (sensitivity = 0.800 and specificity = 0.605). Moreover, we constructed a lncRNA-based nomogram that could effectively predict bone bridge formation [AUC = 0.870 (0.780–0.959) and p < 0.001, and the best Youden Index was 0.637 (sensitivity = 0.900 and specificity = 0.737)]. In conclusion, we uncovered a unique ceRNA signaling network in AS with bone bridge formation and identified novel biomarkers and prediction models with the potential for clinical applications.

4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, has been demonstrated that it had a variety of anti-tumor effects by exerting regulation on cellular proliferation, apoptosis and differentiation. Here, we found that ATPR is critical for alleviating myelodysplastic syndrome (MDS) and acute myelogenous leukemia. USO1, vesicle transport factor, belongs to tether protein family and involved in endoplasmic reticulum to Golgi trafficking of protein which is important to tumorigenesis. How USO1 contribute to MDS remain elusive. USO1 is aberrantly activated in MDS and AML in vivo and vitro, aberration of which might be a dominant mechanism for MDS cell survival. During the ATPR-induced remission of MDS, in vitro, USO1 presents a time and concentration-dependent decrease. Silencing of USO1 promotes myeloid differentiation of MDS cells and inhibits MDS cellular proliferation while USO1 over-expression has the opposite effect, suggesting that reduction of USO1 enhances the sensitivity of SKM-1 cells to ATPR treatment. Mechanistically, USO1 exerts its oncogenic role by inactivating Raf/ERK signaling, while ATPR is access to revise it. Notably, the activity of Raf/ERK pathway is required for the development and maintenance of MDS cell proliferation. Collectively, our results demonstrate the USO1- Raf/ERK signaling axis in MDS and highlight the negative role of USO1 in ATPR-regulated remission of MDS.

Epidemiological evidence suggests that the etiology and pathogenesis of rheumatoid arthritis (RA) are closely associated with estrogen metabolism and deficiency. Estrogen protects against articular damage. Estradiol replacement therapy ameliorates local inflammation and knee joint swelling in ovariectomized models of RA. The mechanistic basis for the protective role of 17β-estradiol (17β-E2) is poorly understood. Acid-sensing ion channel 1a (ASIC1a), a sodium-permeable channel, plays a pivotal role in acid-induced articular chondrocyte injury. The aims of this study were to evaluate the role of 17β-E2 in acid-induced chondrocyte injury and to determine the effect of 17β-E2 on the level and activity of ASIC1a protein. Results showed that pretreatment with 17β-E2 attenuated acid-induced damage, suppressed apoptosis, and restored mitochondrial function. Further, 17β-E2 was shown to reduce protein levels of ASIC1a through the ERα receptor, to protect chondrocytes from acid-induced apoptosis, and to induce ASIC1a protein degradation through the autophagy-lysosomal pathway. Taken together, these results show that the use of 17β-E2 may be a novel strategy for the treatment of RA by reducing cartilage destruction through down-regulation of ASIC1a protein levels.

