Gene Editing in Hematopoietic Progenitor Stem Cells - Free Essay Example

Sample details Pages: 16 Words: 4900 Downloads: 2 Date added: 2019/06/14 Category Biology Essay Level High school Tags: Stem Cell Essay Did you like this example? The genome editing using engineered nuclease has strategically transformed the idea of gene therapy for monogenic diseases including in hematopoietic stem and progenitor cells (HSPCs) (Osborn et al., 2016; Yu et al., 2016). The genome editing technology enables to create a site specific double-strand break (DSB) by the engineered nucleases that programmable triggering the cell’s endogenous repair machinery to edit the genome in a site-specific manner via the non-homology end joining repair (NHEJ) and the homology directed repair (HDR) mechanisms(Branzei and Foiani, 2008). The approach allows the precise alteration of the disease-causing alleles at the specific locus making it a permanent event that maintains the phenotypical gene expression under the control of endogenous regulatory elements.. Don’t waste time! Our writers will create an original "Gene Editing in Hematopoietic Progenitor Stem Cells" essay for you Create order Over the past decade, three major classes of engineered nucleases have been used for genome editing, including zinc-finger nucleases (ZFNs) (Kim et al., 1996; Urnov et al., 2010), transcription activator-like effector nucleases (TALENs) (Li et al., 2011; Miller et al., 2011) and CRISPR–Cas9 (clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated (Cas) protein 9) (Hsu et al., 2014; Sander and Joung, 2014; Tsai and Joung, 2016; Wiedenheft et al., 2012). ZFNs and TALENs are fusions between arrays of ZF or TALE DNA-binding domains and the dimerization-dependent FokI nuclease domain. The both of ZFN and TELENs nucleases exclusively rely on protein–DNA interactions to mediate site-specific recognition of genomic DNA sequences which requires complex protein engineering for each new targets (Kim and Kim, 2014). By contrast, CRISPR–Cas9 nuclease is a RNA-guided endonuclease. Through the guidance of a 23 nucleotides linked to CRISPR-domain RNA (gRNA), CRISPR-Cas9 finds the complementary protospacer DNA target in a genome where it cuts the double stranded DNA precisely 3 base pairs upstream of a PAM (Protospacer Adjacent Motif). The broken DNA ends generated by those nucleases are repaired either by NHEJ resulting in small insertion/deletions (indels) to disrupt target allele, or by HDR to precisely replace desired nucleotides required with delivery homologous DNA template. Compared to ZFNs and TALEN, the CRISPR/Cas9 system has rapidly become the most promising genome editing tool with demonstrated advantages including simplicity, easy programming, low cost and potential multiplexed editing (Bannikov and Lavrov, 2017; Brunetti et al., 2018; Salsman and Dellaire, 2017; Tsai and Joung, 2016) (Minkenberg et al., 2017). Despite of the genome editing holds tremendous promise for the developing novel gene therapy, the technique has been shown to be more refractory in HSPCs than any other cell types due to their quiescent stat us associated with low activity of the HDR machinery, and prone to DSB induced toxicity. However since first publication of using the ZFNs editing on human CD34+ cell (Genovese et al., 2014), the substantial developments have been made in last few years to circumvent the problems. Optimization of gene editing efficiency in HSPCs In vitro expansion of HSPCs Since all nucleases targeted gene editing occurs through cell cycle progress, the increased stimulation HSPCs ex vivo can make them more permissive to editing components. However, increasing stimulation can also promote cell differentiation. To circumvent this, the compounds that agonist HSPC self-renew while maintain their primitive phenotypes have been discovered and applied in the culture (Boitano et al., 2010; Fares et al., 2014; Goessling et al., 2011). Using the compounds in HSPCs culture, researchers have achieved significantly increased percentage of edited HSPCs in vitro and also increased human cell engraftment in vivo (Charlesworth et al., 2018; Genovese et al., 2014). In a recent published study, Psatha et al. have described 5 days HSPC culture condition, in which StemRegenin 1(SR1) was used with a small molecule Ly2228820 (SL), the p38?MAPK14 inhibitor (Psatha et al., 2017). Using this culture condition, they have  successfully expanded highly engraftable CD34+/CD38?/ CD90+  primitive HSPC cells. They then tested if using SR1 and SL condition can also expand edited HSPCs effectively. For this, they cultured edited HSPCs for additional 5 days after the editing, and found that the edited CD34+/CD38?/CD90+ primitive HSPCs can be effectively expanded in vitro without any loss of editing efficiency. Moreover, the expansion of edited cells gave rise to a more than 2-fold higher engraftment compared to their unexpanded counterparts, showing the same editing rate (Psatha et al., 2018). The study highlights a possible way to obtain sufficient engraftable HSPCs by expanding edited cells effectively ex vivo in presence of SR1 and SL.  However, this study was conducted using the NHEJ directed gene editing strategy for disrupting the genomic locus. It would be important to know if the presence of SR1 and SL in culture can also increase the HDR directed gene editing. And also convincing evidence on long-term in vivo engraftment from significantly expande d HSPCs is needed to ensure no oncogenic burden associated with ex vitro expansion. Delivering the editing components In clinical application setting, the approach for delivering nucleases or other components into HSPCs should be transient to avoid the cytotoxicity engendered by prolonged endonucleases activity and immune responses. Therefore, a â€Å"hit-and-run† approach is used, whereby the nuclease complex is transient expression. The mostly used method for delivering DNA or RNA encoding engineered nucleases is via nuclear transfection. The transfection of plasmid DNA encoding the nucleases to HSPCs has been used with success on editing targeted loci (Holt et al., 2010; Mandal et al., 2014). However the main concern from this approach is its potential random integration into the genome which could lead to cytotoxicity in HSPCs and their progenies. And DNA related cytotoxicity, such as cyclic GMP-AMP synthase induced pathway (Sun et al., 2013), could lead to high toxic to primitive HSPCs. Therefore, the transfection of mRNA encoding nucleases synthesized in vitro has become an optimal alte rnative approach (Liang et al., 2015; Wang et al., 2015). It has emerged from recent studies that the mRNA transfection approach indeed has provided an increased efficiency in genome editing in HSPCs (De Ravin et al., 2016; Kuo et al., 2018; Schiroli et al., 2017). In addition, Cas9 can be delivered as the protein or as the precomplexed ribonucleoproteins (RNPs) by mixing gRNAs with Cas9 protein (Dever et al., 2016; Liang et al., 2015). The approach serves in protecting gRNAs from degradation, and reducing cytotoxicity caused by naked RNA stimulated innate immunity. The improved editing efficiency based on such approach has been achieved in targeting HSPCs shown in recent studies (Bak et al., 2017; Kuo et al., 2018; Schiroli et al., 2017; Vakulskas et al., 2018). Apart from above components, a safe and efficient delivering DNA donor template into edited cells is crucial for achieving HDR process. Several donor template platforms have been used. Single-stranded DNA oligonucleotide (ssODN) donor has been shown as a simple and effective approach in genome editing for correction of single-nucleotide mutation in HSPCs, such as for Sickle  cell disease (SCD) (DeWitt et al., 2016).   