Title: The Challenge of Crafting a Drug Resistance Dissertation
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Drug resistance, a critical issue in the field of medicine, presents researchers with a myriad of challenges. As scholars endeavor to explore the mechanisms underlying resistance, analyze data, and draw meaningful conclusions, they often find themselves grappling with the sheer volume of information available. The complexity of the subject matter, combined with the need for meticulous research, makes crafting a drug resistance dissertation a formidable undertaking.
One of the primary challenges faced by researchers is the need for a deep understanding of the molecular and genetic aspects of drug resistance. Examining the intricate mechanisms that allow microorganisms or cancer cells to evade the effects of pharmaceutical interventions requires a nuanced understanding of biology and pharmacology.
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Cancer stem cells may have a relatively low rate of cell proliferation, like stem cells in normal human bone marrow (see Chap. 12, Sec. 12.1.3 ); their proliferative state will determine, in part, their sensitivity to cell-cycle active drugs. Many studies in various types of cancer have shown that increased expression of either of these transporters in tumor cells confers poor clinical outcomes. In this regards, we hereby invite you to submit your next manuscript related to this thematic special issue to publish in Journal of PeerScientist and take full advantage of. On the other hand, CYP1A1 and CYP1A2 metabolize procarcinogens into carcinogenic forms in the liver, and most anticancer drugs are metabolized by this method. For instance, apoptosis is promoted by the tumor suppressor protein p53 ( TP53 ), in response to chemotherapy. CSCs are localized in a specific microenvironment referred to as the niche, which is formed by a variety of cells that promote CSC survival and enhance their characteristics. For example, certain anticancer drugs target topoisomerase II, an enzyme that prevents DNA from becoming super- or under-coiled. There is growing interest in the role of autophagy in tumor development and response to cancer therapy (see Chap. 12, Sec. 12.3.7). Autophagy is a lysosomal degradation pathway for intracellular digestion of cellular macromolecules that maintains cellular metabolism in times of stress such as exposure to hypoxia or to cytotoxic drugs. Lastly, we conclude with a discussion on the emerging topic of epigenetics how it contributes to drug resistance in cancer and its possible role in the development of cancer progenitor cells which are not killed by conventional cancer therapies. One method is to change the “fractionation” and to give lower doses of drugs more frequently or continuously Presentacion plegable 1 Presentacion plegable 1 Leslie M. Similarly, multiple myeloma cells with increased expression of ABCB1 in cell-surface, that was identified by the actively efflux of CDy1 dye identifying a subpopulation of CSCs, exhibited resistance to carfilzomib. Michael Craig - Updates from the CDC Michael Craig - Updates from the CDC Hospital Antibiotic Stewardship ProgramsQualitative analysis of numerous h. Understanding the way microbes are changing around the world will make it easier to develop drugs that will be effective against them. For acute localized infections or in healthy patients, symptom. Epigenetic mechanisms can also influence DNA damage repair. Rapid proliferation of surviving tumor cells (ie, repopulation) between courses of chemotherapy can counter the effects of cell killing and lead to effective resistance. B) Domain organization of ABC transporter drug (and drug metabolite) efflux pumps implicated in drug resistance in malignant cells. Keep on browsing if you are OK with that, or find out how to manage cookies. In contrast, the selection of genetically stable drug-resistant mutant cells in experimental systems is often difficult, and typically requires much higher selection pressures (eg, prolonged exposure to mutagens, higher doses, and longer duration of exposure to anticancer drugs) than may occur during the treatment of human tumors. ABC transporters are transmembrane proteins present not only in human cells, but in all extant phyla, functioning to transport a variety of substances across cellular membranes. Any mutation in their genome that reduces the rate at which drugs eliminate them from the host. In general, tamoxifen-resistant tumors showed denser ER. Once inside the tumor, the macrophages are activated by factors such as IL4 and transformed into TAMs. IL4 also plays an essential role in wound healing. For example, elevated levels of the excision repair cross-complementation group 1 (ERCC1) enzyme, which plays a rate-limiting role in the NER pathway, has been correlated with increased responsiveness to cisplatin-based adjuvant therapy in lung cancer patients (Olaussen et al, 2006). Upper panel, the DNA repair enzyme MGMT causes resistance by removing toxic adducts from the O 6 position of guanine in native DNA. CSCs appear to utilize these mechanisms against anti-cancer therapies. Journal of Manufacturing and Materials Processing (JMMP). Several factors during EMT play significant roles in the development of drug resistance, but these are dependent on the metastatic grade of the tumor, which is defined as the level of differentiation and degree of EMT. The conclusions are justified based on the results presented in the studies.
