Download or read book Molecular Analysis of MDR like Genes and RNA Transcripts in Drug resistant and Drug sensitive Strains of Plasmodium Falciparum written by Michael P. Bogenschutz and published by . This book was released on 1990 with total page 75 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Mechanisms of Drug Resistance in Plasmodium Falciparum written by and published by . This book was released on 1994 with total page 69 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria continues as a major health threat throughout the tropical world and potential demand for antimalarials is higher than for any other medication yet the world faces a crisis--drug resistance is emerging and spreading faster than drugs are being developed and the flow in the pipeline of new drugs has all but stopped. This represents a particular threat to the US military. In a short time there may be parts of the world where no effective antimalarial drug is available. The recent emergence of multidrug resistant malaria parasites has intensified this problem. The goal of this work is to use a molecular genetic approach in the investigation of mechanisms of drug resistance and subsequently to use this information in the identification and development of new antimalarial drugs. These studies were initiated based on the observation that one mechanism of drug resistance in P. falciparum may be similar to multidrug resistance in cancer. During this work, we identified and fully characterized two mdr-like genes in P. falciparum, pfmdrl and pfmdr2 and have found an association with the amplification and over expression of one of these genes, pfmdrl with mefloquine resistance and multidrug resistant parasites both in laboratory derived and field isolated strains of Plasmodium falciparum. As a next step in this work, we have initiated the development methods of functional analysis which are critical both to developing and testing new chemotherapeutic interventions. Malaria, Drug resistance, Recombinant DNA, Tropical disease, Infectious disease.

Download or read book The Harvard MIT Division of Health Sciences and Technology written by Walter H. Abelmann and published by Harvard-Mit Health Sciences. This book was released on 2004 with total page 400 pages. Available in PDF, EPUB and Kindle. Book excerpt: "The present volume was conceived in anticipation of the celebration of the twenty-fifth anniversary of the Harvard-MIT Division of Medical Sciences and Technology in December 1995 to detail the methods, problems, pitfalls, and financial and other experiences in establishing and continuing this unique program, the most enduring collaboration between these two outstanding universities. The volume contains introductory comments by the presidents of both institutions at the time this program was worked out and instituted, as well as historiographic or autobiographical chapters by senior officials of both universities and members of both faculties who helped inaugurate it and steer it through its first quarter century." "This book should prove beneficial to leaders of other educational institutions of higher learning who may be interested in establishing similar or other inter-university, interdepartmental programs."--BOOK JACKET.

Download or read book Genomics and Transcriptomics Approaches to Understanding Drug Resistance Mechanisms in the Malaria Parasite Plasmodium Falciparum written by Justin Allan Gibbons and published by . This book was released on 2019 with total page 184 pages. Available in PDF, EPUB and Kindle. Book excerpt: The malaria parasite Plasmodium falciparum is responsible for about 500,000 deaths a year and is evolving resistance to the front-line treatment of artemisinin-based combination therapy. Resistance is currently confined to South East Asia, however millions of lives will be at risk if resistance spreads to Africa. Understanding the mechanism of resistance to artemisinins would aid containment strategies to prevent the spread of artemisinin resistance. There is also an urgent need to accelerate drug discovery since drug resistance has already been documented to all existing antimalarials. Here, I report on our efforts to understand the function of the gene k13, the gene with the strongest association with artemisinin resistance, and the potential genetic mechanisms associated with resistance to atovaquone, another widely used antimalarial. To precisely study the transcriptome characteristics of an isogenic k13 dysregulation mutant and wild type strain, I developed a new computational algorithm called Dephasing Identifier (DI) that is capable of identifying the genes dysregulated in cell cycle shifts. DI is designed to solve the problem of pinpointing important patterns in complex genomics data with temporal sequences that cannot be resolved by standard pair-wise comparison methods, by using an innovative method that leverages external reference data for systematic comparisons. In the k13 study, I demonstrated that the algorithm identifies co- regulated gene sets that have consistent annotated functions. The DI algorithm successfully identified aberrantly early DNA replication as the driving process of transcriptome changes in the mutant. To understand genome-wide changes that occurred in a set of atovaquone resistance stains, I analyzed whole genome sequencing data previously generated for a P. falciparum strain that underwent in vitro atovaquone selection to create atovaquone resistant strains. I systematically analyzed the genomes of these strains to search for significant genetic changes associated with atovaquone resistance; and used stringent criteria to identify genes involved in regulating transcription and protein modifications as acquiring non- synonymous mutations. Additionally, copy number variations in plasmepsin genes, a family known to be involved in resistance, were found in the resistant strains. In summary, genomics and transcriptomics technologies can be used to rapidly identify resistance mechanisms allowing for faster adjustment of current containment strategies. Future research on the critical targets identified in this study can aid new drug discovery efforts and novel control strategies.

