Acute Myeloid Leukemia: Causes and Treatment Strategies

Acute myeloid Leukemia Causes and knock over-and-take StrategiesPathologyAcute myeloid leukemia is a disease that primarily afflicts adults. The desireliness of being diagnosed with AML increases with age the median age of diagnosis is 65 with very few fictional characters reported in those under the age of 40 4. several(prenominal)(prenominal) seek occurrenceors set rough been familiard with increased incidence of AML including Li-Fraumeni disease, Klinefelters syndrome, radiation exposure, chemotherapy, and chemicals (benzene, herbicides, etc) (See ancillary figure S.1) 4. However, the initiation of AML is a multistep summons and fuel be the burden many distinct heritable aberrations 45. Therefore, the aforementi cardinal(a)d risk factors do non account for each(prenominal) cases of AML 4.Acute myelogenous leukemia is the result of onco element-driven accumulation of immature myeloblasts deep down the bone marrow 5. Myeloblasts atomic number 18 progenitor cel lular telephones, which impart ultimately accommodate rise to neutrophils, basophils, eosinophils, and mast cells (collectively cognise as the granulocytes) 6. In AML, the genes that govern proper distinctiation of myeloblasts into one of the aforementioned cell types argon mutated. This prevents differentiation and leads to a buildup of myeloblasts inwardly the marrow 5. The clinical consequences of myeloblast buildup are marrow failure leading to grim white-blood cell count, low red-blood cell count, and insufficient levels of clotting factors 5. Therefore, clinical symptoms are depressed immune function, anemia, and continued hemorrhaging.The molecular pathogenesis of AML (and all pubic louses) begins with the acquisition of genetic abnormalities. There are twain illustrations that describe how these acquisitions arise. The conventional case of providecer cell initiation proposes that the cell gradually acquires certain mutations to genes involved in mitotic signal ing (KRAS or APC) and tumour suppression (P53), in that respectby allowing the cell to set off uncontrollably 7. However, Recent work by Stephens et al. 8 take the standed that multiple mutations mountainister be generate in a one off event by the random shattering and re-ligation of one or much chromo or sos 8. They termed this event Chromothripsis 8. Chromothripsis results in massive translocations and changes to copy number state, but is distinct from the conventional model of cancer cell initiation by the presence of large-scale inter-chromosomal rearrangements 8. Thus, the chromothripsis model differs from its conventional counter trigger in the time taken for the cell to go across malignancy and the scale to which the genome is altered.Chromothripsis is observed in a portion of AML cases Rausch et al. 9 strand nearly half of the AML cohort showed chromosomal rearrangements logical with chromothripsis 9. This shows that, accumulation of the inevitable mutations that drive AML whitethorn sink by more(prenominal) than one weapon.By every mechanism of AML initiation, myeloblasts lose the top executive to differentiate. The molecular pathogenesis commonly shows two frequent chromosomal aberrations a translocation amongst chromosome 8 and 21, and an inversion of chromosome 16 5. These changes affect two genes crucial for myeloid differentiation (CBF1 and CBF1) 5. The effect of the inversion and translocation results in a gene chimera, which is translated into a protein that interferes with proper CBF1 and CBF1 function 5. However, these limited chromosomal alterations are non observed in every case of AML. deoxyribonucleic acid- impose on _or_ oppress inducing agents like radiation or certain chemicals, may condition aberrations to chromosome 5 and 7, which has also been implicated in the initiation of AML 5. This shows that there are several factors involved in proper myeloid differentiation and that birth control device to any of th em may result in AML.Visual differentiation of legal myeloblasts from leukemic myeloblasts can be challenging. Myeloblasts should contain 3 5 nucleoli, which are in effect(p) of uncondensed chromatin 6. virtually leukemic myeloblasts may show more than 3 5 nucleoli 5. Also, they do not normally contain granules, however, leukemic myeloblasts may amaze granules, which can serve as a potential marker for diagnosis 5. It is core(a) to stress that these morphological changes may not appear in all cases of AML. Therefore, prognosis is confirmed by the presence of greater than 20% myeloblasts in bone marrow biopsy 5. manipulationThere are different avenues for treating AML. Treatment may include supportive care (in innovative cases), chemotherapy, and stem cell transplantation. However, chemotherapy is the most common and effective method of intercession 3. When medicinal chemists began single expose antibiotics produced from bacteria in search of potential leads for drug desi gn, Aurelio Di Marco and his research team up discovered a newfound species