Gα₁₂ gep oncogene deregulation of p53-responsive microRNAs promotes epithelial–mesenchymal transition of hepatocellular carcinoma

Yang, Y M,Lee, W H,Lee, C G,An, J,Kim, E-S,Kim, S H,Lee, S-K,Lee, C H,Dhanasekaran, D N,Moon, A,Hwang, S,Lee, S J,Park, J-W,Kim, K M,Kim, S G Macmillan Publishers Limited 2015 Oncogene Vol.34 No.22

Hepatocellular carcinoma (HCC) has a poor prognosis owing to aggressive phenotype. Gα<SUB>12</SUB> gep oncogene product couples to G-protein-coupled receptors, whose ligand levels are frequently increased in tumor microenvironments. Here, we report Gα<SUB>12</SUB> overexpression in human HCC and the resultant induction of zinc-finger E-box-binding homeobox 1 (ZEB1) as mediated by microRNA deregulation. Gα<SUB>12</SUB> expression was higher in HCC than surrounding non-tumorous tissue. Transfection of Huh7 cell with an activated mutant of Gα<SUB>12</SUB> (Gα<SUB>12</SUB>QL) deregulated microRNA (miRNA or miR)-200b/a/429, -194-2/192 and -194-1/215 clusters in the miRNome. cDNA microarray analyses disclosed the targets affected by Gα<SUB>12</SUB> gene knockout. An integrative network of miRNAs and mRNA changes enabled us to predict ZEB1 as a key molecule governed by Gα<SUB>12</SUB>. Decreases of miR-200a/b, -192 and -215 by Gα<SUB>12</SUB> caused ZEB1 induction. The ability of Gα<SUB>12</SUB> to decrease p53 levels, as a result of activating protein-1 (AP-1)/c-Jun-mediated mouse double minute 2 homolog induction, contributed to transcriptional deregulation of the miRNAs. Gα<SUB>12</SUB>QL induced ZEB1 and other epithelial–mesenchymal transition markers with fibroblastoid phenotype change. Consistently, transfection with miR-200b, -192 or -215 mimic prevented the ability of Gα<SUB>12</SUB>QL to increase tumor cell migration/invasion. In xenograft studies, sustained knockdown of Gα<SUB>12</SUB> decreased the overall growth rate and average volume of tumors derived from SK-Hep1 cell (mesenchymal-typed). In HCC patients, miR-192, -215 and/or -200a were deregulated with microvascular invasion or growth advantage. In the HCC samples with higher Gα<SUB>12</SUB> level, a correlation existed in the comparison of relative changes of Gα<SUB>12</SUB> and ZEB1. In conclusion, Gα<SUB>12</SUB> overexpressed in HCC causes ZEB1 induction by deregulating p53-responsive miRNAs, which may facilitate epithelial–mesenchymal transition and growth of liver tumor. These findings highlight the significance of Gα<SUB>12</SUB> upregulation in liver tumor progression, implicating Gα<SUB>12</SUB> as an attractive therapeutic target.

Probing the impact of quercetin-7-O-glucoside on influenza virus replication influence

Gansukh, E.,Kazibwe, Z.,Pandurangan, M.,Judy, G.,Kim, D.H. G. Fischer 2016 Phytomedicine Vol.23 No.9

