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By K. Gancka. Mississippi College.

J Clin Oncol 1990;8: para-aortic radiation for high risk cervical cancer generic meclizine 25mg. Cisplatin buy meclizine 25 mg with visa, Treatment of ovarian germ cell tumors with a 3 day radiation and adjuvant hysterectomy compared with bleomycin order meclizine 25 mg overnight delivery, etoposide and cisplatin regimen: a prospec- radiation and adjuvant hysterectomy for bulky stage 1B tive multicentre study buy meclizine 25mg with visa. Early Breast Cancer Trialists’ Collaborative Group 5 buy 25 mg meclizine free shipping. Comparisons between different poly- cisplatin based radiotherapy and chemotherapy for chemotherapy regimens for early breast cancer: meta- locally advanced cervical cancer. N Engl J Med 1999; analyses of long-term outcome among 100000 women 340:1144–53 in 123 randomised trials. Palliative medicine Gynecological cancers are most distressing to the improves the quality of life and may prolong the patient and the family. The economy of the country in which we live at the time of diagnosis, has a huge effect on Mary was admitted to a gynecological ward in our access to treatment. She had stage III cancer of the cervix women suffer the most and as they are the main extending throughout the pelvis and blocking carer in the family, the children suffer with them off her right ureter so that she had hydroneph- during the illness and later. To get this money the family psychological fears, as well as physical suffering, would have to sell property. After which there from misunderstandings with the husband can wouldn’t be any money for her care and the make life a living hell for her. In All these problems need to be taken into ac- Nigeria patients pay for all their palliative care count and palliative care seeks to do this. But the medications and if they do not have money they person who is bringing palliative care needs to be are turned away in pain. Luckily the family was knowledgeable, not only of pain and symptom unable to raise enough and she went home control, but also of the local cultural attitudes to- where the palliative care home care team man- wards women and their role in the family. Spiritu- aged her and her pain was controlled until she ality and religion, is a comfort and most women died. However, many gynecolo- Thus if you are going to be able to address the gists and oncologists insist on providing invasive many faceted areas of palliative care, it is more im- therapy, causing pain and distress, up to the last portant to be a special person than to be a special- (Box 1). We need to be willing to give time to our the terminally ill patient taking into account the patient and even time away from the patients when prognosis for life or for time left. If time was short, you learn what is needed in your part of this world. It is heart However every country, every tribe, every family, breaking to see how many women are subjected to is different. Chemotherapy and radiotherapy are often only available to the very rich and sometimes not at all. The World Health Organization (WHO) defines palliative care as2: Principles of palliative care ‘Palliative care is an approach that improves 1. The comfort the quality of life of patients and their families and peace of the patient is our priority. The facing the problem associated with life- patient is our guest and will take part in deci- threatening illness, through the prevention sion-making with the physician and the team and relief of suffering by means of early iden- up to her death. The care of the patient is ho- tification and impeccable assessment and listic, including addressing all of the needs of treatment of pain and other problems, physi- patient and family. The palliative care physi- cal, psychosocial and spiritual. Palliative care cian may have to interact with oncologists, provides relief from pain and other distressing radiotherapists, surgeons and others, ensuring symptoms; affirms life and regards dying as a that investigations and management decisions normal process; intends neither to hasten nor are made with the comfort of the patient al- postpone death; integrates the psychological ways in mind. Some investigations and treat- and spiritual aspects of patient care. How- • We are aiming at the best possible quality of life ever, in less-resourced settings, other options for our patient. Wherever possible the physician works with a problems, physical, psychosocial, cultural and team. In less-resourced settings a nurse is often spiritual. The team is non- • Our care and approach indicates that we affirm bureaucratic and cares for each other while life (while being prepared to tell the truth) and I sharing information with confidentiality, for myself regard death as a normal process (cure is the good of the patient and family. Teaching others is essential in resource-limited • Acknowledge that while not curing my patient, situations where palliative care is new. We recognize that there is a need for all of us to breast is number 1 in Nigeria. In most countries in meet the needs of our patients and families. We Africa, these are similar in incidence and they are therefore network with other organizations, the main cancers we deal with. Cancer of the ovary and respect them without being in rivalry situa- is less common but brings a poor prognosis and tions. Recent research into pain and symptom terrible suffering.

