This thesis focuses on the synthesis and vaccine evaluation of the prostate tumor- associated carbohydrate antigen RM2. The author first presents the use of the [1+2+3] one-pot sequential strategy to successfully synthesise the RM2 antigen and its analogues as single stereoisomers in every glycosylation step, producing good yields and stereoselectivity. He then introduces the conjugation of the synthetic RM2 antigen to the carrier protein CRM197 in an average number of 1–10 to create the prostate cancer vaccine candidate, which is combined with α-galactosylceramide C1, its analogue C34, or Alu. The results of the vaccination studies in mice are also described and indicate that the strongest anti-RM2 antigen titer is exhibited when one molecule of diphtheria toxin (DT) is conjugated with an average of 4.7 molecules of RM2 antigen (DT-RM4.7) and adjuvanted with the glycolipid C34. More importantly, the induced mouse antibodies mediate the effective complement-dependent cytotoxicity (CDC) against the prostate cancer cell line LNCap. The study presented in this thesis is the first ever to successfully synthesize this complex glycan molecule. Owing to the steric hindrance of the adjacent sialyl moiety, the introduction of two sialic acid units to the compact and rigid 3,4 di branched galactoside unit is very challenging and the β-selective and efficient glycosylation of the galactosamine moiety at the 4-position of di branched galactose is also problematic.

In the process of carcinogenesis, certain glycosyltransferases are over-expressed in tumor cells, which lead to different glycosylation patterns than those of normal cells. For example, the Thomsen-Friedenreich (TF), Thomsen-nouveau (Tn) and sialyl-Tn (STn) antigens are expressed abundantly on human breast, ovarian and colon cancer. These tumor-associated-carbohydrate-antigens (TACAs) on tumor cell surfaces provide a potential opportunity for researchers to develop carbohydrate-based anticancer vaccines for therapeutic treatment. This research is focused on the investigation of an entirely-carbohydrate conjugate for immunotherapy of STn-positive cancer. STn is a O-linked disaccharide consisted of a sialic acid residue a-2,6-link to a GalNAca-O-Ser/Thr residue. In early 80s, STn antigen was discovered and identified as a cancer marker, detection of STn was found in a variety human epithelial carcinomas, such as breast and ovarian cancer cells. In the past few decades, there are two major areas in STn related cancer researches: 1) use STn as tumor marker for diagnosis and prognosis in the clinical practice; 2) use the cutting edge immunotherapy strategies to target STn antigen for therapeutic purpose. The design of most STn vaccines choose immunogenic proteins as carriers to cross over into the cellular arm of the immune system because of the inherent T-cell independent nature of TACSs. There are both advantages and disadvantages for this strategy. The reason Andreana's group works with capsular polysaccharide PS A1, is to find an alternative pathway to avoid numerous disadvantages of protein carriers and at same time retain both a cellular and humoral immune response. PS A1 is a zwitterionic polysaccharide (ZPS) found on Bacteroides fragilis' cell wall, consisting of a tetrasaccharide-core repeating unit carrying an electrostatic charge character on adjacent monosaccharides able to induce a specific and selective immune response similar to that noted for exogenous proteins. Thus this study is dedicated to the synthesis of STn-PS A1 conjugate and its immunological evaluation. This work described the preparation and immunological evaluation of STn-PSA1 conjugate in the mice model. First of all, a highly chemical-selective and adaptive synthetic route for aminooxy-STn antigen has been developed, and conjugated to aldehyde-functionalized-PSA1 through an extremely economical oxime linker. The structure of STn-PSA1 also been probably characterized by NMR analysis. The combination of STn-PSA1 and Sigma Adjuvant System demonstrated its capability of inducing anti-STn antibody production in mice, as indicated by an ELISA test. FACS study was performed on several STn expressing cancer cell lines. These results further confirmed the excellent specificity and reactivity of antibodies induced by STn-PSA1 against tumor cell surface STn antigen. Moreover, data collected in an in vitro assay exhibited promising therapeutic potential of anti-STn antibody-inducing complement-dependent cytotoxicity. We speculated that this effector mechanism could be helpful for eradicating STn expressing tumor cells in vivo. These promising results suggest a new approach for the development of a next generation cancer vaccine, and more research is undergoing to investigate the immunological profile of STn-PSA1 immunogen.