AMeta-Analysis of Project DARE Outcome Evaluations is Drug Abuse Resistance Education (DARE’s) core curriculum that is offered to pupils in the last grades of elementary school. These drugs may be classified according to where they bind: the Vinca alkaloids bind to the ends of microtubules, while taxanes bind along the interior surface of the microtubules (Dumontet and Jordan, 2010; see Chap. 18, Sec. 18.5 ). The mechanisms underlying resistance to the microtubuledestabilizing Vinca alkaloids vincristine and vinblastine, and the microtubule-stabilizing taxanes (eg, paclitaxel) are not fully understood. Dr. Tom Shryock - Role of the Presidential Advisory Council on Combating Anti. The disease is transmitted similarly to dengue fever to humans by virus-carrying Aedes. The normal cellular locus of ABCC1 is chromosome 16p13.1. However, in many drug-resistant cell lines where expression of MRP1 is elevated, ABCC1 has been amplified. Finally, once the DNA has been modified, a resistant cell could. The spectrum of drugs that MRP1 transports is slightly different from P-glycoprotein in that MRP1 confers at most low levels of resistance to the hydrophobic paclitaxel and vinblastine. Osteogenesis Imperfecta ( Oi ) Is An Inherited Disorder. Later, if such organisms resynthesize their cell walls, they are fully susceptible to these drugs. Clinicians will be able to treat a patient for their specific infectious disease. Here, we review the recent advances in the study of CSCs, the niche and especially their collective contribution to resistance, since increasingly studies suggest that this interaction should be considered as a target for therapeutic strategies. Many studies in various types of cancer have shown that increased expression of either of these transporters in tumor cells confers poor clinical outcomes. Factors other than genetically determined mechanisms of resistance can lead to clinical resistance of human tumors to anticancer drugs (Sharma et al, 2010). Types of cell death that have been observed following treatment with anticancer drugs include apoptosis, necrosis, mitotic catastrophe, and senescence, whereas autophagy may act (paradoxically) to enhance either death or survival of the cell. Apoptosis has two established pathways: an intrinsic pathway mediated by the mitochondria that involves B-cell lymphoma 2 (BCL-2) family proteins, caspase-9 and Akt, and an extrinsic pathway that involves death receptors on the cell surface. This vasculature plays a key role in the tumor microenvironment because it supplies the tumor with oxygen and nutrients. However, there is emerging evidence that such cells may be more resistant to chemotherapy than other cell populations in the tumor and therefore may selectively survive during drug treatment (Dean et al, 2005; Eyler and Rich, 2008). Novel agents that inhibit the transport function of P-glycoprotein (as well as MRP1, MRP2, MRP4, and ABCG2) are also being investigated for their ability to improve oral absorption of antineoplastic drugs or enable better penetration of drugs into pharmacological sanctuaries (eg, the central nervous system), tissues that are normally protected by these transporters (Leslie et al, 2005; Matsson et al, 2009). Microtubule-associated proteins (eg, tau) can bind to and stabilize microtubules against depolymerization. Most resistance plasmids have two sets of genes: (1) resistance transfer genes that encode the sex pilus and other proteins that mediate transfer of the plasmid DNA during conjugation, and (2) drug resistance genes that encode the proteins that mediate drug resistance. Policy recommendations for improved medication adherence in Europe: the ABC P. Journal of Functional Morphology and Kinesiology (JFMK). Because SCs maintain the pool of cells in an organism, it is biologically essential to keep and protect these SCs. CAFs also promoted the stemness of CSCs in other types of cancer, including gastric and breast. It can also react with positively charged electrophilic molecules, such as the active groups of cisplatin and alkylating agents, rendering them less toxic and more easily excreted. Analyses of the topoisomerase I crystal structure indicate that this region is important for hydrogen bonding to camptothecin and it is close to the catalytic tyrosine residue and the bound DNA (Urasaki et al, 2001). Osteogenesis Imperfecta ( Oi ) Is An Inherited Disorder. Other substrates include the tyrosine kinase inhibitors gefitinib and imatinib (see Chap. 17, Sec. 17.3.1 ). P-glycoprotein also mediates the cellular efflux of other drugs used with cancer chemotherapy, such as ondansetron and granisetron, that are used to control emesis. Cancer progenitor cells are not killed by conventional cancer therapies and are a major cause of cancer relapse. The cysteinyl leukotriene receptor antagonist MK-571 was identified as a relatively potent inhibitor of MRP1-mediated transport, but suffers from a lack of specificity.