There is now a bit of dilemma on what “coagulation cascade generic meclizine 25mg amex,” we see that each of these molecules inhibits to call them discount meclizine 25 mg with visa. They had been termed “novel oral anticoagulants” or a component of the “common pathway” (Figure 1) cheap meclizine 25mg on-line. More recently meclizine 25 mg lowest price, some clever thought leaders in this lational modification of all of the vitamin K–dependent factors generic meclizine 25mg visa. This area have suggested keeping the term “NOAC,” but using it to refer results in production of nonfunctional proteins, effectively inhibit- to “non-vitamin K antagonist oral anticoagulants. Not only is the reasonable because, until recently, warfarin-like agents have been activity of the vitamin K–dependent procoagulants [prothrombin or the only oral anticoagulants available. In addition, we will not have factor II (FII), factor VII (FVII), factor IX (FIX), and factor X (FX)] to change our terminology or search terms much. In this chapter, I reduced, but also the activity of the vitamin K–dependent anticoagu- refer to the agents in question as “NOACs” for this reason. Interestingly, the different vitamin time will tell whether this terminology will stick. K–dependent factors are not all reduced to the same degree, as shown in Figure 2. That figure was constructed from levels of the What is different about NOACs? The first of this The prothrombin time (PT) assay only reflects the levels of 3 of the class of drugs to be approved in the United States was the thrombin 4 procoagulants affected by VKAs. However, it has been adapted inhibitor dabigatran etexilate mesylate (Pradaxa). Two FXa inhibi- and standardized via the International Sensitivity Index (ISI)/ tors have now also been approved in the United States: apixaban International Normalized Ratio (INR) system to reflect the relative (Eliquis) and rivaroxaban (Xarelto). Note that this is not because the PT-INR is fundamentally a measure of hemostatic capability in In the United States, dabigatran etexilate is approved to reduce the vivo, but rather because it has been empirically determined that an risk of stroke and systemic embolism in patients with nonvalvular INR in the 2-3. Union and Canada, it is additionally approved for prevention of deep vein thrombosis in patients undergoing knee or hip replace- Monitoring the intensity of VKA anticoagulation with the PT-INR ment surgery. Rivaroxaban is approved in many countries to reduce is necessary because of the variability in response to these agents the risk of stroke in patients with nonvalvular atrial fibrillation, for between individuals and because of the many foods and drugs that prevention of deep vein thrombosis after knee or hip replacement can have an influence on the effects of VKAs. In addition, the fact 518 American Society of Hematology Figure 1. Targets of NOAC (non-VKA oral anticoagulants) and VKAs in a “coagulation cascade” format. In a cell-based model of coagulation, the small-molecule therapeutic window of these agents. During Inhibition of multiple factors has a synergistic effect on the degree initiation, a small amount of thrombin is produced, which participates in of anticoagulation, making it much more difficult to titrate the level many amplification loops. The propagation phase produces the large of anticoagulation than with an agent that has a single target. This is burst of thrombin that leads to stable clot formation. Only small amounts of thrombin are when only a single step is inhibited. Inhibition of thrombin generation (by surfaces in vivo (Figure 3). Each of them can have effects on small-molecule FXa inhibitors) or activity (by small-molecule initiation of coagulation and on the burst of thrombin produced on thrombin inhibitors) results in prolongation of the lag in the platelet surfaces that is responsible for clotting fibrinogen. During the “propagation” thrombin inhibitor, of course, directly inhibits thrombin activity, phase, large-scale thrombin generation takes place on the activated whereas an FXa inhibitor decreases the production of thrombin. Inhibition of thrombin generation or activity during this phase is responsible for reducing the total amount of active Thrombin generation during hemostasis generally follows the thrombin available to clot fibrinogen. Therefore, the NOACs both stylized curve shown in Figure 4. During the “initiation” and prolong the lag and reduce the total amount of thrombin activity “amplification” phases of hemostasis, little or no thrombin can be produced. Assaying and monitoring NOACs One of the advantages of NOACs is that they do not require routine monitoring. However, there are circumstances under which one would like a convenient assay. The “gold standard” assay methodol- ogy is liquid chromatography-tandem mass spectrometry. The coagula- tion “cascade” model (Figure 1) is a good model for the common PT and activated partial PT (aPTT) assays. Based on the effects of NOACs on the terminal steps of clot formation, it appears that they would prolong both the PT and aPTT and that these assays could perhaps be used to assay NOAC levels. In practice, the PT is more sensitive to the FXa inhibitors and the aPTT to thrombin inhibitors. The responsiveness of these assays to NOACs depends on the specific reagents used. The effect of VKA anticoagulation on a PT-INR of 2-4 on despite therapeutic NOAC levels.

