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Deubiquitination and Stabilization of PD-L1 by CSN5
Lim, Seung-Oe,Li, Chia-Wei,Xia, Weiya,Cha, Jong-Ho,Chan, Li-Chuan,Wu, Yun,Chang, Shih-Shin,Lin, Wan-Chi,Hsu, Jung-Mao,Hsu, Yi-Hsin,Kim, Taewan,Chang, Wei-Chao,Hsu, Jennifer L.,Yamaguchi, Hirohito,Ding Elsevier 2016 Cancer cell Vol.30 No.6
<P><B>Summary</B></P> <P>Pro-inflammatory cytokines produced in the tumor microenvironment lead to eradication of anti-tumor immunity and enhanced tumor cell survival. In the current study, we identified tumor necrosis factor alpha (TNF-α) as a major factor triggering cancer cell immunosuppression against T cell surveillance via stabilization of programmed cell death-ligand 1 (PD-L1). We demonstrated that COP9 signalosome 5 (CSN5), induced by NF-κB p65, is required for TNF-α-mediated PD-L1 stabilization in cancer cells. CSN5 inhibits the ubiquitination and degradation of PD-L1. Inhibition of CSN5 by curcumin diminished cancer cell PD-L1 expression and sensitized cancer cells to anti-CTLA4 therapy.</P> <P><B>Highlights</B></P> <P> <UL> <LI> TNF-α stabilizes cancer cell PD-L1 in response to chronic inflammation </LI> <LI> Activation of NF-κB by TNF-α induces CSN5 expression leading to PD-L1 stabilization </LI> <LI> CSN5 enzyme activity controls T cell suppression via PD-L1 deubiquitination </LI> <LI> Destabilization of PD-L1 by CSN5 inhibitor curcumin benefits anti-CTLA4 therapy </LI> </UL> </P> <P><B>Graphical Abstract</B></P> <P>[DISPLAY OMISSION]</P>
Xi, L.,Muzhou, H.,Lee, M.H.,Li, J.,Wei, D.,Hai, H.,Wu, Y. Elsevier Science, B.V 2014 Applied soft computing Vol.15 No.-
In this paper, in order to optimize neural network architecture and generalization, after analyzing the reasons of overfitting and poor generalization of the neural networks, we presented a class of constructive decay RBF neural networks to repair the singular value of a continuous function with finite number of jumping discontinuity points. We proved that a function with m jumping discontinuity points can be approximated by a simplest neural network and a decay RBF neural network in L<SUP>2</SUP>(@?) by each @? error, and a function with m jumping discontinuity point y=f(x),x@?E@?@?<SUP>d</SUP> can be constructively approximated by a decay RBF neural network in L<SUP>2</SUP>(@?<SUP>d</SUP>) by each ε>0 error. Then the whole networks will have less hidden neurons and well generalization in the same of the first part. A real world problem about stock closing price with jumping discontinuity have been presented and verified the correctness of the theory.
( F. Mcphee ),( L. Wei ),( Q. Xie ),( Y. Suzuki ),( J. Toyota ),( Y. Karino ),( K. Chayama ),( Y. Kawakami ),( M. L. Yu ),( S. H. Ahn ),( N. Zhou ),( H. Kumada ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Aims: Daclatasvir (DCV) plus asunaprevir (ASV) has demonstrated highsustained virologic response (SVR) in HCV genotype (GT-)1b infection.NS5A-Y93H and NS5A-L31 resistance-associated polymorphisms(RAPs) to DCV are known to impact DCV+ASV response in GT-1b-infectedJapanese. The effect of RAPs on SVR at posttreatment week12 (SVR12) to DCV+ASV was explored in mainland Chinese, Korean,and Taiwanese.Methods: Pooled data from 2 studies of DCV (60 mg daily) + ASV(100 mg capsule, twice-daily) for 24 weeks in GT-1b-infected interferon/ribavirin-naive and -experienced patients from mainland China,Korea, and Taiwan. Similar Japanese data (4 studies; n=445) werepooled for comparison. SVR12 with versus without baseline Y93Hand/or L31 RAPs was compared by age (<65 vs ≥65 years), cirrhosisstatus, and baseline HCV-RNA.Results: SVR12 and baseline NS5A sequences were available for 282patients (126 mainland Chinese [45%〕, 80 Koreans [28%〕, 76Taiwanese [27%〕). NS5A-Y93H and/or -L31 RAPs were observed pretreatmentin 8% mainland Chinese, 14% Korean, and 18%Taiwanese patients, compared with 19% in Japanese. SVR12 in allnon-Japanese patients is shown (Figure); rates were broadly similarbetween countries and with Japanese data (Japanese: 96% overallwithout RAPs, 41% with RAPs). Responses were lower among patientswith baseline RAPs. By contrast, SVR12 in patients without RAPs washigh (92-100%), irrespective of cirrhosis, age, or baseline HCV-RNA.Conclusions: At least 95% of HCV GT-1b-infected patients from mainlandChina, Korea or Taiwan without baseline NS5A-Y93H or -L31polymorphisms who had HCV-RNA ≤7 log10 IU/mL achieved SVR12on DCV+ASV, regardless of cirrhosis status and age.