We also consider how the cell heterogeneity inherent in cancerous tumors is involved in the development of drug resistance. Report this Document Download now Save Save Study of Drug Resistance in Bacteria Using Antibio. Similarly, exposure of these mice with Brca1 -associated breast cancer to the topoisomerase I inhibitor topotecan resulted in drug resistance caused by reduced levels of the topoisomerase I drug target and increased expression of the Abcg2 drug efflux pump rather than changes in markers of apoptosis (Zander et al, 2010). The cells within the tumor are considered an ecosystem in which spontaneous mutations and epigenetic changes may confer cells with greater fitness for a specific tumor microenvironment; likewise, the fittest clone will repopulate the tumor after a treatment One method is to change the “fractionation” and to give lower doses of drugs more frequently or continuously. Human breast cancer cells can also exhibit drug resistance via epigenetic mechanisms. For example, methotrexate resistance in MDA-MB-231 breast cancer cells is caused by an inherent defect in drug uptake and a lack of reduced folate carrier (RFC) expression. Homology models of P-glycoprotein, MRP4 and other ABC transporters look very similar. International Journal of Clinical Practice, 2018, 72(3): e13060. Prieto-Vila, M.; Takahashi, R.-u.; Usuba, W.; Kohama, I.; Ochiya, T. Rapid spread of resistance can occur by this mechanism and. In many cases, treatment with chemotherapy such as cisplatin induced apoptosis resistance. Theoretically, a combination of epigenetic drugs with conventional chemotherapy should be more effective in treating tumors and drug resistant cancers. The role of methylation in regulating MGMT is further discussed in the epigenetics section. 2.5. Cell Death Inhibition Cell death by apoptosis and autophagy are two important regulatory events. Stromal cells and cancer cells also secrete factors that regulate EMT. Although these processes are antagonistic to one another, they both contribute to cell death. Thus, besides directly targeting CSCs, simultaneously attacking their microenvironment is a very promising novel strategy. Thus, cancer progenitor cells can cause cancer relapse at the original tumor site or in distant organs. This treatment is currently available in clinical trials and will likely lead the way in the development of effective therapies. These studies have led to the characterization of multiple mechanisms of drug resistance, described in previous sections, many of which are relevant to human cancer. Class I is composed of CYP1A1, CYP1A2, CYP2E1, and CYP3A4, which are well conserved, do not have important functional polymorphisms, and are active in the metabolism of drugs and procarcinogens. MRP1 has been detected in a wide variety of human tumors and normal tissues (Deeley et al, 2006). Several strategies might be used to either modify or complement the distribution of anticancer drugs in solid tumors to improve therapeutic efficacy (Tredan et al, 2007). Journal of Cardiovascular Development and Disease (JCDD). Early Tech Adoption: Foolish or Pragmatic? - 17th ISACA South Florida WOW Con. The disease is transmitted similarly to dengue fever to humans by virus-carrying Aedes. These results are commonly reported as the minimal inhibitory concentration (MIC), which is defined as the lowest concentration of drug that inhibits the growth of the organism. It also had toxicity to normal tissue (Rischin et al, 2010). Not surprisingly, ABC transporters are highly expressed in the epithelium of the liver and intestine, where the proteins protect the body by pumping drugs and other harmful molecules into the bile duct and intestinal lumen. Genevieve Housman, Sarah Heerboth, Karolina Lapinska, Mckenna Longacre, and Nicole Snyder were supported by UROP at BU. As for ionizing radiation, the toxicity of some drugs is dependent on the production of free radicals, and this process depends on availability of oxygen.