Integration defective lentiviral vector (IDLV), that allow incorporating large DNA template, has been used in the ZFN genome editing to target the IL2RG mutations and the  adenosine  deaminase  (ADA) gene (Genovese et al., 2014; Joglekar et al., 2013). However, those early studies showed a very limited gene targeting efficiency in HSPCs, suggesting that IDLV could be more cytotoxicity to HSPCs. The efficiency of IDLV in targeted integration in HSPCs can be significantly improved by using cyclosporine H, which is shown in a very recent study (Petrillo et al., 2018). Certain adenoviral serotypes (Ad5) can transduce human HPSCs and deliver large transgene cassettes (Li et al., 2013) (Saydaminova et al., 2015). However the concern that residual of adenovector particles could be highly immunogenic which may prevent its potential use in clinical application therapy. Recombinant adeno-associated viral vectors (rAAVs) have been shown to naturally mediate HR in mammalian cells without stimulating DSB (Barzel et al., 2015; Mingozzi and High, 2011; Moser and Hirsch, 2016). Hence, rAAV vectors are emerged as ideal delivery approach due to their wide range of tropism, high transduction rate and very low immune response. In particular, the rAAV6 vector has been shown to provide more efficient and robust genome-editing in HSPCs than other delivery vectors shown in recent therapeutic potential application studies (De Ravin et al., 2017; De Ravin et al., 2016; Kuo et al., 2018; Moser and Hirsch, 2016; Schiroli et al., 2017). However, relative small pa ckaging capacity in rAAV6 has limited its use for delivering cassata larger more than 4.5 kb including the both homology arms. To improve the packaging capacity, Bak and Proteus (Bak and Porteus, 2017) have developed a dual-AAV6 donor vector system that enables site-specific integration of large transgene cassette up to 6.5 kb into primary T cells and HSPCs with long-term repopulation capacity. Overall, the conditions for delivery the components used in gene editing should always be optimised for each targeted gene to achieve most efficient targeting and minimum cytotoxicity. A comprehensive detailed protocol using CRISPR/Cas9 with rAAV6 as templet vehicle for HDR-targeted editing in HSPCs has been published by Bak and Daniel recently (Bak et al., 2018), which could be also served as a guide for implement gene editing technique for other nucleases Improve the HDR Unlike NHEJ pathway which occurs throughout the cell cycle, the HDR event is restricted in S/G2 phases of cell cycle which makes the HDR process much less efficient than NHEJ (Gutschner et al., 2016; Heyer et al., 2010). Therefore, inhibiting nuclease activity at G1/M phases and resting cells at S/C2 phases may improve HDR efficiency. The concept has been experimentally tested by Gutschner and colleagues (Gutschner et al., 2016). In which, the hGemCas9 system is generated by incorporating the human geminin domain which allows the nuclease to be ubiquitinated and degraded by APC/Cdh1 complex in G1 and late M phase, therefore leading to increased hGemCas9 activity in S/G2 phases. Using this cell-cycle-tailored hGemCas9 system, Gutschner et al have achieved an increased rate of HDR up to 1.87 fold compared to wild-type Cas9 in cell lines. A further development based on this approach was published recently by Lomova et al. (Lomova et al., 2018). In their study the hGemCas9 was used in c ombination with a cell synchronization compound RO-3306 which functioning in transiently arresting cells at S/G2 phase via inhibiting CDK1(Vassilev et al., 2006). It was shown from Lomova’s study that the ratio of HDR/NHEJ was increased to four-fold on human CD34+ cells compared to the controls in vitro, and a significant improvement of edited HSPCs in immune-deficient mice. The improved HDR has also been achieved by directly inhibiting the NHEJ pathway through targeting DNA ligase IV, a key enzyme in the NHEJ pathway, using the inhibitor Scr7 (Hu et al., 2018; Maruyama et al., 2015). Although high increased efficiency in HDR has been achieved in human cell lines and cancer cells, so far, there has been no published data of using Scr7 on human HSPCs. The assessment off-target sites Although ideal engineered nucleases would have singular genome-wide specificity, unintended off-targets can occur, particularly at loci with homologous to the intended targeting site. Several the off-target detection methods have been used in HSPCs gene editing studies. An early developed assay is based on using the silico prediction off-targets sites that have degree of similarity to the on-targets, and then followed by targeted sequencing (Fine et al., 2014) (Hsu et al., 2013). This initially developed method is still mostly used in the HSPCs editing studies as it is more practicable assay. However the fundamental limitation with this approach is it is not designed to identify off-target sites in an unbiased manner as the sites that not fit the computational criteria will not be discovered, To achieve unbiased off-target detection, the cell based genome-wide assays have been developed. On of such assay used in HSPCs editing studies is Integrase-defective lentiviral vector (IDLV) capture assay, which was designed to capture IDLV into sites of nuclease-induced DSBs. Then clustered sites of integrations are recovered by linear amplification-mediated PCR (LAM-PCR) and mapped using high-throughput sequencing (Gabriel et al., 2011). Although the IDLV capture can directly identify DSBs in living cells, it is relatively insensitive, owing to its low absolute integration efficiencies that require positive selection to overcome (Gabriel et al., 2011). And the assay may have high background due to event of random integration IDLVs into cellular genomes even in the absence of nuclease-induced DSBs (Gabriel et al., 2011). Whole genome sequencing (WGS) has been proposed as an unbiased method for defining engineered nuclease specificity. Although this method is useful for the analysis of single-cell clones (Veres et al., 2014), it lacks sensitivity, particularly for those low frequencies off-target in a population cells (Tsai and Joung, 2014). With existing deep sequencing technology, it is impractical to perform WGS on millions of cellular genomes, and it is inadequate to confirm the off-target sites at Therapeutic potential of HSPC gene editing Non-homologous end joining-based strategy NHEJ DNA repair pathway triggered by engineered nucleases is the active random repair process, leading to the alteration of nucleotide sequencing at the specific site via in-frame deletions, insertions. Sine it is not involved in harnessing the HDR machinery, it has become a viable genome editing option for correcting gene mutations. Two HSPC targeted loci, chemokine coreceptor 5 (CCR5) and BCL11A, have received the most early attention as their potential therapeutic benefits via NHEJ process. The concept of editing CCR5 was intrigued by the report that the transplantation of a donor HSCs with a naturally occurring  CCR5  mutation confers a loss of detectable  HIV-1 RNA and proviral DNA in a HIV patient (Hutter et al., 2009). Holt et al. first published the report of the successful disrupting CCR5 using the ZFNs (Holt et al., 2010). In their study, NSG mice transplanted with ZFN-modified HSPCs underwent rapid selection for CCR5(-/-) cells when challenged with CCR5-tropic HIV-1, showed significantly lower HIV-1 level compared to the controls. Several studies publishes later have also demonstrated the feasibility of CCR5 disruption in HSPCs that lead to resistance to HIV infection in vivo model (DiGiusto et al., 2016; Li et al., 2013; Xu et al., 2017). Among them, DiGiusto et al. conducted a preclinical study to assess efficacy and safety of the ZFN-based CCR5 disruption in HSPCs on the clinical-scale delivering CCR5-specific ZFN-mRNA to normal adult HSPCs. In which, they demonstrated effective biallelic CCR5 disruption of 40-60% in liquid culture cells, and in up to 72.9% of modified colony forming units from edited HSPCs. The edited HSPCs preserved long-term multiple lineage potential  in vivo with no demonstrated potential for tumorigenesis or leukemagenesis (DiGiusto et al., 2016). Based on this, further safety and feasibility studies are ongoing in subjects infected with HIV-1 ([emailprotected]). Targeting HSPCs genomic locus BCL11A via NHEJ gene editing has been developed for potential treatment of the ?