Targeting the Colchicine Binding Site on Tubulin to Overcome Multidrug Resistance and Anticancer Efficacy of Selective Survivin Inhibitors

Tubulin inhibitors are widely used as chemotherapeutic agents, and their successis attributed to their ability to target microtubule dynamics and disrupt critical cellular functions including cell signaling, motility, intracellular trafficking, and mitosis. Interference with microtubule dynamics consequently disrupts mitotic progression and ultimately leads to apoptosis, validating microtubule dynamics as an excellent target for anticancer agents. While this class of drug has proven to be effective against many cancer types, the clinical efficacy of current tubulin inhibitors is often limited by the development of multidrug resistance. The most common form of resistance to these agents arises from the overexpression of drug efflux transporters. Extensive research efforts have attempted to develop colchicine binding site inhibitors, which are reported to be significantly less susceptible to multidrug resistance and have therapeutic advantages over agents that target the taxane and vinca alkaloid site. Herein, we evaluated the anticancer activity of novel small-molecules that target the colchicine binding site, focusing on the most promising compounds from several structural scaffolds including indolyl-imidazopyridines (DJ95 and DJ101), VERU-111 analogs with a modified indole moiety (10ab and 10bb) or 3,4,5-trimethoxyphenyl moiety (13f), and heterocyclic pyrimidines (4a, 6a, 5a, and 5b). We demonstrated the cytotoxic potency of these compounds against a variety of cancer cell lines, including malignant melanomas, taxaneresistant prostate cancer cells, and drug efflux pump-overexpressing cell lines. Their mechanism of action was revealed through tubulin polymerization inhibition, disruption of microtubule networks and mitotic spindle formation, and confirmed through X-ray crystallography, which detailed their specific molecular interactions with tubulin in the colchicine binding pocket. Furthermore, these compounds exhibited hallmark characteristics of colchicine binding site agents, such as arresting cells in the G2/M phase of the cell cycle, inducing apoptosis in a concentration-dependent manner, and impeding cancer cell proliferation and migration. Finally, the compounds were efficacious in vivo against melanoma and taxane-resistant prostate cancer xenograft tumors. Several agents were evaluated for ability to prevent melanoma metastases to the lungs in experimental mouse models, and they potently inhibited the development metastatic foci. Safety assessment by pharmacological profiling demonstrated minimal interactions to physiologically important targets and pathophysiological analysis of major organs from the in vivo treatment groups did not expose apparent drug-related injury. Several of the investigated compounds also demonstrated vascular disrupting properties by targeting tumor vasculature and inhibiting capillary-like network formation of endothelial cells. Ultimately, these compounds exhibit strong anticancer efficacy, specifically target the colchicine binding site, and have great potential as cancer therapeutics, particularly for multidrug resistance phenotypes. Another target we explored for anticancer intervention was survivin. Survivin is the smallest member the inhibitor of apoptosis protein family and its overexpression in tumor cells is been positively correlated with the development of multidrug resistance and radiation resistance. Because it is differentially expressed in healthy tissues and tumors, it is an attractive therapeutic target. Using the scaffold of UC-112, which was previously identified through virtual screening, we evaluated a series of analogs designed to optimize potency and improve selectivity to survivin over other inhibitor of apoptosis proteins. We identified compound 10f, which was highly cytotoxic to melanoma and Pglycoprotein overexpressing cell lines, induced apoptotic cascades in a concentrationdependent manner, specifically downregulated survivin protein levels, and significantly inhibited tumor growth in vivo. Ultimately, these results validated our in-depth biological investigation of novel scaffolds of survivin inhibitors and verified the anticancer efficacy of 10f

Declining mortality following acute myocardial infarction in the Department of Veterans Affairs Health Care System

