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Attractive Strategy (attractive + strategy)
Selected AbstractsNew developments in small molecules targeting p53 pathways in anticancer therapyDRUG DEVELOPMENT RESEARCH, Issue 6 2008Chit Fang Cheok Abstract The tumor suppressor p53 is frequently inactivated in a wide variety of cancers and point mutations or deletions of the p53 gene are associated with poor prognosis in cancer. About half of all human tumors carry wildtype p53 but p53 wildtype functions are often suppressed by the overexpression of murine double minute 2 (MDM2), a negative regulator of p53. Restoration of p53 functions in tumor cells, therefore, represents an attractive strategy in combating cancer and has been the focus of intensive anticancer drug discovery. One strategy is to antagonize MDM2 functions and initial success was demonstrated in vitro and in xenograft tumor models using newly discovered small molecule inhibitors and antisense oligonucleotides. The new discovery of a compound targeting SirT1 (a member of the sirtuin family) in a p53-dependent reporter screen highlighted the importance of another negative regulator of p53 and offers an additional avenue for drug discovery and research on p53-activating therapeutics. Here, we discuss the developments of p53-activating small molecules and their potential use in combination therapy with established chemotherapeutics. These small molecules were discovered from chemical library screening using biochemical assays or cellular-based assays, and/or structure-based rational drug design strategies. Drug Dev Res 69:289,296, 2008. © 2008 Wiley-Liss, Inc. [source] An algorithm for fast optimal Latin hypercube design of experimentsINTERNATIONAL JOURNAL FOR NUMERICAL METHODS IN ENGINEERING, Issue 2 2010Felipe A. C. Viana Abstract This paper presents the translational propagation algorithm, a new method for obtaining optimal or near optimal Latin hypercube designs (LHDs) without using formal optimization. The procedure requires minimal computational effort with results virtually provided in real time. The algorithm exploits patterns of point locations for optimal LHDs based on the ,p criterion (a variation of the maximum distance criterion). Small building blocks, consisting of one or more points each, are used to recreate these patterns by simple translation in the hyperspace. Monte Carlo simulations were used to evaluate the performance of the new algorithm for different design configurations where both the dimensionality and the point density were studied. The proposed algorithm was also compared against three formal optimization approaches (namely random search, genetic algorithm, and enhanced stochastic evolutionary algorithm). It was found that (i) the distribution of the ,p values tends to lower values as the dimensionality is increased and (ii) the proposed translational propagation algorithm represents a computationally attractive strategy to obtain near optimum LHDs up to medium dimensions. Copyright © 2009 John Wiley & Sons, Ltd. [source] MicroRNA-34a is an important component of PRIMA-1-induced apoptotic network in human lung cancer cellsINTERNATIONAL JOURNAL OF CANCER, Issue 2 2010Wenrui Duan Abstract Restoration of p53 function in tumor cells would be an attractive strategy for lung cancer therapy because p53 mutations are found in more than 50% of lung cancers. The small molecule PRIMA-1 has been shown to restore the tumor suppression function of p53 and to induce apoptosis in human tumor cells. The mechanism of apoptosis induced by PRIMA-1 remains unclear. We investigated the effects of PRIMA-1 in apoptosis with Western immunoblot analysis, TaqMan microRNA real-time PCR, cell viability analysis and flow cytometry using human lung cancer cell lines containing mutant (H211 and H1155), wild-type (A549) or null (H1299) p53. PRIMA-1 induced massive apoptosis in the H211 and H1155 cells, but was less toxic to the A549 and H1299 cells. Western immunoblot analysis showed cleavage of PARP in H211 and H1155 cells but not in A549 and H1299 cells following treatment with PRIMA-1. In addition, p53 protein was also phosphorylated in H211 and H1155 cells. TaqMan microRNA assay showed that the expression of microRNA-34a was increased in the H211 and H1155 cells posttreatment. Knockdown microRNA-34a decreased the rate of apoptosis caused by PRIMA-1. The above results suggest that microRNA-34a is one of the important components of PRIMA-1-induced apoptotic network in the cancer cells harboring mutant p53. [source] INHIBITORY POTENTIAL OF WINE AND TEA AGAINST ,-AMYLASE AND ,-GLUCOSIDASE FOR MANAGEMENT OF HYPERGLYCEMIA LINKED TO TYPE 2 DIABETESJOURNAL OF FOOD BIOCHEMISTRY, Issue 1 2008YOUNG-IN KWON ABSTRACT Natural ,-amylase and ,-glucosidase inhibitors from food-grade plants offer an