Feasibility of proposed single-nucleotide polymorphisms as predictive markers for targeted regimens in metastatic colorectal cancer

Kim, J C,Ha, Y J,Roh, S A,Choi, E Y,Yoon, Y S,Kim, K P,Hong, Y S,Kim, T W,Cho, D H,Kim, S Y,Kim, Y S Nature Publishing Group 2013 The British journal of cancer Vol.108 No.9

<P><B>Background:</B></P><P>Surrogate biomarkers for metastatic colorectal cancer (mCRC) are urgently needed to achieve the best outcomes for targeted therapy.</P><P><B>Methods:</B></P><P>A clinical association analysis was performed to examine the three single-nucleotide polymorphisms (SNPs) that were previously proposed as markers of chemosensitivity to the cetuximab (124 patients) and bevacizumab regimens (100 patients) in mCRC patients. In addition, biological correlations were examined for the candidate SNPs in terms of their regulatory pathway.</P><P><B>Results:</B></P><P>For cetuximab regimens, patients homozygous for the wild-type alleles (<I>GG</I>) of <I>LIFR rs3729740</I> exhibited a 1.9 times greater overall response rate (ORR) and 1.4 months longer progression-free survival (PFS) than those homozygous or heterozygous for the mutant allele (<I>GA</I> and <I>AA</I>; <I>P</I>=0.022 and 0.027, respectively). For bevacizumab regimens, patients homozygous for the minor alleles (<I>TT</I>) of <I>ANXA11 rs1049550</I> exhibited an ORR twice as high as those homozygous or heterozygous for the ancestral allele (<I>CC</I> and <I>CT</I>; <I>P</I>=0.031). Overall response rate gain was achieved up to 10% in patients with wild-type <I>LIFR rs3729740</I> patients either with wild-type <I>KRAS</I> or skin toxicity (<I>P</I>=0.001) respectively. Specifically in clones treated with cetuximab and bevacizumab regimens, active p-ERK and MMP-9 expressions were significantly reduced in clones expressing wild-type <I>LIFR rs3729740</I> (<I>P</I>=0.044) and in those expressing minor-type <I>ANXA11 rs1049550</I> (<I>P</I>=0.007), respectively.</P><P><B>Conclusion:</B></P><P><I>LIFR rs3729740</I> and possibly <I>ANXA11 rs1049550</I> may be useful as biomarkers for predicting whether mCRC patients are sensitive to relevant target regimens, although further validation in large cohorts is needed.</P>

Genome-wide and candidate gene approaches of clopidogrel efficacy using pharmacodynamic and clinical end points—Rationale and design of the International Clopidogrel Pharmacogenomics Consortium (ICPC)

Bergmeijer, Thomas O.,Reny, Jean-Luc,Pakyz, Ruth E.,Gong, Li,Lewis, Joshua P.,Kim, Eun-Young,Aradi, Daniel,Fernandez-Cadenas, Israel,Horenstein, Richard B.,Lee, Ming Ta Michael,Whaley, Ryan M.,Montane Elsevier 2018 American Heart Journal Vol.198 No.-

<P><B>Rationale</B></P> <P>The P2Y<SUB>12</SUB> receptor inhibitor clopidogrel is widely used in patients with acute coronary syndrome, percutaneous coronary intervention, or ischemic stroke. Platelet inhibition by clopidogrel shows wide interpatient variability, and high on-treatment platelet reactivity is a risk factor for atherothrombotic events, particularly in high-risk populations. <I>CYP2C19</I> polymorphism plays an important role in this variability, but heritability estimates suggest that additional genetic variants remain unidentified. The aim of the International Clopidogrel Pharmacogenomics Consortium (ICPC) is to identify genetic determinants of clopidogrel pharmacodynamics and clinical response.</P> <P><B>Study design</B></P> <P>Based on the data published on www.clinicaltrials.gov, clopidogrel intervention studies containing genetic and platelet function data were identified for participation. Lead investigators were invited to share DNA samples, platelet function test results, patient characteristics, and cardiovascular outcomes to perform candidate gene and genome-wide studies.</P> <P><B>Results</B></P> <P>In total, 17 study sites from 13 countries participate in the ICPC, contributing individual patient data from 8,829 patients. Available adenosine diphosphate–stimulated platelet function tests included vasodilator-stimulated phosphoprotein assay, light transmittance aggregometry, and the VerifyNow P2Y<SUB>12</SUB> assay. A proof-of-principle analysis based on genotype data provided by each group showed a strong and consistent association between <I>CYP2C19</I>*2 and platelet reactivity (<I>P</I> value=5.1 × 10<SUP>−40</SUP>).</P> <P><B>Conclusion</B></P> <P>The ICPC aims to identify new loci influencing clopidogrel efficacy by using state-of-the-art genetic approaches in a large cohort of clopidogrel-treated patients to better understand the genetic basis of on-treatment response variability.</P>

