New catalytic reactions of (unsaturated) nitriles via metal-ligand cooperative activation of the C≡N bond

The nitrile functional group is a very versatile intermediate which can be converted into amides, carboxylic acids, amines and imines, and thus, catalytic conversion of the C≡N bond under mild condition is an important field from an organic synthetic perspective. Recent developments in the area of transition metal pincer complexes has created new possibilities in this area, generally via efficient pathways and under mild conditions. Especially, non-innocent ligands enable the corresponding transition metal complexes to active nitriles via metal-ligand cooperation (e.g. Milstein Ru PNN complex). This new approach allows chemists to explore new challenging reactions with nitriles under mild conditions. The research described in this thesis was aimed at the catalytic (conjugate) addition of weak nucleophiles to (unsaturated) nitriles using transition metal pincer complexes via a metal-ligand cooperative pathway. In addition, chiral transition metal pincer complexes were synthesized and further evaluated in the enantioselective conjugate addition of alcohols to α,β-unsaturated nitriles

A Bayesian adaptive phase II clinical trial design accounting for spatial variation

Conventional phase II clinical trials evaluate the treatment effects under the assumption of patient homogeneity. However, due to inter-patient heterogeneity, the effect of a treatment may differ remarkably among subgroups of patients. Besides patient’s individual characteristics such as age, gender, and biomarker status, a substantial amount of this heterogeneity could be due to the spatial variation across geographic regions because of unmeasured or unknown spatially varying environmental and social exposures. In this article, we propose a hierarchical Bayesian adaptive design for two-arm randomized phase II clinical trials that accounts for the spatial variation as well as patient’s individual characteristics. We treat the treatment efficacy as an ordinal outcome and quantify the desirability of each possible category of the ordinal efficacy using a utility function. A cumulative probit mixed model is used to relate efficacy to patient-specific covariates and geographic region spatial effects. Spatial dependence between regions is induced through the conditional autoregressive priors on the spatial effects. A two-stage design is proposed to adaptively assign patients to desirable treatments according to each patient’s spatial information and individual covariates and make treatment recommendations at the end of the trial based on the overall treatment effect. Simulation studies show that our proposed design has good operating characteristics and significantly outperforms an alternative phase II trial design that ignores the spatial variation

A Bayesian adaptive marker‐stratified design for molecularly targeted agents with customized hierarchical modeling

It is well known that the treatment effect of a molecularly targeted agent (MTA) may vary dramatically, depending on each patient's biomarker profile. Therefore, for a clinical trial evaluating MTA, it is more reasonable to evaluate its treatment effect within different marker subgroups rather than evaluating the average treatment effect for the overall population. The marker‐stratified design (MSD) provides a useful tool to evaluate the subgroup treatment effects of MTAs. Under the Bayesian framework, the beta‐binomial model is conventionally used under the MSD to estimate the response rate and test the hypothesis. However, this conventional model ignores the fact that the biomarker used in the MSD is, in general, predictive only for the MTA. The response rates for the standard treatment can be approximately consistent across different subgroups stratified by the biomarker. In this paper, we proposed a Bayesian hierarchical model incorporating this biomarker information into consideration. The proposed model uses a hierarchical prior to borrow strength across different subgroups of patients receiving the standard treatment and, therefore, improve the efficiency of the design. Prior informativeness is determined by solving a “customized” equation reflecting the physician's professional opinion. We developed a Bayesian adaptive design based on the proposed hierarchical model to guide the treatment allocation and test the subgroup treatment effect as well as the predictive marker effect. Simulation studies and a real trial application demonstrate that the proposed design yields desirable operating characteristics and outperforms the existing designs

Collisions of young disc galaxies in the early universe

In the local universe, disc galaxies are generally well evolved and Toomre stable. Their collisions with satellite galaxies naturally produce ring structures, which has been observed and extensively studied. In contrast, at high redshifts, disc galaxies are still developing and clumpy. These young galaxies interact with each other more frequently. However, the products of their collisions remain elusive. Here we systematically study the minor collisions between a clumpy galaxy and a satellite on orbits with different initial conditions, and find a new structure that is different from the local collisional ring galaxies. The clumpness of the target galaxy is fine-tuned by the values of Toomre parameter, $Q$. Interestingly, a thick and knotty ring structure is formed without any sign of a central nucleus in the target galaxy. Our results provide a promising explanation of the empty ring galaxy recently observed in R5519 at redshift $z=2.19$. Moreover, we show that the clumpy state of the collided galaxy exists for a much longer timescale, compared to isolated self-evolved clumpy galaxies that have been widely investigated.Comment: 12 pages, 11 figures, accepted for publication in Ap

Cost-effectiveness analysis of advanced radiotherapy techniques for post-mastectomy breast cancer patients

Background: Prior cost-effectiveness studies of post-mastectomy radiotherapy (PMRT) only compared conventional radiotherapy versus no radiotherapy and only considered tumor control. The goal of this study was to perform cost-effectiveness analyses of standard of care (SOC) and advanced PMRT techniques including intensity-modulated radiotherapy (IMRT), standard volumetric modulated arc therapy (STD-VMAT), non-coplanar VMAT (NC-VMAT), multiple arc VMAT (MA-VMAT), Tomotherapy (TOMO), mixed beam therapy (MIXED), and intensity-modulated proton therapy (IMPT). Methods: Using a Markov model, we estimated the cost-effectiveness of various techniques over 15 years. A cohort of women (55-year-old) was simulated in the model, and radiogenic side effects were considered. Transition probabilities, utilities, and costs for each health state were obtained from literature and Medicare data. Model outcomes include quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratio (ICER). Results: For the patient cohort, STD-VMAT has an ICER of $32,617/QALY relative to SOC; TOMO is dominated by STD-VMAT; IMRT has an ICER of$19,081/QALY relative to STD-VMAT; NC-VMAT, MA-VMAT, MIXED are dominated by IMRT; IMPT has an ICER of $151,741/QALY relative to IMRT. One-way analysis shows that the probability of cardiac toxicity has the most significant impact on the model outcomes. The probability sensitivity analyses show that all advanced PMRT techniques are more cost-effective than SOC at a willingness-to-pay (WTP) threshold of$100,000/QALY, while almost none of the advanced techniques is more cost-effective than SOC at a WTP threshold of $50,000/QALY. Conclusion: Advanced PMRT techniques are more cost-effective for breast cancer patients at a WTP threshold of$100,000/QALY, and IMRT might be a cost-effective option for PMRT patients

Statistical Methods for Bioinformatics: Estimation of Copy N umber and Detection of Gene Interactions

Identification of copy number aberrations in the human genome has been an important area in cancer research. In the first part of my thesis, I propose a new model for determining genomic copy numbers using high-density single nucleotide polymorphism genotyping microarrays. The method is based on a Bayesian spatial normal mixture model with an unknown number of components corresponding to true copy numbers. A reversible jump Markov chain Monte Carlo algorithm is used to implement the model and perform posterior inference. The second part of the thesis describes a new method for the detection of gene-gene interactions using gene expression data extracted from micro array experiments. The method is based on a two-step Genetic Algorithm, with the first step detecting main effects and the second step looking for interacting gene pairs. The performances of both algorithms are examined on both simulated data and real cancer data and are compared with popular existing algorithms. Conclusions are given and possible extensions are discussed

Comparison of conventional and advanced radiotherapy techniques for left-sided breast cancer after breast conserving surgery

Whole breast radiotherapy (WBRT) after breast conserving surgery is the standard treatment to prevent recurrence and metastasis of early stage breast cancer. This study aims to compare seven WBRT techniques including conventional tangential, field-in-field (FIF), hybrid intensity-modulated radiotherapy (IMRT), IMRT, standard volumetric modulated arc therapy (STD-VMAT), noncoplanar VMAT (NC-VMAT), and multiple arc VMAT (MA-VMAT). Fifteen patients who were previously diagnosed with left-sided early stage breast cancer and treated in our clinic were selected for this study. WBRT plans were created for these patients and were evaluated based on target coverage and normal tissue toxicities. All techniques produced clinically acceptable WBRT plans. STD-VMAT delivered the lowest mean dose (1.1 ± 0.3 Gy) and the lowest maximum dose (7.3 ± 4.9 Gy) to contralateral breast, and the second lowest lifetime attributable risk (LAR) (4.1 ± 1.4%) of secondary contralateral breast cancer. MA-VMAT delivered the lowest mean dose to lungs (4.9 ± 0.9 Gy) and heart (5.5 ± 1.2 Gy), exhibited the lowest LAR (1.7 ± 0.3%) of secondary lung cancer, normal tissue complication probability (NTCP) (1.2 ± 0.2%) of pneumonitis, risk of coronary events (RCE) (10.3 ± 2.7%), and LAR (3.9 ± 1.3%) of secondary contralateral breast cancer. NC-VMAT plans provided the most conformal target coverage, the lowest maximum lung dose (46.2 ± 4.1 Gy) and heart dose (41.1 ± 5.4 Gy), and the second lowest LAR (1.8 ± 0.4%) of secondary lung cancer and RCE (10.5 ± 2.8%). MA-VMAT and NC-VMAT could be the preferred techniques for early stage breast cancer patients after breast conserving surgery

Catalytic Conversion of Nitriles by Metal Pincer Complexes

The nitrile is an extremely useful functional group in organic synthesis: it can be transformed into amides, carboxylic acids, amines and imines; yet it is relatively stable and can be easily carried through several synthetic steps before being converted. The conversions of nitriles under mild conditions are thus very important transformations. Great progress has been made in the last decade in the use of metal pincer complexes as catalysts for quite a number of reactions of nitriles and nitrile-containing molecules. The selective hydrogenation of nitriles either to the amines or to the imines usually follows a Noyori-type outer-sphere mechanism. Coordination of aliphatic nitriles to the metal centre renders the α-proton rather acidic allowing deprotonation followed by carbon-carbon coupling reactions. The pyridine-based metal pincer complexes introduced by Milstein allow for novel mechanisms based on metal-ligand cooperativity in which the pyridine undergoes dearomatisation induced by deprotonation of one of the side arms. The nitrile can undergo a cycloaddition to the complex in its dearomatised form, creating a new bond between the nitrogen atom and the metal, whereas the nitrile carbon atom forms a C-C bond with the carbon atom of one of the pincer side-arms. The resulting metalimide undergoes nucleophilic addition more easily than the nitrile. It can also easily rearrange to the enamide, which can undergo C-C bond forming reactions. Also, oxo- and aza-Michael reactions are facilitated on the unsaturated nitriles, such as acrylonitriles or pentenitriles. Most reactions proceed under mild conditions in excellent yields.</p

Antimicrobial compounds from Athyrium sinense damage the cell membrane of Clavibacter michiganensis subsp. sepedonicus

Clavibacter michiganensis subsp. sepedonicus is a widely distributed pathogen that causes ring rot of potato. Antimicrobial activity assays demonstrated that petroleum ether extracts from Athyrium sinense was a fraction with strong activity against C. michiganensis subsp. sepedonicus. The aim of this study was to determine the chemical compounds in this fraction, and to investigate the antimicrobial mechanism. The dominant components were palmitic acid (25.78%), neophytadiene (13.66%), linoleic acid (8.95%), oleic acid (8.20%), phloretic acid (7.48%), methyl sinapate (6.92%), e-11-hexadecen-1-ol (6.10%), 1-hexadecanol (5.41%), and stearic acid (2.87%). Electron micrographs showed that application of the petroleum ether extracts seriously altered the morphology of C. michiganensis subsp. sepedonicus. Release of alkaline phosphatase and leakage of intracellular soluble protein confirmed that the integrity of the cell membrane was destroyed. Furthermore, ATPase activity, intracellular DNA content, and cell membrane potential were all demonstrated to be inhibited. In addition, the petroleum ether extract penetrated through the damaged cell membrane, and subsequently disrupted the cell cycle of the bacteria. We concluded that the petroleum ether fraction of ethanolic Athyrium sinense extracts was effective to inhibit C. michiganensis subsp. sepedonicus by damaging the cell membrane, and could be used as a natural alternative for C. michiganensis subsp. sepedonicus control