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Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) and bevacizumab plus chemotherapy were effective for EGFR-mutant patients. However, the appropriated treatment orders remained controvertible. We investigated the efficacy of treatment orders between bevacizumab plus chemotherapy and EGFR-TKIs for EGFR-mutant patients with advanced pulmonary adenocarcinoma.Patients and methods: This study involved 40 EGFR-mutant patients with advanced pulmonary adenocarcinoma who were treated with bevacizumab plus carboplatin and paclitaxel (Bev + CP) and EGFR-TKIs in different treatment orders or gemcitabine plus cisplatin (GP) in first-line setting. Seventeen patients were treated with Bev + CP and 10 cases with GP in first-line treatment. Thirteen patients received EGFR-TKIs after first-line Bev + CP regimen, while 13 patients were treated with first-line EGFR-TKIs. Progression-free survival (PFS), the response rate (ORR) and overall survival (OS) were evaluated.Results: Median PFS of Bev + CP treatment was significantly longer in first-line than non-first-line settings (11.7 vs. 5.6 months, P = 0.003). Median OS was 37.8 months for EGFR-mutant patients with first-line Bev + CP followed by second-line EGFR-TKIs and 31.0 months for those with first-line EGFR-TKIs and non-first-line Bev + CP, respectively (P = 0.509). Median PFS was 11.7 (95% CI 10.6–12.8) months for Bev + CP group and 4.7 (95% CI 4.4–5.0) months for GP group with the hazard ratio of 0.17 (P = 0.001). ORR was 70.6 and 50.0% in the two groups, respectively (P = 0.415). However, there was no significant difference in median OS (33.7 vs 27.8 months, P = 0.293).Conclusions: First-line Bev + CP followed by EGFR-TKIs might possibly provide favorable prognosis for EGFR-mutant patients. Bev + CP regimen significantly prolonged PFS in first-line than non-first-line settings. These findings warrant further investigations. [ABSTRACT FROM AUTHOR]

Background: A phase III trial was conducted to compare the safety and efficacy of erlotinib with that of gefitinib in advanced non-small cell lung cancer harbouring epidermal growth factor receptor mutations in exon 19 or 21.Methods: Eligible patients were randomised to receive erlotinib (150 mg per day) or gefitinib (250 mg per day) orally until disease progression or unacceptable toxicity. We aimed to determine whether erlotinib is superior to gefitinib in efficacy. The primary end point was progression-free survival.Results: A total of 256 patients were randomised to receive erlotinib (N=128) or gefitinib (N=128). Median progression-free survival was not better with erlotinib than with gefitinib (13.0 vs 10.4 months, 95% confidence interval (CI) 0.62-1.05, P=0.108). The corresponding response rates and median overall survival were 56.3% vs 52.3% (P=0.530) and 22.9 vs 20.1 months (95% CI 0.63-1.13, P=0.250), respectively. There were no significant differences in grade 3/4 toxicities between the two arms (P=0.172).Conclusions: The primary end point was not met. Erlotinib was not significantly superior to gefitinib in terms of efficacy in advanced non-small cell lung cancer with epidermal growth factor receptor mutations in exon 19 or 21, and the two treatments had similar toxicities. [ABSTRACT FROM AUTHOR]

The objective of this study was to analyze the predictive roles of VEGF/KDR/Ras/MAPK gene expression in patients with advanced non-small-cell lung cancer (NSCLC) treated with bevacizumab plus chemotherapy. Twenty-five patients participating in an open-label phase IV trial (SAİL, MOI9390) with available tumor tissues were analyzed. The mRNA expression levels of VEGF, kinase Insert domain receptor (KDR), Ras, and mitogen-activated protein kinase (MAPK) in tumor tissues were detected using real-time quantitative PCR methods. The relationships between gene expression and disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) were assessed. Patients with lower Ras expression had a longer PFS and OS than patients with higher expression (median PFS, 9.9 vs 5.5 months, χ² = 3.944, P= 0.047; OS, 19.3 vs 7.1 months, χ² = 9.384, P = 0.002). The PFS and OS of patients with lower and higher MAPK expression exhibited a marginal and significant difference (median PFS, 9.9 vs 5.5 months, χ² = 3.464, P = 0.063; OS, 19.3 vs 9.7 months, χ² =5.298, P= 0.021), respectively. Multivariate analyses using Cox's proportional hazards model showed that Ras is an independent predictor of OS (χ² = 9.384, P = 0.002). No differences in DCR were found according to Ras expression level. The results indicate that Ras is an independent predictor of OS. Thus, patients with lower Ras expression are most likely to benefit from bevacizumab plus chemotherapy treatment regimen. Patients with higher levels of Ras should receive other inhibitors that target Ras. The results also suggest that gene therapies that decrease RAS expression combined with bevacizumab may improve lung cancer treatment. Although there is a very Important implication to patient selection in the target therapy, the data in this study are very preliminary owing to the too small sample size. Therefore, further research involving large numbers of patients and a prospective assessment of low and high RAS mRNA expressions getting the same treatments need to be done before conclusions can be made. [ABSTRACT FROM AUTHOR]