of bacteria, Streptomyces peucetius, in spite of appearance a soil sampling they obtained from an area near Bari, Italy 1011. This new strain of bacteria was produced a obscure that was efficacious as a chemotherapeutic agent against many tumors the coalesce was later named daunorubicin and is now con typefacered a key intervention administered to diligents with AML 12. Daunorubicin and doxorubicin are part of the class of antibiotics collectively known as the anthracyclines.Anthracyclines can cause cytotoxicity by different mechanisms depending on their intracellular assimilation. As re suasioned by Gerwitz 13, in vitro studies show there are several possible mechanisms for the anti-tumor effects of these agents including Inhibition of deoxyribonucleic acid synthesis, free radical generation leading to either desoxyribonucleic acid damage or lipid peroxidation, inhibition of deoxyribonucleic acid t opoisomerase resulting in helix super-coiling, desoxyribonucleic acid alkylation, and DNA cross-linking 13. The induction of apoptosis was also mentioned as a mechanism of cytotoxicity, but it is likely that apoptosis is a byproduct of the aforementioned cellular stresses, kinda than a direct consequence of anthracycline exposure 13. It is important to blood that these mechanisms were observed in vitro, and that in vitro conditions allow for exposure at niggardnesss that may greatly exceed in vivo concentrations 13.PharmacodynamicsAlthough, daunorubicin and doxorubicin are thought to cause cytotoxicity by several different processes, their ability to bind to DNA and prevent DNA replication or transcription is sum uped to be the primary means of anti-tumor application in vivo 1314. This is because replication is inhibited at anthracycline concentrations that can be reached in vivo following a standard dosage 13. The two anthracyclines appear to add preferentially to regions of DNA with select base-pair composition, specifically, regions with CGATCG sequences 14. Rabanni, Finn, Ausio 15 suggest that intercalation stabilizes hydrogen bonds mingled with the two strands of DNA 15. This means that the energy required to separate the strands is higher, and cannot be achieved by DNA helicase 15. Thus, strand separation is inhibited, preventing DNA replication and tumor cell proliferation.For both(prenominal) compounds, the chromophore portion (DCBA in fig. 1) of the molecule intercalates amid completing guanine-cytosine (GC)base pairs on each side of the DNA double-helix (fig. 2). The compound is stabilise in this position by hydrogen bonds on either side of the molecule. The D side of the molecule is held in position with aid from a solvent atom (believed to be ionic sodium), which forms hydrogen bonds between oxygen 4 and 5 tonitrogen 7 of guanine12 (fig. 2) 14. The A side of either drug is coordinated by hydrogen bonds from oxygen 9 to nitrogens 2 and 3 of guanine 2 (fig. 2) 14. As previously mentioned, all of these interactions occur between both daunorubicin/doxorubicin and C/G DNA sequences. However, the added hydroxyl gathering on C14 of doxorubicin creates an extra association. The hydroxyl appears to shift solvent molecules such that verifying interactions between itself and the phosphate backbone of DNA are created (fig. 3) 14. This added interaction talent explain the slightly higher in vitro affinity constant between doxorubicin-DNA (Ka = 1.610-5) as compared to daunorubicin-DNA (Ka = 1.210-5) (in vitro Ka determination performed at 37C in 10% fetal calf serum) 17.Doxorubicin is more potent than daunorubicin. In the case of anthracycline induced inhibition of DNA strand separation, the potency and efficacy are straightaway related. The increased binding affinity of doxorubicin means that it depart associate with DNA and prevent DNA separation at a lower concentration (See supplementary fig.S2). Therefore, pharmacolo gical factors aside, it will be more potent and will prevent tumor cell proliferation at lower concentrations.SynthesisDoxorubicin is a semi-synthetic analog of daunorubicin. The daunorubicin producing bacteria, Streptomyces peucetius, was mutated to the doxorubicin producing exchangespecies Streptomyces peucetius subsp. caesius 18. This mutated strain was found to carry an oxidizing cytochrome P450 isoform capable of hydroxylating the C14 of daunorubicin 19. The gene that encodes this P450 is called doxA 19. Although, this gene is crucial for doxorubicin production, its presence does not guarantee collectable quantities of doxorubicin (See secondary figure S.2) 20. Enzymes, such as dnrH and dnrX, may further oxidize or reduce the newly formed doxorubicin into other metabolites that do not have antitumor abilities 18. Therefore, in order to make doxorubicin production sustainable, the down mandate of such genes is required to increase doxorubicin yield.PharmacokineticsDespite the ir akin(predicate) molecular structure, daunorubicin and doxorubicin have distinct pharmacokinetic properties. This section will begin by contrasting the differences