Download or read book Molecular Basis of Drug Design and Resistance written by G. H. Coombs and published by Cambridge University Press. This book was released on 1997 with total page 172 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume is the specially commissioned supplement to the journal Parasitology, volume 114.

Download or read book Malaria written by Institute of Medicine and published by National Academies Press. This book was released on 1991-02-01 with total page 312 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is making a dramatic comeback in the world. The disease is the foremost health challenge in Africa south of the Sahara, and people traveling to malarious areas are at increased risk of malaria-related sickness and death. This book examines the prospects for bringing malaria under control, with specific recommendations for U.S. policy, directions for research and program funding, and appropriate roles for federal and international agencies and the medical and public health communities. The volume reports on the current status of malaria research, prevention, and control efforts worldwide. The authors present study results and commentary on the: Nature, clinical manifestations, diagnosis, and epidemiology of malaria. Biology of the malaria parasite and its vector. Prospects for developing malaria vaccines and improved treatments. Economic, social, and behavioral factors in malaria control.

Download or read book The Harvard MIT Division of Health Services and Technology written by and published by . This book was released on 2004 with total page 402 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Download or read book Transport of Molecules Across Microbial Membranes written by J. K. Broome-Smith and published by Cambridge University Press. This book was released on 1999-10-14 with total page 292 pages. Available in PDF, EPUB and Kindle. Book excerpt: This volume details the transport of molecules, large and small, across the membranes of prokaryotic and eukaryotic microbial cells. An international group of contributors unify a diverse range of phenomena with the discussion of the signal peptides that target proteins to particular destinations, and the role of chaperonins. Topics covered include secretion of proteins out of the bacterial cell by Type I, II, and III mechanisms, including the newly recognized bacterial signal recognition pathway in Type II; passage across internal membranes of eukaryotic proteins, whether destined for secretion or en route to internal organelles such as chloroplasts and peroxisomes; how bacteria obtain energy required for solute uptake; the role of phosphorylation and evolutionary relationships of the proteins involved; and efflux pumps for toxic substances in bacterial, animal, and plant cells.

Download or read book New Drugs and Drug Resistance in Malaria Molecular Genetic Analysis written by and published by . This book was released on 1998 with total page 90 pages. Available in PDF, EPUB and Kindle. Book excerpt: Drug resistance has emerged as a major problem in the treatment of all microbial agents and in many cancer chemotherapies. Drug resistance has become particularly acute in malaria where resistance to chloroquine, the cheapest and most efficacious antimalaria has spread throughout the endemic parts of the world and resistance to other antimalarials is rapidly developing and spreading. The goal of this work is to understand the mechanism of drug resistance and to eventually use that information to develop new aproaches to chemotherapy. The approach we have taken is to develop a method for the functional analysis of genes in the malaria parasite. This methodology has proven invaluable in the analysis of drug resistance in other microbial systems, including our own recent work in leishmaniasis and particularly in multidrug resistance neoplastic cells. The initial aim of this work will be to test the function of genes implicated in drug resistance. This is a multistep process in which we first developed a method for the introduction and transient expression of foreign DNA into the parasite, we then developed a method for the stable introduction of DNA using selectable markers and finally, we have developed methods to test the role of the malaria MDR like genes in drug resistance and in other parasite functions using overexpression and gene knockout by homologous recombination. In parallel, we have continued development of the functional complementation system in yeast in which we are expressing the pfmdrl gene. This system could prove extremely useful in testing drugs as potential resistance reversers.