<p>Abstract</p> <p>Background</p> <p>Mortality from acute myocardial infarction (AMI) is declining worldwide. We sought to determine if mortality in the Veterans Health Administration (VHA) has also been declining.</p> <p>Methods</p> <p>We calculated 30-day mortality rates between 2004 and 2006 using data from the VHA External Peer Review Program (EPRP), which entails detailed abstraction of records of all patients with AMI. To compare trends within VHA with other systems of care, we estimated relative mortality rates between 2000 and 2005 for all males 65 years and older with a primary diagnosis of AMI using administrative data from the VHA Patient Treatment File and the Medicare Provider Analysis and Review (MedPAR) files.</p> <p>Results</p> <p>Using EPRP data on 11,609 patients, we observed a statistically significant decline in adjusted 30-day mortality following AMI in VHA from 16.3% in 2004 to 13.9% in 2006, a relative decrease of 15% and a decrease in the odds of dying of 10% per year (p = .011). Similar declines were found for in-hospital and 90-day mortality.</p> <p>Based on administrative data on 27,494 VHA patients age 65 years and older and 789,400 Medicare patients, 30-day mortality following AMI declined from 16.0% during 2000-2001 to 15.7% during 2004-June 2005 in VHA and from 16.7% to 15.5% in private sector hospitals. After adjusting for patient characteristics and hospital effects, the overall relative odds of death were similar for VHA and Medicare (odds ratio 1.02, 95% C.I. 0.96-1.08).</p> <p>Conclusion</p> <p>Mortality following AMI within VHA has declined significantly since 2003 at a rate that parallels that in Medicare-funded hospitals.</p

Gene-enhanced tissue engineering for dental hard tissue regeneration: (2) dentin-pulp and periodontal regeneration

Potential applications for gene-based tissue engineering therapies in the oral and maxillofacial complex include the delivery of growth factors for periodontal regeneration, pulp capping/dentin regeneration, and bone grafting of large osseous defects in dental and craniofacial reconstruction. Part 1 reviewed the principals of gene-enhanced tissue engineering and the techniques of introducing DNA into cells. This manuscript will review recent advances in gene-based therapies for dental hard tissue regeneration, specifically as it pertains to dentin regeneration/pulp capping and periodontal regeneration

Research activity as an integral component of engineering education

The international aerospace industry needs to hire specialists who possess a broad range of skills and are able to work independently in a diverse, multi-disciplinary team, generate innovative ideas, solve non-standard problems and make important decisions. To meet new challenges, universities promote active learning and encourage students to participate in research activities. This paper studies the organization of research activities at universities, and factors that benefit their productivity. It also presents the results of a short survey among bachelor students of the Institute of Non-Destructive Testing, Tomsk Polytechnic University, showing their interest and active participation in research work

Harnstoff, Kreatinin, Harnstoff- und Kreatinin-Clearance: Untersuchungen an 25 gesunden Probanden über ein Jahr

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Tubulin Inhibitor-Based Antibody-Drug Conjugates for Cancer Therapy

Antibody-drug conjugates (ADCs) are a class of highly potent biopharmaceutical drugs generated by conjugating cytotoxic drugs with specific monoclonal antibodies through appropriate linkers. Specific antibodies used to guide potent warheads to tumor tissues can effectively reduce undesired side effects of the cytotoxic drugs. An in-depth understanding of antibodies, linkers, conjugation strategies, cytotoxic drugs, and their molecular targets has led to the successful development of several approved ADCs. These ADCs are powerful therapeutics for cancer treatment, enabling wider therapeutic windows, improved pharmacokinetic/pharmacodynamic properties, and enhanced efficacy. Since tubulin inhibitors are one of the most successful cytotoxic drugs in the ADC armamentarium, this review focuses on the progress in tubulin inhibitor-based ADCs, as well as lessons learned from the unsuccessful ADCs containing tubulin inhibitors. This review should be helpful to facilitate future development of new generations of tubulin inhibitor-based ADCs for cancer therapy

Research activity as an integral component of engineering education

The international aerospace industry needs to hire specialists who possess a broad range of skills and are able to work independently in a diverse, multi-disciplinary team, generate innovative ideas, solve non-standard problems and make important decisions. To meet new challenges, universities promote active learning and encourage students to participate in research activities. This paper studies the organization of research activities at universities, and factors that benefit their productivity. It also presents the results of a short survey among bachelor students of the Institute of Non-Destructive Testing, Tomsk Polytechnic University, showing their interest and active participation in research work