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1.
George Pentheroudakis Georgia Raptou Vassiliki Kotoula Ralph M. Wirtz Eleni Vrettou Vasilios Karavasilis Georgia Gourgioti Chryssa Gakou Konstantinos N. Syrigos Evangelos Bournakis Grigorios Rallis Ioannis Varthalitis Eleni Galani Georgios Lazaridis George Papaxoinis Dimitrios Pectasides Gerasimos Aravantinos Thomas Makatsoris Konstantine T. Kalogeras George Fountzilas 《PloS one》2015,10(5)
Background
Although host immune response is an emerging prognostic factor for colorectal cancer, there is no consensus on the optimal methodology, surrogate markers or tissue for study.Patients and Methods
Tumour blocks were prospectively collected from 344 patients with stage II/III colorectal cancer (CRC) treated with adjuvant chemotherapy. Whole section lymphocytic infiltration was studied along with mRNA expression of CD3Z, CD8, CD4, CXCL9, CXCL13, IGHM, FOXP3, SNAI2 and ESR1 by qRT-qPCR in tissue microarray (TMA) cores from the centre of tumour, invasive margin and adjacent normal mucosa.Results
Lymphocytic infiltration, deficient MMR (10.9%), KRAS (40.7%) and BRAF (4.9%) mutations or single mRNA gene expression were not prognostic. Tumour ESR1 gene expression (Hazard Ratio [HR] for relapse 2.33, 95% CI 1.35-4.02; HR for death 1.74, 95% CI 1.02-2.97) and absence of necrosis (HR for relapse 1.71, 95% CI 1.05-2.71; HR for death 1.98, 95% CI 1.14-3.43) were adverse prognostic features. We used CD3Z and CD8 expression in order to devise the mRNA-based Immune Score (mIS) and proceeded to partitioning analysis in 267 patients, with age, stage, tumour site (Right vs Left CRC), KRAS mutation and tumour mIS as input factors. Only in patients with stage III right-sided colon cancer, a low immune response was associated with inferior disease-free survival (mIS-low, HR for relapse 2.28, 95% CI 1.05-8.02). No prognostic significance was seen for tumour mIS in any other stage or site of CRC, or for a similar mIS score derived from adjacent normal mucosa. Independent adverse prognostic significance was retained in multivariable analysis for absence of necrosis, tumour ESR1 expression in all patients and low tumour mIS in stage III right-sided CRC.Conclusions
In localised CRC, mRNA-based CD3Z/CD8 profiling of tumour immune response may have stage, site and tissue-specific prognostic significance, along with ESR1 expression.Trial Registration
ANZCTR.org.au ACTRN12610000509066 相似文献2.
Futile plasma membrane cycling of ammonium (NH4+) is characteristic of low-affinity NH4+ transport, and has been proposed to be a critical factor in NH4+ toxicity. Using unidirectional flux analysis with the positron-emitting tracer 13N in intact seedlings of barley (Hordeum vulgare L.), it is shown that rapid, futile NH4+ cycling is alleviated by elevated K+ supply, and that low-affinity NH4+ transport is mediated by a K+-sensitive component, and by a second component that is independent of K+. At low external [K+] (0.1 mM), NH4+ influx (at an external [NH4+] of 10 mM) of 92 micromol g(-1) h(-1) was observed, with an efflux:influx ratio of 0.75, indicative of rapid, futile NH4+ cycling. Elevating K+ supply into the low-affinity K+ transport range (1.5-40 mM) reduced both influx and efflux of NH4+ by as much as 75%, and substantially reduced the efflux:influx ratio. The reduction of NH4+ fluxes was achieved rapidly upon exposure to elevated K+, within 1 min for influx and within 5 min for efflux. The channel inhibitor La3+ decreased high-capacity NH4+ influx only at low K+ concentrations, suggesting that the K+-sensitive component of NH4+ influx may be mediated by non-selective cation channels. Using respiratory measurements and current models of ion flux energetics, the energy cost of concomitant NH4+ and K+ transport at the root plasma membrane, and its consequences for plant growth are discussed. The study presents the first demonstration of the parallel operation of K+-sensitive and -insensitive NH4+ flux mechanisms in plants. 相似文献
3.