in voiding, transfiguration, and distribution. Bioavailability will not be contrasted because both of these agents are administered intravenously. The section will therefore conclude with a description of tissue distribution, intracellular distribution, and toxicity. plaqueAs already mentioned, both anthracyclines are administered via intravenous injection 2122. They should not be injected subcutaneously or intramuscularly due to the significant risk of tissue death at and near the injection site 23. The study dosage schedule for both daunorubicin and doxorubicin is dependant on several different factors including age, health, pre-exisiting heart conditions, and renal functioning, therefore exact dosages vary among different patient populations. In terms of daunorubicin, dosage ranges between 30 and 45 mg/m2, wher eas doxorubicin dosages range between 40 and 75 mg/m2 during the initial note of treatment 2425.EliminationBoth compounds are eliminated from the blood plasma via urinary and atrabilious mechanisms 23. However, a much greater proportion of a daunorubicin dose is excreted done the kidneys (14-23%) as compared to doxorubicin (5%), while alarger proportion of doxorubicin was reported to be excreted through the bowels (50%) compared to daunorubicin (40%) 23.Daunorubicin and doxorubicin are considered to be high clearance drugs. They have a similar clearance value of 1-2 L/Kgh 26. The elimination of either drug, along with their metabolites, follows a triphasic decline in plasma concentration 23. After a 60ml/m2 infusion of daunorubicin/doxorubicin, the plasma concentration/time interpret shows that both drugs are eliminated with a similar rate (fig.3) 26. However the Medsafe 23 datasheet for daunorubicin/doxorubicin reports that the plasma T1/2 for the start-off phase averages 45m in daunorubicin and 12min doxorubicin, while the second phase is 18.5hrs daunorubicin, 3.3hrs doxorubicin. metabolismThe primary metabolites of daunorubicin and doxorubicin are daunorubicinol and doxorubicinol respectively. Because of their similar structures, the metabolism of either compound occurs in a likewise fashion. The enzyme most implicated in metabolism is NADPH (nicotinamide-adenine-dinucleotide-phosphate) dependent cytochrome P450 reductase 27. This enzyme reduces the ketone at C13 to an alcohol to produce daunorubicinol and doxorubicinol 28. These two products are believed to retain their cytotoxicity and are cleared from the plasma at a similar rate 2829.another(prenominal) common metabolite for either compound is generated via reducing of the glycosidic bond by gycosidases. Glycosidic reduction results in removal of the amino-sugar that is bonded to C7 28. This reaction eliminates the anti-tumor capabilities of either compound 28. Following removal of the amino-sugar , the remaining aglycone is demethylated and then undergoes phase II metabolism (sulfonation or glucuronidation) 23. chassis II metabolism by sulfonation or glucuronidation increases plasma clearance and enhances elimination. 2 other metabolites are listed in literature, 7-deoxydoxorubincolone and 7-deoxydoxorubinone, however the enzyme or enzymes that facilitate these reactions were not noted 30.Two other enzymes metabolize both daunorubicin and doxorubicin under aerophilic conditions, xanthine dehydrogenase and xanthine oxidase, and produce reduced semiquinones and oxygen radicals 31. These radicals could provide added efficacy to the drug therapy. It has been suggested that advanced stage cancer cells exhibit high oxidative stress and that it may be advantageous to exploit this finding to preferentially and specifically onrush and destroy them 30. Under anaerobic conditions, xanthine dehydrogenase metabolizes doxorubicin to 7- deoxydoxorubicin aglycone, which has been found t o be efficacious in the reduction of the drugs toxicity 31.Volume of DistributionDaunorubicin and doxorubicin focus in the tissues. The Vd for daunorubicin is 39.2 L/Kg, while the Vd for doxorubicin is 24.6 L/Kg 26. This indicates that both compounds have high tissue distribution 26. Although the addition of a hydroxyl crowd at C14 markedly reduces doxorubicins ability to break up into the tissues (relative to daunorubicin), doxorubicin remains within leukemic cells for a longer duration than daunorubicin (fig. 5) 26. Upon administration, daunorubicin accumulates within leukemic cells more rapidly than does doxorubicin (fig 5). This is likely because of the increased polar surface area brought on by the added hydroxyl group of doxorubicin, which hinders its ability to cross membranes. However, the added hydroxyl group provides increased binding affinity to DNA 17. Therefore, it will not make the cell as rapidly because it will remain bound to DNA 26.ToxicityThe clinical use of d oxorubicin and daunorubicin may be limited by their similar inherent toxicity. It goes with expose saying that chemotherapeutics should not be administered to women who are pissed or pregnant due to significant health complications that can