attractive strategy to manage postprandial hyperglycemia for type 2 diabetes management via control of starch breakdown and intestinal glucose absorption. In this study, four random sources of red and white wines as well as four types of teas were investigated for ,-amylase and ,-glucosidase inhibitory potential. Water extracts of black tea had the highest ,-glucosidase inhibitory activity, followed by white tea and oolong tea. All the randomly selected red wines had significant ,-glucosidase inhibitory activity compared to white wine. The ,-glucosidase inhibitory activity of the tea and wines correlated to the phenolic content, antioxidant activity and phenolic profile of the extracts. Further, these extracts had less or no ,-amylase inhibitory activity, indicating potential to overcome the side effects of undigested starch. This research has relevance for managing hyperglycemia and related oxidation-linked dysfunction and concurrently reducing problems of undigested starch. PRACTICAL APPLICATIONS In this study anti-diabetic-relevant potential of wines and teas were confirmed in four types of red and white wines as well as four types of commonly available teas using in vitro enzyme assays for alpha-glucosidase and alpha-amylase inhibitory activities. In vitro inhibitory activities of these enzymes provide a strong biochemical rationale for further in vivo studies and dietary management strategy for type 2 diabetes through the control of glucose absorption. Further this phenolic antioxidant-enriched dietary strategy using specific beverage combinations can generate a whole food profile that has the potential to reduce hyperglycemia-induced pathogenesis and also associated complications linked to cellular oxidation stress. [source] Microalgal-luffa sponge immobilized disc: a new efficient biosorbent for the removal of Ni(II) from aqueous solutionLETTERS IN APPLIED MICROBIOLOGY, Issue 2 2003N. Akhtar Abstract Aims: The aim was to develop a new, efficient and cost-effective biosorbent for the removal of heavy metals from aqueous solution. Methods and Results: A new biosorbent was developed by immobilizing a unicellular green microalga Chlorella sorokiniana within luffa sponge discs and used for the removal of metal ions from aqueous solution. Microalgal-luffa sponge immobilized discs (MLIDs) removed Ni(II) very rapidly, with 97% of equilibrium loading being reached in 5 min. MLIDs were tested for their potential to remove Ni(II) from aqueous solution in fixed-bed column bioreactor. The regenerated MLIDs retained 92·9% of the initial binding capacity for Ni(II) up to five cycles of reuse. Conclusions: In this study for the first time, C. sorokiniana biomass immobilized within luffa sponge disc was successfully used as a metal biosorbent for the removal of Ni(II). It appears that MLIDs can be used as an effective biosorbent for efficient removal of Ni(II) or other metals from aqueous solution. Significance and Impact of the Study: MLIDs biosorption system was shown to have good biosorption properties with respect to Ni(II). Efficient metal removal ability of MLIDs, low cost and simplicity of the technique used for the preparation of MILDs could provide an attractive strategy for developing high-affinity biosorption system for heavy metal removal. [source] HIV-1 integrase inhibitors: 2005,2006 updateMEDICINAL RESEARCH REVIEWS, Issue 1 2008Raveendra Dayam Abstract HIV-1 integrase (IN) catalyzes the integration of proviral DNA into the host genome, an essential step for viral replication. Inhibition of IN catalytic activity provides an attractive strategy for antiretroviral drug design. Currently two IN inhibitors, MK-0518 and GS-9137, are in advanced stages of human clinical trials. The IN inhibitors in clinical evaluation demonstrate excellent antiretroviral efficacy alone or in combination regimens as compared to previously used clinical antiretroviral agents in naive and treatment-experienced HIV-1 infected patients. However, the emergence of viral strains resistant to clinically studied IN inhibitors and the dynamic nature of the HIV-1 genome demand a continued effort toward the discovery of novel inhibitors to keep a therapeutic advantage over the virus. Continued efforts in the field have resulted in the discovery of compounds from diverse chemical classes. In this review, we provide a comprehensive report of all IN inhibitors discovered in the years 2005 and 2006. © 2007 Wiley Periodicals, Inc. Med Res Rev, 28, No. 1, 118,154, 2008 [source] Blocking leukocyte influx and function to prevent chronic lung disease of prematurityPEDIATRIC PULMONOLOGY, Issue 5 2003Richard L. Auten MD Abstract Inflammation is strongly linked to the pathogenesis of chronic lung disease of prematurity (CLD). Premature gas-breathing of ambient or supplemental oxygen in a host