Eleni Timotheadou Konstantine T. Kalogeras Georgia-Angeliki Koliou Ralph M. Wirtz Flora Zagouri Angelos Koutras Elke Veltrup Christos Christodoulou George Pentheroudakis Aris Tsiftsoglou Pavlos Papakostas Gerasimos Aravantinos Vasilios Venizelos Dimitrios Pectasides Paris Kosmidis Charisios Karanikiotis Christos Markopoulos Helen Gogas George Fountzilas 《Translational oncology》2017,10(4):589-598
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Summary The influence of the internal dynamics of two polypeptides comprising transmembrane -helix A or two -helices A and B of bacterioopsin on experimentally accessible 15N NMR relaxation rates was investigated by molecular dynamics (MD) simulations, combined with more simple mechanic considerations. Model-free order parameters and correlation times of internal motions [Lipari, G. and Szabo, A. (1982) J. Am. Chem. Soc., 104, 4546–4559] were calculated for these models. It was found that both peptides exhibit two types of internal motions of the amide bonds, on the pico- and nanosecond time scales, affecting 15N NMR relaxation. The fast fluctuations are local and correspond to the librational motions of the individual N–H vectors in an effective potential of atoms of the surrounding matrix. In contrast, the motions on the nanosecond time scale imply concerted collective vibrations of a large number of atoms and could be represented as bending oscillation of -helices, strongly overdamped by the ambient solvent. A few other molecular mechanisms of slow internal motion were found, such as local distortions of the -helices (e.g., -aneurysm), delocalized distortions of the -helical backbone, as well as oscillations of the tilt angle between the axes of the -helices A and B. The results are compared with 15N NMR relaxation data measured for the (1–36)bacterioopsin and (1–71)bacterioopsin polypeptides in chloroform-methanol (1:1) and in SDS micelles [Orekhov, V.Yu., Pervushin, K.V. and Arseniev, A.S. (1994) Eur. J. Biochem., 219, 887–896].Abbreviations C2
baeterioopsin-(7–63)-peptide
- sA
bacterioopsin-(7–32)-peptide
- CPMG
Carr-Purcell-Meiboom-Gill
- MD
molecular dynamics
- rmsd
root-mean-square deviation 相似文献
6.
McGuire TR Hoie EB Manouilov KK Gwilt PG 《In vitro cellular & developmental biology. Animal》2003,39(7):280-282
Summary The purpose of this study was to characterize the activation of zidovudine (ZDV) and lamivudine (3TC) in human umbilical vein
endothelial cells (HUVEC) with and without hydroxyurea (HU) pretreatment. HUVEC were pretreated with HU or control media for
24 h and then incubated for an additional 3 h with ZDV or 3TC. Intracellular concentrations of parent drugs and the phosphorylated
forms were determined by high-performance liquid chromatography. Pretreatment with HU resulted in more than a threefold increase
in intracellular concentrations of total ZDV, with the major intracellular form being the monophosphate (>80%). The relative
percentage of each ZDV form was similar between control and HU-treated cells. On the other hand, intracellular concentrations
of total 3TC increased only slightly (14%) with HU pretreatment. Although the parent drug remained the major intracellular
form of 3TC, there was nearly a 400% increase in the 3TC triphosphate after HU pretreatment. These data demonstrate that HU
causes a large increase in the intracellular accumulation of total ZDV, whereas it increases total 3TC only slightly but improves
its triphosphorylation. Given the increase in intracellular concentrations of ZDV monophosphate after HU pretreatment and
that the monophosphate has no antiviral activity but is associated with toxicity, the use of HU is not a good strategy to
improve ZDV activation in human endothelium. There is improved production of the active antiviral 3TC triphosphate with HU
pretreatment. The combination may be beneficial in treating potential sanctuary sites such as endothelium. 相似文献
7.
The influence of operational sex ratio on the mating behavior of female field crickets,Gryllus pennsylvanicus, was investigated. Females were predicted to be more discriminating under conditions of high mate availability and show less selectivity when males were rare. Such selectivity was indicated in this study with the proportion of courtships leading to a mating changing with sex ratio. Females accepted almost 70% of all courtships at the female-biased sex ratio, but only about half of all courtships were successful at even or male-biased sex ratios. Females moved least at the female-biased sex ratio. There was also a trend for females to be guarded more under male-biased conditions. Female weight did not influence any of the behaviors examined. 相似文献
8.
