Design, synthesis and anti-tumor activity studies of novel pyrido[3, 4-d]pyrimidine derivatives.

In order to find high-efficiency and low-toxic anti-tumor drugs, 29 pyrido[3,4-d]pyrimidine compounds were designed, synthesized and evaluated by MTT assay in vitro. The results presented that most of the compounds had good antitumor activities, among which compound 30 had the best anti-tumor activity on MGC803 cells (IC50 = 0.59 µM). Mechanistic studies exhibited that compound 30 inhibited migration of MGC803 and induced apoptosis. It was proved that compound 30 up-regulated expression of Bid and PARP, down-regulated expression of CycD1 by western blot experiments. This study indicated that compound 30 might be served as a lead agent for the treatment of human gastric cancers.

Microwave Pulse-Coherent Technique-Based Clock With a Novel Magnetron-Type Cavity.

We report a high-performance pulsed optically pumped (POP) Rb clock based on a novel magnetron-type microwave cavity. The cavity has a volume of 30 mL, enabling a highly homogenous microwave field distribution. With the laser frequency tuning to the ground-state hyperfine level F = 2 of the D2 line, we observe a Ramsey fringe contrast of 52% in terms of optical absorption detection. The resultant shot noise limit is estimated to be [Formula: see text]. The clock frequency stability is measured as [Formula: see text] (1-100 s), which is limited by the relative intensity noise of the light.

Steering optical comb frequencies by rotating the polarization state.

We demonstrate a new approach to steer the frequencies of a nonlinear polarization-rotation mode-locked laser, where a specially designed intrcavity electro-optic modulator tunes the polarization state of the laser signal. This approach not only results in the broadband associated with high performance, but also results in a large dynamic range associated with good robustness. Our experimental results show that frequency control dynamic ranges are at least one order of magnitude larger than those of the previous ultra-fast frequency control techniques, reaching hundreds of hertz and hundreds of megahertz for repetition rate (fr) and carrier-envelope-offset frequency (fceo), respectively.

Numerical investigation of a microfiber-plane-grating composite optical waveguide for gas refractive index sensing.

In this paper, we propose a microfiber-plane-grating composite optical waveguide (MPGCOW), which is formed by immobilizing a tapered microfiber on the surface of a plane grating with one defect, for gas refractive index (RI) sensing. Its optical properties and gas RI sensing properties are investigated by the finite difference time domain method. Results show that the MPGCOW has a photonic stop band and is very sensitive to the ambient gas RI variation. The largest gas RI sensing sensitivity of 486.67 nm/RIU and detection limit of 2×10-6 are obtained by immersing the structure in the mixture gas of N2 and He with various mixture ratios.

Robust optical-frequency-comb based on the hybrid mode-locked Er:fiber femtosecond laser.

We demonstrate an optical frequency comb in which an Er:fiber-based femtosecond laser employs nonlinear amplifier loop mirror (NALM) and nonlinear polarization evolution (NPE) mode-locking mechanisms. The laser combines advantages of good robustness of NALM and low noise feature of NPE. Our experimental results show that the hybrid mode-locked laser has high power, low relative intensity noise and self-started property, enabling the construction of a robust optical frequency comb system. In-loop relative instabilities of both stabilized repetition rate and carrier-envelope-offset frequency are well below 1 × 10-17 at 1 second integration time.

Design, synthesis and preliminary biological evaluation of new [1,2,3]triazolo[4,5-d]pyrimidine/thiourea hybrids as antiproliferative agents.