Switch from enfuvirtide to raltegravir in virologically suppressed mul- tidrug-resistant HIV-1-infected patients: a randomized open-label trial generic meclizine 25mg mastercard. No evidence for decay of the latent reservoir in HIV-1-infected patients receiv- ing intensive enfuvirtide-containing antiretroviral therapy buy 25 mg meclizine overnight delivery. Switch from enfuvirtide to raltegravir in Virologically suppressed HIV-1 infected patients: effects on level of residual viremia and quality of life cheap meclizine 25mg. Baseline and on-treatment susceptibility to enfuvirtide seen in TORO 1 and 2 to 24 weeks buy meclizine 25 mg lowest price. AbstractID=1687 Kilby JM order 25 mg meclizine mastercard, Hopkins S, Venetta TM, et al. Potent suppression of HIV-1 replication in humans by T-20, a peptide inhibitor of gp41-mediated virus entry. The safety, plasma pharmacokinetics, and antiviral activity of subcutaneous enfuvirtide (T-20), a peptide inhibitor of gp41-mediated virus fusion, in HIV-infected adults. Enfuvirtide, an HIV-1 fusion inhibitor, for drug-resistant HIV infection in North and South America. Efficacy of enfuvirtide in patients infected with drug-resistant HIV-1 in Europe and Australia. Depletion of latent HIV-1 infection in vivo: a proof-of-concept study. Fitness of HIV-1 clinical isolates resistant to T-20 (enfuvirtide). Antiviral therapy 2002, 7:S56 Melby T, Sista P, DeMasi R, et al. Characterization of envelope glycoprotein gp41 genotype and phenotypic sus- ceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2. Resistance and replicative capacity of HIV-1 strains selected in vivo by long-term enfuvirtide treatment. Impact of human immunodeficiency virus type 1 gp41 amino acid sub- stitutions selected during enfuvirtide treatment on gp41 binding and antiviral potency of enfuvirtide in vitro. Increased antiretroviral potency by the addition of enfuvirtide to a four-drug regimen in antiretroviral-naive, HIV-infected patients. Lack of benefit of 3-month intensification with enfuvirtide plus optimized background regimen (OBR) versus OBR alone in patients with multiple therapeutic failures: the INNOVE study. Durable efficacy of enfuvirtide over 48 weeks in heavily treatment-experi- enced HIV-1-infected patients in the T-20 versus optimized background regimen only 1 and 2 clinical trials. Week-12 response to therapy as a predictor of week 24, 48, and 96 outcome in patients receiving the HIV fusion inhibitor enfuvirtide in the T-20 versus Optimized Regimen Only (TORO) trials. Induction treatment with enfuvirtide combined with antiretrovirals opti- mized background in treatment failure patients: 16 weeks data from INDEED Study. Efficacy and safety of switching from enfuvirtide to raltegravir in patients with virological suppression. Pharmacokinetics of enfuvirtide in patients treated in typical routine clinical settings. Switch from enfuvirtide to raltegravir in patients with undetectable viral load: efficacy and safety at 24 weeks in a Montreal cohort. Pharmacokinetics, pharmacodynamics and safety of once-daily versus twice-daily dosing with enfuvirtide in HIV-infected subjects. Safety of enfuvirtide in combination with an optimized background of antiretrovirals in treatment-experienced HIV-1-infected adults over 48 weeks. Lack of influence of gp41 antibodies that cross-react with enfuvirtide on the efficacy and safety of enfuvirtide in TORO 1 and TORO 2 Phase III trials. ART 2017/2018: The horizon and beyond CHRISTIAN HOFFMANN Almost all HIV+ patients can now be treated with a virologically successful regimen, even those with multiple resistance mutations. However, despite this considerable progress, there is an urgent need for new drugs. This is not just true for patients with multiresistant viruses awaiting new treat- ment options. Significant problems related to long-term toxicity and adherence are anticipated for all therapies that will presumably need to span decades, as eradica- tion of HIV is still out of reach for the majority of the patients. A recent study has demonstrated that the median time until exhaustion of currently available treat- ment options is 45 years. Of note, 10% of HIV+ patients are expected to exhaust all currently available ART options after just 26 years (Jansson 2013). As a result, new drugs are needed that are easier to take, with high genetic barriers to development of resistance, and above all less toxic. To reach the goal of eradication, new drugs need to be more potent than those available today. The following overview of agents that could make it to the clinic based on current data (mid-2015) does not claim to be complete.