George Papaxoinis Vassiliki Kotoula Zoi Alexopoulou Konstantine T. Kalogeras Flora Zagouri Eleni Timotheadou Helen Gogas George Pentheroudakis Christos Christodoulou Angelos Koutras Dimitrios Bafaloukos Gerasimos Aravantinos Pavlos Papakostas Elpida Charalambous Kyriaki Papadopoulou Ioannis Varthalitis Ioannis Efstratiou Thomas Zaramboukas Helen Patsea Chrisoula D. Scopa Maria Skondra Paris Kosmidis Dimitrios Pectasides George Fountzilas 《PloS one》2015,10(10)
Background
The PI3K-AKT pathway is frequently activated in breast cancer. PIK3CA mutations are most frequently found in the helical (exon 9) and kinase (exon 20) domains of this protein. The aim of the present study was to examine the role of different types of PIK3CA mutations in combination with molecular biomarkers related to PI3K-AKT signaling in patients with early breast cancer.Methods
Tumor tissue samples from 1008 early breast cancer patients treated with adjuvant chemotherapy in two similar randomized trials of HeCOG were examined. Tumors were subtyped with immunohistochemistry (IHC) and FISH for ER, PgR, Ki67, HER2 and androgen receptor (AR). PIK3CA mutations were analyzed by Sanger sequencing (exon 20) and qPCR (exon 9) (Sanger/qPCR mutations). In 610 cases, next generation sequencing (NGS) PIK3CA mutation data were also available. PIK3CA mutations and PTEN protein expression (IHC) were analyzed in luminal tumors (ER and/or PgR positive), molecular apocrine carcinomas (MAC; ER/PgR negative / AR positive) and hormone receptor (ER/PgR/AR) negative tumors.Results
PIK3CA mutations were detected in 235/1008 tumors (23%) with Sanger/qPCR and in 149/610 tumors (24%) with NGS. Concordance between the two methods was good with a Kappa coefficient of 0.76 (95% CI 0.69–0.82). Lobular histology, low tumor grade and luminal A tumors were associated with helical domain mutations (PIK3CAhel), while luminal B with kinase domain mutations (PIK3CAkin). The overall incidence of PIK3CA mutations was higher in luminal as compared to MAC and hormone receptor negative tumors (p = 0.004). Disease-free and overall survival did not significantly differ with respect to PIK3CA mutation presence and type. However, a statistically significant interaction between PIK3CA mutation status and PTEN low protein expression with regard to prognosis was identified.Conclusions
The present study did not show any prognostic significance of specific PIK3CA mutations in a large group of predominantly lymph-node positive breast cancer women treated with adjuvant chemotherapy. Further analyses in larger cohorts are warranted to investigate possible differential effect of distinct PIK3CA mutations in small subgroups of patients. 相似文献9.
Konstantine V. Pervushin Alexander S. Arseniev Alexander T. Kozhich Vadim T. Ivanov 《Journal of biomolecular NMR》1991,1(4):313-322
Summary The conformation of the synthetic 32-residue polypeptide, an analog of the membrane spanning segment B (residues 34-65) ofHalobacterium halobium bacteriobpsin, incorporated into perdeuterated sodium dodecyl sulfate micelles in the presence of trifluoroethanol was investigated by1H NMR spectroscopy. The spectrum resonances were assigned by means of phase-sensitive DQF-COSY, TOCSY and NOESY techniques. Interproton nuclear Overhauser effects and deuterium exchange rates of individual NH groups were derived from two-dimensional NMR spectra. Analysis of the obtained data showed that segment B has a right-handed a-helical stretch from Lys41 to Leu62 with a kink at Pros50. The-helix in the C-terminal part is terminated at Gly63, which adopts a conformation typical of amino acid residues in a left-handed helix. The N-terminal part (residues 34–40) has no ordered conformation. NMR data are provided for comparison of the segment B conformation in the isotropic system of an organic solvent, in SDS micelles and in the purple membrane bacterioopsin. Factors affecting the conformation of membrane spanning segment B in various milieus are discussed.Dedicated to the memory of Professor V.F. Bystrov 相似文献
10.
Andrew L. Lomize Konstantine V. Pervushin Alexander S. Arseniev 《Journal of biomolecular NMR》1992,2(4):361-372
Summary The spatial structure of a synthetic 32-residue polypeptide, an analog of the membrane-spanning segment B (residues 34–65) of bacterioopsin ofHalobacterium halobium, incorporated into perdeuterated sodium dodecyl sulfate micelles, was determined from1H NMR data. The structure determination included the following steps: (1) local sructure analysis; (2) structure calculations using the distance geometry program DIANA; (3) systematic search for energetically allowed side-chain rotamers consistent with NOESY crosspeak volumes; (4) random generation of peptide conformations in allowed conformational space. The obtained structure has a righ-handed -helicl region from Lys41 to Leu62 with a kink of 27 at Pro50. The C-cap Gly63 adopts a conformation with =87±6, =43±10o typical to a left-handed helix. The N-terminal part (residues 34–40) is exposed to the aqueous phase and lacks an ordered conformation. The secondary structure of segment B in micelles is consistent with the high-resolution electron cryomicroscopy model of bacteriorhodopsin (Henderson et al. (1990)J. Mol. Biol.,213, 899–929). 相似文献