A series of new [1,2,3]triazolo[4,5-d]pyrimidine/thiourea hybrids were designed and synthesized through the scaffold replacement/ring cleavage strategy. SARs studies revealed that the N-heteroarene moiety attached to the thiourea is preferred over the phenyl ring for the R2 substituents, while the hydrophobic aromatic group is beneficial for improving the activity. Among these compounds, compound 5r significantly inhibited cell growth of lung cancer cell lines H1650 and A549 (IC50 = 1.91, 3.28 µM, respectively), but was less toxic against the normal cell line GES-1 (IC50 = 27.43 µM). Mechanistic studies showed that compound 5r could remarkably inhibit the colony formation of H1650 cells, induced apoptosis possibly through the intrinsic apoptotic pathways, and arrested the cell cycle at G2/M phase. Our studies suggest that the [1,2,3]triazolo[4,5-d]pyrimidine/thiourea hybrids are a new class of chemotypes possessing interesting antiproliferative activity against lung cancer cells and could be potentially utilized for designing new antitumor agents.

Design, synthesis and preliminary antiproliferative activity studies of new diheteroaryl thioether derivatives.

A series of structurally new diheteroaryl thioether analogs was designed, prepared and screened toward MGC-803, MKN-45, EC-109 and H1650. Most of the target compounds displayed moderate to potent antiproliferative activities. Among them, compound 5 showed the best antiproliferative activity against the tested cell lines with the half maximal inhibitory concentration (IC50) values below 10µM. In addition, flow cytometry analysis showed that compound 5 increased Bax expression, down-regulated expression of Bcl-2, cleaved caspases-3/9, finally inducing apoptosis of MKN-45 cells as well asarrested the cell cycle at G2/M phase. This study suggests that the diheteroaryl thioethers are a class of emerging chemotypes for developing antitumor agents or biological probes, and compound 5 could serve as a good starting point to design new apoptosis inducers.

LPE-1, an orally active pyrimidine derivative, inhibits growth and mobility of human esophageal cancers by targeting LSD1.

Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC50=0.336±0.003µM) significantly suppressed proliferation, induced apoptosis, arrested cell cycle of EC109 cells at G2/M phase, and caused changes of the associated protein markers correspondingly. We also found that compound LPE-1 potently inhibited the migration and invasion of EC-109 cells. Docking studies showed that the cyano group formed hydrogen bonds with Val811 and Thr810. Additionally, the thiophene moiety formed arene-H interaction with Trp761 residue. In vivo studies showed that compound LPE-1 inhibited tumor growth of xenograft models bearing EC-109 without obvious toxicity. Collectively, our findings indicate that LSD1 may be a potential therapeutic target in ESCC, and compound LPE-1 could serve as a lead compound for further development for anti-ESCC drug discovery.

Electro-optic modulator with ultra-low residual amplitude modulation for frequency modulation and laser stabilization.

The reduction of the residual amplitude modulation (RAM) induced by electro-optic modulation is essential for many applications of frequency modulation spectroscopy requiring a lower system noise floor. Here, we demonstrate a simple passive approach employing an electro-optic modulator (EOM) cut at Brewster's angle. The proposed EOM exhibits a RAM of a few parts per million, which is comparable with that achieved by a common EOM under critical active temperature and bias voltage controls. The frequency instability of a 10 cm cavity-stabilized laser induced by the RAM effect of the proposed EOM is below 3×10-17 for integration times from 1 to 1000 s, and below 4×10-16 for comprehensive noise contributions for integration times from 1 to 100 s.

Design, synthesis and biological evaluation of [1,2,3]triazolo[4,5-d]pyrimidine derivatives possessing a hydrazone moiety as antiproliferative agents.

A series of [1,2,3]triazolo[4,5-d]pyrimidine derivatives bearing a hydrazone moiety were designed, synthesized and evaluated for their antiproliferative activity against several cancer cell lines of different origins by MTT assay. Most of the synthesized compounds demonstrated moderate to good activity against the cancer cell lines selected. Especially, compound 43 showed the most potent antiproliferative activity as well as good selectivity between cancer and normal cells (IC50 values of 0.85 µM against MGC-803 and 56.17 µM against GES-1). In addition, compound 43 evidently inhibited the colony formation of MGC-803 cells at 0.8 µM. Further mechanism studies revealed that compound 43 could induce apoptosis of MGC-803 cells probably through the mitochondrial pathway accompanied with decrease of the mitochondrial membrane potential (MMP), activations of caspase-9/3, up-regulation of the expression of Bax, Bak and PUMA, as well as down-regulation of that of Bcl-2 and Mcl-1.