-hemoglobinopathies, which are inherited monogenic blood disorders due to the mutations in ?-globin gene causing either Thalassemis (abnormal haemoglobin production) or sickle cell disease (SCD) (abnormal haemoglobin tetramer) (Steinberg, 1999). The observed fact of that the severity of both conditions can be ameliorated by the induction of Fetal haemoglobin (HbF) (Collins et al., 1995) led to discover the BCL11A transcription factor as a repressor for HbF (Bauer and Orkin, 2015), and BCL11A erythroid-specific enhancer, GATAA in association with fetal-to-adult haemoglobin switching (Canver et al., 2015), which could be targeted for inducing HbF in HSPCs for potential treatment of those conditions. To this end, Bjurstom et al. conducted the genome editing strategy to disrupt the BCL11A exon2 in HSPCs using the engineered nucleases ZFNs, TALENs or CRISPR-Cas9 (Bjurstrom et al ., 2016). It was shown in their study that the ZFNs gave rise to more allelic disruption in the  targeted  locus which is associated with increased levels of  HbF  in erythroid cells derived from nuclease-treated CD34+  cells in vitro. However, a low level of disruption in the BCL11A gene in bone marrow (4%) was observed after engraftment into NSG mice. Using the ZFNs approach Chang et al. performed study to compare targeted disruption of the  BCL11A, either within exon 2 or at the GATAA motif (Chang et al., 2017). It was shown from their study that the allelic disruption of GATAA not only give rise to robust  long-term  engraftment  leading to elevated level of  HbF  expression in erythroid  cells, but also prevent the adverse effect of erythroid enucleation seen in the  BCL11A exon2 ablation. Using same strategy, a comprehensive preclinical study has been carried out in HSPCs from adult donors and two patients with ?-Thalassemia Major (Psatha et al., 2018 ). The modification of GATAA motif in mobilized  CD34+  cells  from ?-thalassemia patients resulted in a readily detectable increased ?-globin with a preferential increase in G-gamma, leading to an improved phenotype that likely to give a survival advantage for maturing erythroid  cells. A phase 1/2 clinical trial for correcting the ?-thalassemia phenotype by genome  editing is currently being evaluated by the same group. Homologous recombination based strategy In larger majority genetic blood diseases, the homologous directed repair strategy is required for correcting genotype, with delivering exogenous DNA template. The process is much more challenging than NHEJ-based gene editing due to its low efficiency, particular in targeting primitive HSPCs. However, the promising progress in targeted integration in HSPCs for some PIDs has been made in recent years. Interleukin-2 receptor common gamma-chain (IL2RG) The first attempt using the ZFNs for gene knockin in HSPCs was demonstrated by Genovese et al. (Genovese et al., 2014). In this study, two genomic loci, AAVS1 â€Å"safe harbour† or a mutational hotspot of IL2RG were targeted with a GFP cassette delivered with IDLV vector. Although there was 24-26% indels found in the ZFN target sites, only 5% GFP+ colonies were found in colony-forming cells (CFU) assay. At 8 weeks after transplantation edited CD34+ cells into NSG mice, the frequency of 2% GFP+ cells were found among primitive and committed progenitors in the BM. To improve gene targeting efficiency, Genovese et al. tailored the culture condition by extending cell activation time making them more permissive for the editing molecules, and by adding the compounds into the culture to preserve the stemness in primitive HSPCs (Genovese et al., 2014). The modified protocol indeed gave rise to significantly increased GFP+ cells (?2-fold) in primitive cell population in vitro and also in vivo in long-term engrafted HSPCs. Using improved the ZFNs protocol Genovese et al. performed the IL2RG gene correction in CD34+ cells derived from SCID-X1 patient with delivering IDLV vector consisting of the exons 5-8 IL2RG cDNA and a PGK-GFP cassette flanked by homologous sequences. In which, they found 3% GFP+ cells in primitive HSCs and up to 11% GFP+ in committed progenitors in liquid culture. The CFU assay yield 3 GFP+ colonies out of 100 scored, with a myeloid progeny colony showed reconstituted normal IL2RG protein expression. The data from this study highlighted the problem with targeting primitive HSCs for homologous recombination. A recent development in targeting integration of IL2RG has been demonstrated by same group (Schiroli et al., 2017). In order to establish therapeutic potential of a gene correction strategy for the treatment of SCID-X1, a humanise SCID-X1 mouse model was used to evaluate efficacy and safety of the edited HSPCs in a preclinical setting. To i mprove editing efficiency, they made the modification on the ZFN mRNA by incorporating the base analogs to prevent recognition by cellular sensors that associated with the activation of the interferon-responsive genes by exogenous RNAs. This modification results in a significant reduced cytotoxicity caused by in vitro electroporation of the ZFN mRNA, leading to high HDR (25%) in CD34+ cells derived from a SCID-X1 patient. By changing to use AAV6 as donor DNA vehicle following the ZFN mRNA electroporation, they achieved up to fivefold higher HDR-mediated gene editing in the most primitive CD34+ CD133+ CD90+ cells over the IDLV vehicle approach. It was also demonstrated in this study that optimised clinical relevant protocol is transferable to the clinic scale, showing reproducible editing efficiency even in a large scale 2.5107 HSPCs. More importantly, the edited cells preserved long-term engraftments in NSG mice, showing an average 12% HDR in HSPCs at 23 weeks end point, which excee ded the threshold (10%) of functional HSPCs required for fully reconstitute immune function at a standard transplant dose established in the their study (Schiroli et al., 2017). The off-target assay did not detect significant amounts of modification above the threshold of sensitivity in any of the off-target sites identified previously by genome-wide screening for the ZFN set (Gabriel et al., 2011). Based on these data, it would be interesting to see if the optimised protocol could lead to adequate editing efficiency in HSPCs derived from the SCID-X1 patient, which could paves the way to translation HSPCs gene editing into the therapy. X-linked chronic granulomatous disease (X-CGD) Two recent studies published by De Ravin et al. presented the promising results on the targeted integration of CYBB gene encoding gp91phox for the treatment of X-CGD (De Ravin et al., 2017; De Ravin et al., 2016). Their initial study (De Ravin et al., 2016) was based on the ZFNs targeted integration of transgene into a genomic â€Å"safe habour†AASV1 with the aim to overcome insertional mutagenesis by the