The synthesis of 4-benzylamino-6-methyl-1H-pyrrolo[3, 2-c]pyridine and 4-benzylamino-6-methyl-1H-pyrrolo[2, 3-b]pyridine

4-Benzylamino-6-methyl-1H-pyrrolo[3,2-c]pyridine ( 2 ) and 4-benzylamino-6-methyl-1H-pyrrolo[2,3-b]pyridine ( 3 ) were synthesized as deaza analogues of the anxiolytic agent 4-benzylamino-2-methyl-7H-pyrrolo[2,3-d]pyrimidine ( 1 ). The 1-deaza analogue (2) was prepared via a multi-step procedure from a pyrrole precursor, 1-benzyl-2-formylpyrrole ( 4 ) while the 3-deaza analogue 3 was synthesized from a pyridine precursor, 2-amino-3,6-dimethylpyridine ( 12 ).     

Investigation of the influence of high-risk human papillomavirus on the biochemical composition of cervical cancer cells using vibrational spectroscopy

The main aetiology of cervical cancer is infection with high-risk human papillomavirus (HPV). Cervical cancer is almost 100% curable if detected in the early stages. Thus, information about the presence and levels of HPV in patient samples has high clinical value. As current screening methods, such as the Pap smear test, are highly subjective and in many cases show low sensitivity and specificity, new supportive techniques are desirable to improve the quality of cervical cancer screening. In this study, vibrational spectroscopic techniques (Raman and Fourier Transform Infra Red absorption) have been applied to the investigation of four cervical cancer cell lines: HPV negative C33A, HPV-18 positive HeLa with 20-50 integrated HPV copies per cell, HPV-16 positive SiHa with 1-2 integrated HPV strands per cell and HPV-16 positive CaSki containing 60-600 integrated HPV copies per cell. Results show that vibrational spectroscopic techniques can discriminate between the cell lines and elucidate cellular differences originating from proteins, nucleic acids and lipids. Similarities between C33A and SiHa cells were exhibited in the Raman and infrared spectra and were confirmed by Principal Component Analysis (PCA). Analysis of the biochemical composition of the investigated cells, with the aid of PCA, showed a clear discrimination between the C33A-SiHa group and HeLa and CaSki cell lines indicating the potential of vibrational spectroscopic techniques as a support to current methods for cervical cancer screening.     

Analysing the impact of the implementation of lean manufacturing strategies on profitability

Under standard cost accounting systems, reductions in inventories lead to falling reported profits. Rapid reductions in inventories intensify the impact to the bottom line. When a company embarks on an improvement programme such as lean manufacturing, a likely result will be an initial drop in reported profits due to the leaning out of inventories. This paper examines the impact of the adoption of such strategies on the key external financial performance measure of net profit as reported by the GAAP and SEC approved financial accounting methods and others. ANOVA analysis of data generated using a simulated manufacturing environment that includes a discrete event model of a manufacturing operation and a Microsoft Excel-based ERP system are discussed. The paper analyses both the magnitude of the reduction in reported profits and the span of reporting periods affected under three inventory reduction scenarios. This research was not concerned with finding justification for lean manufacturing strategies. Rather, it evaluates the inadequacies of standard financial reporting methods to accurately reflect operational improvements through the early stages of a lean programme.     

Cellular delivery of MRI contrast agents

Magnetic resonance imaging (MRI) is a powerful tool for acquiring images of opaque living animals with the benefit of tracking events over extended periods of time on the same specimen. Contrast agents are used to enhance regions, tissues, and cells that are magnetically similar but histologically distinct. A principal barrier to the development of MRI contrast agents for investigating biological questions is the delivery of agents across cellular membranes. Here, we describe the synthesis and in vitro testing of Gd(III)-based MRI contrast agents containing varying length polyarginine oligomers capable of permeating cell membranes. We examine the effect of the length of oligomer on T(1) enhancement and cellular uptake. Furthermore, the effect of incubation time, concentration, and cell type on uptake is explored. Toxicity and washout studies are performed in addition to MRI phantom studies.     

Nonelectrolyte Solvation in Aqueous Dimethyl Sulfoxide—A Calorimetric and Infrared Spectroscopic Study

We report enthalpies of solution of formamide, N,N-dimethylformamide,N,N-dimethylacetamide, acetic acid, methyl acetate, and acetonitrile in water +dimethylsulfoxide mixed solvents. These, along with literature data for additional solutes,are analyzed in terms of the extended coordination model of solvation. We alsoanalyze infrared data for several of these solutes. These analyses show thatN,N-dimethylformamide and N,N-dimethylacetamide are preferentially hydrated,while the other solutes appear to be preferentially solvated by dimethylsulfoxide.In all cases, the extent of preferential solvation is relatively small. It is also foundthat the degrees of preferential solvation recovered from analyses of the enthalpydata correspond closely to those recovered from the infrared data, although thelatter refer only to the polar chromophores on the solute molecules. It is foundthat the extent to which the solutes disrupt the solvent-solvent interactions variessystematically with the area of the nonpolar surfaces of the solute molecules.     

Correlation of p16(INK4A) expression and HPV copy number with cellular FTIR spectroscopic signatures of cervical cancer cells

Cervical cancer, a potentially preventable disease, has its main aetiology in infection by high risk human papillomavirus (HR-HPV). Approaches to improving cervical cancer screening and diagnostic methodologies include molecular biological analysis, targeting of biomarker proteins, but also exploration and implementation of new techniques such as vibrational spectroscopy. This study correlates the biomarker protein p16(INK4A) expression levels dependent on HPV copy number with the infrared absorption spectral signatures of the cervical cancer cell lines, HPV negative C33A, HPV-16 positive SiHa and CaSki and HPV-18 positive HeLa. Confocal fluorescence microscopy demonstrated that p16(INK4A) is expressed in all investigated cell lines in both nuclear and cytoplasmic regions, although predominantly in the cytoplasm. Flow cytometry was used to quantify the p16(INK4A) expression levels and demonstrated a correlation, albeit nonlinear, between the reported number of integrated HPV copies and p16(INK4A) expression levels. CaSki cells were found to have the highest level of expression, HeLa intermediate levels, and SiHa and C33A the lowest levels. FTIR spectra revealed differences in nucleic acid, lipid and protein signatures between the cell lines with varying HPV copy number. Peak intensities exhibited increasing tendency in nucleic acid levels and decreasing tendency in lipid levels with increasing HPV copy number, and although they were found to be nonlinearly correlated with the HPV copy number, their dependence on p16(INK4A) levels was found to be close to linear. Principal Component Analysis (PCA) of the infrared absorption spectra revealed differences between nuclear and cytoplasmic spectroscopic signatures for all cell lines, and furthermore clearly differentiated the groups of spectra representing each cell line. Finally, Partial Least Squares (PLS) analysis was employed to construct a model which can predict the p16(INK4A) expression level based on a spectral fingerprint of a cell line, demonstrating the diagnostic potential of spectroscopic techniques.