be incurred by the infant or fetus, respectively, therefore these drugs should not be considered in these populations 33. The use of these agents in a long-term manner is cautioned due to their ability to cause cardiotoxicity 29. Under aerobic conditions, the semiquinone radical that may be produced during metabolism undergoes redox cycling 27. Accumulation of reaction oxygen species soon occurs and can cause cytotoxicity 27. This is believed to account for tissue death in cardiac cells, and is one of the major implications of using the anthracycline class of anti-tumors agents 27. The cardiotoxicity itself includes effects such as functional damage to mitochrondrial DNA, interference of cytochrome c oxidase, and dysfunctional lipid peroxidatio n 13.Personalised crabmeat Treatment Known Markers in TreatmentPersonalised Cancer Treatment Known Markers in TreatmentPersonalised cancer treatment known markers and what they mean for treatmentContents (Jump to)Known markers and what they mean for treatmentOver enchantdo drugs target markersDiagnostic and prognostic markersMeta descriptionKeywordsCopyscapeKnown markers and what they mean for treatmentOver estimatePersonalised, targeted and hormonal treatments all depend on genetic mutations that can be identified in cancer cells to be effective. These mutations are sometimes referred to as markers. The markers can manifest through over- port, lack of expression or mutated expression of specific proteins.Some markers can be targeted using specific treatments whereas some can act as measurements for disease diagnosis, prognosis and treatment response. drug target markersThe genes listed below have all been associated in cancer, the majority of which can also be treated.(*) Target able genes and proteins that can also be measured to set apart treatment response, cancer diagnosis and prognosis.Diagnostic and prognostic markersThe following markers are all related to diagnosis, prognosis and treatment progress.Meta descriptionCancer markers can help with the diagnosis and treatment of cancer and can give rile to targeted therapies.KeywordsCancer markers, genetic markers, diagnostic markers, drug target markersCopyscapeChecked family 2014CIGNPOST KNOWN MARKERS AND WHAT THEY MEAN FOR TREATMENT Cignpost Ltd 2014PAGE 1EB1If these are genes not proteins then they should be in italics mental science Christianity Five Views Eric L. fannysonPsychology Christianity Five Views Eric L. Johnson refresh of Psychology Christianity- Five Views by Eric L. Johnson.Title Psychology Christianity Five Views agent Eric L. JohnsonPublisher InterVarsity Press. (U.S.A.) 2000Price 14.37ISBN 978-0-8308-2848-7IntroductionIn this obtain review, I delineate to cover the follow ing outcomes evaluate psychological theories against biblical teaching, discuss the theatrical role psychology has to make to Christian counsel, assess the compatibility of psychology (research and psychotherapy) with Christian counsellor and critical examination of psychological theories.About the editorEric L. Johnson is a teacher, editor, spring and director. He attended Toronto Baptist Seminary and proceeded on to Calvin College before going on to naut mi State University where he bagged his PhD. He is an academic psychologist and initially lectured for nine age at the Northwestern College in Minnesota teaching Christian worldview, psychology and theology. Johnson wrote Foundations for Soul Care A Christian Psychology Proposal and contributed several articles for the Baker Encylopedia of Psychology and Counselling. He implored for the necessity of theology in way and psychological research. He is with the Journal of Psychology and Theology as an associate editor. Joh nson edited a special issue of the Journal of Psychology and Christianity, empower Psychology within the Christian Tradition in 1998. He do contributions in two books Christianity and Psychology Four Views and immortal under dismissal Modern Scholarship Reinvents God in addition to editing this book that I am reviewing. Johnson is currently the director of the Society for Christian Psychology and the Lawrence and Charlotte Hoover Professor of Pastoral Care at The Southern Baptist theological Seminary in Louisville, Kentucky.About the BookPsychology and Christianity Five Views, is divided into sevener chapters and has three hundred and nineteen pages. It is a review and expansion of the first edition titled Psychology and Christianity Four Views. This book essentially lends to give a precise studying of human genius and this is an issue that has refused to go. In page 104, we see that Adams argues that the password is sufficient to understand human nature and there is nothing psychology can offer but there are opposing arguments. Freud cited in Chapman (200741) argues that religion is an illusion. However, Crabb cited in Lutzer (199872) argues that we can corrupt the Egyptians take the best of both Christianity and Psychology for our use and become more effective as long as they are not in conflict with the