Objective:To explore the correlation between sarcopenic obesity and disease activity, osteoporosis in patients with rheumatoid arthritis (RA).Methods:Four hundred and eighteen RA patients from January 2016 to December 2018 were enrolled into the study. One hundred and fifty-six age and sex-matched normal subjects were enrolled as control group. Clinical and laboratory indicators in RA patients were also recorded in detail. Bone mineral density (BMD) at lumbar vertebra and total hip were detected by dual energy X-ray absorptiometry (DEXA) in RA patients and control group, skeletal muscle mass and body fat percentage (PBF) were measured by bioelectrical electrical impedance. All individuals were divided into 4 groups (normal, obesity, sarcopenia, sarcopenic obesity) according to the presence of PBF and sarcopenia. Numerical data and categorical data comparisons were analyzed using χ2 test, non-parametric test, correlation analysis and logistic regression analysis test. Results:① Median of PBF in RA patients was higher than that in the control group ( Z=1.993 , P=0.046). There were obvious differences in the composition ratio of different sarcopenic obesity groups between the two groups ( χ2=100.575, P<0.01). ② There was no significant difference in sarcopenic obesity composition among groups with different disease activity (including in low disease activity, moderate disease activity and high disease activity) in RA patients (normal, obesity, sarcopenia, sarcopenic obesity, χ2=9.577, P=0.144). ③ Among different sarcopenic obesity groups, the erythrocyte sedimentation rate (ESR), disease activity score in 28 joints (DAS28) and Healthassessment questionnaire (HAQ) levels of RA patients were significantly different ( P<0.05), which were higher in sarcopenia and sarcopenic obesity groups. There was no significant difference about disease activity indicators in RA pa-tients among different sarcopenic obesity groups ( P>0.05). ④ Among different sarcopenic obesity groups, BMD of RA patients was significantly different ( P<0.01), with a trend of gradual decreasing. Incidences of osteoporosis (OP) were significantly different among different sarcopenic obesity groups in RA ( P=0.02), which was higher in sarcopenia and sarcopenia obesity groups. ⑤ Among different sarcopenia obesity groups (normal, obesity, sarcopenia, sarcopenic obesity), X-ray staging ratio {[normal group (stage Ⅰ (28.6%): stage Ⅱ (23.8%): stage Ⅲ (32.1%): stage Ⅳ (15.5%)]; obesity group (stage Ⅰ (27.2%): stage Ⅱ (13.6%): stage Ⅲ (35.0%): stage Ⅳ (24.3%)]: sarcopenia group [(stage Ⅰ (16.7%): stage Ⅱ (15.3%): stage Ⅲ (36.1%): stage Ⅳ (31.9%)]: sarcopenic obesity group (stage Ⅰ (9.7%): stage Ⅱ (21.5%): stage Ⅲ (34.0%): stage Ⅳ (34.7%); χ2=26.002, P<0.01]} and sharp scores were sign-ificantly different in RA patients [10.00(2.00, 47.00); 14.00(2.00, 71.00); 48.00 (12.00, 111.00); 55.00 (7.00, 130.00), Z=29.240, P<0.01], with a trend of gradual increasing. ⑥ Correlation analysis showed that PBF was positively correlated with joint function ( r=0.124, P=0.007), X-ray staging ( r=0.192, P<0.01) of both hands and Sharp scores ( r=0.179, P<0.01) of RA patients. There were negative linear correlations between PBF and BMD (femoral neck and total hip) in patients with RA ( P<0.01). ⑦ Logistic regression analysis revealed that female, advanced age and sarcopenia obesity were risk factors for OP in RA patients ( P<0.01). Conclusion:Incidence of sarcopnic obesity is increased in RA patients, which is closely associated with disease activity and OP in RA patients.