viral vector gene therapy, where 3 X-CGD patients underwent the gene therapy developed myelodysplasia due to the integration at MDS-EV11 locus (Stein et al., 2010). De Ravin et al. carried out extensive experiments firstly to explore the optimised conditions in clinical relevant approaches for delivery of the ZFNs, and AAV6 delivery of donor construct containing promoter-less Venus marker cDNA into the intron 1of the PPP1R12C gene at AAVS1 locus. The results from their study showed up to 58% Venus-positive HSCs in vitro and 6–16% human cell marking were observed follow ing engraftment into NSG mice. Using their optimised approach, they then targeted HSPCs derived from X-CGD/gp91phox patients with donor constructs containing either a promoter less gp91phox (2A-2A-gp91), or gp91phox driven by a synthetic MND promoter (MND-91). Although the both approaches showed a similar targeted integration efficiencies (~15% gp91phox expression), a robust functional correction through MND promoter, rather than the endogenous PPP1R12C promoter was obtained with significant high MFI of gp91expression and DHR oxidase activity in edited HSPCs in vitro. At 8 weeks following transplantation of edited HSPCs into NSG mice, the MND-91 and 2A-2A-gp91 corrected HSPCs grafted average 3.7 ±4.2% and 10.7 ±4.2% of human CD45+ cells respectively from bone marrow gp91expressing cells. Since the gene therapy corrected cells in X-CGD patients do not entail a selective advantage, the question is if the level of reconstituted gp91expressing cells achieved in this study would be sufficient for the disease phenotype correction. Nerveless, the data presented in the study has provided the first promising alternative approach in correction of X-CGD. However, long-term efficiency in vivo still remain to be established, and the safety issue of disrupting PPP1R12C gene encoding for a phosphatase in stem cells also need to be determined. In a later study led by the same group (De Ravin et al., 2017), De Ravin et al. have achieved the targeted correction of the point mutation C676T X-CGD using CRISPR/Cas9 and delivering single strand oligo nucleotide (ssODN). The C676T mutation, accounted for 6% of X-CGD patients, occurs at the exon 7 of CYBB gene resulting in a premature stop codon and an inactive gp91phox protein. Following experiments to optimise the targeting CYBB 676 locus in normal CD34+ cells, they achieved level of HDR editing efficiency even within primitive (CD34+CD133+CD90+) HSPCs at ~30%, which is high than any previously reported. In CD34+ cells derived from CYBB 676 patient, they achieved targeted repair of 20% of HSPCs and restored gp91expression to 31% in myeloid cells differentiated from edited HSPCs, which resulted in restoration of the function of NADPH oxidase activity and superoxide radical production. Analysing of transplantation of gene-repaired X-CGD HSPCs into NSG mice at 8 and 20 weeks, they demonstrated not only improved stable human engraftment and corrected CYBB alleles, but also the production of functional mature human myeloid and lymphoid cells for up to 20 weeks. The off-target sequencing analysis on computationally predicted off- target sites in edited CD34+ cells from the patient revealed one single indel (3 bp) at the RP11-454H19.2 gene at a high read depth 1,200,000x, but not at 10,000 read depth. However, one single indel observed in the uncorrected healthy control CD34+ HSPCs, indicating that this could be due to amplification/sequencing errors at high level of coverage. Whole-exome sequencing at 800Ãâ€" coverage of corrected patient CD34+ HSPCs also failed to detect any off-targets. Using same approach, De Ravin et al. have tried to correct a second X-CGD patient with CYBB 676 mutation (De Ravin et al., 2017). Although the gene repair efficiency was achieved in a similar level to the patient 1 in vitro, a less than 50% of the gene repair rate was observ ed after transplantation into NSG mice. This has highlighted the necessity of careful validation of editing condition at every level to achieve a consistent outcome. Nerveless, this study presented a viable approach in correction of a missense mutation in HSPCs by targeted integration that restore gene function under the control of the genes endogenous promoter. X-linked hyper-IgM syndrome (XHIM) XHIM is a primary immunodeficiency due to mutations in CD40 ligand gene (CD40L) expressed on the activated T cells. The mutated CD40L fail to bind CD40 on B cells which affect immunoglobulin class switch recombination that represented by the absence of IgG, IgA, IgE with normal to elevated IgM. XHIM patients are susceptible to bacterial infection, with development of autoimmunity and malignancies in some X-HIM individuals (Hayward et al., 1997; Levy et al., 1997). XHIM can be treated by allogenic HSCT, but has been associated with some sever site effects. Although the experimental gene therapy using viral vector in XHIM mouse model showed the correction of immune defect, the mice developed abnormal lymphoproliferation due to unregulated expression of the gene from ectopic genomic loci (Brown et al., 1998; Sacco et al., 2000). Therefore, using gene editing tools in targeted integration of XHIM gene under control of its endogenous promoter has become an optimal alternative approach for treating the disease. Using the TALEN as targeted gene editing approach Hubbard et al. have first demonstrated the feasibility in restoration of normal expression of CD40L and rescued IgG class switching in XHIM  patient  T cells (Hubbard et al., 2016). A later study by Kuo et al. developed the both TALEN and CRISPR/Cas9 platforms to achieve site-specific editing of a human CD40L cDNA, at the 5’UTR of the gene allowing bypassing all known disease-causing mutations in XHIM (Kuo et al., 2018). The both approaches were tested in T cells derived from XHIM patient. Although the TALEN approach resulted in CD40L expression at the baseline in unstimulated cells, an up-regulated CD40L expression to 20% was detected upon anti-hCD3/anti-hCD28 immune stimulation which is comparable to stimulated T cells from healthy donors. The corrected XHIM T cells demonstrated a normal receptor-binding activity to recombinant chimeric CD40-muIg. The data highlighted that a proportionally small n umber of gene-corrected T cells in XHIM may be sufficient to allow enough class-switching to ameliorate the disease. In CRISPR/Cas9 treated XHIM T cells, high rates of targeted gene integration was attained with restore physiologically-regulated CD40L expression and function. In targeting CD34+ cells from healthy donor, Kuo et al. have shown that both platforms gave rise to a similar level of allelic disruption rate in samples from 8 biological replicate, 4 PBSC donors (29.1  ± 7.8% with TALEN, average 33% with CRISP/Cas9). A relative high targeted gene integration rate was observed in CRISP/Cas9 treated cells, particular when gRNA and Cas9 protein delivered as RNP (to 20.8  ± 6.6%). By adding the adenovirus helper protein that co-introduced as mRNA during electroporation with TALENs or CRISPRs, a 2-fold enhanced gene modification was achieved. However, this augment effect was not observed in engrafted NSG mice in vivo. Following transplantation of edited cells into NSG mice at 12-20 weeks, the targeted gene integration was detected in the bone marrow from 80% of mice, with integration rates ranged from 0.3% to 22%, a mean of 4.4% across all treatment groups. The analysing of thymus from engrafted mice showed 60% mice had thymic reconstitution, With frequency of engraftment trending higher in those analysed at 5 months compared to 3 months post-transplant. The off-target activity was