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BACKGROUND@#Liver cancer is largely resistant to chemotherapy. This study aimed to identify the effective chemotherapeutics for β-catenin-activated liver cancer which is caused by gain-of-function mutation of catenin beta 1 ( CTNNB1 ), the most frequently altered proto-oncogene in hepatic neoplasms.@*METHODS@#Constitutive β-catenin-activated mouse embryonic fibroblasts (MEFs) were established by deleting exon 3 ( β-catenin Δ(ex3)/+ ), the most common mutation site in CTNNB1 gene. A screening of 12 widely used chemotherapy drugs was conducted for the ones that selectively inhibited β-catenin Δ(ex3)/+ but not for wild-type MEFs. Untargeted metabolomics was carried out to examine the alterations of metabolites in nucleotide synthesis. The efficacy and selectivity of methotrexate (MTX) on β-catenin-activated human liver cancer cells were determined in vitro . Immuno-deficient nude mice subcutaneously inoculated with β-catenin wild-type or mutant liver cancer cells and hepatitis B virus ( HBV ); β-catenin lox(ex3)/+ mice were used, respectively, to evaluate the efficacy of MTX in the treatment of β-catenin mutant liver cancer.@*RESULTS@#MTX was identified and validated as a preferential agent against the proliferation and tumor formation of β-catenin-activated cells. Boosted nucleotide synthesis was the major metabolic aberration in β-catenin-active cells, and this alteration was also the target of MTX. Moreover, MTX abrogated hepatocarcinogenesis of HBV ; β-catenin lox(ex3)/+ mice, which stimulated concurrent Ctnnb1- activated mutation and HBV infection in liver cancer.@*CONCLUSION@#MTX is a promising chemotherapeutic agent for β-catenin hyperactive liver cancer. Since repurposing MTX has the advantages of lower risk, shorter timelines, and less investment in drug discovery and development, a clinical trial is warranted to test its efficacy in the treatment of β-catenin mutant liver cancer.
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Mice , Animals , Humans , Methotrexate/therapeutic use , Mice, Nude , beta Catenin/metabolism , Fibroblasts/metabolism , Liver Neoplasms/metabolism , Hepatitis B virus , NucleotidesABSTRACT
Objective@#To evaluate the application of calcium suppressed (CaSupp) spectral CT technique in evaluating disk position and measuring the thickness of the posterior band of temporomandibular joint (TMJ).@*Methods@#The twenty-three temporomandibular disorder patients [mean age 23(12~62) years, male/female=14/9] were performed with oblique sagittal and coronal proton density weighted imaging (PDWI) and spectral CT scans from February to July, 2019 in Department of Radiology, Hainan Hospital of General Hospital of Chinese PLA, and 45 TMJ joints were evaluated. The subjects were classified into two groups according to the scanning modalities: MRI measurement group and CaSupp spectral-based CT group. The CaSupp technique were applied with the spectral-based CT images and CaSupp images were generated. The oblique sagittal and coronal CaSupp imaged were reformatted by perpendicular to the long axis of the condyle. The TMJ disk positions were evaluated on oblique sagittal and coronal images, and the maximal disk thickness were measured on the oblique sagittal images.@*Results@#The joint position was basically consistent on MRI and CaSupp images for the 45 TMJ joints. The intra-class coefficient value was 0.843 (0.712, 0.914) for the measurement of the posterior band of the TMJ disk between MRI and CaSupp images. Bland-Altman presented that the [95.6% (43/45)] points with the difference located in the 95% agreement interval. Wilcoxon paired text demonstrated that there was no significant different for the thickness of the posterior band between MRI [2.57 (1.76, 3.65) mm] and CaSupp images [2.67 (1.74, 4.56) mm] (P=0.07).@*Conclusions@#The CaSupp spectral-based CT could be used to evaluated the TMJ disk position and the thickness of the posterior band.