Bible because the Bible will alship canal be superior. The Methodist Quadrilateral advocates that quad factors (Scripture, Tradition, Experience and Reason) must be considered when reaching decisions. In view of all this on-going debates, Johnson tries in this book to advance the argument for a relationship between Psychology and Christianity, and address the issue of lot Christians to understand and grasp the nettle of psychology.In this edition, there is a fifth view which has been added to the first edition of four views. This fifth view is contributed by John H. Coe and Todd W. Hall and it is titled A Transformational Psychology view. The other four view contributors were still involved in this edition but with rewrite contributions. The authors put forward five different views of how Psychology and Christianity can be integrated. They are David G. Myers who deals with the levels of comment an integration view by Stanton L. Jones, biblical steering view by David A. Powlison and Christian psychology by Robert C. Roberts co-authored by P.J. Watson. Johnson wrote the break chapter discussing the history of Christian psychology and also the closing chapter which talks intimately gaining understanding through the five views put forward by the various(a) authors.The authors gave very considerably account of themselves in their respective views. Every chapter is concise, well laid out and the thought flow pattern is quite consistent and credible.Content of the bookJohnson sandwiches the five views in between two chapters that he authored. He started in this first chapter by looking at the history of Christians in Psycho logy. In this chapter, Johnson looks at a generic background of psychology but with special reference to how psychology is viewed today. He argues (page 10) that science is a gift from God and that the scientific revolution was initiated by mostly Christians. Some Christians have unreservedly incorporated modern psychology while others like (Bobgan Bobgan 1987) have out-rightly rejected it and called it psychoheresy. Johnson explained in this chapter well-nigh the unbiassedity of this book and that it is rather a picture of the views of the majority of Christians.The second chapter was by David Myers and it deal with levels of explanation. This chapter delves into the theatre of operations of human characteristics. This view recognises that Christian theology and Psychology are different and should be treated so but that both should combine well. Myers argues (page 49) that both vary in crabby in the methodology of research and so each should free to explore as they deem fit. H e further argues (page 72-74) that scientific data has enabled him along with some other Christian thinkers to shift from their view of seeing homosexuality as a sin, to understanding the biological explanation of prenatal influences to brain differences especially also considering the fact that the Bible did not have much coverage on the subject matter.Stanton Jones wrote the third chapter which is on the integration view. He shares the same view as Myers that both Christian theology and Psychology have something to contribute to each other and wherefore should be integrated an aspect that is contrary to Myers view that they should be separated. Christianity is Gods word and psychology is Gods work. Jones argues (page 101) that Gods sovereignty prevails over every facet of human life and that Christian psychologists should benefit from that. However, Jones also shares a common view as Myers with regards to the fact that the Bible does not address some issues adequately (page 101). Jones shares a person-to-person testimony of the tension levels that he struggled with in-between Christianity and Psychology. (103-104). Jones became more confused as he desired to be tactile sensationful to the Bible, yet, he could not argue with the result that he was actually learning a lot about human nature in Psychology and so through exclusion, he found himself blending both Psychology and Christian theology.The fourth chapter deals with Christian psychology and was co-authored by Roberts and Watson. They argue that understanding God which is revelation (general and special) should be the starting point for the development of psychological theories. These authors (page 155-156) argue that Christian sermons (using deliverer sermon on the Mount as an example) are hireed at helping people to live well dealing with character and transformation of persons and that psychology also deals with how to live, and changing a persons character with the aim of living well. They iden tify terminology as the only difference between both. They argue (page 157) that sermon conceptualises psychology.John Coe and Todd Hall co-authored this fifth chapter which deals with the transformational view. They set out, not to develop or defend a model but to knock off light on their argument, (page 200) that psychology and Christianity are closely related and that psychology is only an expression of faith and