Download or read book A Novel RCC1 like Protein is a Crucial Regulator of the Intraerythrocytic Cycle of the Human Malaria Parasite Plasmodium Falciparum written by and published by . This book was released on 2015 with total page 58 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria is a deadly infection caused by a single celled protozoan of the Plasmodium genus. Plasmodium spp. are transmitted to humans by mosquitoes, and initially invade the liver, but the disease is caused by the blood stage of the infection. Approximately 500 million cases of malaria are documented annually and over 1 million of those result in death. Plasmodium falciparum is the most lethal of five species known to infect humans. To further compound this problem, drug-resistant parasite strains have been documented for every currently available antimalarial drug, making the need to identify new drug targets more urgent than ever. Modern genetics have found that more than 50% of the Plasmodium genome codes for proteins of unknown functions, with no significant sequence homology to any known eukaryotic genes. Recent advances in forward genetics and the use of transposable elements to manipulate the genome of P. falciparum have made tremendous contributions to discovering the functions of these unknown genes, which is critical to rapidly advance antimalarial drug development. In this study we have identified a gene of unknown function, PF3D7_1143500, that is significant for intraerythrocytic development of Plasmodium. This gene exhibits weak similarities to the human regulator of chromatin condensation 1 protein (RCC1) and appears to belong to the class of RCC1-like proteins that perform diverse functions in eukaryotes. A thorough cellular and molecular analysis of an insertional knockout mutant of PF3D7_1143500 in P. falciparum has revealed a critical role for this gene in the production of merozoites during the intraerythrocytic cycle. The insertional mutant parasite strain displays a significant delay in initiating nuclear division, which results in a 40% reduction in the number of merozoites produced at the end of the intraerythrocytic cycle, thereby severely attenuating the parasite growth rate. PF3D7_1143500 localizes to the microtubule organization centers within the nucleus during the early stages of parasite development, suggesting it functions in regulating mitosis. Since cell cycle regulatory mechanisms are largely unknown in Plasmodium, the identification of this novel RCC1-like protein promises to offer new insights into this critical biological pathway that has high potential as an antimalarial drug target.

Download or read book Biochemical Protozoology As A Basis For Drug Design written by Graham H. Coombs and published by CRC Press. This book was released on 1991-10-07 with total page 656 pages. Available in PDF, EPUB and Kindle. Book excerpt: A compilation of articles on protozoological biochemistry which reviews the subject area and offers information on current research. Included in the Topics Covered Are Energy Metabolism Of Anaerobic Parasitic Protists, proteinases of African

Download or read book Treatment and Prevention of Malaria written by Henry M. Staines and published by Springer Science & Business Media. This book was released on 2012-01-06 with total page 318 pages. Available in PDF, EPUB and Kindle. Book excerpt: Malaria has defeated previous efforts at eradication and remains a massive global public health problem despite being readily preventable and treatable. It is a devastating disease that also extracts huge economic costs from the poorest countries in endemic regions. Starting with an overview of the disease and its current political, financial and technical context, this Milestones in Drug Therapy volume describes the history, chemistry, mechanisms of action and resistance, preclinical and clinical use, pharmacokinetics and safety and tolerability of the current range of antimalarial drugs. There is particular emphasis on artemisinins and related peroxides, as these drugs have now become the frontline treatment for malaria. Next generation antimalarials, molecular markers for detecting resistance, the importance of diagnostics and disease prevention are also covered in detail.

Download or read book Characterization of Plasmodium Falciparum Resistance to Novel Drugs written by Sonia Edayé and published by . This book was released on 2015 with total page pages. Available in PDF, EPUB and Kindle. Book excerpt: "Plasmodium falciparum is the deadly protozoan parasite responsible for malaria. Malaria is one of the most important infectious diseases that has been raging for millennia and affecting almost half of the world's population. The treatment regimen that was based on quinoline drugs such as chloroquine (CQ), was efficient for decades. Nowadays, the use of this class of drugs is doomed to failure due to the emergence of quinoline-resistant parasites. Today, artemisinin-based combination therapies (ACTs) are the first-line drugs for uncomplicated falciparum malaria treatment. ACTs improve the cure rate of malaria and thus are seen as efficient treatment against uncomplicated forms of the disease. Despite their efficiency, these drugs are currently facing the development of resistance. PfCRT and PfMDR1, which are membrane transporters, have been shown to be involved in malaria parasites drug resistance. To tackle the inefficiency of existing drugs in regard to the development of resistance, alternative therapies must be discovered. In this thesis, antimalarial activity of novel potential drugs against P. falciparum is assessed and the interaction of these drugs with PfCRT and PfMDR1 is determined. Furthermore, because many ABC transporter genes play a key role in drug resistance, the characterization of an ABC transporter member of the ABCG family in Plasmodium is addressed and its role in drug resistance investigated.In the first part of this thesis, MK571 (a quinoline analogue) activity against P. falciparum parasites is investigated. MK571 is found to be more toxic to most of the CQ-resistant strains than to the CQ-sensitive strains. In addition, we determine that MK571 is not a substrate of PfCRT as are other quinoline drugs, but is instead a substrate of PfMDR1. Therefore, it can be a good complement to existing quinoline drugs in the treatment of uncomplicated malaria. In the second part, novel compound analogues of chloroquine are tested for their antimalarial activity against CQ-sensitive and -resistant parasites. Although chloroquine analogues tested possess the quinoline ring structure of chloroquine, they are less efficient than chloroquine and are not substrates of PfCRT. One of the analogues (3-ICQ) reverses the resistance of CQ-resistant strains to chloroquine and therefore, could be used in combination with chloroquine in cases of CQ-resistant malaria. In the third part of the thesis we conduct the characterization of PfABCG, the sole member of the P. falciparum ABCG family. The characterization study demonstrates that PfABCG is localized on the parasite plasma membrane and is expressed throughout the asexual life cycle of the parasite. In addition, PfABCG is differentially expressed in various Plasmodium strains. This expression does not correlate with the resistance to chloroquine but to the sensitivity of the parasite to an antihistaminic drug named ketotifen. Overall, this thesis sheds light on challenges and understanding of the complex resistance machinery deployed by the P. falciparum parasite from novel drug discovery to characterization of proteins. " --