Determination of N* amplitudes from associated strangeness production in p+p collisions

Mü,nzer, R.,Fabbietti, L.,Epple, E.,Lu, S.,Klose, P.,Hauenstein, F.,Herrmann, N.,Grzonka, D.,Leifels, Y.,Maggiora, M.,Pleiner, D.,Ramstein, B.,Ritman, J.,Roderburg, E.,Salabura, P.,Sarantsev, A.,B North-Holland Pub. Co 2018 Physics letters. Section B Vol.785 No.-

<P><B>Abstract</B></P> <P>We present the first determination of the energy-dependent amplitudes of N<SUP>⁎</SUP> resonances extracted from their decay in KΛ pairs in p+p → <SUP> pK + </SUP> Λ reactions. A combined Partial Wave Analysis of seven data samples with exclusively reconstructed p+p → <SUP> pK + </SUP> Λ events measured by the COSY-TOF, DISTO, FOPI and HADES Collaborations in fixed target experiments at kinetic energies between 2.14 to 3.5 GeV is used to determine the amplitude of the resonant and non-resonant contributions into the associated strangeness final state. The contribution of seven N<SUP>⁎</SUP> resonances with masses between 1650 MeV/c<SUP>2</SUP> and 1900 MeV/c<SUP>2</SUP> for an excess energy between 0 and 600 MeV has been considered. The Σ–p cusp and final state interactions for the p–Λ channel are also included as coherent contributions in the PWA. The N<SUP>⁎</SUP> contribution is found to be dominant with respect to the phase space emission of the pK Λ + final state at all energies demonstrating the important role played by both N<SUP>⁎</SUP> and interference effects in hadron–hadron collisions.</P>

The SAURON project – XIX. Optical and near‐infrared scaling relations of nearby elliptical, lenticular and Sa galaxies

Falcó,n‐,Barroso, J.,van de Ven, G.,Peletier, R. F.,Bureau, M.,Jeong, H.,Bacon, R.,Cappellari, M.,Davies, R. L.,de Zeeuw, P. T.,Emsellem, E.,Krajnović,, D.,Kuntschner, H.,McDermid, R. Blackwell Publishing Ltd 2011 MONTHLY NOTICES- ROYAL ASTRONOMICAL SOCIETY Vol.417 No.3

<P><B>ABSTRACT</B></P><P>We present ground‐based MDM Observatory <I>V</I>‐band and <I>Spitzer</I>/InfraRed Array Camera 3.6‐<IMG src='/wiley-blackwell_img/equation/MNR_19372_mu1.gif' alt ='inline image'/>m‐band photometric observations of the 72 representative galaxies of the SAURON survey. Galaxies in our sample probe the elliptical E, lenticular S0 and spiral Sa populations in the nearby Universe, both in field and cluster environments. We perform aperture photometry to derive homogeneous structural quantities. In combination with the SAURON stellar velocity dispersion measured within an effective radius (σ<SUB>e</SUB>), this allows us to explore the location of our galaxies in the colour–magnitude, colour–σ<SUB>e</SUB>, Kormendy, Faber–Jackson and Fundamental Plane scaling relations. We investigate the dependence of these relations on our recent kinematical classification of early‐type galaxies (i.e. slow/fast rotators) and the stellar populations. Slow rotator and fast rotator E/S0 galaxies do not populate distinct locations in the scaling relations, although slow rotators display a smaller intrinsic scatter. We find that Sa galaxies deviate from the colour–magnitude and colour–σ<SUB>e</SUB> relations due to the presence of dust, while the E/S0 galaxies define tight relations. Surprisingly, extremely young objects do not display the bluest (<I>V</I>−[3.6]) colours in our sample, as is usually the case in optical colours. This can be understood in the context of the large contribution of thermally pulsing asymptotic giant branch stars to the infrared, even for young populations, resulting in a very tight (<I>V</I>−[3.6])–σ<SUB>e</SUB> relation that in turn allows us to define a strong correlation between metallicity and σ<SUB>e</SUB>. Many Sa galaxies appear to follow the Fundamental Plane defined by E/S0 galaxies. Galaxies that appear offset from the relations correspond mostly to objects with extremely young populations, with signs of ongoing, extended star formation. We correct for this effect in the Fundamental Plane, by replacing luminosity with stellar mass using an estimate of the stellar mass‐to‐light ratio, so that all galaxies are part of a tight, single relation. The new estimated coefficients are consistent in both photometric bands and suggest that differences in stellar populations account for about half of the observed tilt with respect to the virial prediction. After these corrections, the slow rotator family shows almost no intrinsic scatter around the best‐fitting Fundamental Plane. The use of a velocity dispersion within a small aperture (e.g. <I>R</I><SUB>e</SUB>/8) in the Fundamental Plane results in an increase of around 15 per cent in the intrinsic scatter and an average 10 per cent decrease in the tilt away from the virial relation.</P>