<P>Background: Influenza virus is still at large and seriously affects social welfare and health. Dianthus superbus is a well-known medicinal plant widely used in Mongolian and Chinese traditional medicine for anti-inflammatory purposes. Purpose: To investigate the influence of this novel herbal medicinal product over virus infection and virus-induced symptoms Method: Quercetin-7-O-glucoside was isolated by bioassay (anti-influenza)-guided fractionation. The structural elucidation was made with 1H-NMR and 13C-NMR. Influenza A/Vic/3/75 (H3N2), A/PR/8/34 (H1N1), B/Maryland/1/59 and B/Lee/40 viruses were used for the evaluation of the antiviral activity. Virus-induced reactive oxygen species and autophagy formation levels were studied. The antiviral mechanism was elucidated via time-dependent, pre-, post-incubation assay methods. The viral RNA replication inhibition of Q7G was analyzed using quantitative RT-PCR method. The blocking of polymerase basic protein subunits of influenza viral RNA polymerase by Q7G was detected by in silico molecular docking assays using AutoDock Vina program with m(7)GTP. Additionally, Q7G was tested against M-MuLV RNA polymerase. Results: Q7G was not cytotoxic (CC50 > 100 mu g/ml) in MDCK cells and it showed 3.1 mu g/ml, 6.61 mu g/ml, 8.19 mu g/ml and 5.17 mu g/ml IC50 values against influenza A/PR/8/34, A/Vic/3/75, B/Lee/40 and B/Maryland/1/59 virus strains, respectively. Treatment of Q7G highly reduced ROS and autophagy formation induced by influenza virus infection. Q7G did not reduce NA activity and did not directly interact with the virus particles. Since viral RNA synthesis was blocked by treatment of Q7G. We targeted viral RNA polymerase for further probing. Interestingly, the binding energy of Q7G on viral PB2 protein was -9.1 kcal/mol and was higher than m(7)GTP recorded as -7.5 kcal/mol. It also was observe to block M-MuLV RNA polymerase. Conclusion: Isolated compound Q7G showed strong inhibition activity against influenza A and B viruses. It also reduced virus-induced ROS and autophagy formation. Q7G does not directly bind to the virus particles and did not affect NA activity. These results indicated that Q7G inhibits viral RNA polymerase, and that it occupies the binding site of m(7)GTP on viral PB2 protein. (C) 2016 Elsevier GmbH. All rights reserved.</P>

HCV, Alcoholic : PE-134 ; Hemoglobin decline during peginterferon Alfa-2B (PEG-2B)/ribavirin (RBV) treatment in real-Life is associated with favorable SVR rates in difficult-to-treat patients with HCV genotype 1 (G1) infection

( G Teuber ),( S Mauss ),( D Huppe ),( E Zehnter ),( M P Manns ),( T Dahhan6 ),( U Meyer ),( T Witthoft ),( B Moller9,),( N Dikopoulos ),( J Brack ),( B Stade ),( M Bilzer ),( The Bng Hepatitis Study 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.-

Background and Aims: Recently, it has been shown for the overall G1 population that anemia as well as the maximal hemoglobin (Hb) decline during peginterferon/RBV treatment is associated with higher SVR rates. We here investigated whether the maximal Hb decline influences SVR rates in difficult-to-treat patients undergoing Peg2b/RBV therapy for HCV G1 infection in real-life. Methods: Data of patients treated for G1 infection within the German Peg2b/RBV observational study were retrospectively analyzed. In this real-life cohort study G1 infection was treated with Peg2b 1.5 μg/kg/wk + weight-based RBV (800-1200 mg/day) for up to 48 wks at 285 sites. Subjects who discontinued for non-response or for any other reasons were included in the analysis. SVR was defined as undetectable serum HCV-RNA 24 wks after EOT response. Only one patient received erythropoietin treatment for anemia. Results: 1851 patients had baseline and at least one Hb measurement during therapy. Overall SVR rate was 42.6% (789/1851). SVR rates were only slightly higher for subjects with an absolute Hb decline >3 g/dL (44.3%, 493/1114) compared to those with maximum Hb declines <3 g/dL (40.2%, 296/737) (p=0.08). In contrast, a significant (p=0.0004) difference in SVR rates was obtained by comparing subjects with Hb declines >2 g/dL (44.6%, 673/1510) with those who experienced Hb declines <2 g/dL (34.0%, 116/341). Similar SVR rates of 46.1% (164/356) and 44.1% (509/1154) in patients with Hb declines >2 g/dL even if they did/did not become anemic (Hb<10 g/dL) strongly support Hb decline, and not anemia, as primary beneficial mechanism improving SVR. As summarized in the table, Hb declines >2 g/dl were significantly associated with higher SVR rates in difficult-to-treat patients, such as subjects elder than 50 years or subjects with high baseline viral load >600.000 IU/ml. Interestingly no beneficial effect was observed in patients with low platelet count (<150/nL), an indicator of advanced fibrosis/cirrhosis. Patients who first developed a Hb decline >2 g/dL during weeks 0-4 were likely to achieve similar SVR (41.3%, 365/883) than those who developed a Hb decline <2 g/dL (44.9%, 386/859). In contrast, a Hb decline >2 g/dL compared to <2 g/dL during weeks 0-4 was associated with a 2-3 fold higher risk of anemia in female (16.6% vs 40.5%) and male patients (7.3% vs 19.0%) when compared with a Hb decline <2 g/dL. Conclusions: Patients with HCV genotype 1 infection and in particular the subgroup of difficult-to-treat patients elder than 50 years or with HVL, achieve up to 15% higher SVR rates when they develop a Hb decline >2 g/dL during Peg2b/RBV therapy. However, patients with low platelet count <150/nL do not achieve this beneficial virologic effect.