with relatively deficient and poorly inducible antioxidant defenses may itself be injurious, and further amplified by mechanical stretch injury in the surfactant-insufficient lung.1 Cellular injury provokes an inflammatory response. Since inflammation is often detected at birth in the lungs of newborns who later develop CLD,2 it has been an attractive strategy to abrogate inflammation, but the arsenal is limited. Glucocorticoids have been widely used but are acknowledged to be potentially harmful to neurologic and somatic development, and are not recommended outside controlled trials.3 The number that benefit is comparable to the number harmed, according to meta-analysis.4 More specific blockade of harmful inflammation could overcome this obstacle. Examination of the inflammatory pathways that initiate and propagate lung injury and subsequent abnormal development points to promising new strategies that may one day be tailored to individual patients. Pediatr Pulmonol. 2003; 35:335,341. © 2003 Wiley-Liss, Inc. [source] A Human Anti-CD40 Monoclonal Antibody, 4D11, for Kidney Transplantation in Cynomolgus Monkeys: Induction and Maintenance TherapyAMERICAN JOURNAL OF TRANSPLANTATION, Issue 8 2009T. Aoyagi Blockade of CD40,CD154 signaling pathway is an attractive strategy to induce potent immunosuppression and tolerance in organ transplantation. Due to its strong immunosuppressive effect shown in nonhuman primate experiments, anti-CD154 monoclonal antibodies (mAbs) have been tried in clinical settings, but it was interrupted by unexpected thromboembolic complications. Thus, inhibition of the counter molecule, CD40, has remained an alternative approach. In the previous preliminary study, we have shown that 4D11, a novel fully human anti-CD40 mAb, has a fairly potent immunosuppressive effect on kidney allograft in nonhuman primates. In this study, we aimed to confirm the efficacy and untoward events of the 2-week induction and 180-day maintenance 4D11 treatments. In both, 4D11 significantly suppressed T-cell-mediated alloimmune responses and prolonged allograft survival. Addition of weekly 4D11 administration after the induction treatment further enhanced graft survival. Complete inhibition of both donor-specific Ab and anti-4D11 Ab productions was obtained only with higher-dose maintenance therapy. No serious side effect including thromboembolic complications was noted except for a transient reduction of hematocrit in one animal, and decrease of peripheral B-cell counts in all. These results indicate that the 4D11 appears to be a promising candidate for immunosuppression in clinical organ transplantation. [source] Production of a recombinant cholera toxin B subunit-insulin B chain peptide hybrid protein by Brevibacillus choshinensis expression system as a nasal vaccine against autoimmune diabetesBIOTECHNOLOGY & BIOENGINEERING, Issue 7 2005Yoshikazu Yuki Abstract Mucosally induced tolerance is an attractive strategy for preventing or reducing autoimmune diseases. Here, we produced a recombinant CTB fusion protein linked with autoantigen T cell epitope of insulin B chain peptide 9,23 (C19S) at levels up to 200 mg/L culture media in Brevibacillus choshinensis secretion-expression system. Receptor-competitive assay showed that the CTB-insulin peptide binds to GM1 receptor almost equivalent degree as the native form of CTB. Non-obese diabetes (NOD) mice that spontaneously develop an insulin-dependent diabetes were nasally immunized with CTB-insulin peptide (5 µg) for three times. The nasal treatment significantly reduced the development of insulin-dependent diabetes and peptide specific DTH responses after systemic immunization with the insulin peptide B 9,23(C19S) in CFA. Nasal administration of as high as 50 µg of the peptide alone demonstrated a similar level of the disease inhibition. In contrast, all mice given 5 µg of the insulin peptide alone or 5 µg of insulin peptide with 25 µg of the free form of CTB did not lead to the suppression of diabetes development and DTH responses. Because molecular weight of the insulin peptide is about one tenth of that of the CTB-insulin peptide, the results demonstrate that the recombinant hybrid of autoantigen and CTB increased its tolerogenic potential for nasal administration by up 100-fold on molar base of autoantigen peptide. Taken together, nasally-induced tolerance by administration of the recombinant B.choshinensis -derived hybrid protein of CTB and autoantigen T cell-epitope peptide could be useful mucosal immunetherapy for the control of T cell-mediated autoimmune diseases. © 2005 Wiley Periodicals, Inc. [source] Use of Glycol Ethers for Selective Release of Periplasmic Proteins from Gram-Negative BacteriaBIOTECHNOLOGY PROGRESS, Issue 5 2007Jeffrey R. Allen Genetic modification of Gram-negative bacteria to