High expression of S100A8 gene is associated with drug resistance to etoposide and poor prognosis in acute myeloid leukemia through influencing the apoptosis pathway.

S100A8 has been increasingly recognized as a biomarker in multiple solid tumors and has played pivotal roles in hematological malignancies. S100A8 is potentially an indicator for poor survival in acute myeloid leukemia (AML) in retrospective studies. However, the mechanisms of S100A8 are diverse in cancers. In this study, we investigated the correlation of S100A8 at the transcription level with clinical parameters in 91 de novo AML patients and explored its mechanisms of chemoresistance to etoposide in vitro. The transcription level of S100A8 was significantly lower at initial and relapse stages of AML samples than at complete remission (P<0.001) and than in the control group (P=0.0078), while no significant difference could be found between initial and relapse stages (P=0.257). Patients with high transcription levels of S100A8 exhibited a shorter overall survival (P=0.0012). HL-60 cells transfected with S100A8 showed resistance to etoposide with a higher level IC50 value and lower apoptosis rate compared with HL-60 cells transfected with empty vector. Thirty-six genes were significantly downregulated and 12 genes were significantly upregulated in S100A8 overexpression group compared with control group in which 360 genes involved in apoptotic genes array were performed by real-time reverse transcriptase polymerase chain reaction. Among them, the caspase-3, Bcl-2, and Bax were verified by Western blot analysis which indicated that the role of S100A8 in resistance to chemotherapy was closely related with antiapoptosis. In conclusion, critical S100A8 provided useful clinical information in predicting the outcome of AML. The main mechanism of S100A8 which promoted chemoresistance was antiapoptosis.

A multiple testing procedure for multi-dimensional pairwise comparisons with application to gene expression studies.

BACKGROUND: Often researchers are interested in comparing multiple experimental groups (e.g. tumor size) with a reference group (e.g. normal tissue) on the basis of thousands of features (e.g. genes) and determine if a differentially expressed feature is up or down regulated in a pairwise comparison. There are two sources of false discoveries, one due to multiple testing involving several pairwise comparisons and the second due to falsely declaring a feature to be up (or down) regulated when it is not (known as directional error). Together, the total error rate is called the mixed directional false discovery rate (mdFDR). RESULTS: We develop a general powerful mdFDR controlling testing procedure and illustrate the methodology by analyzing uterine fibroid gene expression data (PLoS ONE 8:63909, 2013). We identify several differentially expressed genes (DEGs) and pathways that are specifically enriched according to the size of a uterine fibroid. CONCLUSIONS: The proposed general procedure strongly controls mdFDR. Several specific methodologies can be derived from this general methodology by using appropriate testing procedures at different steps of the general procedure. Thus we are providing a general framework for making multiple pairwise comparisons. Our analysis of the uterine fibroid growth gene expression data suggests that molecular characteristics of a fibroid changes with size. Our powerful methodology allowed us to draw several interesting conclusions regarding the molecular characteristics of uterine fibroids. For example, IL-1 signaling pathway (Sci STKE 2003:3, 2003), associated with inflammation and known to activate prostaglandins that are implicated in the progression of fibroids, is significantly enriched only in small tumors (volume < 5.7 cm (3)). It appears that the molecular apparatus necessary for fibroid growth and development is established during tumor development. A complete list of all DEGs and the corresponding enriched pathways according to tumor size is provided for researchers to mine these data. Identification of these DEGs and the pathways may potentially have clinical implications.

On generalized fixed sequence procedures for controlling the FWER.