HCV : PE-134 ; Hemoglobin decline during peginterferon Alfa-2B (PEG-2B)/ribavirin (RBV) treatment in real-life is associated with favorable SVR rates in difficult-to-treat patients with HCV genotype 1 (G1) infection

( G Teuber ),( S Mauss ),( D Huppe ),( E Zehnter ),( M P Manns ),( T Dahhan ),( U Meyer ),( T Witthoft ),( B Moller ),( N Dikopoulos ),( J Brack ),( B Stade ),( M Bilzer ),( Bng Hepatitis Study Group 대한간학회 2012 춘·추계 학술대회 (KASL) Vol.2012 No.1

Background and Aims: Recently, it has been shown for the overall G1 population that anemia as well as the maximal hemoglobin (Hb) decline during peginterferon/RBV treatment is associated with higher SVR rates. We here investigated whether the maximal Hb decline influences SVR rates in difficult-to-treat patients undergoing Peg2b/RBV therapy for HCV G1 infection in real-life. Methods: Data of patients treated for G1 infection within the German Peg2b/RBV observational study were retrospectively analyzed. In this real-life cohort study G1 infection was treated with Peg2b 1.5 μg/kg/wk + weight-based RBV (800-1200 mg/day) for up to 48 wks at 285 sites. Subjects who discontinued for non-response or for any other reasons were included in the analysis. SVR was defined as undetectable serum HCV-RNA 24 wks after EOT response. Only one patient received erythropoietin treatment for anemia. Results: 1851 patients had baseline and at least one Hb measurement during therapy. Overall SVR rate was 42.6% (789/1851). SVR rates were only slightly higher for subjects with an absolute Hb decline >3 g/dL (44.3%, 493/1114) compared to those with maximum Hb declines <3 g/dL (40.2%, 296/737) (p=0.08). In contrast, a significant (p=0.0004) difference in SVR rates was obtained by comparing subjects with Hb declines >2 g/dL (44.6%, 673/1510) with those who experienced Hb declines <2 g/dL (34.0%, 116/341). Similar SVR rates of 46.1% (164/356) and 44.1% (509/1154) in patients with Hb declines >2 g/dL even if they did/did not become anemic (Hb<10 g/dL) strongly support Hb decline, and not anemia, as primary beneficial mechanism improving SVR. As summarized in the table, Hb declines >2 g/dl were significantly associated with higher SVR rates in difficult-to-treat patients, such as subjects elder than 50 years or subjects with high baseline viral load >600.000 IU/ml. Interestingly no beneficial effect was observed in patients with low platelet count (<150/nL), an indicator of advanced fibrosis/cirrhosis. Patients who first developed a Hb decline >2 g/dL during weeks 0-4 were likely to achieve similar SVR (41.3%, 365/883) than those who developed a Hb decline <2 g/dL (44.9%, 386/859). In contrast, a Hb decline >2 g/dL compared to <2 g/dL during weeks 0-4 was associated with a 2-3 fold higher risk of anemia in female (16.6% vs 40.5%) and male patients (7.3% vs 19.0%) when compared with a Hb decline <2 g/dL. Conclusions: Patients with HCV genotype 1 infection and in particular the subgroup of difficult-to-treat patients elder than 50 years or with HVL, achieve up to 15% higher SVR rates when they develop a Hb decline >2 g/dL during Peg2b/RBV therapy. However, patients with low platelet count <150/nL do not achieve this beneficial virologic effect.