Antiseptic chlorhexidine in activated sludge: Biosorption, antimicrobial susceptibility, and alteration of community structure

Keerthisinghe, Tharushi P.,Nguyen, Luong N.,Kwon, Eilhann E.,Oh, Seungdae Elsevier 2019 Journal of environmental management Vol.237 No.-

<P><B>Abstract</B></P> <P>Chlorhexidine (CHX) is a broad-spectrum antimicrobial, which may pose environmental health risks. This study examined the removal potential and the mechanisms regulating the fate of CHX in activated sludge (AS). Bioreactors inoculated with AS removed 74 ± 8% and 81 ± 6% of CHX at steady state while receiving 0.5 and 1 mg/L CHX, respectively. Analysis of the removal pathways showed that biosorption, rather than biological breakdown or other abiotic losses, largely (>70%) regulated the removal of CHX. 16S rRNA gene-based analysis revealed that CHX selected for <I>Luteolibacter</I> (4.3–10.1-fold change) and <I>Runella</I> (6.2–14.1-fold change) with potential multi-drug resistance mechanisms (e.g., efflux pumps). In contrast, it significantly reduced core members (<I>Comamonadaceae</I> and <I>Flavobacteriaceae</I>) of AS, playing a key role in contaminant removal and floc formation directly associated with the performance of WWTPs (e.g., wastewater effluent quality). Antimicrobial susceptibility testing showed that 0.4–1.3 mg/L of CHX can be sublethal to AS. Our work provided new insights into the fate of CHX in urban waste streams and the potential toxicity and effects on the structure and function of AS, which has practical implications for the management of biological WWTPs treating CHX.</P> <P><B>Highlights</B></P> <P> <UL> <LI> Activated sludge-inoculated bioreactors removed 70–80% of CHX at steady state. </LI> <LI> CHX was removed in activated sludge largely by biosorption. </LI> <LI> CHX could be inhibitory to activated sludge at environmentally relevant levels. </LI> <LI> CHX selected for <I>Luteolibacter</I> and <I>Runella</I> with potential multi-drug resistance mechanisms. </LI> <LI> CHX reduced core members of activated sludge<I>.</I> </LI> </UL> </P> <P><B>Graphical abstract</B></P> <P>[DISPLAY OMISSION]</P>

Expression phenotype changes of EBV-transformed lymphoblastoid cell lines during long-term subculture and its clinical significance

Lee, J.-E.,Nam, H.-Y.,Shim, S.-M.,Bae, G.-R.,Han, B.-G.,Jeon, J.-P. Blackwell Publishing Ltd 2010 Cell proliferation Vol.43 No.4