( Wei Ying Jen ),( Margaret L Teng ),( Wee Chuan Hing ),( Valerie Ma ),( Shridhar Ganpathi Iyer ),( Chung Cheen Chai ),( Horng Ruey Chua ) 대한내과학회 2014 대한내과학회 추계학술대회 Vol.2014 No.1
Background: Premixed hypotonic solutions of 0.33% saline + 5% dextrose + 10mmol/ L potassium-chloride (0.33S, tonicity 133mEq/L) and 0.9% saline ±dextrose (NS, tonicity 308mEq/L) are common peri-operative maintenance fiuids, but their effects on serum biochemistry are unclear. Methods: Using a single-centre, prospectively-maintained electronic database, we retrospectively examined post-operative biochemistry in adults maintained on exclusively 0.33S or NS peri-operatively, from March 2012 to September 2013. Outcomes included new-onset post-operative hyponatremia, hypokalaemia, hypoglycaemia, and acute kidney injury (AKI, =1.5x increase in serum creatinine); multivariate analyses were adjusted for demographics, comorbidities, surgery-types/duration, infusion time/ volumes, and hospital length-of-stay. Results: We studied 279 patients given 0.33S, and 279 NS controls matched for cumulative infusion volume. Mean age was 59(±18) years. More NS patients had diabetes mellitus, ischemic heart disease and chronic kidney disease (p<0.05). Surgery types included gastrointestinal/hepatobiliary (43%), orthopaedic (30%) and nephrectomy (3%). Mean fi uid volumes administered were 6.9(±3.3)L of 0.33S and 7.1(±5.6)L of NS (p=0.57), with 100% versus 52% of drips containing dextrose, respectively. More 0.33S patients (versus NS) developed hyponatremia (30% versus 17%, p<0.001); this difference was signifi cant for gastrointestinal/hepatobiliary (p=0.001) but not orthopaedic (p=0.74) surgeries. Less 0.33S patients (versus NS) had hypokalaemia (1% versus 10%, p<0.001), hypoglycaemia (1% versus 4%, p=0.01), and AKI (3% versus 8%, p=0.007). On multivariate analyses, 0.33S, gastrointestinal/hepatobiliary surgeries and nephrectomy were independently associated with hyponatremia; while NS, hypertension, longer infusion hours, and nephrectomy were independently associated with AKI (p<0.05). Conclusions: 0.33S infusion in post-surgical patients, especially post-gastrointestinal/ hepatobiliary surgeries, is strongly associated with hyponatremia, but with less hypokalaemia or hypoglycaemia, compared with NS. The association between NS administration and AKI is heavily confounded by baseline comorbidities and requires further prospective evaluation. Both fi uid types are not appropriate for isolated use, and more balanced maintenance fi uids are desired.
Wei, L.,Cao, X.,Wang, Z.,Gao, Y.,Hu, S.,Wang, L.,Wu, G.,Shen, D. Published for the American Association of Physicis 2017 Medical physics Vol.44 No.12
<P>Conclusions: The proposed new learning-based registration method have tackled the challenging issues in registering infant brain images acquired from the first year of life, by leveraging the multi-output random forest regression with auto-context model, which can learn the evolution of shape and appearance from a training set of longitudinal infant images. Thus, for the new infant image, its deformation field to the template and also its template-like appearances can be predicted by the learned models. We have extensively compared our method with state-of-the-art deformable registration methods, as well as multiple variants of our method, which show that our method can achieve higher accuracy even for the difficult cases with large appearance and shape changes between subject and template images. (C) 2017 American Association of Physicists in Medicine</P>
( L. Wei ),( K. Chayama ),( W. L. Chuang ),( S. H. Bae ),( J. Y. Jang ),( R. Bhore ),( V. Vazquez ),( L. Mo ),( M. Linaberry ),( M. Treitel ),( H. Kumada ) 대한간학회 2016 춘·추계 학술대회 (KASL) Vol.2016 No.1
Aims: The combination of daclatasvir (DCV) plus asunaprevir (ASV)has demonstrated high sustained virologic response (SVR) rates andis generally well tolerated in clinical studies. This integrated analysisevaluated the safety profile of DCV (60mg once daily) and ASV (100mgsoftgel capsule or 200mg tablets twice daily in genotype 1b (GT1b)infected patients enrolled in four phase 3 and two phase 2 clinicalstudies conducted globally, including Asia.Methods: Integrated safety data from 1218 treatment-naive or treatment-experienced patients were analyzed for adverse events (AEs),serious AEs, discontinuations due to AEs and grade 3/4 AEs andlaboratory abnormalities reported on-treatment.Results: Patients were 58% female, median age was 58 years and23% had compensated cirrhosis. DCV+ASV was associated with infrequentserious AEs and discontinuations due to AEs (Table). Twelvepatients reported treatment-related serious AEs. The most commonAEs (any grade) were diarrhea, nausea, fatigue, and headache. Onepatient died due to coronary heart disease (not treatment-related).The most common grade 3/4 laboratory abnormalities were aminotransferaseelevations (more frequent among Japanese patients); however,all grade 3/4 laboratory abnormality occurred in <5% of patientsoverall. Grade 3/4 total bilirubin elevations were reported in <1%of patients. The DCV+ASV safety profile was similar in patients withor without cirrhosis.Conclusions: DCV+ASV was generally well tolerated across globalnon-Asian patient populations and in Asian patients from Japan, mainlandChina, Korea, and Taiwan.