not detected based on silico predicted off-target sites for both TALENs and CRISPR in K562 edited cells. However, using IDLV capture approach in TALENs edited K562 cell, three off-target loci (OT1, OT2 and OT3) were observed. High-throughput sequencing of off-target sites in HSPCs and K562 cell treated with TALENs mRNA demonstrated statistically significant gene disruption at OT1 in HSPCs, and OT2 in both cells. However, there was no off-target site identified in CRISPR treaded cells using another cell based assay GUIDE-seq, which was designed recently with a high sensitivity for detecting the off-target sites mutagenized by Cas9-gRNA (Tsai et al., 2015). Taking together, CRISPR approach showed some advantages over TALENs in targeting integration of XHIM gene. Overall, this study paves an important step toward to developing a curative therapy for XHIM through site-specific gene correction. The major hurdles in HSPCs gene editing Despite the genome editing holds tremendous promise for the developing novel gene therapy, HSPCs targeted editing is still in its infancy, and many issues regarding this new technology are remained to be addressed before translating it into safe clinical application. One major hurdle facing in HSPCs targeted editing is low efficiency, particularly in vivo following transplantation of edited cells, where the engrafted cells and frequency of edited cells decline significantly within 8 to 12 weeks and continuously decline in prolonged period. This suggests the â€Å"real† long-term HSPCs either have failed to undergo genome editing due to their quiescence and more resistance to homologous recombination, or they have been damage by DSBs due to exposure to nuclease and lost their self-renew property underwent apoptosis.

Persuasive Essay On Abortion - 1028 Words

Introduction/ Opinion In this paper I will be arguing about the topic that the government is intervening too much with abortion and it is the woman s choice. In my opinion, I think that it is the woman s choice to have an abortion if she chooses. In addition to that I don t believe that a woman should just keep having abortions over and over again because after the first time they should think of preventing it better with birth control or just not having intercourse. After the first abortion, I think that it should be slightly harder to get another one unless there is good reasoning such as rape or they wouldn t be able to physically go through giving birth. Abortion Procedures There are several different types of abortion today,†¦show more content†¦Wade and adopted a less restrictive standard for state regulations. The decision allowed states to impose waiting periods before a woman can obtain an abortion, allowed some legislative interference in the first trimester in the interests of a woman s health, and permitted parental consent requirements for minors seeking abortions. [107]The Court ruled that none of these conditions imposed an undue burden upon women seeking abortions, but some pro-choice advocates warned that Roe v. Wade had been significantly weakened and that states would limit abortion access. [108][109] On Nov. 5, 2003, after passing in the US House of Representatives (281-142) and the US Senate (64-34), the Partial-Birth Abortion Ban Act of 2003 [58] was signed into law by President George W. Bush. This federal legislation banned physicians from providing intact dilation and extraction (aka partial-birth abortion), a late-term (after 21 weeks gestation) method which accounted for 0.17% of abortion procedures in 2000. [43] The act defines a partial-birth abortion as an abortion in which the provider deliberately and intentionally vaginally delivers a living fetus until... the entire fetal head is outside the body of the mother, or... any part of the fetal trunk past the navel is outside the body of the mother, for the purpose of performing an overt act that the person knows will kill the partially delivered living fetus. Pro-choice advocates challenged theShow MoreRelatedPersuasive Essay About Abortion993 Words   |  4 Pagesin two peoples perspectives. The story consisted of a da ughter (Deb) and mother’s perspective after the death of her father. The purpose of this layout is to show how they are both grieving in individual ways. Writing for the persuasive was presented as an essay on why abortion should be accessible in every country, and to also outline the shame women receive. Purpose Purpose for writing publication- Purpose for writing a real-estate article was to inform a potential buyer on the house showed. AlsoRead MoreAbortion Persuasive Essay1119 Words   |  5 Pages To begin with, there has always been an extensive issue with the topic of abortion, why? Well, it’s a tough subject and can get extremely emotional and very defensive. Honestly, people just need to open up their eye’s and understand that its murder and not just a choice. It is murder because two can create a blessing and the choice of aborting it, is more like a sacrifice for the reason a mother can’t carry a baby for nine months. Whether a person is a minor, young adult, or an adult and is inRead MoreAbortion Persuasive Essay755 Words   |  4 Pagesinstead these babies are torn limb by limb, burned, and many other tortuous methods to end the precious life. Abortion is murder and is not only very cruel to the unborn baby but it also harms the mother. Pro-choice is an escape from the harsh reality that a baby is being murdered, and in my eyes a life should only be terminated if God himself is ready to call them home. One reason why abortion is wrong is because they are many other safe solutions that would give the child a chance at life. AdoptionRead MorePersuasive Essay On Abortion917 Words   |  4 PagesAbortions in Texas consist of ending a pregnancy of an unborn child before it can live out of the mother womb. However if the pregnancy ends not on purpose before the twenty four week mark then technically it would be considered a miscarriage. Though inducing the abortion on purpose has caused a lot of controversy over the past century. Deliberately putting people on one of two sides of this issues, of either being for it, which would be considered Pro Choice. Or in the other category of the ProRead MorePersuasive Essay On Abortion1635 Words   |  7 Pagessolve this issue the option of abortion was brought to the forefront by scientists and advocates such as Dan Savage who mentioned that abortion should be mandatory for the next 30 years in or to control the population. (Ertlet) For countri es such as the U.S. with a growth rate being 1.6%, the proposal of widespread abortion is highly recommended as mentioned by obstetricians and gynecologists. (MumfordKessel) Who now leaves the question as to if the option of abortion should be used as a means ofRead MorePersuasive Essay On Abortion1228 Words   |  5 Pagesmillion pregnancies each year in the United States, 1.6 million end up in abortion† (Hern). Because of the numerous traumatic psychological, physical, and overall irresponsible behavior or actions constantly encouraged due to abortion, it should be banned, and forever illegal. Killing one’s own fetus has been linked to psychological distress which has been channeled into many different cases of substance abuse. â€Å"Induced abortion has been linked to increased rates of substance abuse, especially amongRead MoreAbortion Persuasive Essay804 Words   |  4 Pagesfamily with someone. Often times accidents happen in which people didn’t plan for, and can lead to many financial problems or neglect of one’s child because the parents weren’t prepared to be parents. This is why there should be the option of abortion. Abortion needs to be an option for everyone because it helps from long lasting mental states, infection, economical problems, and or having conceived from a non consensual circumstance. Pregnancy is a hard and unforgiving to the woman’s body. In factRead MorePersuasive Essay On Abortion954 Words   |  4 Pagesand nations who destroy life by abortion and euthanasia are the poorest. I do not say legal or illegal, but I think that no human hand should be raised to kill life, since life is God’s life in us, even in an unborn child.