The expression of hTERT gene, encoding the catalytic subunit of telomerase, is a feature of most cancer cells. Changes in the chromatin environment of its promoter and binding of transcriptional factors have been reported in differentiating cells when its transcription is repressed. However, it is not clear whether these changes are directly involved in this repression or only linked to differentiation. In a maturation-resistant acute promyelocytic leukemia (APL) cell line (NB4-LR1), we have previously identified a new pathway of retinoid-induced hTERT repression independent of differentiation. Using a variant of this cell line (NB4-LR1SFD), which resists to this repression, we show that although distinct patterns of histone modifications and transcription factor binding at the proximal domain of hTERT gene promoter could concur to modulate its expression, this region is not sufficient to the on/off switch of hTERT by retinoids. DNA methylation analysis of the hTERT promoter led to the identification of two distinct functional domains, a proximal one, fully unmethylated in both cell lines, and a distal one, significantly methylated in NB4-LR1SFD cells, whose methylation was further re-enforced by retinoid treatment. Interestingly, we showed that the binding to this distal domain of a known hTERT repressor, WT1, was defective only in NB4-LR1SFD cells. We propose that epigenetic modifications targeting this distal region could modulate the binding of hTERT repressors and account either for hTERT reactivation and resistance to retinoid-induced hTERT downregulation. [ABSTRACT FROM AUTHOR]

Complete deficiency of complement C4 is among the strongest genetic risk factors for human systemic lupus erythematosus (SLE). C4 is a constituent of the RP–C4–CYP21–TNX (RCCX) module in the human leukocyte antigen (HLA) that exhibits inter-individual copy-number and gene-size variations. Here, we studied two North-African families with complete C4 deficiency and SLE. The first included a Moroccan male SLE patient (1P) and a sibling, who were both homozygous for HLA-A*02 B*17 DRB1*07. The second had an Algerian female SLE patient (2P) homozygous for HLA-A*01 B*17 DRB1*13. Early SLE disease onset, the presence of photosensitive rashes, anti-Ro/SSA, renal disease and high titers of antinuclear antibodies were the common features of complete C4 deficiency. Southern blot analyses showed that 1P had monomodular RCCX with a long C4A, whereas 2P had bimodular RCCX with one long C4A and one short C4B. Genomic DNA fragments for these mutant genes were amplified and sequenced. A C>T transition that created the R540X nonsense mutation in C4A was found in 1P. An identical 4-bp insertion that generated the Y1537X nonsense mutation was discovered in both C4A and C4B of 2P. The high concordance of SLE and C4 deficiency among patients with non-DR3 and non-DR2 haplotypes underscores the importance of C4 proteins in the protection against SLE.Genes and Immunity (2009) 10, 433–445; doi:10.1038/gene.2009.10; published online 12 March 2009 [ABSTRACT FROM AUTHOR]