<P>Abstract</P><P>Objectives: </P><P>The EBV-transformed lymphoblastoid cell line (LCL) is a useful resource for population-based human genetic and pharmacogenetic studies. The principal objective here was to assess expression phenotype changes during long-term subculture of LCLs, and its clinical significance.</P><P>Materials and methods: </P><P>We searched for genes that were differentially expressed in 17 LCLs at late (p161) passage compared to early passage (p4) using microarray assay, then validated them by real-time RT-PCR analysis. In addition, we estimated correlations between expression phenotypes of 20 LCL strains at early passage and 23 quantitative clinical traits from blood donors of particular LCL strains.</P><P>Results: </P><P>Transcript sequences of 16 genes including nuclear factor-&kgr;B (NF-&kgr;B) pathway-related genes (such as <I>PTPN13</I>, <I>HERC5</I> and miR-146a) and carcinogenesis-related genes (such as <I>XAF1</I>, <I>TCL1A</I>, <I>PTPN13</I>, <I>CD38</I> and miR-146a) were differentially expressed (>2-fold change) in at least 15 of the 17 LCL strains. In particular, <I>TC2N</I>, <I>FCRL5</I>, <I>CD180</I>, <I>CD38</I> and miR-146a were downregulated in all 17 of the evaluated LCL strains. In addition, we identified clinical trait-associated expression phenotypes in LCLs.</P><P>Conclusion: </P><P>Our results showed that LCLs acquired expression phenotype changes involving expression of NF-&kgr;B pathway- and carcinogenesis-related genes during long-term subculture. These differentially expressed genes can be considered to be a gene signature of LCL immortalization or EBV-induced carcinogenesis. Clinical trait-associated expression phenotypes should prove useful in the discovery of new candidate genes for particular traits.</P>

Identification of a novel <i>FAM83H</i> mutation and microhardness of an affected molar in autosomal dominant hypocalcified amelogenesis imperfecta

Hyun, H.-K.,Lee, S.-K.,Lee, K.-E.,Kang, H.-Y.,Kim, E.-J.,Choung, P.-H.,Kim, J.-W. Blackwell Publishing Ltd 2009 International endodontic journal Vol.42 No.11

<P>Abstract</P><P>Aim </P><P>To determine the underlying molecular genetic aetiology of a family with the hypocalcified form of amelogenesis imperfecta and to investigate the hardness of the enamel and dentine of a known <I>FAM83H</I> mutation.</P><P>Methodology </P><P>Mutational screening of the <I>FAM83H</I> on the basis of candidate gene approach was performed. All exons and exon–intron boundaries was amplified and sequenced. A microhardness test was performed to measure the Vickers microhardness value.</P><P>Results </P><P>A novel nonsense mutation (c.1354C>T, p.Q452X) was identified in the last exon of <I>FAM83H</I>, which resulted in soft, uncalcified enamel. The affected enamel was extremely soft (about 17% of the normal control), but the underlying dentine was as hard as the normal control.</P><P>Conclusions </P><P>Mutational analysis revealed a novel mutation in <I>FAM83H</I> gene. Hardness of dentine was not affected by the mutation, whilst the enamel was extremely soft.</P>

Golimumab, a human antibody to tumour necrosis factor α given by monthly subcutaneous injections, in active rheumatoid arthritis despite methotrexate therapy: the GO-FORWARD Study

Keystone, E C,Genovese, M C,Klareskog, L,Hsia, E C,Hall, S T,Miranda, P C,Pazdur, J,Bae, S-C,Palmer, W,Zrubek, J,Wiekowski, M,Visvanathan, S,Wu, Z,Rahman, M U BMJ Publishing Group 2009 Annals of the Rheumatic Diseases Vol.68 No.6

<P><B>Objective:</B></P><P>The phase III GO-FORWARD study examined the efficacy and safety of golimumab in patients with active rheumatoid arthritis (RA) despite methotrexate therapy.</P><P><B>Methods:</B></P><P>Patients were randomly assigned in a 3 : 3 : 2 : 2 ratio to receive placebo injections plus methotrexate capsules (group 1, n  =  133), golimumab 100 mg injections plus placebo capsules (group 2, n  =  133), golimumab 50 mg injections plus methotrexate capsules (group 3, n  =  89), or golimumab 100 mg injections plus methotrexate capsules (group 4, n  =  89). Injections were administered subcutaneously every 4 weeks. The co-primary endpoints were the proportion of patients with 20% or greater improvement in the American College of Rheumatology criteria (ACR20) at week 14 and the change from baseline in the health assessment questionnaire-disability index (HAQ-DI) score at week 24.</P><P><B>Results:</B></P><P>The proportion of patients who achieved an ACR20 response at week 14 was 33.1% in the placebo plus methotrexate group, 44.4% (p = 0.059) in the golimumab 100 mg plus placebo group, 55.1% (p = 0.001) in the golimumab 50 mg plus methotrexate group and 56.2% (p<0.001) in the golimumab 100 mg plus methotrexate group. At week 24, median improvements from baseline in HAQ-DI scores were 0.13, 0.13 (p = 0.240), 0.38 (p<0.001) and 0.50 (p<0.001), respectively. During the placebo-controlled portion of the study (to week 16), serious adverse events occurred in 2.3%, 3.8%, 5.6% and 9.0% of patients and serious infections occurred in 0.8%, 0.8%, 2.2% and 5.6%, respectively.</P><P><B>Conclusion:</B></P><P>The addition of golimumab to methotrexate in patients with active RA despite methotrexate therapy significantly reduced the signs and symptoms of RA and improved physical function.</P>