Reparative, Neuroprotective and Anti-neurodegenerative Effects of Granulocyte Colony Stimulating Factor in Radiation-Induced Brain Injury Model

Gökhan Gürkan,Özüm Atasoy,Nilsu Çini,İbrahim Halil Sever,Bahattin Özkul,Gökhan Yaprak,Cansın Şirin,Yiğit Uyanıkgil,Ceren Kızmazoğlu,Mümin Alper Erdoğan,Oytun Erbaş 대한신경외과학회 2023 Journal of Korean neurosurgical society Vol.66 No.5

Objective : This animal model aimed to compare the rat group that received brain irradiation and did not receive additional treatment (only saline) and the rat group that underwent brain irradiation and received Granulocyte colony stimulating factor (G-CSF) treatment. In addition, the effects of G-CSF on brain functions were examined by magnetic resonance (MR) imaging and histopathologically. Methods : This study used 24 female Wistar albino rats. Drug administration (saline or G-CSF) was started at the beginning of the study and continued for 15 days after whole-brain radiotherapy (WBRT). WBRT was given on day 7 of the start of the study. At the end of 15 days, the behavioral tests, including the three-chamber sociability test, open field test, and passive avoidance learning test, were done. After the behavioral test, the animals performed the MR spectroscopy procedure. At the end of the study, cervical dislocation was applied to all animals. Results : G-CSF treatment positively affected the results of the three-chamber sociability test, open-space test and passive avoidance learning test, cornu Ammonis (CA) 1, CA3, and Purkinje neuron counts, and the brain levels of brain-derived neurotrophic factor and postsynaptic density protein-95. However, G-CSF treatment reduced the glial fibrillary acidic protein immunostaining index and brain levels of malondialdehyde, tumor necrosis factor-alpha, nuclear factor kappa-B, and lactate. In addition, on MR spectroscopy, G-CSF had a reversible effect on brain lactate levels. Conclusion : In this first designed brain irradiation animal model, which evaluated G-CSF effects, we observed that G-CSF had reparative, neuroprotective and anti-neurodegenerative effects and had increased neurotrophic factor expression, neuronal counts, and morphology changes. In addition, G-CSF had a proven lactate-lowering effect in MR spectroscopy and brain materials.

Evaluation of the effects of two novel irrigants on intraradicular dentine erosion, debris and smear layer removal

Melahat Görduysus,Selen Küçükkaya,Nursel Pekel Bayramgil,Mehmet Ömer Görduysus 대한치과보존학회 2015 Restorative Dentistry & Endodontics Vol.40 No.3

Objectives: To evaluate the effects of copolymer of acrylic acid and maleic acid (Poly[AA-co-MA]) and calcium hypochlorite (Ca(OCl)2) on root canal dentin using scanning electron microscope (SEM). Materials and Methods: Twenty-four singlerooted teeth were instrumented and the apical and coronal thirds of each root were removed, leaving the 5 mm middle thirds, which were then separated into two pieces longitudinally. The specimens were randomly divided into six groups and subjected to each irrigant for 5 min as follows: G1, Ca(OCl)2; G2, Poly(AA-co-MA); G3, Ca(OCl)2 + Poly(AA-co-MA); G4, sodium hypochlorite (NaOCl); G5, ethylenediaminetetraacetic acid (EDTA); G6, NaOCl+EDTA. The specimens were prepared for SEM evaluation. Smear layer, debris and erosion scores were recorded by two blinded examiners. One image from G3 was analyzed with energy dispersive spectroscopy (EDS) on suspicion of precipitate formation. Data were analyzed using the Kruskal-Wallis and Dunn tests. Results: G1 and G4 showed the presence of debris and smear layer and they were statistically different from G2, G3, G5 and G6 where debris and smear layer were totally removed (p < 0.05). In G1 and G4, erosion evaluation could not be done because of debris and smear layer. G2, G3 and G5 showed no erosion, and there was no significant difference between them. G6 showed severe erosion and was statistically different from G2, G3 and G5 (p < 0.05). EDS microanalysis showed the presence of Na, P, and Ca elements on the surface. Conclusions: Poly(AA-co-MA) is effective in removing the smear layer and debris without causing erosion either alone or with Ca(OCl)2.