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Objective To investigate the correlation between blood pressure rhythm and left ventricular structure and function in elderly hypertensive patients. Methods A total of 147 elderly patients with high blood pressure in the First Hospital of Longyan Affiliated to Fujian Medical University were selected. All the patients received 24h ambulatory blood pressure examination. According to the rhythm of blood pressure, the patients were divided into the dipper blood pressure group,the-non dipper type blood pressure group and the anti-dipper type blood pressure group. All patients were examined by echocardiography. Results According to the results of 24h dynamic blood pressure,the type of dipper blood pressure accounted for 11.56% (17 cases) in 147 elderly patients, non-dipper type blood pressure type accounted for 51.02% (75 cases),and the anti-dipper type of blood pressure type accounted for 37.41% (55 cases).The ventricular septal thickness(IVST),left ventricular diastolic inner diameter (LVEDD),left atrium inner diameter(LAD),left ventricle posterior wall thickness( LVPWT) and left ventricle mass index(LVMI) of the non-dipper blood pressure group were (10.56 ± 1.51)mm,(50.17 ± 4.31) mm,(34.65 ± 5.78)mm,(9.26 ± 0.98)mm,(102.31 ± 23.23)g/m2 ,respectively.The IVST,LVEDD,LAD,LVPWT and LVMI of the anti-dipper blood pressure group were (10.51 ± 1.86)mm,(50.20 ± 3.66)mm,(36.96 ± 4.22)mm,(9.42 ± 0.99)mm,(110.47 ± 31.96) g/m2 ,respectively.The IVST,LVEDD,LAD,LVPWT and LVMI of the dipper blood pressure group were (9.53 ± 1.53) mm,(47.59 ± 2.27) mm,(30.47 ± 4.17) mm,(8.88 ± 1.12) mm,(84.98 ± 15.48) g/m2 , respectively. The differences of IVST, LVEDD, LAD, LVPWT and LVMI in the three groups were statistically significant(F=1.172,3.428,1.006,0.135,all P<0.05).The maximum blood flow velocity in early diastolic period of mitral valve blood flow spectrum(E peak)/maximum blood flow velocity in late diastolic period(A peak)(E/A)of the non-dipper blood pressure group and anti-dipper blood pressure group were (0.89 ± 0.30), (0.80 ± 0.28),respectively,which was significantly lower than that of dipper blood pressure group [(1.35 ± 0.63)] (t= -2.890,-3.440,all P<0.05).The left ventricular ejection score(LVEF) of the anti-dipper blood pressure group was (65.31 ± 6.74)% ,which was significantly lower than that of the dipper blood pressure group[(70.12 ± 10.76)% ],the difference was statistically significant(t= -2.209,P<0.05).The 24 h mean systolic pressure,24 h mean diastolic pressure and daytime mean diastolic pressure in the three groups of dynamic blood pressure parameters had no statistically significant differences (all P>0.05).The average daytime systolic pressure in the dipper blood pressure group was (143.06 ± 13.70) mmHg,which was higher than that in the non-dipper blood pressure group [(133.25 ± 13.28)mmHg] and anti-dipper blood pressure group[(131.16 ± 12.26)mmHg],the differences were statistically significant(t= -2.734,-3.401,all P <0.05).The mean evening systolic pressure and the average nocturnal diastolic pressure of anti -dipper blood pressure group were ( 139.04 ± 15.01 ) mmHg and ( 80.18 ± 10.29) mmHg, respectively, which were higher than those of the dipper and non - dipper blood pressure group [(123.24 ± 14.49)mmHg and (72.24 ± 7.97) mmHg,(127.40 ± 13.30) mmHg,(73.45 ± 11.43) mmHg],the differences were statistically significant ( t =3. 822, 4. 666, 2. 919, 3. 456, all P <0. 05 ). LVMI was positively correlated with age,body mass index(BMI),low density lipoprotein( LDL-C),daytime average systolic pressure, night average systolic pressure,night average diastolic pressure,and 24h average systolic pressure(r=0.256,0.241, 0.687,0.251,0.380,0.203,0.243,all P <0.05). Conclusion Anti -dipper blood pressure and non -dipper blood pressure have more significant damage to cardiac function and structure than dipper blood pressure in elderly patients with hypertension,and the elevation of nocturnal blood pressure is closely related to left heart structure and function damage.There is a high correlation between abnormal circadian rhythm of blood pressure and left ventricular hypertrophy in elderly hypertensive patients.