Hypoxia or hypoxia mimetic has been shown to induce differentiation together with the accumulation of hypoxia-inducible factor-1α (HIF-1α) protein of myeloid leukemic cells and normal hematopoietic progenitors. To provide direct evidence for the role of HIF-1α in acute myeloid leukemia (AML) cell differentiation and its mechanisms, we generated myeloid leukemic U937T transformants, in which HIF-1α was tightly induced by tetracycline withdrawal. The results showed that the conditional HIF-1α induction triggered granulocytic differentiation of these transformants, while the suppression of HIF-1α expression by specific short hairpin RNAs (shRNAs) effectively inhibited hypoxia-induced differentiation of U937 cells, as evidenced by morphology, maturation-related antigens as well as expressions of myeloid differentiation signatures and hematopoietic cells-specific cytokine receptors. The specific shRNAs-inhibited expression of HIF-1β, an essential partner for transcription activity of HIF-1, failed, while the inhibition of hematopoietic differentiation-critical CCAAT/enhancer-binding protein-α (C/EBPα) significantly eliminated HIF-1α-mediated myeloid leukemic cell differentiation. Collectively, this work provided several lines of direct evidence for the role of HIF-1α protein through its nontranscriptional activity in myeloid cell differentiation, in which C/EBPα elicits a role as an effector downstream to HIF-1α. These discoveries would shed new insights for understanding mechanisms underlying leukemogenesis and designing the new therapeutic strategy for differentiation induction of AML.Oncogene (2008) 27, 519–527; doi:10.1038/sj.onc.1210670; published online 16 July 2007 [ABSTRACT FROM AUTHOR]

Arsenic trioxide (ATO) and proteasome inhibitor bortezomib have been successfully applied to treat acute promyelocytic leukemia (APL) and multiple myeloma (MM), respectively. Their synergistic effects with other anticancer drugs have been widely studied. Here, we investigated the potential synergy of bortezomib and ATO on Bcr-Abl+ leukemic K562 cells. The results showed that cotreatment of bortezomib at 32 nM, a half concentration for growth arrest, and ATO at 1 μM, a dose with no significant cytotoxic effect, synergistically induced apoptosis in the cell line, followed by enhanced mitochondrial dysfunction, release of cytochrome c and apoptosis-inducing factor, caspase-3 cleavage and degradation of poly-adenosine diphosphate-ribose polymerase together with the decreased Bcr-Abl protein. These two drugs synergistically induced proteolytic activation of protein kinase Cδ (PKCδ) with enhanced activation of two mitogen-activated protein kinases phospho-c-Jun NH2-terminal kinase and p38. The specific PKCδ inhibitor rottlerin markedly decreased bortezomib plus ATO-induced apoptosis, suggesting that PKCδ plays an important role in bortezomib plus ATO-induced apoptosis. Moreover, apoptosis synergy of bortezomib and ATO could also be seen in some kinds of acute leukemic cell lines and primary cells. Totally, our results indicate that combined regimen of bortezomib and ATO might be a potential therapeutic remedy for the treatment of leukemia.Leukemia (2007) 21, 1488–1495; doi:10.1038/sj.leu.2404735; published online 10 May 2007 [ABSTRACT FROM AUTHOR]

The strong phases and CP violation in the rare B̄0→K+K-, K*±K∓, K*+K*- decays are investigated. As these decays proceed only via annihilation type diagrams in the standard model (SM), a dynamical gluon mass is introduced to avoid the infrared divergence in the soft endpoint regions. The Cutkosky rule is adopted to deal with a physical-region singularity of the on-mass-shell quark propagators, which leads to a big imaginary part and hence a large strong phase. As a consequence, large CP asymmetries are predicted in those decay modes due to a big interference between the annihilation amplitudes from penguin and tree operators, which may be tested in future more precise experiments. [ABSTRACT FROM AUTHOR]

The strong phases and CP violation in the rare B̄0→K+K-, K*±K∓, K*+K*- decays are investigated. As these decays proceed only via annihilation type diagrams in the standard model (SM), a dynamical gluon mass is introduced to avoid the infrared divergence in the soft endpoint regions. The Cutkosky rule is adopted to deal with a physical-region singularity of the on-mass-shell quark propagators, which leads to a big imaginary part and hence a large strong phase. As a consequence, large CP asymmetries are predicted in those decay modes due to a big interference between the annihilation amplitudes from penguin and tree operators, which may be tested in future more precise experiments. [ABSTRACT FROM AUTHOR]