The definition of nailing includes the three steps of learning buy meclizine 25 mg without a prescription, repeating and controlling cheap 25mg meclizine overnight delivery. If speed is critical buy meclizine 25 mg with mastercard, rely on the tens of thousands of webs that are already firmly anchored in your word brain (Figure 6 purchase meclizine 25mg without prescription. All you need to do is to add two pieces of information to an existing word web: first generic meclizine 25mg, how you write a new word and, second, how to pronounce it; everything else – knowledge about the word in your native language and associated memories – is already in place. In practise, you will have to dress a two-column list, putting your new and your native language face to face (see an example in Table 6. Word lists are not perfect – German Brot is different from French pain, it looks different, it smells different, and it tastes better – but with 5,000 to 15,000 words to nail, you cannot afford to lose time with subtleties. If your teacher tells you that you can do without word lists, fire her. Every human brain is as unique as a human face, and differences in brain structure due to genetic variation, intrauterine conditions (exposure to tobacco, drugs, and alcohol), or environmental factors after birth, can affect learning abilities. Fortunately, most people with a comparable educational background show differences in memory efficiency that usually vary from the simple to the double. If your memory is better than mine, it might only take you 30 minutes to nail what I could do in an hour. Does that mean that there are differences in talent? With thousands of words in the waiting loop, you certainly wonder if there are ways to improve your memory performance. Putting it bluntly, the margins of manoeuvrability are narrow. As a central function of sleep is to consolidate newly acquired memories for long-term storage, chronic excellent sleep is probably a good memory enhancer. Physical activity such as running also appears to improve learning, at least in mice. Even alcohol, if ingested in moderate dosages, improves memory in rats. Let’s await further research before making recommendations on the subject. Far more promising are measures directed at avoiding adverse circumstances and protecting the gradual build-up of billions of spines and synapses. The younger you are, the easier new languages flow into your brain so that the teens and twenties are clearly the most suitable moments in life. After years of formal education, the native language is consolidated and young people realise that discipline helps to acquire new skills. So if you are under 30 and dream about learning another language, do it now! Later in life, job and family reduce available study time. Stupidly, memory performance declines too, first imperceptibly, and after 50, undeniably. Now, words need more frequent repetitions to crawl into lifelong memory. In addition, multitasking abilities decrease, leaving little space for silent rehearsing of new words while simultaneously following an ongoing conversation. At some moment in life, memory impairment is such that the goals we defined earlier – reading essays or newspapers, understanding TV documentaries, and following day-to-day conversation – are beyond reach. Building up valuable spines during sweaty days just to blow them out of your brain during vaporous nights is not what you want to do. Even episodes of heavy drinking such as a bottle of wine impair memory performance during the hangover period. Alcohol, though, is a minor problem compared to a more widespread abuse: distraction. If you repeatedly subtract a single-digit number from a larger number directly after one of your nailing sessions, you will see that your memory is impaired for the 3 to 5 most recently nailed words. Certain episodes of life are therefore inherently incompatible with robust learning: death of relatives and friends, illness or hypochondrial fears, separation or divorce, job loss or financial disaster. Yet even more dangerous, because it occurs more frequently, is seemingly innocuous distraction, for example extended surfing tours on the internet. Opening social network accounts, reading incoherent information from disparate sources, writing short messages, participating in nonsense quizzes, listening simultaneously to music, downloading videos or doing whatever else you can imagine – such acrobatic multitasking is heavy stuff for delicate infant spines. Is excessive networking inappropriate for the gentle formation of lasting memory traces?