† Do you know what abortion really is? Abortion is the ending of pregnancy by removing a fetus or embryo before it can survive outside the uterus. Abortion seems to be more common in today’s society. Numerous amounts of individuals support abortion, and do not realize how it affectsRead MoreAbortion Persuasive Essay736 Words   |  3 Pagesfavor of abortion rights. The decision was 7-2, it stated that it showed a â€Å"right of privacy.†Abortions have been performed for thousands of years all around the world, even though many women died from it. Women nowadays have a choice of whether they want to get an abortion. Abortions do come with risk, one of them being death, but women should still have a right and say what they want to do with pregnancy and not be judged by others for doing so. Today the debate across the world is if abortion shouldRead MorePersuasive Essay On Abortion1321 Words   |  6 Pagessomeone who may be suicidal or who is suicidal himself/herself. As for taking away fetus’ lives, the damage that abortion makes on life can be proven with the statistics. According to Casey, â€Å"over the past 44 years, one-sixth (60,000,000) of the American population has been killed by elective abortion. Twenty-five percent of African-Americans are killed in the womb America,† (Should Abortion Be Legal n.p.). The figure 60,000,000 is a depressing number considering that these children could have been future

Essay on Fashion Photographer Cecil Beaton - 1121 Words

T here have been many great photographers throughout history who have left their mark on the industry. Cecil Beaton is an inspiring fashion photographer from the 1930s. He was born in 1904 in Hampstead, England, he moved to London and continued to live there until his passing in 1980. This British photographer launched his career as a society photographer in 1926 (A Gallery for Fine Photography, 2001). His first camera was a Kodak 3A which was a very popular model in its time. Beaton used this camera to teach himself the basics of photography often using his family members as subjects. Ignoring his dislike of further education Beaton studied history, art and architecture at ST John’s College, Cambridge (Search.com Reference, 2010). In†¦show more content†¦He was never known as a technically skilled photographer, he relied on his ability to sculpt a subjects body into an ideal pose and place them in a flattering scene to compliment the feel of the photograph that he was aiming to achieve (Search.com Reference, 2010). Beaton was a great photographer however his photographs were not about capturing reality; he used his art so that we may perceive his subjects to be more attractive then they truly appear. Early on in his career he learnt flattery was the key to portraiture (Patrick, 2009). Beaton was able to transform ordinary subjects to look younger, more attractive and sophisticated through his photography. This was achieved by careful manipulation of their posturing (Patrick, 2009). These subjects would trust Beaton to transform what ought to be an ordinary photograph into something more elegant and stylish. Clients could easily have faith in Beaton’s creativity as his photographic style followed the current trends in society (Patrick, 2009). Beaton was known as a natural socialite however later it became evident that he was not a loyal friend at all. After Beaton’s diaries were discovered readers uncovered a stranger, and those who knew the photographer where shocked. These diaries were found to be the scripture of Beaton himself and personal thoughts no one should have to hear. Beaton’s self-created faà §ade worked perfectly within high society although it wasShow MoreRelatedFashion Promotion in 5 Years Essay1727 Words   |  7 PagesWhat is the role of fashion promotion within the fashion industry, and how will it develop over the next 5 years? Fashion promotion is the glue that holds together everything fashion related. Its all very well having a great designer who can create stunning garments out of fabulous materials, but fashion promotion is what advertises those garments, and sells them, and puts them out there for the world to see. If there werent photographers and buyers and journalists and stylistsRead MoreFashion : The Window Of The Soul Essay1639 Words   |  7 Pages Fashion: The Window to the Soul Fashion is a combination of Art, love and History. It gives a person a voice without speaking and a purpose. Fashion has been around for decades before it was given a name. In Queen Elizabeth I Era one s clothing showed social status, individuality, and grace. Women were mostly into fashion, their clothes were unrealistic ; wide hips and small waist (corset). 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Hence, the first task was to find out the current situation of film industry and fashion photography in Bangladesh. Though photography in Bangladesh has developed a lot in past few years but it is still under develop in the sector of fashion photography. The fashion photography sector in our country

The Biological Processes Of Obesity - 1527 Words

Obesity can develop when the cumulative energy intake exceeds energy expenditure, when this happens the excess is stored primarily as fat in adipose tissues. The biological processes that regulate the energy balance are highly regulated and this mechanism can be overwhelmed, because of a need to eat when not hungry, if attractive high calorie food is presented in attractive settings, and if individuals are regularly non-mobile for extended periods. The control pathways that include short-term signaling of hunger and engorgement to the central nervous system with the hormones that come from the gastrointestinal tract, long-term signaling of energy stores to the brain via leptin and insulin, as well as the control of metabolism. Rare genetic syndromes also play a role and these present in early childhood with severe obesity these include mutations in the pro-opiomelanocortin gene and deficiencies in the leptin this demonstrates that the pathways are biologically important in humans. Mo st obesity cases develop because of modern lifestyles in genetically susceptible individuals. The changes include excessive consumption of high-energy food in tandem with low levels of physical activity and that in many societies; less affluent people have a higher incidence (Lee et al 2013). Other causes of obesity that are considered include some drugs that can cause an increase in appetite and structural damage to areas of the nervous system that control appetite. Though men and women areShow MoreRelatedThe Obesity Epidemic Of Children1437 Words   |  6 Pageslink to obese children The obesity epidemic holds the responsibility to annihilate many of the health benefits that have contributed to the increased durability recognised in the world today. In 2014, approximately 41 million children under 5 years of age were affected by overweight or obesity. Today, progress in extinguishing childhood obesity has been gradual and conflicting. 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Ethics for the Real World Free Essays