express a desired protein within the cellapos;s periplasmic space, located between the inner cytoplasmic membrane and the outer cell wall, can offer an attractive strategy for commercial production of therapeutic proteins and industrial enzymes. In certain applications, the product expression rate is high, and the ability to isolate the product from the cell mass is greatly enhanced because of the productapos;s compartmentalized location within the cell. Protein release methods that increase the permeability of the outer cell wall for primary recovery, but avoid rupturing the inner cell membrane, reduce contamination of the recovered product with other host cell components and simplify final purification. This article reports representative data for a new release method employing glycol ether solvents. The example involves the use of 2-butoxyethanol (commonly called ethylene glycol n -butyl ether or EB) for selective release of a proprietary biopharmaceutical protein produced in the periplasmic space of Pseudomonas fluorescens. In this example, glycol ether treatment yielded ,65% primary recovery with ,80% purity on a protein-only basis. Compared with other methods including heat treatment, osmotic shock, and the use of surfactants, the glycol ether treatment yielded significantly reduced concentrations of other host cell proteins, lipopolysaccharide endotoxin, and DNA in the recovered protein solution. The use of glycol ethers also allowed exploitation of temperature-change-induced phase splitting behavior to concentrate the desired product. Heating the aqueous EB extract solution to 55 °C formed two liquid phases: a glycol ether-rich phase and an aqueous product phase containing the great majority of the product protein. This phase-splitting step yielded an approximate 10-fold reduction in the volume of the initial product solution and a corresponding increase in the productapos;s concentration. [source] Rhamnolipid Surfactants: An Update on the General Aspects of These Remarkable BiomoleculesBIOTECHNOLOGY PROGRESS, Issue 6 2005Marcia Nitschke Pseudomonas strains are able to biosynthesize rhamnose-containing surfactants also known as rhamnolipids. These surface-active compounds are reviewed with respect to chemical structure, properties, biosynthesis, and physiological role, focusing on their production and the use of low-cost substrates such as wastes from food industries as alternative carbon sources. The use of inexpensive raw materials such as agroindustrial wastes is an attractive strategy to reduce the production costs associated with biosurfactant production and, at same time, contribute to the reduction of environmental impact generated by the discard of residues, and the treatment costs. Carbohydrate-rich substrates generated low rhamnolipid levels, whereas oils and lipid-rich wastes have shown excellent potential as alternative carbon sources. [source] Cost-effectiveness of targeted and tailored interventions on colorectal cancer screening useCANCER, Issue 4 2008David R. Lairson PhD Abstract BACKGROUND. Colorectal cancer (CRC) screening is cost-effective but underused. The objective of this study was to determine the cost-effectiveness of targeted and tailored behavioral interventions to increase CRC screening use by conducting an economic analysis associated with a randomized trial among patients in a large, racially and ethnically diverse, urban family practice in Philadelphia. METHODS. The incremental costs per unit increase were measured in individuals who were screened during the 24 months after intervention. Percent increase in screening was adjusted for baseline differences in the study groups. Each intervention arm received a targeted screening invitation letter, stool blood test (SBT) cards, informational booklet, and reminder letter. Tailored interventions incrementally added tailored messages and reminder telephone calls. RESULTS. Program costs of the targeted intervention were $42 per participant. Additional costs of adding tailored print materials and of delivering a reminder telephone call were $150 and $200 per participant, respectively. The cost per additional individual screened was $319 when comparing the no intervention group with the targeted intervention group. CONCLUSIONS. The targeted intervention was more effective and less costly than the tailored intervention. Although tailoring plus reminder telephone call was the most effective strategy, it was very costly per additional individual screened. Mailed SBT cards significantly boosted CRC screening use. However, going beyond the targeted intervention to include tailoring or tailoring plus reminder calls in the manner used in this study did not appear to be an economically attractive strategy. Cancer 2008. © 2007 American Cancer Society. [source] | ||||||||||||||||