This paper reviews the studies of cavitation resonance carried out by the authors. Cavitation-associated pressure fluctuation in hydraulic systems is an important phenomenon that affects the design, operation and safety of systems. Under certain conditions, the amplitude of one particular component of the fluctuations will become extremely high, causing a resonance. This phenomenon was firstly noticed and studied by one of the author (Li S C) in early 1980’s on cavitating Venturi flows. Later on, the cavitation resonance was also observed on a model turbine system. Currently, an investigation is being carried out on the Warwick Venturi by the authors of this paper with preliminary results also supporting the proposed hypothesis of the (macroscopic) mechanism. In this review, the observed phenomenon on these three flow systems is briefly introduced. The hypothesis of the (macroscopic) mechanism reduced from experimental obser-vations is then described and further investigations on the unknown aspects of the phenomenon are suggested. [ABSTRACT FROM AUTHOR]

High-level expression of Rad51, a key factor in homologous recombination, has been observed in a variety of human malignancies. This study was aimed to evaluate Rad51 expression to serve as prognostic marker in non-small-cell lung cancer (NSCLC). A total of 383 non-small-cell lung tumours were analysed immunohistochemically on NSCLC tissue microarrays. High-level Rad51 expression was observed in 29.4% (100 out of 340) of cases. Patients whose tumours displayed high-level Rad51 expression showed a significantly shorter median survival time of 19 vs 68 months (P<0.0001, log-rank test). Similarly T status, N status, M status, clinical stage and histological tumour grade were significant prognostic markers in univariate Cox survival analysis. Importantly, Rad51 expression (P<0.0001) together with tumour differentiation (P<0.009), clinical stage (P=0.004) and N status (P=0.0001) proved to be independent prognostic parameters in multivariate analysis. Rad51 expression predicted the outcome of squamous cell cancer as well as adenocarcinoma of the lung. Our results suggest that Rad51 expression provides additional prognostic information for surgically treated NSCLC patients. We hypothesise that the decreased survival of NSCLC patients with high-level expression of Rad51 is related to an enhanced propensity of tumour cells for survival, antiapoptosis and chemo-/radioresistance. [ABSTRACT FROM AUTHOR]

We discuss the time-dependent CP asymmetry of the decay B → &phis;Ks in an extension of the standard model with both a two Higgs doublet and additional fourth-generation quarks. We show that, although the standard model with a two Higgs doublet and the standard model with fourth-generation quarks alone are not likely to largely change the effective sin 2β from the decay B → &phis;Ks, the model with both an additional Higgs doublet and fourth-generation quarks can easily account for the possible large negative value of sin 2β without conflicting with other experimental constraints. In this model, additional large CP violating effects may arise from the flavor-changing Yukawa interactions between neutral Higgs bosons and the heavy fourth-generation down type quark, which can modify the QCD penguin contributions. With the constraints obtained from b → s&smacr;s processes such as B → Xsγ and δmB2o , this model can lead to an effective sin 2β as large as -0.4 in the CP asymmetry of B → &phis;Ks. [ABSTRACT FROM AUTHOR]

Hydrogen storage in carbon nanotubes (CNTs) is investigated at ambient temperature and pressures of 0–12 MPa, using 35–85 g multi-wall carbon nanotube (MWNT) samples that were synthesized in a nano-agglomerate fluidized bed reactor. The volume of hydrogen gas released by the CNTs was measured by a volumetric flow meter. The capability of H[sub 2] storage in the CNT samples of mass of up to 85 g can be obtained with a precision of 0.01 wt. %. MWNTs with average diameters ranging from 10–30 nm and were pretreated using nitric acid or a sodium hydroxide solution wash and a high temperature treatment. The influence of the hydrogen pressure, hydrogen storage time and treatment method were studied. All data show that the amount of hydrogen released by the MWNTs at room temperature is no more than 0.30 wt. %, while hydrogen released by MWNT at 77 K can reach 2.27 wt. %. [ABSTRACT FROM AUTHOR]

We investigate in detail both the Cabibbo-allowed and singly Cabibbo-suppressed D → PV decays based on the diagrammatic decomposition in the factorization formalism. Two sets of solutions discarded in the literature are picked up and discussed carefully. It is found that one of these solutions can provide satisfactory explanation in a natural manner on the process D+ → &Ksline;0 K*+ which is thought to be a puzzle. The relations EV + EP = 0 and AV + AP = 0 are badly broken, which indicates that the exchange and annihilation diagrams may receive contributions from more sources other than the qq intermediate state interactions. It is shown that, to have a consistent explanation to the experimental data with reasonable values for the parameters a1 and a2, the SU(3) symmetry breaking effects have to be considered. The SU(3) flavor symmetry breaking effects due to mass factors and due to formfactors and decay constants are analyzed in detail. [ABSTRACT FROM AUTHOR]