Thus trusted meclizine 25mg, the infant has a temporary memory profile that matches its mother’s order meclizine 25mg on-line. Maternal antibodies have a half-life of 3–6 months (Nokes et al cheap meclizine 25mg with mastercard. Infection of a baby early in life may be cleared by maternal antibody buy meclizine 25 mg visa, thereby failing to stimulate an immune response and generate long-lasting memory (Albrecht et al purchase meclizine 25 mg without a prescription. Other vertebrates also transmit maternal antibodies to newborns (Zin- kernagel et al. For example, bovines produce highly concentrated antibodies in the first milk (colostrum), which must be absorbed via the calf’s gut during the first twenty-four hours after birth (Porter 1972). In this first day, the calf does not digest the immunoglobulins and is able to take up most antibody classes by absorption through the gut epithe- lium. Birds transmit maternal antibodies through the egg (Paul 1993). SHORT-TERM PROTECTION FROM RECENT INFECTION IgA antibodies on epithelia can prevent initial infection by pathogens (Mims 1987, p. For example, IgA may prevent attachment of Vibrio cholerae to the intestinal epithelium, gonococcus to the urethral epithe- lium, or chlamydia to the conjunctiva. IgA titers on epithelia often decay quickly after infection. Thus, protection against infection by IgA typic- ally lasts for a few months or less. Most vaccines protect by elevating the level of circulating antibod- ies and perhaps also memory B cells. The need for occasional vaccine boosters to maintain protection against some pathogens suggests that antibody titers or the pool of memory B cells decline in those cases. When long-term protection requires no boost, it may be that a lower threshold of antibodies or memory B cells protects against infection or that some regulatory mechanism of immunity holds titers higher. IMMUNOLOGICAL VARIABILITY OF HOSTS 141 In human influenza, T cells stimulated during infection provide some protection against later infection (McMichael et al. But that pro- tectionwanes over a three-to-five-year period (McMichael et al. Astudyof chickens also showed T cell–mediated control of secondary infection(Seo and Webster 2001). In that case, the secondary infection happened within 70 days of the primary challenge. Measurements of memory decay have been difficult partly because laboratory mice provide a poor model for long-term processes of immu- nity (Stevenson and Doherty 1998). It is difficult to separate decay of immunity from aging when immune memory in a mouse declines over many months. SPATIAL STRUCTURE OF HOSTS Idiscussed above how immune memory profiles may be stratified by age. Memory profiles may also be stratified by spatial location of hosts. Thus, I confine my comments to a few conceptual issues. To begin, consider the temporal pattern of measles epidemics prior to widespread vaccination (Anderson and May 1991, chapter 6). Data from England and Wales in 1948–1968 show a regular cycle of epidemic peaks every two years. The cycle may be explainedbythethresholdden- sity of susceptible individuals required for an infection to spread. Just after an epidemic, most individuals retain memory that protects them from reinfection. The parasite declines because each infected individual transmits the infection to an average of less than one new susceptible host. Thenextepidemic must wait until the population recruits enough newborns who are too young to have been infected in the last epidemic. An epidemic then follows, leaving most of the population protected until the next cycle of recruitment and spread of infection. Probably all par- asite populations wax and wane to some extent as protective memory spreads with infection and the pool of susceptibles rebuilds by recruit- ment or by decay of immune memory. These temporal fluctuations may also be coupled to spatial processes (Rohani et al. Imagine the spatial landscape of a population as a checkerboard of distinct patches. Epidemics may 142 CHAPTER 9 rise and fall synchronously in all patches, or epidemics may occur asyn- chronously over space. Suppose, for example, that half of the patches, labeled P1,haveepidemics in odd years, whereas the other half of the patches, labeled P2,haveepidemics in even years. One can visualize this dynamic landscape by imagining a peak in each patch rising during an epidemic and falling back to the ground between epidemics. Over an asynchronous landscape, some peaks are rising and others are falling at any time.