string(64) " This topic was expounded clearly in the beginning of the book\." ETHICS FOR THE REAL WORLD Creating a personal code to guide decisions in work and life RONALD A. HOWARD CLINTON D. KORVER Hanle Ying Special Topics in Accounting March. We will write a custom essay sample on Ethics for the Real World or any similar topic only for you Order Now 16, 2011 Introduction Within the development of human culture, ethics has been more and more emphasized in human beings. Ethics is not only requested in the work place, but also it should be requested in individuals. Ethics is an extremely helpful in human daily life. For the work place, ethics can help people to trust each other, allow people to know clearly what they can do or not do, and assist their efforts with each other to create a true market in the world. For the individuals, ethics can help to correct people’s attitude about life and to help them build a positive outlook. However, no matter whether in the work place or in an individual’s life, ethics can create a personal code to help people to make the right decision. Reading ETHICS FOR THE REAL WORLD-creating a personal code to guide decisions in work and life not only can help us know what ethics is and how we can draft a personal code to help us make the right decision, but it also lets us know how we can use ethics to transform our life and work. It’s really a good book on ethics and very practical for human beings. This book represents the different thinking of ethics and provides a personal code for people who working; individuals can use the code of ethics to examine their own ethical problems so they can make the right decisions during work. In the real world, there are many behaviors that look ethical, but are not. Conversely, some behaviors look unethical, but are ethical. Since we cannot always discriminate what is really ethical, we sometimes have a dilemma in making a decision. However, the description in this book, expressed by the authors help us to know what ethics is and he helps us to build an ethical framework and draft a personal code in our mind. We can use the ethical framework and the personal code to help us make the right decision. The authors also demonstrate that people can use three steps to help them to clarify the ethical issue, evaluate the consequence of the behavior, and in the end, make the right decision. Moreover, ethics not only can help people make the right decision, but it also can help people to transform the work and life. Author Biography The names of the authors are Ronald A. Howard and Clinton D. Korver. â€Å"Ronald A. Howard is one of the founders of DEF, who is the academic director of the Strategic Decision and Risk Management certificate program at Stanford University. He supervises teaching and research in the Decision Analysis Program of the Department of Management Science and Engineering and he also is the director of the department’s Decision and Ethics Center. Moreover, Mr. , Howard is a professor in the Stanford Graduate School of Business. His experience covers many fields in decision analysis project, from investment planning to research strategy, and from hurricane seeding to nuclear waste isolation† (2011). Furthermore, â€Å"Mr. Howard has been a consultant to several companies and was a founding director and chairman of Strategic Decision Group† (2011). Clinton D. Korver not only is the co-author of Ethics for the Real World, but also â€Å"he is a partner and co-founder at Ulu Ventures, a Silicon Valley venture capital firm investing in early-stage information technology companies. He is also a Kauffman Fellow, co-founder and co-president of Stanford Angels Entrepreneurs, and a venture partner at Crescendo Ventures† (2008). Moreover, â€Å"Mr. Korver is the founder and CEO of DecisionStreet, which provides Web-based tools to help consumers make information life decisions about health, wealth, housing, and family affairs† (2008). Mr. Howard and Mr. Korver wrote Ethics for the Real World-creating a personal code to guide decisions in work and life in 2008. In order to create the habit of highly ethical behavior, Howard and Korver help us to know what ethics is and how we can discriminate ethical issues in our daily lives. In addition, they help us to use ethics to make the best decision in every situation. Summary of Book It’s a good book on ethics, and the authors use a practical approach to talk about what ethics is. The purpose of the authors in this book is not to stimulate people to get high ethics in their mind. Contrarily, they want people to know and study ethics through the tiny little things around us. People do some things or make some decision unethically because they think he decision seems unimportant; however, they still want others to respect and trust them. They even want to continue live in a harmonious environment. But their actions and thoughts are reversed. As a result, this is one of the reasons why people sink into the ethical dilemma. The book provided many theories to help people to understand and study ethics, such as some behavior seems ethical for one, but he still has to confirm if it’s ethical for another; one could look analyze another’s ethical behavior when one sinks into the ethical dilemma; and one could set up an ethical code to help him to correct his ethical problems. But the one of reason why people do the unethical things are they often misunderstand the meaning of ethical, legal, and moral. Someone considered poor ethical as poor moral. Also the legal behavior is considered ethical, and illegal behavior is considered unethical. Actually, there is a total difference between ethical, legal, and moral. Something could be legal, but it’s unethical, such as lie, using profanity to someone. Something could be illegal, but it might be ethical, such as killing terrorists. Therefore, the most important issue for people when knowing ethics is to be able to discriminate the meaning of ethical, legal, and moral. This topic was expounded clearly in the beginning of the book. This book combined four parts: Introduction, seven chapters, an epilogue, and two appendices. Furthermore, the authors combined these four parts very logically, especially in the seven chapters. The authors provided the almost ethical at first, and give a roughly ethical frame in people’s mind, through know and study the ethics to create the personal code. And then use the personal code to do the ethical behavior or make the ethical decision. In the end, the authors demonstrate that the ethics can help people transform their work and life. This sequence is coincidence with people’s thinking and easier to be understood by people. The Introduction not only reflects the rough content of the rest of the book, but it also includes a short summary of each chapter, the engineering approach, and the clarification of the difference between ethical, legal, and moral. Moreover, it also includes the experience of both authors. This introduction is very helpful for people to know what the book is and how to use this book. In addition, the introduction also talks about the skill of making the right decision, it is a weakness we often have because we have little education in this area. The seven chapters can be divided into four parts: the first three chapters, the fourth chapter, the fifth chapter, and the last two chapters. The first three chapters represent what ethics is and the problem of setting up an ethical bottom line. Actually, ethics is not very strange for each person; everyone has a rough framework about ethics, but most of us don’t know the real meaning of ethics. Everyone wants to be an ethical person, and most people have an ethical