A systematic investigation on the muon's anomalous magnetic moment and a related lepton flavor-violating process such as µ → eγ, τ → eγ and τ → µγ is made at the two-loop level in the models with flavor-changing scalar interactions. The two-loop diagrams with double scalar exchanges are studied and their contributions are found to be compatible with the ones from the Barr-Zee diagram. By comparing with the latest data, the allowed ranges for the relevant Yukawa couplings Yij in the lepton sector are obtained. The results show the hierarchical structure Yµe,τe ... Yµτ... Yµµ in the physical basis if Δa&micro: is found to be > 50 × 10-11. It deviates from the widely used ansatz in which the off-diagonal elements are proportional to the square root of the products of the related fermion masses. An alternative Yukawa coupling matrix in the lepton sector is suggested to understand the current data. With such a reasonable Yukawa coupling ansatz, the decay rate of τ → µγ is found to be near the current experiment upper bound. [ABSTRACT FROM AUTHOR]

The LRPIM method is adopted to simulate the two-dimensional natural convection problems within enclosed domain of different geometries. In this paper, the vorticity-stream function form of N-S equations is taken as the governing equations. It was observed that the obtained results agreed very well with others available in the literatures, and with the same nodal density, the accuracy achieved by the LRPIM method is much higher than that of the finite difference (FD) method. The numerical examples show that the present LRPIM method can successfully deal with incompressible flow problems on randomly distributed nodes. [ABSTRACT FROM AUTHOR]

The radial basis functions (RBFs) have been proven to have excellent properties for interpolation problems, which can be considered as an efficient scheme for function approximation. In this paper, we will explore another type of approximation problem, that is, the derivative approximation, by the RBFs. A new approach, which is based on the differential quadrature (DQ) approximation for the derivative with RBFs as test functions, is proposed to approximate the first, second, and third order derivatives of a function. The performance of three commonly-used RBFs for some typical expressions of derivatives as well as the computation of one-dimensional Burgers equation are studied. Furthermore, the proposed method is applied to simulate natural convection in a concentric annulus by solving Navier–Stokes equations. The obtained results are compared well with exact data or benchmark solutions. [ABSTRACT FROM AUTHOR]

A realistic scheme for masses and mixing of leptons is investigated in the model with gauged SO(3) lepton flavor symmetry. Within this scheme, a nearly bimaximal neutrino mixing pattern with a maximal CP-violating phase is found to be the only possible solution for reconciling both solar and atmospheric neutrino flux anomalies. Three Majorana neutrino masses are nearly degenerate and large enough to play a significant cosmological role. Lepton flavor-violating effects via SO(3) gauge interactions can be as large as the present experimental limits. Masses of the SO(3) gauge bosons are bounded to be above 24 TeV when the SO(3) gauge boson mixing angle $\theta_{F}$ and coupling constant $g'_{3}$ are taken to be the same as those ( $\theta_{W}$ and g) in the electroweak theory. [ABSTRACT FROM AUTHOR]

There were errors in Fig. 1 of the originally published article. Correct fig. 1 is presented here. [ABSTRACT FROM AUTHOR]

Many remarkable properties of graphene are derived from its large energy window for Dirac-like electronic states and have been explored for applications in electronics and photonics. In addition, strong electron-phonon interaction in graphene has led to efficient photo-thermo energy conversions, which has been harnessed for energy applications. By combining the wavelength independent absorption property and the efficient photo-thermo energy conversion, here we report a new type of applications in sound wave generation underlined by a photo-thermo-acoustic energy conversion mechanism. Most significantly, by utilizing ultrafast optical pulses, we demonstrate the ability to control the phase of sound waves generated by the photo-thermal-acoustic process. Our finding paves the way for new types of applications for graphene, such as remote non-contact speakers, optical-switching acoustic devices, etc. [ABSTRACT FROM AUTHOR]