The cytosolic GSTs are a highly polymorphic multigene family of enzymes that are often classified by their isoelectric points, as well as by their relative sequence homology: the major classes are the basic (. Stochastic model: This model is based on the postulate of Charles Darwin as described in his book “The Origin of Species” , in which the fittest organism is best suited to survive These interactions can modify, partially degrade, or complex the drug with other molecules or proteins, ultimately leading to its activation. For example, staphylococcal penicillinase is inducible by penicillin and is secreted into the medium. Several strategies might be used to either modify or complement the distribution of anticancer drugs in solid tumors to improve therapeutic efficacy (Tredan et al, 2007). Disease Antibiotic resistance threats in the United States, 2013. Apr. The small R factors are not conjugative and contain only the resistance genes. Few studies have assessed the rate of repopulation of human tumors following chemotherapy. All articles published by MDPI are made immediately available worldwide under an open access license. No special. Eg. Enzymatic deactivation of penicillin G in some penicillin resistant. The human ABC superfamily contains 48 proteins, which are organized into 7 subfamilies ( A through G ) based on the relative similarities of their amino acid sequences (Dean and Allikmets, 2001). Another example for CSC-targeting therapies in vitro and xenografted human cancers is salinomycin, a polyether ionophore antibiotic that is isolated from Streptomyces albus. This difference is one of the reasons why some patients are more responsive to treatments than the other. In this last study, epigenetic drug treatment resulted in the re-expression of RGS10, an important regulator of cell survival and chemoresistance in ovarian cancer. Then, the PCR products are immobilized on a strip, and detection is achieved via a colorimetric reaction. This treatment is currently available in clinical trials and will likely lead the way in the development of effective therapies. ELISA assay to measure chikungunya-specific IgM levels. ALL the evidence webinar: Appraising and using evidence about community conte. One set encodes the enzymes that degrade or modify drugs, and the other encodes the proteins that mediate conjugation, the main process by which resistance genes are transferred from one bacterium to another. Epigenetic alteration of MGMT expression has been associated with a modified chromatin configuration. This possibility exists in all forms of cancer, as all tumors are heterogeneous, due to aberrant DNA repair mechanisms and cell death pathway dysregulation. DNA damage caused by chemotherapeutic agents can cause a delay in cell-cycle progression in order to allow time for the damage to be repaired. The leading cause of treatment failure is cancer cells resistance to drug treatment, which leads to tumor recurrence and metastasis. Increased expression has been observed in several types of drug-resistant human tumors, such as lung cancer and some leukemias, and in many cell lines derived from human tumors. It is often impossible to determine whether a cancer cell is intrinsically drug-resistant before beginning treatment. Anti microbial program nepal Anti microbial program nepal 2018: FIND AMR Strategy 2018: FIND AMR Strategy Recently uploaded Dental Hygiene Library session Searching - 2nd class Dental Hygiene Library session Searching2nd class HVCClibrary Report Back from San Antonio Breast Cancer Symposium (SABCS) 2023: Spotlight. This effect may help to explain why the presence of hypoxia in tumors is a poor prognostic factor after all types of management (including surgery). In vitro studies show that single amino acid substitutions can markedly alter the substrate specificity of P-glycoprotein (Loo and Clarke, 2005). Transport of drug metabolites, including those conjugated to glutathione (GS-X), glucuronide (Gluc-X), and sulphate (SO 4 -X) (right) by MRP1 (and MRP2) usually does not require GSH. The current paradigm suggests that a combination of environmental and genetic changes, such as random mutations, increased signaling processes, stromal influences, hormonal imbalances, and germ-line mutations make adult and stem cells susceptible to progenitor cell formation.