Applications of nuclear magnetic resonance span a wide range of scientific disciplines, from physics to medicine. This series has provided an essential digest of the NMR literature for more than four decades and each volume provides unrivalled coverage of the literature on this topic. Continuous coverage on some topics such as theoretical and physical aspects of nuclear shielding is balance by the desire for coverage on newer topics like applications in biological systems and materials science. For those wanting to become rapidly acquainted with NMR or seasoned practitioners, this is an invaluable source of current methods and applications.

Advanced Chemical Biology The modern approach to teaching chemical biology Advanced Chemical Biology is organized around the central dogma of life, progressing from genes to proteins and higher-order cellular structures, including core application areas such as imaging, chemical genetics, activity-based protein profiling, and natural product discovery and biosynthesis. Advanced topics and applications in, e. g., microbiology, developmental biology, and neurobiology, are covered in separate sections. Every chapter is homogeneous in style and layout, consisting of a short historical introduction followed by a description of the underlying concepts and a selection of recent examples of how the concept has been turned into practice. The subdivision of the contents into core and supplemental chapters enables a flexible use in teaching, both for a one-semester and a two-semester course. Written by authors and editors coming from the leading scientific institutions that have developed the concepts and technologies for this discipline, Advanced Chemical Biology includes specific information on topics like: DNA function, synthesis and engineering, chemical approaches to genome integrity, and RNA function, synthesis, and probing Chemical approaches to transcription and RNA regulation in vivo, chemical biology of genome engineering, and peptide/protein synthesis and engineering Directed evolution for chemical biology, chemical biology of cellular metabolism, chemical biology of lipids, and protein post-translational modifications Chemical glycobiology, chemical and enzymatic modification of proteins, genetic code expansion, bio-orthogonal chemistry, and cellular imaging With its broad scope and focus on turning concepts into applications, Advanced Chemical Biology is an excellent starting point for anyone entering the field and looking for a guide to the wide range of available methods and strategies that chemical biology has to offer. With a Foreword by Nobel Laureate Carolyn Bertozzi.

This book is the first of its kind entirely dedicated to carbohydrate vaccines written by renowned scientists with expertise in carbohydrate chemistry and immunochemistry. It covers the synthesis of carbohydrate antigens related to bacteria and parasites such as: Heamophilus influenza, Streptococcus pnemoniae, Shigella flexneri, Candida albicans, Mycobacterium tuberculosis, and Chlamydia. The first three chapters are of wide interest as they cover fundamental concerns in new vaccine developments. The first one presents the immune system and how carbohydrate antigens are processed before protective antibodies are produced. It also illustrates antigen presentation in the context of major histocompatibility complexes (MHCs). The second chapter describes regulatory issues when carbohydrate vaccines are involved while the third one discuss several techniques used in conjugation chemistry and the implication of certain chemical linkages that may induce unexpected anti-linker antibodies. This section will be particularly appealing for those involved in drug-conjugate design, pro-drug developments, and drug vectorization. The book concludes with one chapter that illustrates the principle through which peptide antigens can functionally mimic carbohydrate epitopes, thus, unraveling the potential for peptide surrogates as replacement for complex carbohydrate structures. This book is unique in that it covers all aspects related to carbohydrate vaccines including the success story with the first semi-synthetic bacterial polysaccharide vaccine against Heamophilus influenza type b responsible for pneumonia and meningitis, liable for more than 600,000 infant deaths worldwide in developing countries. The book also presents regulatory issues and will thus be vital for government agencies approving candidate vaccines. It widely covers synthetic methodologies for the attachment of carbohydrate antigens to peptides and immunogenic protein carriers. Vaccines against bacterial antigens, cancer, and parasites are also discussed by worldwide experts in this field in details. No other book contains such a wide panel of different expertise. It will also be useful to students and researchers involved with the immunology of forreings antigens and how the under appreciated carbohydrate antigens are processed by the immune system.

Divided into twelve sections that cover the entirety of anesthetic practice, this is a case-based, comprehensive review of anesthesiology that covers the basics of anesthetic management and reflects all new guidelines and recently developed standards of care. Each chapter of Anesthesiology: Clinical Case Reviews begins with a specific clinical problem or a clinical case scenario, followed by concise discussions of preoperative assessment, intraoperative management, and postoperative pain management. In addition to residents and fellows, this book is written for practicing anesthesiologists, student nurse anesthetists, and certified registered nurse anesthetists (CRNAs).