Objective:To investigate the synergistic effect of sarcopenia and osteoporosis on the occurrence of spinal osteoporotic fracture (OPF) in patients with rheumatoid arthritis (RA).Methods:A total of 389 hospitalized RA patients and 156 age and sex-matched normal subjects (control group) were recruited. Dual energy X-ray absorptiometry (DEXA) method was used to measure bone mineral density (BMD) of lumbar spine and hip, and bioelectrical impedance method was applied to determine skeletal muscle mass of limbs. X-ray examination of spin was conducted and spinal OPF was diagnosed according to semi-quality method. Student's t test was used for comparison of measurement date between the two groups, χ2 test was used for comparison of intergroup rates, and Logistic Regression(Backward LR) method was used for multivariate Regression analysis of binomial classification data. Results:BMD of all test sites in RA patients was significantly lower than that in the control group ( P<0.01). The incidence of total OP in RA group was significantly higher than that in the control group [(32.9% vs 12.8%), χ2=22.706, P<0.01]. A total of 84 patients with RA developed spinal OPF, with an incidence of 21.6% which was higher than that in the control group [(3.8%), χ2=25.439, P<0.01]. The incidence of sarcopenia in RA was 54.8%, significantly higher than that in the control group [(9.6%), χ2=93.241, P<0.01]. The incidence of sarcopenia combined with osteoporosis in RA group (28.5%) was significantly higher than that in the control group [(5.8%), χ2=118.110, P<0.01]. Comparison of the incidence of spinal OPF in RA patients among groups with different bone mass (normal bone mass, osteopenia, osteoporosis) showed that the incidence of spinal OPF among these groups was statistically different ( χ2=43.373, P<0.01), and the incidence of spinal OPF increased along with the decrease of bone mass ( χ2=43.003, P<0.01). The incidence of spinal OPF in RA patients with sarcopenia (27.2%, 58/213) was significantly higher than that in RA patients without sarcopenia [(14.8%, 26/176), χ2=8.833, P=0.003]. All participants were divided into three groups: group 1=no OP and sarcopenia, group 2=with sarcopenia or OP, group 3=both sarcopenia and OP. Difference of incidence of spine OPF in RA patients among three groups was statistically significant ( χ2=33.832, P<0.01), and the incidence of spinal OPF raised gradually in group 1 and 3, ( χ2=37.164, P<0.01). Incidences of sarcopenia, OP and spinal OPF in RA treated with glucocorticoid (GC) were higher than those in RA without GC ( P<0.05, P<0.01). Results of logistic regression showed advanced age[ OR(95% CI)=1.069(1.038, 1.101), P<0.01], usage of GC [ OR(95% CI)=3.169(1.679, 5.984), P<0.01] and sarcopenia combined with OP [ OR(95% CI)=2.113(1.430, 3.124), P<0.01] were risk factors for spinal OPF in RA patients. Conclusion:Incidences of sarcopenia, OP and spinal OPF in RA patients are higher than that in normal controls. Sarcopenia and OP have a synergistic effect on spinal OPF in RA patients.

Acid-sensitive ion channels (ASICs) as Ca2+ and Na+ cation channels are activated by changing in extracellular pH, which expressed in various diseases and participated in underlying pathogenesis. ASIC1a is involved in migration and invasion of various tumor cells. Rheumatoid arthritis fibroblast-like synoviocytes (RA-FLSs) located at the edge of the synovium were identified as key players in the pathophysiological process of rheumatoid arthritis and reported to have many similar properties to tumor cells. Here, we investigated the roles of ASIC1a in synovial invasion in vivo and the migration and invasion of RA-FLSs in vitro. Our results showed ASIC1a highly expressed in RA synovial tissues and RA-FLSs. Inhibition of ASIC1a by PCTX-1 reduces synovial invasion and the expressions of MMP2, MMP9, p-FAK to protect articular cartilage in AA rats. Moreover, the acidity-promoted invasion and migration as well as the expressions of MMP2, MMP9, p-FAK of RA-FLSs were down-regulated by ASIC1a-RNAi and PCTX-1 while they were increased by overexpression-ASIC1a. ASIC1a mediated Ca2+ influx and the activation of Ras-related C3 botulinum toxin substrate 1(Rac1), which was decreased by the intracellular calcium chelating agent BAPTA-AM. Meanwhile, the migration and invasion as well as the expressions of MMP2, MMP9, p-FAK of RA-FLSs were decreased by Rac1 specific blocker NSC23766. In conclusion, this study indicated that ASIC1a may be a master regulator of synovial invasion via Ca2+/Rac1 pathway.