Testing a sequence of pre-ordered hypotheses to decide which of these can be rejected or accepted while controlling the familywise error rate (FWER) is of importance in many scientific studies such as clinical trials. In this paper, we first introduce a generalized fixed sequence procedure whose critical values are defined by using a function of the numbers of rejections and acceptances, and which allows follow-up hypotheses to be tested even if some earlier hypotheses are not rejected. We then construct the least favorable configuration for this generalized fixed sequence procedure and present a sufficient condition for the FWER control under arbitrary dependence. Based on the condition, we develop three new generalized fixed sequence procedures controlling the FWER under arbitrary dependence. We also prove that each generalized fixed sequence procedure can be described as a specific closed testing procedure. Through simulation studies and a clinical trial example, we compare the power performance of these proposed procedures with those of the existing FWER controlling procedures. Finally, when the pairwise joint distributions of the true null p-values are known, we further improve these procedures by incorporating pairwise correlation information while maintaining the control of the FWER. Copyright © 2015 John Wiley & Sons, Ltd.

Demonstration of CNOT gate with Laguerre Gaussian beams via four-wave mixing in atom vapor.

We present an experimental study of controlled-NOT (CNOT) gate through four-wave mixing (FWM) process in a Rubidium vapor cell. A degenerate FWM process in a two level atomic system is directly excited by a single diode laser, where backward pump beam and probe beam are Laguerre Gaussian mode. By means of photons carrying orbital angular momentum, we demonstrate the ability to realize CNOT gate with topological charges transformation in this nonlinear process. The fidelity of CNOT gate for a superposition state with different topological charge reaches about 97% in our experiment.

Generation of Airy beams by four-wave mixing in Rubidium vapor cell.

We report on an experimental generation of Airy beams by four-wave mixing (FWM) in atomic vapor cells. This is achieved by using a non-degenerate FWM process, which occurs with two Gaussian pump beams and one Airy signal beam in hot Rubidium vapor. After satisfying the phase matching condition, a FWM field with the profile of an Airy beam can be generated. In our experiment, the diffraction-free and self-healing behaviors of the generated FWM beam are examined. The results shown that the generated FWM beam is an Airy beam. The nonlinear generation process can be extended to other configurations in the atomic medium, which will be useful for manipulation and application of Airy beams in atomic systems.

Transfer and conversion of images based on EIT in atom vapor.

Transfer and conversion of images between different wavelengths or polarization has significant applications in optical communication and quantum information processing. We demonstrated the transfer of images based on electromagnetically induced transparency (EIT) in a rubidium vapor cell. In experiments, a 2D image generated by a spatial light modulator is used as a coupling field, and a plane wave served as a signal field. We found that the image carried by coupling field could be transferred to that carried by signal field, and the spatial patterns of transferred image are much better than that of the initial image. It also could be much smaller than that determined by the diffraction limit of the optical system. We also studied the subdiffraction propagation for the transferred image. Our results may have applications in quantum interference lithography and coherent Raman spectroscopy.

Deutsch's algorithm with topological charges of optical vortices via non-degenerate four-wave mixing.

We propose a scheme to implement the Deutsch's algorithm through non-degenerate four-wave mixing process. By employing photon topological charges of optical vortices, we demonstrate the ability to realize the necessary four logic gates for all balanced and constant functions. We also analyze the feasibility of the proposed scheme on the single photon level.

Analysis of high dimensional data using pre-defined set and subset information, with applications to genomic data.

BACKGROUND: Based on available biological information, genomic data can often be partitioned into pre-defined sets (e.g. pathways) and subsets within sets. Biologists are often interested in determining whether some pre-defined sets of variables (e.g. genes) are differentially expressed under varying experimental conditions. Several procedures are available in the literature for making such determinations, however, they do not take into account information regarding the subsets within each set. Secondly, variables (e.g. genes) belonging to a set or a subset are potentially correlated, yet such information is often ignored and univariate methods are used. This may result in loss of power and/or inflated false positive rate. RESULTS: We introduce a multiple testing-based methodology which makes use of available information regarding biologically relevant subsets within each pre-defined set of variables while exploiting the underlying dependence structure among the variables. Using this methodology, a biologist may not only determine whether a set of variables are differentially expressed between two experimental conditions, but may also test whether specific subsets within a significant set are also significant. CONCLUSIONS: The proposed methodology; (a) is easy to implement, (b) does not require inverting potentially singular covariance matrices, and (c) controls the family wise error rate (FWER) at the desired nominal level, (d) is robust to the underlying distribution and covariance structures. Although for simplicity of exposition, the methodology is described for microarray gene expression data, it is also applicable to any high dimensional data, such as the mRNA seq data, CpG methylation data etc.