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Objective To observe the genetic predisposition of complement C5 gene polymorphisms in proliferative diabetic retinopathy (PDR) in Chongqing Han population.Methods 400 type 2 diabetes (T2D) patients (case group) and 600 age-and sex-matched healthy controls (control group) were enrolled in this study.There were 8 PDR patients in case group.All the subjects were Han ethnic people.The immune-related representative SNP locus of C5 gene including rs2269067,rs7040033,rs7027797 were screened by linkage disequilibrium analysis.Locus rs1017119 was selected by TagSNP and was around the above three loci.Subjects' peripheral venous blood was collected and DNA was extracted.Genotyping was examined by PCR-restriction fragment length polymorphism method.The level of C5 plasma protein was measured by enzyme-linked immunoabsorbent assay.Results The frequency of GG genotype of rs2269067 was significantly increased in PDR patients in cases group compared with controls (Pc=3.4 × 10-5,OR=1.87,95％CI=1.43-2.44;P=3.1 × 10-6).There was no differences in frequency of G,CC and CG genotype of rs2269067 between two groups (P=1.4 × 10-4,1.000,1.0 × 10-6).There were no differences in frequency of G,CC,CG,GG genotype of rs7040033,rs1017119,and rs7027797 between two groups (P＞0.05).The production of C5 plasma protein was significantly increased in case group as compare with control group (P=0.0004).An increased production of C5 plasma protein was observed in rs2269067 GG genotype cases compared to CG or CC cases (P=0.003,0.001).Conclusion C5 rs2269067 GG genotype may be associated with the PDR of T2D in Chongqing Han population.
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@#Objective To determine the concept of functional evaluation for children with congenital heart disease in the views of International Classification of Functioning, Disability and Health (Children and Youth Version) (ICF-CY). Methods Clinical researches on children and adolescents with congenital heart disease nearly a decade were recalled from MEDLINE/PubMed and EMBASE. The concepts extracted were linked with ICF-CY. Results 224 researches were recalled. The oncepts linked with ICF-CY in 12 first categories, 28 second categories, of which 17 items were of body function, 2 of body structure, 6 of activities and participation, and 3 of environmental factors.Conclusion ICF-CY is a useful framework for functional assessment for children with congenital heart disease. It is important to make the measurement uniformity for comparability of the researches.
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Objective:To explore significance of brain natriuretic peptide (BNP)and N terminal pro brain natriuretic peptide (NT-proBNP)for diagnosis of acute respiratory distress syndrome and its guidance of treatment.Methods:A total of 124 cases with definite organic heart disease and sudden respiratory distress syndrome (measurement group) received measurement of BNP and NT-proBNP to judge whether they suffered from heart failure or not.Another 110 patients with acute respiratory distress syndrome but no receiving BNP and NT-proBNP measurement were en-rolled as no measurement control group.Relevant data,including diagnosis time,length of hospital stay,hospitali-zation cost and mortality rate etc,were collected in all patients.Results:Compared with no measurement control group,there were significant reductions in diagnosis time [(24.2±6.4)min vs.(16.3±5.2)min],length of hospi-tal stay [(12.5±3.5)d vs.(8.5±4.5)d]and mortality rate (8.18% vs.4.84%)in measurement group,P0.05).Conclusion:Measurement of brain natriuretic peptide and N terminal pro brain natriuretic peptide possesses important value for early diagnosis,elevating therapeutic effect and improving prognosis in patients with acute respiratory distress syn-drome.
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Objective To investigate the change of plasma cholinesterases (CHEs) in the people with diabetes or fatty liver or overweight , and explore the role of CHE in these diseases .Methods The plasma CHEs in 2834 subjects were detected , and these subjects were divided into five groups , including diabetes , fatty liver , overweight , diabetes with fatty liver , and the normal groups . Results The plasma CHE activities in diabetes group , fatty liver group , overweight group , and diabetes with fatty liver group were all higher than the normal group [(8943 ±1896)U/L, (9716 ±1673)U/L, (8798 ±1710)U/L, (9385 ±1687)U/L vs (8028 ±1621) U/L], and the CHE level in the fatty liver group was highest among five groups .However, the CHE level in diabetes group or fatty liv-er group was not significantly different from that in the diabetes with fatty liver group .The CHE level of the people with components of metabolic syndrome (MS) was significantly higher than that without MS component [(8786 ±1514)U/L, (9141 ±1771)U/L, (9705 ±1628)U/L, (9138 ±1768)U/L, (9530 ±1607)U/L vs (7821 ±1324)U/L]),but the CHE level was not increased gradually with the increased MS component.The plasma CHE had a negative correlation with age ( P =0.00),but it had a positive correlation with triglyceride (TG), total cholesterol (TC), and body mass index (BMI)( P =0.00).Conclusions The plasma CHE activity was el-evated in diabetes group , fatty liver group , and overweight group , which might be a risk factor in these diseases .Controlling the plas-ma CHE might help to treat the metabolism diseases .