Acid-sensitive ion channel 1a (ASIC1a) is a member of the extracellular H+ activated cation channel family. Studies have shown that tissue acidification contributes to the formation of microvessels in rheumatoid arthritis (RA) synovial tissue, but its underlying mechanisms remain unclear. The purpose of this study was to investigate the role of tissue acidification in microvascular formation of arthritic synovial tissue and the effect of ASIC1a on vascular endothelial growth factor (VEGF) release from arthritic synovial tissue. Our results indicate that ASIC1a expression, VEGF expression, and microvessel density (MVD) are elevated in RA synovial tissue and adjuvant arthritis (AA) rat synovial tissue. When AA rats were treated with ASIC1a-specific blocker psalmotoxin-1 (PcTx-1), the expression of ASIC1a, VEGF expression, and MVD were all reduced. Acidification of RA synovial fibroblasts (RASF) can promote the release of VEGF. PcTx-1 and ASIC1a-short hairpin RNA can inhibit acid-induced release of VEGF. In addition, the ASIC1a overexpression vector can promote acid-induced VEGF release. This indicates that extracellular acidification induces the release of VEGF by RASF via ASIC1a. These findings suggest that blocking ASIC1a mediates the release of VEGF from synoviocytes may provide a potential therapeutic strategy for RA therapy. Both ASIC1a and VEGF are highly expressed in rheumatoid arthritis synovial tissue and are associated with vascular disease. Interfering with ASIC1a in vitro using silencing, blocking, and overexpression interferes with the release of VEGF under acid stimulation. Blocking ASIC1a in the articular cavity of rats with adjuvant arthritis not only reduces the expression of VEGF in the synovium, but also reduces the proliferation and lesions of blood vessels and interferes with the development of the disease.

Myelodysplastic syndrome (MDS) is a heterogeneously cloned hematopoietic stem cell malignancy with a high risk of developing acute myeloid leukemia (AML). 4-amino-2-trifluoromethyl-phenyl resinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed in our group, was proved to be a tumor inhibitor in diverse types of cancer cells in vitro. However, little has been known about the effects of ATPR on MDS. To analyze if and to what extent it's anti-tumor activity on MDS, we performed CCK-8, Flow Cytometry, Wright-Giemsa staining, qRT-PCR, and Western blot to analyze the SKM-1 cells state after ATPR treatment in multiplex detection angles. As expected, our results proved that ATPR could effectively induce cell differentiation and reduce cell proliferation of SKM-1 cell lines. Subsequently, to further analyze the potential mechanisms, we applied Label-free proteomic techniques to discover relevant protein that may be involved. Most notably, a series of factors related to RNA behavioral regulation were changed. Among them, we demonstrated that DEAD-box RNA helicase DDX23 was abnormally ablated in MDS patients and could be restored after ATPR treatment in vitro. Besides, our results suggested that ATPR-induced SKM-1 cell maturation was counteracted when knockdown DDX23, underscoring that DDX23 might be involved. In conclusion, we confirmed that ATPR could induce SKM-1 cells differentiation and its positive influence of DDX23 may provide a new idea to relieve MDS.

Myelodysplastic syndromes (MDS) are a varied set of hematologic neoplasms and a high risk of progression to acute myeloid leukemia (AML). 4-Amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative, play an important role in various types of cancer cells as a tumor inhibitor. However, little is known concerning its antitumor effect on MDS. The cell viability and the percentage of apoptotic cells were used to measure MTT, Flow Cytometry and Hoechst 33342/PI staining. In addition, real-time quantitative RT-PCR (qRT-PCR) and western blotting were used to analyzed the expression of p53, as well as the levels of BNIP3, apoptosis proteins of Caspase-3, BAX and BCL-2. After SKM-1 cells were incubated with DAC, ATRA and ATPR, the viability of the SKM-1 cells was inhibited in a dose- and time-dependent manner. Both Hoechst staining and flow cytometry showed the apoptosis of SKM-1 cells was increased. Moreover, SKM-1 cells treated with ATPR unveiled elevated mRNA and protein levels of p53, BNIP3, BAX and Caspase-3 expression and decreased BCL-2 expression. However, silencing p53 suppressed the pro-apoptosis function of ATPR. Consequently, these data provide the first evidence for ATPR increased apoptosis in SKM-1 cells by p53 that is mutually dependent on and obligatorily linked to BNIP3 gene activation.