Controlling false discoveries in multidimensional directional decisions, with applications to gene expression data on ordered categories.

Microarray gene expression studies over ordered categories are routinely conducted to gain insights into biological functions of genes and the underlying biological processes. Some common experiments are time-course/dose-response experiments where a tissue or cell line is exposed to different doses and/or durations of time to a chemical. A goal of such studies is to identify gene expression patterns/profiles over the ordered categories. This problem can be formulated as a multiple testing problem where for each gene the null hypothesis of no difference between the successive mean gene expressions is tested and further directional decisions are made if it is rejected. Much of the existing multiple testing procedures are devised for controlling the usual false discovery rate (FDR) rather than the mixed directional FDR (mdFDR), the expected proportion of Type I and directional errors among all rejections. Benjamini and Yekutieli (2005, Journal of the American Statistical Association 100, 71-93) proved that an augmentation of the usual Benjamini-Hochberg (BH) procedure can control the mdFDR while testing simple null hypotheses against two-sided alternatives in terms of one-dimensional parameters. In this article, we consider the problem of controlling the mdFDR involving multidimensional parameters. To deal with this problem, we develop a procedure extending that of Benjamini and Yekutieli based on the Bonferroni test for each gene. A proof is given for its mdFDR control when the underlying test statistics are independent across the genes. The results of a simulation study evaluating its performance under independence as well as under dependence of the underlying test statistics across the genes relative to other relevant procedures are reported. Finally, the proposed methodology is applied to a time-course microarray data obtained by Lobenhofer et al. (2002, Molecular Endocrinology 16, 1215-1229). We identified several important cell-cycle genes, such as DNA replication/repair gene MCM4 and replication factor subunit C2, which were not identified by the previous analyses of the same data by Lobenhofer et al. (2002) and Peddada et al. (2003, Bioinformatics 19, 834-841). Although some of our findings overlap with previous findings, we identify several other genes that complement the results of Lobenhofer et al. (2002).

Adaptive choice of the number of bootstrap samples in large scale multiple testing.

It is a common practice to use resampling methods such as the bootstrap for calculating the p-value for each test when performing large scale multiple testing. The precision of the bootstrap p-values and that of the false discovery rate (FDR) relies on the number of bootstraps used for testing each hypothesis. Clearly, the larger the number of bootstraps the better the precision. However, the required number of bootstraps can be computationally burdensome, and it multiplies the number of tests to be performed. Further adding to the computational challenge is that in some applications the calculation of the test statistic itself may require considerable computation time. As technology improves one can expect the dimension of the problem to increase as well. For instance, during the early days of microarray technology, the number of probes on a cDNA chip was less than 10,000. Now the Affymetrix chips come with over 50,000 probes per chip. Motivated by this important need, we developed a simple adaptive bootstrap methodology for large scale multiple testing, which reduces the total number of bootstrap calculations while ensuring the control of the FDR. The proposed algorithm results in a substantial reduction in the number of bootstrap samples. Based on a simulation study we found that, relative to the number of bootstraps required for the Benjamini-Hochberg (BH) procedure, the standard FDR methodology which was the proposed methodology achieved a very substantial reduction in the number of bootstraps. In some cases the new algorithm required as little as 1/6th the number of bootstraps as the conventional BH procedure. Thus, if the conventional BH procedure used 1,000 bootstraps, then the proposed method required only 160 bootstraps. This methodology has been implemented for time-course/dose-response data in our software, ORIOGEN, which is available from the authors upon request.