비만에 따른 요통환자의 체중분포와 요부 근력차이에 관한 비교분석

한길수 ( G. S. Han ),김건도 ( G. D. Kim ),임동춘 ( D. C. Lim ) 한국운동생리학회(구-한국운동과학회) 2010 운동과학 Vol.19 No.4

이 연구의 목적은 비만에 따른 요통환자의 체중분포와 요부 근기능 및 안정화 비율의 차이를 비교·분석하는 데 있다. 서울 강남에 소재한 J병원에 내원한 남성 만성요통환자 60명 중 체질량지수(Body Mass Index: BMI)가 25kg/m² 이상인 G1그룹 30명과 이하인 G2그룹 30명을 대상으로 Tetrax와 MedX를 이용하여 분석한 결과 다음과 같은 결론을 얻었다. 체중분포에서 G1그룹은 왼쪽 발뒤꿈치 1.97%(p>.05), 오른쪽 발뒤꿈치 2.37%에서 높게 나타났고(p>.05), G2그룹에서는 왼쪽 발앞꿈치 2.75%(p>.05), 오른쪽 발앞꿈치 1.97%(p>.05)에서 더 높은 체중이 실리는 것으로 나타났다. 요부 각도별 신전근력에서 G1그룹이 G2그룹에 비해 모든 각도에서 높은 근력을 나타냈고, 0°(p>.05), 12°(p>.05)를 제외한 24°(p<.05), 36°(p<.01), 48°(p<.001), 60°(p<.001), 72°(p<.001)에서 통계적으로 유의한 차이를 나타냈다. 요부 안정화 비율에서는 G1그룹의 경우 2.75+_1.31, G2그룹 2.48+_2.23로 나타났다(p>.05). 결론적으로 요부 각도별 신전근력에서 G1그룹이 G2그룹에 비해 모든 각도에서 근력이 높게 나타냈고. 발의 체중분포에서 G1그룹은 비만에 따른 요추의 전만을 증가시켜 힘의 중심을 더 후방으로 유지하려는 경향을 보이고 있는데, 이는 요부 신전근력의 약화로 이어져 안정화 비율에도 영향을 미치는 것으로 사료된다. This study was aimed to determine the effect for the weight distribution and lumbar extension strength associated with obesity index in male patients of Chronic Low Back Pain. Sixty subjects(obesity group(BMI:25Kg/m2): n=30, non obesity group: n=30) participated on this study. Both group were tested on lumbar extension using by MedX machine. Front heels and back heels were measured twice using by the Tetrax Portable Multiple System. Independent sample t-test was used to analyze the difference between the two groups. Study results showed that the obese back pain group(G1) had more weight loaded on both heels than the normal back pain group(G2), but there was no significant difference between the groups (p>.05). As for the lumbar extension strength at each angle, the obese back pain group appeared higher muscular strength than the normal group at 0°, but was stronger at angles 12°, 24°, 36°, 48°, 60°, and 72°. The ratio of lumbar flexion 72° and 0° angle showed 2.75:1 in G1 group and 2.48:1 in G2 group. Overall, the back pain group of obesity(G1) according to weight distribution tended to maintain their center of force more backwards by increasing the lordosis degree with abdominal distension.