Download or read book Malaria Drugs Disease and Post genomic Biology written by David Sullivan and published by Springer Science & Business Media. This book was released on 2006-01-09 with total page 447 pages. Available in PDF, EPUB and Kindle. Book excerpt: Despite rapid increases in knowledge, malaria continues to kill more than a million people each year and causes symptomatic disease in a further 300 million individuals. This volume brings some of the world's best investigators to describe recent advances in both the scientific and clinical aspects of malaria, and bridges between the two.

Download or read book Multi Drug Resistance in Cancer written by Jun Zhou and published by Humana Press. This book was released on 2012-08-09 with total page 492 pages. Available in PDF, EPUB and Kindle. Book excerpt: Chemotherapy is one of the major treatment options for cancer patients; however, the efficacy of chemotherapeutic management of cancer is severely limited by multidrug resistance, in that cancer cells become simultaneously resistant to many structurally and mechanistically unrelated drugs. In the past three decades, a number of mechanisms by which cancer cells acquire multidrug resistance have been discovered. In addition, the development of agents or strategies to overcome resistance has been the subject of intense study. This book contains comprehensive and up-to-date reviews of multidrug resistance mechanisms, from over-expression of ATP-binding cassette drug transporters such as P-glycoprotein, multidrug resistance-associated proteins, and breast cancer resistance p- tein to the drug ratio-dependent antagonism and the paradigm of cancer stem cells. The book also includes strategies to overcome multidrug resistance, from the development of compounds that inhibit drug transporter function to the modulation of transporter expression. In addition, this book contains techniques for the detection and imaging of drug transporters, methods for the investigation of drug resistance in animal models, and strategies to evaluate the efficacy of resistance reversal agents. The book intends to provide a state-of-the-art collection of reviews and methods for both basic and clinician investigators who are interested in cancer multidrug resistance mechanisms and reversal strategies. Tianjin, China Jun Zhou v Contents Preface. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix 1 Multidrug Resistance in Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 Bruce C. Baguley 2 Multidrug Resistance in Oncology and Beyond: From Imaging of Drug Efflux Pumps to Cellular Drug Targets . . . . . . . . . . . . . . . . . . . . . . . . . .

Download or read book Antimicrobial Resistance written by Donald L. Jungkind and published by Springer Science & Business Media. This book was released on 2013-06-29 with total page 247 pages. Available in PDF, EPUB and Kindle. Book excerpt: Development and Implications of Antimicrobial Resistance One of the most ominous trends in the field of antimicrobial chemotherapy over the past decade has been the increasing pace of development of antimicrobial resistance among microbial pathogens. The hypothesis that man can discover a magic bullet to always cure a particular infection has proved false. Physicians are now seeing and treating patients for which there are few therapeutic alternatives, and in some cases, none at all. Until recently there was little concern that physicians might be losing the war in our ability to compete with the evolving resistance patterns of microbial pathogens. Now the general public is very aware of the threat to them if they become infected, thanks to cover story articles in major magazines such as Time, Newsweek, newspapers, and other news sources. Antimicrobial resistance is not a novel problem. Shortly after the widespread introduction of penicillin in the early 1940s, the first strains of penicillin-resistant staphylococci were described. Today it is an uncommon event for a clinical laboratory to isolate an S. aureus that is sensitive to penicillin. Other gram-positive strains of bacteria have become resistant, including the exquisitely sensitive Streptococcus pneumoniae. Sensitivity to vancomycin was once so uniform that it was used in routine clinical laboratories as a surrogate marker for whether an organism should be classified as a gram-positive. That criterion can no longer be relied upon because of emerging resistance among some species. Gram-negative bacteria, viruses, fungi, and parasites all have succeeded in developing resistance.

Download or read book Cumulated Index Medicus written by and published by . This book was released on 1997 with total page 1860 pages. Available in PDF, EPUB and Kindle. Book excerpt: