A Computational Study of the Proton-Transfer Chemistry of the Silaformyl Anion

Proton-transfer reactions involving the silaformyl anion, HSiO-, and its conjugate acids, HSiOH and H2SiO, have been investigated with ab initio methods. Calculations through fourth-order perturbation theory suggest possible routes for proton transfer. Accurate estimates for the acidity of H2SiO and HSiOH are presented and discussed in light of earlier experimental estimates

Discovery and Characterization of Molecular Subtypes in High-grade Urothelial Carcinoma

Bladder Cancer is the 4th most commonly diagnosed cancer in men and the 8th most deadly. While non-muscle invasive bladder cancer has a relatively high 5 year survival rate, muscle invasive bladder cancer (≥T2) has a 5 year survival rate of ~50% with the number decreasing to 15% for non-organ confined disease. Multiple groups have performed molecular characterization of bladder tumors in an effort to identify bladder cancer subtypes. These groups have been able to effectively differentiate non-muscle invasive disease (low-grade) from muscle invasive (high-grade); since pathologists can reliably identify LG and HG tumors, molecular signatures of these two groups are not clinically useful. We sought to define whether there are intrinsic molecular subtypes of high-grade bladder cancer. Consensus Clustering performed on gene expression data from a meta-dataset of high-grade, muscle invasive bladder tumors identified two intrinsic, molecular subsets of high-grade bladder cancer: “luminal” and “basal-like” that have characteristics of different stages of urothelial differentiation, reflect the luminal and basal-like molecular subtypes of breast cancer, and have clinically meaningful differences in outcome. Prediction analysis of microarrays (PAM) defined a gene set predictor: Bladder cancer Analysis of Subtypes by Expression (BASE47) that accurately classifies the subtypes. Our data demonstrate that there are at least two molecularly and clinically distinct subtypes of high-grade bladder cancer. As an appreciation of subtype heterogeneity has revolutionized the care of breast cancer, these results also suggest stratification for therapy is indicated in bladder cancer as well.Doctor of Philosoph

Synthetic and Computational Studies of Silametacyclophanes: Macrocyclic Cage Compounds

Multiple Pd(O)-catalyzed coupling reactions of9-borabicyclo[3.3.1]nonane (9-BBN) adducts of allylsilanes and bromo benzenes are used to prepare several unusual silametacyclophanes. Reaction of the 9-BBN adduct of dimethyldiallylsilane and 1,3-dibromobenzene gives 4-dimethyl-4-sila[7]metacyclophane in 32% yield, while reaction of the 9-BBN adduct of methyltriallylsilane and 1,3,5-tribromobenzene leads to 4-methyl-4-sila[34•10][7]metacyclophane in 4% yield. NMR data are presented to help characterize these compounds. Computational studies of the cyclophanes HE[-Y-(CH2)n-hCsH3 forE= C, Si, Y = CH2, 0, and n = 2, 3 reveal various important factors in stabilizing compounds with H atE inside the cage. These include that the macrocycle be large enough to accommodate the EH bond and that the EH bond be polarized so that its H atom is positive when directed toward the 1r cloud of the benzene ring. Even the small n = 2 macrocycles are only moderately strained at both E and the benzene base

Developmental inhibition in Drosophila using dihydroxybenzoic acid isomers

Five isomers of dihydroxybenzoic acid were added to a standard culture medium of Drosophila melanogaster and their effect on development time and progeny yield examined. Each isomer produced a distinct level of inhibitive influence throughout continuous inbred generations. The degree of developmental perturbation from a particular isomer was dependent on its protondonating power. Details of the alterations indicated enzyme inhibitions associated with the reaction kinetics of oxidative processes. A simple withdrawal of oxygen by briefly submerging pupae in water also altered the ontogenetic cycle suggesting an analogue of the isomer effect. Lengthened development produced by oxygen withdrawal in first-generation pupae was transferred to succeeding inbred generations. Published pharmacological studies in which drugs were introduced into Drosophila medium are given an interpretation based on the findings with the dihydroxybenzoic acid isomers.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32997/1/0000381.pd

A Nested Semiparametric Method for Case-control study with missingness

We propose a nested semiparametric model to analyze a case-control study where genuine case status is missing for some individuals. The concept of a noncase is introduced to allow for the imputation of the missing genuine cases. The odds ratio parameter of the genuine cases compared to controls is of interest. The imputation procedure predicts the probability of being a genuine case compared to a noncase semiparametrically in a dimension reduction fashion. This procedure is flexible, and vastly generalizes the existing methods. We establish the root-n asymptotic normality of the odds ratio parameter estimator. Our method yields stable odds ratio parameter estimation owing to the application of an efficient semiparametric sufficient dimension reduction estimator. We conduct finite sample numerical simulations to illustrate the performance of our approach, and apply it to a dilated cardiomyopathy study

Carbon-13 and silicon-29 NMR spectra of some [tris(trimethylsilyl)methyl]-substituted silanes and related compounds

Fourier Transform 13C and 29Si NMR spectra are reported for series of [tris-(trimethylsilyl)methyl] dimethylsilanes, [tris(trimethylsilyl)methyl] diphenylsilanes, and for related compounds. Analysis of chemical shift values indicates that such information can be useful in determining the structure in these highly hindered, but structurally similar compounds. In particular, the carbon and silicon atoms of the trimethylsilyl groups absorb in a narrow shift range, while other carbon and silicon atoms more characteristically reflect the substitution patterns in these compounds.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/23894/1/0000133.pd

Facile collection of two-dimensional electronic spectra using femtosecond pulse-shaping technology

This letter reports a straightforward means of collecting two-dimensional electronic (2D-E) spectra using optical tools common to many research groups involved in ultrafast spectroscopy and quantum control. In our method a femtosecond pulse shaper is used to generate a pair of phase stable collinear laser pulses which are then incident on a gas or liquid sample. The pulse pair is followed by an ultrashort probe pulse that is spectrally resolved. The delay between the collinear pulses is incremented using phase and amplitude shaping and a 2D-E spectrum is generated following Fourier transformation. The partially collinear beam geometry results in perfectly phased absorptive spectra without phase twist. Our approach is much simpler to implement than standard non-collinear beam geometries, which are challenging to phase stabilize and require complicated calibrations. Using pulse shaping, many new experiments are now also possible in both 2D-E spectroscopy and coherent control.open798

Development and validation of a NanoString BASE47 bladder cancer gene classifier

Background Recent molecular characterization of urothelial cancer (UC) has suggested potential pathways in which to direct treatment, leading to a host of targeted therapies in development for UC. In parallel, gene expression profiling has demonstrated that high-grade UC is a heterogeneous disease. Prognostic basal-like and luminal-like subtypes have been identified and an accurate transcriptome BASE47 classifier has been developed. However, these phenotypes cannot be broadly investigated due to the lack of a clinically viable diagnostic assay. We sought to develop and evaluate a diagnostic classifier of UC subtype with the goal of accurate classification from clinically available specimens. Methods Tumor samples from 52 patients with high-grade UC were profiled for BASE47 genes concurrently by RNAseq as well as NanoString. After design and technical validation of a BASE47 NanoString probeset, results from the RNAseq and NanoString were used to translate diagnostic criteria to the Nanostring platform. Evaluation of repeatability and accuracy was performed to derive a final Nanostring based classifier. Diagnostic classification resulting from the NanoString BASE47 classifier was validated on an independent dataset (n = 30). The training and validation datasets accurately classified 87% and 93% of samples, respectively. Results Here we have derived a NanoString-platform BASE47 classifier that accurately predicts basal-like and luminal-like subtypes in high grade urothelial cancer. We have further validated our new NanoString BASE47 classifier on an independent dataset and confirmed high accuracy when compared with our original Transcriptome BASE47 classifier. Conclusions The NanoString BASE47 classifier provides a faster turnaround time, a lower cost per sample to process, and maintains the accuracy of the original subtype classifier for better clinical implementation