It also had toxicity to normal tissue (Rischin et al, 2010). For Later 75% (4) 75% found this document useful (4 votes) 3K views 10 pages Study of Drug Resistance in Bacteria Using Antibioti Uploaded by Ashwin Rockzz Study of Drug Resistance in Bacteria Using Antibiotics investigatory Project for class 12 CBSE Full description Save Save Study of Drug Resistance in Bacteria Using Antibio. Cure or long-term remission of tumors may be governed by a small population of cells with high proliferative potential (although not necessarily high proliferative rate), so called tumor stem cells (see Chap. 13, Sec. 13.4 ), and it is the sensitivity of these cells that may ultimately determine success of chemotherapy. Additionally, higher expression of metalloproteases on the surface of tumors helps to clear the road for the cells to move outward, promoting metastasis. Thus, cancer progenitor cells can cause cancer relapse at the original tumor site or in distant organs. The ABCC1 gene is located on chromosome 16p13.1 and encodes a 190-kDa phosphoglycoprotein with 17 transmembrane a -helices, 5 more than P-glycoprotein. Each of the MSDs contains 6 transmembrane segments (a-helices) except for MSD0 of MRP1 and MRP2 which contains just 5. Nongenetic changes, which are of lesser importance, are discussed on page 90. World Journal of Gastroenterology, 2017, 23(25): 4654-4660. Also, the presence of foreign bodies makes successful antibiotic treatment more difficult. Abstract 206. Sarkar, S.; Goldgar, S.; Byler, S.; Rosenthal, S.; Heerboth, S. Demethylation and re-expression of epigenetically silenced tumor suppressor genes: Sensitization of cancer cells by combination therapy. Cancer stem cells may have a relatively low rate of cell proliferation, like stem cells in normal human bone marrow (see Chap. 12, Sec. 12.1.3 ); their proliferative state will determine, in part, their sensitivity to cell-cycle active drugs. Many chemotherapeutic agents cause a variety of toxic DNA lesions that lead to cell death unless the damage is repaired. Stained cells were abundant in the telencephalon, both in the. Agents that modify the stromal cells or extracellular matrix may also improve drug distribution. Although drug resistance in many cultured tumor cell lines is caused by gene mutation or amplification, the relevance of these mechanisms to clinical drug treatments is variable. Hypoxia is involved in drug resistance mainly by two systems: Stem-related pathway activation and quiescence promotion. How elevated ?III-tubulin mediates resistance and enhances cell survival is complex, but this tubulin subunit helps to protect cells against the genotoxic stress induced by cytotoxic drugs. For example, Tuveson et al have generated a genetically engineered mouse model of human pancreatic cancer that has dense stromal tissue, poor vascular perfusion, high interstitial fluid pressure, and resistance to chemotherapy, similar to human pancreatic cancer (Olive et al, 2009). Drugs that require active transport into cells are dependent on ATP, and anaerobic metabolism is much less efficient than oxidative phosphorylation in producing ATP. Three transporters multidrug resistance protein 1 (MDR1), multidrug resistanceassociated protein 1 (MRP1), and breast cancer resistance protein (BCRP) are implicated in many drug resistant cancers. Is it possible to prevent or delay the spread of anti-malaria drug resistance. Higher expression of the MDR1 gene could be one mechanism by which they acquire drug resistance. The proapoptotic and antiapoptotic members of the bcl-2 family, the kinases and phosphatases that regulate their activity and subcellular localization, the initiator and effector caspases, the various inhibitors of apoptosis proteins (IAPs), as well as the presence of wild-type or mutant p53, are all examples of proteins that might influence the sensitivity of tumor cells to apoptotic cell death (Brown and Attardi, 2005). Note that although these bacteria are resistant to other drugs as well, for simplicity, only the most characteristic drugs are listed. For instance, apoptosis is promoted by the tumor suppressor protein p53 ( TP53 ), in response to chemotherapy. It is often impossible to determine whether a cancer cell is intrinsically drug-resistant before beginning treatment. All authors participated in writing and editing the manuscript. The therapeutic potential of targeting DDR mechanisms is especially exciting due to the prevalent dependence of cancers on a compensatory repair mechanism. Response of lung cancer patients to the EGFR-targeted tyrosine kinase inhibitors erlotinib and gefitinib occurs in a subset of patients whose tumors have amplification of or mutations in the kinase domain of the EGFR gene (Gazdar, 2009).