Impact of Myelopathy Severity and Degree of Deformity on Postoperative Outcomes in Cervical Spinal Deformity Patients

Peter G. Passias,Katherine E. Pierce,Nicholas Kummer,Oscar Krol,Lara Passfall,M. Burhan Janjua,Daniel Sciubba,Waleed Ahmad,Sara Naessig,Bassel Diebo 대한척추신경외과학회 2021 Neurospine Vol.18 No.3

Objective: Malalignment of the cervical spine can result in cord compression, leading to a myelopathy diagnosis. Whether deformity or myelopathy severity is stronger predictors of surgical outcomes is understudied. Methods: Surgical cervical deformity (CD) patients with baseline (BL) and up to 1-year data were included. Modified Japanese Orthopaedic Association (mJOA) score categorized BL myelopathy (mJOA=18 excluded), with moderate myelopathy mJOA being 12 to 17 and severe myelopathy being less than 12. BL deformity severity was categorized using the mismatch between T1 slope and cervical lordosis (TS-CL), with CL being the angle between the lower endplates of C2 and C7. Moderate deformity was TS-CL less than or equal to 25° and severe deformity was greater than 25°. Categorizations were combined into 4 groups: group 1 (G1), severe myelopathy and severe deformity; group 2 (G2), severe myelopathy and moderate deformity; group 3 (G3), moderate myelopathy and moderate deformity; group 4 (G4), moderate myelopathy and severe deformity. Univariate analyses determined whether myelopathy or deformity had greater impact on outcomes. Results: One hundred twenty-eight CD patients were included (mean age, 56.5 years; 46% female; body mass index, 30.4 kg/m2) with a BL mJOA score of 12.8±2.7 and mean TS-CL of 25.9°±16.1°. G1 consisted of 11.1% of our CD population, with 21% in G2, 34.6% in G3, and 33.3% in G4. At BL, Neck Disability Index (NDI) was greatest in G2 (p=0.011). G4 had the lowest EuroQol-5D (EQ-5D) (p<0.001). Neurologic exam factors were greater in severe myelopathy (p<0.050). At 1-year, severe deformity met minimum clinically important differences (MCIDs) for NDI more than moderate deformity (p=0.002). G2 had significantly worse outcomes compared to G4 by 1-year NDI (p=0.004), EQ-5D (p=0.028), Numerical Rating Scale neck (p=0.046), and MCID for NDI (p=0.001). Conclusion: Addressing severe deformity had increased clinical weight in improving patient-reported outcomes compared to addressing severe myelopathy.

Characteristic polynomial of a generalized complete product of matrices

Hwang, S.G.,Park, J.W. North Holland [etc.] 2011 Linear algebra and its applications Vol.434 No.5

For a simple graph G, let G@? denote the complement of G relative to the complete graph and let P<SUB>G</SUB>(x)=det(xI-A(G)) where A(G) denotes the adjacency matrix of G. The complete product G@?H of two simple graphs G and H is the graph obtained from G and H by joining every vertex of G to every vertex of H. In [2]P<SUB>G@?H</SUB>(x) is represented in terms of P<SUB>G</SUB>, P<SUB>G@?</SUB>, P<SUB>H</SUB> and P<SUB>H@?</SUB>. In this paper we extend the notion of complete product of simple graphs to that of generalized complete product of matrices and obtain their characteristic polynomials.

Injective colorings of sparse graphs

Cranston, D.W.,Kim, S.J.,Yu, G. North-Holland Pub. Co ; Elsevier Science Ltd 2010 Discrete mathematics Vol.310 No.21

Let mad(G) denote the maximum average degree (over all subgraphs) of G and let χ<SUB>i</SUB>(G) denote the injective chromatic number of G. We prove that if mad(G)@?52, then χ<SUB>i</SUB>(G)@?Δ(G)+1; and if mad(G)<4219, then χ<SUB>i</SUB>(G)=Δ(G). Suppose that G is a planar graph with girth g(G) and Δ(G)>=4. We prove that if g(G)>=9, then χ<SUB>i</SUB>(G)@?Δ(G)+1; similarly, if g(G)>=13, then χ<SUB>i</SUB>(G)=Δ(G).