Crystallization Modes of Poly(3-dodecylthiophene)-Based Block Copolymers Depend on Regioregularity and Morphology

Coote, Jonathan P.,Kim, Jin-Seong,Lee, Byeongdu,Han, Junghun,Kim, Bumjoon J.,Stein, Gila E. American Chemical Society 2018 Macromolecules Vol.51 No.22

<P>Conjugated block copolymers (BCPs) can self-assemble into highly ordered nanostructures in a melt state. However, when cooled below the melting temperature, crystal growth can disrupt the self-assembled structure and produce a poorly ordered fibrillar texture. We demonstrate that crystallization modes of conjugated BCPs based on poly(3-dodecylthiophene) (P3DDT) and poly(2-vinylpyridine) (P2VP) can be tuned through P3DDT regioregularity (RR), as this attribute controls the melting temperature and crystallization rates of P3DDT. When RR is low (70-80%), crystallization is observed at temperatures near or below the glass transition of P2VP, so crystal growth is largely confined by the glassy cylindrical or lamellar BCP structure. When RR is high (94%), crystallization occurs at 40 K above the glass transition of P2VP, so there is no longer a restriction of glassy domains. Importantly, crystal growth remains confined by the rubbery P2VP lamellae, but breaks through the rubbery P2VP cylinders. This morphology-dependent behavior is attributed to geometric compatibility of P3DDT crystal growth and the self-assembled symmetry. In a lamellar phase, the P3DDT chain orientations at the P3DDT-<I>block</I>-P2VP interface are compatible with crystal growth, and both the alkyl-stacking and π-π growth directions are unrestricted within a lamellar sheet. In a cylindrical phase, the radial orientation of P3DDT chains at the P3DDT-<I>block</I>-P2VP interface is not compatible with crystal growth, and the hexagonal close-packed symmetry only allows for one direction of unrestricted crystal growth. Significantly, these studies demonstrate that tuning RR of polyalkylthiophenes can open up multiple crystallization modes with the same monomer chemistries and block lengths, thereby decoupling the parameters that govern classical BCP self-assembly and crystal growth.</P> [FIG OMISSION]</BR>

Foxp3 is a key downstream regulator of p53-mediated cellular senescence

Kim, J-E,Shin, J-S,Moon, J-H,Hong, S-W,Jung, D-J,Kim, J H,Hwang, I-Y,Shin, Y J,Gong, E-Y,Lee, D H,Kim, S-M,Lee, E Y,Kim, Y S,Kim, D,Hur, D,Kim, T W,Kim, K-p,Jin, D-H,Lee, W-J Macmillan Publishers Limited 2017 Oncogene Vol.36 No.2

<P>The downstream events and target genes of p53 in the process of senescence are not fully understood. Here, we report a novel function of the forkhead transcription factor Foxp3, which is a key player in mediating T-cell inhibitory functions, in p53-mediated cellular senescence. The overexpression of Foxp3 in mouse embryonic fibroblasts (MEFs) accelerates senescence, whereas Foxp3 knockdown leads to escape from p53-mediated senescence in p53-expressing MEFs. Consistent with these results, Foxp3 expression resulted in the induction of senescence in epithelial cancer cells, including MCF7 and HCT116 cells. Foxp3 overexpression also increased the intracellular levels of reactive oxygen species (ROS). The ROS inhibitor N-acetyl-L-cysteine rescued cells from Foxp3-expression-induced senescence. Furthermore, the elevated ROS levels that accompanied Foxp3 overexpression were paralleled by an increase in p21 expression. Knockdown of p21 in Foxp3-expressing MEFs abrogated the Foxp3-dependent increase in ROS levels, indicating that Foxp3 acts through the induction of p21 and the subsequent ROS elevation to trigger senescence. Collectively, these results suggest that Foxp3 is a downstream target of p53 that is sufficient to induce p21 expression, ROS production and p53-mediated senescence.</P>