Publications by authors named "McHugh R"

The preparation of unsymmetrical cyclic ureas bearing novel biaryl indazoles as P2/P2' substituents was undertaken, utilizing a Suzuki coupling reaction as the key step. Compound 6i was equipotent to the lead compound of the series SE063.

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Efavirenz (SUSTIVA) is a potent non-nucleoside reverse transcriptase inhibitor. Due to the observation of breakthrough mutations of the reverse transcriptase enzyme during Efavirenz therapy, we sought to develop an optimized second generation series. To that end, SAR of the substituents on the aromatic ring was undertaken and the results are summarized here.

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Modification of tumor cells with one or more costimulatory adhesion molecules has been proposed as a means to develop therapeutic cancer vaccines for use in human immunotherapy. Expression of B7-1 (CD80) in tumors by gene transfer creates an immunogenic tumor cell that induces antitumor immunity and protects mice from further challenge with wild-type tumor cells. In this report, we demonstrate that protein transfer of glycosyl-phosphatidylinositol (GPI)-anchored costimulatory molecules into tumor cell membranes could be used as an alternative to gene transfer for tumor immunotherapy.

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Thymectomy at day 3 of life (d3Tx) results in the development of organ-specific autoimmunity. We have recently shown that d3Tx BALB/c mice which develop autoimmune gastritis contain CD4+ T cells specific for the gastric parietal cell proton pump, H/K ATPase. Here, we demonstrate that freshly explanted gastric lymph node (LN) cells from d3Tx mice react significantly to the H/K ATPase alpha chain, but only marginally to the beta chain.

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Cyclic urea SD146, a potent HIV protease inhibitor bearing a flat resistance profile, possessed poor solubility and bioavailability, which precluded further development of the compound. In an effort to improve upon the pharmacokinetic profile of the compound, several analogs modified at the P1/P1' residues were prepared and evaluated. Several of those compounds displayed significant improvement of physical properties.

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The costimulatory molecule B7-1 (CD80) has been shown to be an important component for T cell immune responses. We have generated several monoclonal antibodies (PSRM-1, -2, -3, -6, and -7) against B7-1 using a human glycosylphosphatidylinositol-anchored B7-1 (GPI-B7-1) as an antigen. These monoclonal antibodies are able to detect B7-1 by flow cytometry, ELISA, and Western blotting.

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High-resolution X-ray structures of the complexes of HIV-1 protease (HIV-1PR) with peptidomimetic inhibitors reveal the presence of a structural water molecule which is hydrogen bonded to both the mobile flaps of the enzyme and the two carbonyls flanking the transition-state mimic of the inhibitors. Using the structure-activity relationships of C2-symmetric diol inhibitors, computed-aided drug design tools, and first principles, we designed and synthesized a novel class of cyclic ureas that incorporates this structural water and preorganizes the side chain residues into optimum binding conformations. Conformational analysis suggested a preference for pseudodiaxial benzylic and pseudodiequatorial hydroxyl substituents and an enantiomeric preference for the RSSR stereochemistry.

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Recently mouse models have shown that expression of costimulatory molecules such as B7-1 on tumor cells can induce tumor-specific immunity, suggesting that tumor cells modified to express costimulatory molecules can be a potential tumor vaccine. To investigate the importance of B7-1 co-stimulation in induction of autologous tumor immunity in humans, we established a renal carcinoma cell line, RCC-1, from a tumor resection and studied the patient's antitumor immune responses in vitro. The RCC-1 cell line constitutively expressed major histocompatibility complex (MHC) class I, intercellular adhesion molecule (ICAM)-1, and leukocyte function-associated antigen (LFA)-3 molecules, and MHC class II molecules were induced by interferon-gamma (IFN-gamma) treatment in vitro.

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To generate a potent cell-mediated immune response, at least two signals are required by T cells. One is engagement of the T-cell receptor with peptide-bearing major histocompatibility complex molecules. The other signal can be delivered by various molecules on the antigen-presenting cell, such as B7-1 (CD80).

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Heat-stable antigen (HSA/J11d/possibly homologous to CD24), a cell adhesion molecule capable of providing a co-stimulatory signal for T cell proliferation, is expressed on B cells, activated T cells, monocytes, granulocytes, Langerhans cells and thymocytes. Recent studies have demonstrated that co-stimulatory signals provided by cell adhesion molecules such as B7-1 play an essential role in generation of an anti-tumor immune response. To examine whether the co-stimulatory signal provided by HSA can induce an anti-tumor immune response, we have transfected HSA cDNA into the murine melanoma cell line K1735M2, and examined the ability of this transfected cell line to induce tumor-specific T cell responses.

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Situations often arise in a large-scale household survey where a complex probability sample of clusters rather than of individuals is drawn from a large population. Typically, the clusters of such complex samples include a number of correlated members. The responses of these members are then weighted to obtain estimates for the population.

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The "single-consent design" was devised by Zelen to circumvent the reluctance of some patients and physicians to participate in certain types of randomized clinical trials. Crucial to the validity of Zelen's design is randomized allocation of patients. Randomization theory is therefore the key theoretical base of the approach taken in this paper to an examination of the efficiency of this design.

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A new sample size formula is derived herein for matched-pair case-control studies. This result is based on an unconditional approach to the use of McNemar's statistic. We contrast this method for determining sample size and power with Schlesselman's conditional approach and compare the results numerically in a Monte Carlo study.

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A new approach is presented to the study of heterogeneity of the odds ratio in a case-control design when the possible interaction effects are associated with the variables used for multiple matching. This analysis does not require stratification on the matching covariates.

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Limited information is available comparing the relative longitudinal effectiveness with respect to tooth type of scaling and root planing alone and scaling and root planing followed by flap procedures. The purpose of this study was to investigate these treatment methods as applied to molar and nonmolar teeth on a longitudinal basis in humans. Seventeen subjects with chronic periodontitis received thorough scaling and root planning as well as oral hygiene instruction.

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Employing randomization theory, this note examines the manner in which a clinical trial employing Zelen's randomized consent design yields an estimated treatment effect free of selection bias. We also examine the concept of 'treatment dilution' in this design.

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The general procedure for sample size determination based upon the confidence interval approach is reviewed and presented for both absolute and relative precision stipulations. The relationship between precision and sample size is discussed and methods for sample size determination for clinical trials are presented and illustrated with numerical examples.

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"Several models have been proposed for the analysis of cohort mortality in the presence of competing risks...

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Many well designed clinical studies have established the effectiveness of periodontal therapy. Surgical procedures have been shown to be effective in treating periodontitis when followed by appropriate maintenance care. Scaling and root planing alone have recently been compared to scaling and root planing plus soft tissue surgery in several longitudinal trials.

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A topic of current biometric discussion is whether stratification should be used in randomized clinical trials and, if so, which kind. An approach based upon randomization theory is used to evaluate pre- versus post-stratification. The results obtained relate specifically to the effect of the size of the clinical trial on the bias and precision of estimated treatment contrasts.

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A new biometric model is presented for the rate of thermal disinfection of a microbial population. Unlike the usual approach, this model incorporates random errors arising at two stages into exponential kinetics. The first such stage is a result of sampling at the initial time of deposition of the microorganisms.

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