( L. Wei ),( F. Wang ),( M. Zhang ),( J. Jia ),( A.A. Yakovlev ),( W. Xie ),( E.Z. Burnevich ),( J. Niu ),( Y.J. Jung ),( X. Jiang ),( M. Xu ),( X. Chen ),( Q. Xie ),( J. Li ),( J. Hou ),( H. Tang ),( 대한간학회 2017 춘·추계 학술대회 (KASL) Vol.2017 No.1
Background/Aims: Treatment-naive GT 1b-infected patients from mainland China, South Korea and Russia were assessed for SVR at follow-up week 12 (SVR12) after receiving daclatasvir (60 mg, QD) and asunaprevir (100 mg, BID) (DCV+ASV). Methods: Patients were randomized 3:1 to receive DCV+ASV (24 weeks; immediate treatment [IM]) or 12 weeks of placebo followed by DCV+ASV (24 weeks; placebo-deferred treatment [PD]). The primary endpoint was to evaluate SVR12 in the IM arm to the historical rate for peginterferon/ribavirin (70%). Secondary endpoints included overall safety and safety comparisons between the treatment arms during the first 12 weeks. Results: 207 patients were randomized to IM (n=155) or PD (n=52); Asian (86%), female (59%), IL28B CC genotype (68%) and median age 49 (range 18-73) years; cirrhosis (13%), HCV RNA ≥6x106 IU/mL (53%). SVR12 in the IM arm was 92% and broadly unaffected by most baseline factors assessed (Figure); SVR12 was higher in patients without (96%) baseline NS5A-L31M/V or Y93H polymorphisms. There were 6 virologic breakthroughs, 6 relapses and 1 detectable HCV RNA at end-of-treatment in the IM arm. Safety was mostly comparable between the two arms during the first 12 weeks. The most frequent adverse events (AEs; ≥5%) during DCV+ASV (24 weeks) treatment in both arms were aminotransferase, bilirubin and INR elevations, hypertension, fatigue and respiratory tract infections; the most frequent treatment-emergent grade 3/4 laboratory abnormalities were aminotransferase (≤4.5%) and hematologic, lipase and total bilirubin abnormalities (≤2%); one patient (IM) discontinued DCV+ASV for aminotransferase elevations, nausea and jaundice (all reversible); one patient PD) discontinued DCV+ASV for a fatal AE unrelated to treatment. Conclusions: These data demonstrate that DCV+ASV is a highly efficacious and well tolerated treatment for treatment-naive HCV GT 1b-infected patients. Those treated immediately with DCV+ASV achieved a 92% SVR12 rate which was unaffected by factors known to attenuate response to interferon.
L Guang Wei,Chen Liming,Toda Kiyoshi,Zhang Shuting The Korean Society for Biotechnology and Bioengine 2004 Biotechnology and Bioprocess Engineering Vol.9 No.6
In the course of anaerobic storage of excess sludge, odors due to chemicals such as hydrogen sulfide are produced. These odors cause many problems. Many methods have been developed to eliminate odors, but all current methods are not only costly, but also largely ineffective. In this paper, we investigate the process of transformation of sludge microorganism cultures through intense aeration under nutrient-poor conditions, in terms of the selective adjustment and control of microorganism culture. The aerated sludge is subsequently returned to the adjusting pool, where the microorganisms inhibit odors, thus the excess sludge itself will act as an odor inhibitor. The process can be verified in terms of viability, in that the degradation capacity of the sludge was maintained after the intensely-aerated sludge was returned to the treatment system.