bottom line to contrast their ethical behavior. This bottom line is very important for each person. But people always sink into the ethical trouble because the ethical bottom line. Certainly, someone utilize this bottom line and the loopholes in the law to build a gray area, doing something between right and wrong. Everybody knows that to tell a lie is unethical behavior, but some use white lies to prevent crime or war; why not? I think most of us would rather to tell this lie. Therefore, there are no fixed rules for people to study ethics. People should learn and analyze the ethics of other’s ethical behavior and set an own ethical bottom line to do the right things or decisions. The fourth chapter is based on the first three chapters. After people know what ethics is and set up an ethical bottom line to distinguish what they can do or not do, they should create their own ethical code to complete their ethical framework. The main purpose of the fourth chapter is to show people how to draft someone’s own ethical code. The fifth chapter talks about how some people to do nothing when facing unethical issues. Although people can make the ethical code by themselves, it does not mean they will be ethical all the time. In this situation, people have to re-clarify the ethical issue and try to create alternatives. Moreover, in order to ensure the feasibility of their alternatives, people have to evaluate the alternatives and then re-make the ethical decision. The last two chapters stated how people use their personal ethical codes to transform their personal life and work life. Having a good ethical code is very important to our daily lives. It not only helps us to distinguish what we can do or not do, but also it can make us face life and work peacefully. This has the most positive effect on our daily lives. The book is composed by the skill of ethical thinking and the ethical decision making. The main purpose in the Epilogue stated how people developed the habit by this skill. However, the habit is developed through constant practice, and the practice is directed by thoughts. Therefore, having good ethical thinking skills not only can help people to make the ethical decision, but also can help develop the right habit in their life. The Appendix A is the flow chart of ethical decision making process which not only helps us know better what ethics is, but also we can use this flow chart to compare our ethical frame to correct and complete our weakness in ethics. The Appendix B talks about the three people’s ethical code that has totally different backgrounds. And the Appendix B let us know no matter what background people have, as long as they are willing to understand and study ethics, they can possess the ethical code. Personal Reflection and Conclusion I always ask myself what does ethics mean? What kind of action belongs to ethical or unethical? Is any behavior within laws ethical issue? However, we have to face ethical decisions in our daily lives, and we always sink into the ethical dilemma because of these decisions. For example, we will make some excuses to avoid trouble, and we will use some white lies to make others feel more acceptable. We always ignore ethics in some trivial things, and ethics becomes strangers around us. This book has very helpful to me. I know that I am not a real ethical man. For example, I used fake excuses to explain my absences; or a bad grade to my parents, as well as use profanity to someone. Now all these behaviors seem wrong. In the past time, I always use different excuses to avoid responsibility when I got into some troubles, and put all the blame upon someone or something else. Now I think carefully; avoiding responsibility is unethical behavior. Individual development and social development should not lack communication and responsibility. If everyone is not sincere and they choose to avoid responsibility when faced the trouble, the individual and social development cannot be achieved, not mention to creating a real life environment. Therefore, building a good personal code is very important to everyone. We are always bothered by the issue that seems ethical, but indeed it’s not. Different people have different values, so they have different ethical lines. Some consider that the white lie is moral; someone may consider that the rational avoidance tax also is moral. People always abandon their principle to do some things which they consider are ethical, but indeed they are not. Thus, people slowly lose their moral bottom line because of these tiny little issues, and then, make them into the gray areas to do something that seems legal, but indeed it’s unethical. If everyone stays in the gray area, nobody will be honest with each other anymore. Therefore, in order to correct our values and life attitude, we should build a personal code which cannot be broken by any excuses. Before doing anything or making any decision, we should consider own personal code and use it to restrain our behaviors, which give us no excuse to do anything that violates ethics. The authors Ronald A. Howard and Clinton D. Korver together created Ethics for the Real World-creating a personal code to guide decisions in work and life, they clearly define what ethics is and use bright black and white contrast to make us know better the meaning of ethics. Moreover, because of the sufficient experience, the essence of this book is easier to be accepted and studied and has a profound meaning in our daily work and life. The reason why I choose this book is I am always bothered by the ethics bottom line in the daily work and life. Sometimes ignore ethics because of the tiny little things. As a result, I slowly lose my ethics bottom line. Now think carefully; this is a wrong behavior and life attitude. This book opened my eyes; it teaches me that not only everyone should have their own ethical code and personal code, but also we should build our principle to do everything. No matter when we do anything or make decisions, we should base them on this personal code. Let our life be surrounded by ethics. Reference Clinton D. Korver, Bloomberg Businessweek, 2008, Retrieved from: http://www. businessweek. com/bios/Clinton_D. _Korver. htm Clinton D. â€Å"Clint† Korver’89 2001, Grinnell College, 2008, Retrieve from: http://www. grinnell. edu/offices/president/trustee/memberintro/korver Ronald A. Howard, Decision Education Foundation, 2011, Retrieve from: http://www. decisioneducation. org/about-DEF/board-of-directors/ronald-howard How to cite Ethics for the Real World, Papers

Mammography free essay sample

A look at the history of mammography and its benefits. This paper addresses the history of mammography, new developments and technological improvement, and a discussion of the benefits and supporting statistics of increased mammogram use to increase womens quality of life. Mammograms have saved the lives of tens of thousands of women over the past 20 years. While not perfect, their ability to detect small tumors gives doctors and their patients the option of treating the cancer while it is in an early, more curable stage. Carcinoma of the breast remains a serious threat to womens health as we enter the 21st century. Breast cancer is the most common female malignancy excluding skin cancers, the number one cause of premature death in women, and the send most common cause of death from cancer. Approximately 1 of 8 women will have breast cancer during her lifetime, and one of 30 will die of the disease (American Cancer Society, 1995). We will write a custom essay sample on Mammography or any similar topic specifically for you Do Not WasteYour Time HIRE WRITER Only 13.90 / page