love. This view is the view that has just been added in this edition making it five views. They argue (page 200) in favour of the process and methodology of psychology as a process to new ways of transforming people. This approach looks into the psychologists transformation (emotional and spiritual).David Powlison authored the sixth chapter which discusses a Biblical counselling view. He started with a very bold statement Christian faith is a psychology. Also that Christian ministry is a therapy These statements summarises his view. Powlison argues (page 245) that the S criptures talks about thoughts and intentions of the heart. He further argues that God through the scriptures reveals how human beings should achieve their potentials and a clear change process of attaining such too. Powlison assumes a very new approach in his view the approach is to delve into the meanings of the word psychology in the very context in which it is used. He argues (page 248) that obviously the meaning is relative. In a bid to drive home his argument, he develops sub themes Psych 1 6. Psych 1 looks at how you work, Psych 2 looks at the detailed companionship of human functioning Pych 3 looks at the competing theories of human personality Psych 4 deals with the practical application to psychotherapy Psych 5 looks at a form of professional and institutional arrangements and Psych 6 deals with a mass of ethos. Powlison was really express emotion on ensuring that his readers have a very clear understanding of his view and goes a step further with a case study as he a rgues (page 262) that looking at cases is the best way to understand psychological views including biblical counselling.Eric Johnson authored the seventh and closing chapter where he made reference to similar books that has multiple views on the same subject. According to him, this book helps to highlight the point that a group of people, and specifically Christians in this instance, have the same belief but varied perspectives even within the same belief. Johnson (page 293) uses Proverbs 1215 to affirm that a wise man will be humbled, by that awareness of what he does not know. No one has absolute knowledge except God. He argues that because we are finite creatures, we are limited in terms of views but God is the omniscient observer. He further argues that the more views we are open to, the better our understanding will be, and he encourages his readers especially Christians to dialogue, engage, critique and integrate the strengths of these views as it will enhance their understand ing and stage setting in other to develop their own postformal synthesis (page 309).There is something I found very fascinating about this book. I found out that each chapter have contributing responses from the perspective of the other authors set off the strengths and weaknesses of the particular view in light of their own view.My thought.I think that the committal to writing style is easy to read and understand. The chapters are logically laid out and concise and the literary genre is prose. The subsequent contributions from diverse perspectives to each chapter are not common and made it all seem like a conference, answering most questions that readers could have raised. I am the pastor of my local church I encourage members through prayers, teaching, preaching and pastoral care, establish on the Scriptures. I have found myself at crossroads in some contemporary issues which are similar to the observations of Myers and Jones, where they have found the Bible silent on some iss ues and inadequately addressing some other issues. This is one of my reasons of studying Counselling, and a book like this has opened me up to differing views highlighting both strengths and weaknesses of those views. This review has been an eye opener for me.CONCLUSIONIn conclusion, I consider the book well-structured as Johnson sets the stage with the historical background and aft(prenominal) taking the five views, he borders the book at the end, encouraging scholars to critically and constructively engage to progress the work.Finally, I observe that Johnson claims (page 10) that the book is neutral and that the views represent the collective views of a majority of Christians. This is a very good claim but it would have been very good if he had kaput(p) a step further to substantiate his claim with data. However, overall, I consider this book to be of immense value to any Christian psychologists irrespective of their chosen model it will open them up to differing views even with in the Christian community of Psychotherapists. . I identify with Stanton Jones who authored the Integrative view and I will recommend this book to anyone who is seeking a clearer understanding of the endogenetic model of counselling.ReferencesChapman, C.N. (2007). Freud, Religion, and Anxiety. regular army Lulu.com. Page 41Lutzer, E.W. (1998) Pastor to Pastor Tackling the Problems of Ministry. USA Kregel Publications. Page 72Peter Emordi Psychology of Christian Counselling COU2001 1