4-amino-2-trifluoromethyl-phenyl retinate (ATPR), a novel all-trans retinoic acid (ATRA) derivative designed and synthesized by our team, has been demonstrated its anti-tumor effect through inducing differentiation and inhibiting proliferation. Eukaryotic initiation factor 3a (eIF3a) plays a critical role in affecting tumor cell proliferation and differentiation. However, whether eIF3a is implicated in chronic myeloid leukemia cells differentiation remains unclear. Our results demonstrated that eIF3a could be suppressed by ATPR in K562 cells. The results also confirmed that ATPR could arrest cell cycle in G0/G1 phase and induced differentiation. Moreover, over-expression of eIF3a promoted not only protein expression of c-myc and cyclin D1, but also prevented the expression of p-Raf-1, p-ERK and the myeloid differentiation markers CD11b and CD14 and had an influence on inducing the morphologic mature. However, silencing eIF3a expression by small interfering RNA could have an adverse effect on K562 cells. In addition, PD98059 (a MEK inhibitor) could block cell differentiation of CML cells and contributed to the expression of c-myc and cyclin D1. In conclusion, these results indicated that eIF3a played an important role in ATPR-induced cell differentiation in K562 cells, its mechanism might be related to its ability in regulating the activation of ERK1/2 signaling pathway in vitro.

4-Amino-2-Trifluoromethyl-Phenyl Retinate (ATPR), an all-trans retinoic acid (ATRA) derivative, possesses the ability to relief several carcinoma. Here, we explored the potential molecular mechanism of eukaryotic translation initiation factor 6 (eIF6) in ATPR-induced leukemia cell differentiation. Our research showed that ATPR could inhibit cell proliferation and promote cell differentiation in several leukemia cell lines. Besides, ATPR remarkably reduced the expression of eIF6 in vitro. Interestingly, the reduction of eIF6 contributed to restraining proliferation of K562 cells by inhibiting CyclinD1, C-myc and blocking cell cycle, as well as promoting differentiation of K562 cells by increasing the expression of C/EBPε, cell surface antigen CD11b and inducing renal-shrinkage of nuclear. Furthermore, the over-expression of eIF6 restrained the effects of ATPR on cell proliferation and maturation in K562 cells. In Addition, Notch1/CBF-1 signal activated by Chrysin could increase expression of eIF6 and restrain the differentiation in ATPR-induced K562 cells. Taken together, all above results indicated that ATPR induced differentiation of leukemia cells by decreasing eIF6 through Notch1/CBF-1 signal, which might exert an innovative treatment for leukemia.

The efficacy of erlotinib treatment for advanced non-small cell lung cancer (NSCLC) is due to its action as an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI). Patients treated with erlotinib experience different drug responses. The effect of germline mutations on therapeutic responses and adverse drug responses (ADRs) to erlotinib in Chinese patients requires elucidation. Sixty Han Chinese advanced non-small cell lung cancer patients received erlotinib monotherapy and, for each participant, 76 candidate genes (related to EGFR signaling, drug metabolism and drug transport pathways) were sequenced and analyzed. The single-nucleotide polymorphisms (SNPs) rs1042640 in UGT1A10, rs1060463, and rs1064796 in CYP4F11, and rs2074900 in CYP4F2 were significantly associated with therapeutic responses to erlotinib. Rs1064796 in CYP4F11 and rs10045685 in UGT3A1 were significantly associated with adverse drug reaction. Moreover, analysis of a validation cohort confirmed the significant association between rs10045685 in UGT3A1 and erlotinib adverse drug response(unadjusted p = 0.015). This study provides comprehensive, systematic analyses of genetic variants associated with responses to erlotinib in Chinese advanced non-small cell lung cancer patients. Newly-identified SNPs may serve as promising markers to predict responses and safety in erlotinib-treated advanced non-small cell lung cancer patients after chemotherapy doublet.