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Objective To study the effect of 5-lipoxygenase(5-LOX) inhibitor nordihyroguaiaretic acid (NDGA) combined the selective cyclooxygenase-2 (COX-2) inhibitor Celecoxib on the apoptosis of human colon carcinoma cell line HT-29. Methods Different concentration of NDGA and Celecoxib combinations were used to process cancer cell, and thiazolyl blue tetrazlium bromide (MTT) and phase contrast microscope and Annexin V/PI fluorescence staining and reverse transcription polymerase chain reaction (RT-PCR) were used to study the proliferation inhibited effect and apoptosis induced effect caused by combination of NDGA combined Celecoxib. Results MTT results showed that the viability of NDGA group, Celecoxib group and the group of NDGA combined Celecoxib (0.432±0.024,0.425±0.013,0.303±0.014 vs 0.693±0.018,t＝18.79,25.75,37.64,P＜0.01) was obviously lower than control group. The group of NDGA combined Celecoxib was significantly lower than NDGA group or Celecoxib group (t＝10.21, 14.14,P＜0.01). Under inverted phase contrast microscope, cell morphology significantly changed, and the group of NDGA combined Celecoxib changed most obviously. Apoptosis was observed by laser scanning confocal microscope (LSM) after NDGA and Celecoxib were used to process the HT-29. RT-PCR showed that up-regulation of Caspase-3 after treatment, and the combination of two drugs increased the most. Conclusions NDGA combined Celecoxib inhibited proliferation and induced apoptosis in human colon carcinoma cell line HT-29, and combined therapy had better effect than that of any drug used separate-ly. The mechanism may be associated with up-regulation of Caspase-3.
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Objective To investigate the effects of cyclooxygenase-2 (COX-2) selective inhibitor combined with 5-lipoxygenase (5-LOX) inhibitor docebenone (AA861) on cell proliferation and migration of human colon cancer cell line HT-29. Methods Cultured in vitro of HT-29 cells in high metastatic colon cancer, A A861 and celecoxib on colon cancer cell drugs for 48 h, the cell proliferation was assayed by MTT; the migration of cell was detected by Transwell; immunofluorescence staining of intracellular changes in ICAM-1 protein, RT-PCR detect the gene expression of ICAM-1 and VEGF. Results MTT and Transwell experiments showed that the inhibition on celecoxib and AA861 on colon cancer was dose-dependent and time-dependent. And the inhibition of AA861 and celecoxib 100 μmol/L alone on colon cancer cells proliferation were 43.2 % and 42.8%, and when the two drugs 100 μmol/L combined on colon cancer cells the inhibition was 53.8%, and the difference between alone group and combined group was statistical (P ＜0.001). The inhibition of AA861 and celecoxib 100 μmol/L alone on colon cancer cells migration were 32.0 % and 29.3%, and when the two drugs 100 μ,mol/L combined on colon cancer cells the inhibition is 57.8 %, and the difference of between alone group and combined group was statistical (P ＜0.001). Immunefluorescence staining and RT-PCR results suggested that the two drugs can inhibit ICAM-1 and VEGF protein and gene expression, and when the two drugs combined, a stronger inhibition effect appeared than used alone (P＜0.001). Conclusion Low-dose celecoxib and AA861 combined has a synergistic inhibited effect on colon cancer cells invasion and metastasis, and the mechanism relates with the VEGF and ICAM-1 expression.
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Nuclear factor κB (NF-κB) is an important cellular transcription factor. The important role of NF-κB-mediated cell signal transduction pathway in apoptosis is a hot topic at home and abroad. In order to discover new regulators in NF-κB signaling pathway, a high-throughput cell-based screening model based on dual luciferase reporters system was established, a number of genes that can activate NF-κB signal pathway were obtained by screening of 439 novel function genes. Among them, TMEM9B can obviously activate NF-κB signaling pathway. Further experiments showed that TMEM9B activated NF-κB signaling pathway in a dose-dependent pattern. Western blotting and EMSA experiments confirmed that TMEM9B can promote the degradation of IκBα (a cytoplasm inhibitor of NF-κB), and cause NF-κB shift from the cytoplasm to nucleus. At the same time, flow cytometry result demonstrated TMEM9B can induce apoptosis in HEK293T and HeLa cells. In short, a stable and effective screening system for NF-κB has been established, through which TMEM9B was identified to be able to significantly activate NF-κB signal transduction pathway and thus cause cells apoptosis.