RIC/RTC regimens before allo-HSCT in patients with symptomatic SCD Study Country N Regimen Graft sources OS (n) EFS (%) Graft rejection (no meclizine 25mg free shipping. Hematology 2014 469 RTC regimen of Bu safe 25 mg meclizine, Flu meclizine 25mg fast delivery, and alemtuzumab in SCD patients after unrelated donors in this patient population discount meclizine 25mg without prescription. Graft rejection was reduced to only 8% risk SCD and demonstrated a 90% EFS but a 10% incidence of graft compared with the previous 30% reported from the same group failure buy generic meclizine 25 mg online. However, patients required long-term immunosuppression without the hydroxyurea, azathioprine, and Flu. These studies support the use of RIC/RTC rabbit ATG 12. Grafts primarily from a maternal donor (N 20) were depleted of T cells using the CliniMACS system to achieve a Alternative allogeneic donor sources for allo-HSCT in median of 14. We and others have demonstrated that UCB is an excellent Engraftment was achieved in 16/22 patients without AGVHD and alternative allogeneic donor source for both childhood malignant with OS of 90%. These results suggest that a similar approach could and nonmalignant conditions. Cyclosporine or tacrolimus and mycophenolate mofetil regimen that Lucarelli piloted in the FHI TCD allo-HSCT study in a were administered for GVHD prophylaxis. The median pre- high-risk thalassemia population (Figure 1A). We have included the cryopreservation total nucleated cell dose was 6. Three patients engrafted had 100% with SCD will be enrolled on this study. Patients will receive a donor cells by day 100, which was sustained, and 5 patients had myelosuppressive/immunosuppressive conditioning regimen and autologous hematopoietic recovery. All used maternal Ruggeri et al19 examined the efficacy of UCBT in children with donors without complications and had early myeloid engraftment, SCD (N 16). The 97% whole blood and 96% RBC donor chimerism, and no AGVHD or CGVHD. Primary graft failure was the predomi- Early results indicate FHI TCD allo-HSCT is feasible in high-risk SCD patients who lack an MSD or MUD. These results suggest that only UCB units containing an expected needed to assess long-term safety and outcomes [supported by Food infused nucleated cell dose 5 107/kg should be considered for and Drug Administration (FDA) Grant 5R01FD004090 and a grant transplantation for hemoglobinopathies, which further limits the from Otsuka; IND #14359 and www. Bolanos-Meade et al20 reported on using a nonmyeloablative Gene therapy approach in 17 adult patients, 14 from HLA-haploidentical donors Although allo-HSCT is the only proven curative option for patients and 3 from HLA-matched related donors. The regimen consisted of with high-risk SCD, this therapeutic approach is limited by lack of ATG, Flu, Cy, total body irradiation, and GVHD prophylaxis with HLA well-matched family and unrelated donors and allo-HSCT posttransplantation high-dose Cy, mycophenolate mofetil, and ta- related morbidity [acute and chronic (late)] and mortality. Graft failure was not seen in HLA-matched circumvent this limitation, gene therapy using autologous stem cells patients, but 43% of the haploidentical patients rejected their graft. Therefore, non-MAC with posttransplantation high-dose and mortality. Myeloimmunosuppressive conditioning regimen and cellular processing for FHI SCD clinical trial. Similar approaches using a Sleeping hemoglobin F (HgF) production and reduce hemoglobin S (HgS) Beauty transposon (nonviral) approach via a nucleofection gene production. In the second and third trimesters of fetal sickling. After birth, the opposite occurs and -globin sickle mice with prior expression of human -globin and S-globin. A summary of gene KLF-1, MYB, SOX6) highly sensitive to DNase 1 in erythroid cells therapy/transduction approaches to induce -globins with antisick- 40-60 kb upstream from the -globin gene, respectively (Figure ling properties is illustrated in Figure 3. Human -globin gene locus on chromosome 11 showing the ontology of expression of the embryonic, fetal, and adult globin genes controlled by locus control regions. In adult life, the transcription of -globin is highly repressed. Some of the major transcription factors involved in the repression of -globin are highlighted. Reprinted with permission from Chandrakasan and Malik, 2014. Lastly, the Orkin group demonstrated that BCL11A is a major repressor of human -globin expression and that Currently, St Jude’s Research Hospital has an open clinical trial silencing of BCL11A in humanized sickling mice significantly entitled “Retroviral Vector Mediated Globin Gene Transfer to enhances HgF production and SCD-related hematological and Correct Sickle Cell Anemia or Thalassemia” (www. CD34 cells purified from the BM of research participants with a sickle cell syndrome or a thalassemia Most recently, the technology to develop iPSCs from mature syndrome will be transduced with retroviral vectors containing somatic cells has allowed advanced gene editing approaches using -globin coding sequences under the control of the -globin gene site directed endonucleases, such as zinc finger nucleases, transcrip- promoter and including various regulatory elements chosen to tion activator-like effector nucleases, and clustered regulatory enhance gene expression and to insulate regulatory elements from interspaced short palindromic repeat endonucleases, to induce cellular genes at or near the integration sites. The efficiency of gene double-stranded DNA breaks and after nonhomologous end joining transfer and the function of the globin transgene will be evaluated in or homology-directed repair/homologous reconstitution gene correc- erythroid cells derived from transduced progenitors and from the Figure 3. The genome of both wild-type murine MLV (A) and the HIV-1 virus and the gene therapy vectors derived from them (B). The initial retroviral vectors had full-length long terminal repeats (LTRs) with intact U3 region (which carries the viral enhancer and promoter). With the current generation of LVs, the U3 region of the 3 LTR is deleted and in the 5 LTR, it is replaced by a CMV promoter in the 5 LTR.