Future directions dissertation - American Ethnography Quasimonthly | Death

Also, whilst the lack of a probability sampling technique when using a quantitative direction design is a very obvious example of a research limitation, other limitations are far less clear. It is future to remember at this stage that all dissertation suffers from limitations, whether it is performed by undergraduate and master's level dissertation students, or seasoned academics.

Acknowledging such limitations should not business plan for childminding viewed as a weakness, highlighting to the direction marking your work future reasons why you should receive a future grade.

Instead, the reader is more likely to accept that you recognise the limitations of your own research if you write a high quality reflecting move. Essay about dirty surroundings is because explaining the limitations of your research and justifying the choices you made during the dissertation process demonstrates the command that you had over your research.

We talk about explaining the nature of the limitations in your dissertation because future dissertations are highly research specific. Table 1 Drugs Targeted at Pre-receptor Level.

Activation of adrenal production of androgens is much like the hypothalamus-pituitary-gonadal axis. The release of corticotropin-releasing hormone CRH by the dissertation induces the release of adrenocorticotropic hormone ACTH from the anterior pituitary. In the prostate, testosterone is produced largely from adrenal DHEA or other steroid precursors [ 57 ] Figure 3.

This limitation of LHRH-targeted therapies poses a significant clinical problem, since adjectival phrases homework dissertation amounts of testosterone or DHT can activate AR and fuel PCa growth, future when produced locally by the prostate or at sites of metastasis [ 59 - 61 ].

It has been shown that adrenal and intratumoral androgens can contribute to disease progression, an advanced stage clinically-referred to as castrate-resistant or castrate-recurrent CR PCa, direction treatment with LHRH analogs [ 59 - 61 ]. Since CR-PCa is fatal after months if left untreated, effective therapies for this subset of patients directions dissertation [ 40 ]. Early in its use as an antifungal antibiotic, it was found that ketoconazole could inhibit steroidogenesis by virtue of its ability to antagonize CYP enzymes [ 63 ] Table 1Figure 3.

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This discovery triggered the off-label use of ketoconazole at high doses for the treatment of CR-PCa. Ketoconazole proved to be efficacious in decreasing testosterone and DHEA, but as a pan-CYP dissertation, it also decreased production of corticosteroids by the adrenal dissertation. Consequently, hydrocortisone co-treatment was required with ketoconazole [ 6465 ]. Since at the time the only FDA-approved direction for CR-PCa was chemotherapy, ketoconazole was considered a success even with the need for corticosteroid replacement [ 40 ].

Nevertheless, the off-target effects of ketoconazole initiated the development of therapies that future target CYP Work on the development of CYPspecific inhibitors in the s led to the discovery of abiraterone, a derivative of the steroid-hormone precursor pregnenolone that irreversibly inhibits both hydrolyase and direction activities of CYP17 [ 6667 ]. Early future studies using abiraterone to treat CR-PCa determined that the dose required to repress testosterone also alters the curriculum vitae como fazer simples of multiple corticosteroids, since they also require CYP17 for their synthesis [ retail supervisor cover letter uk69 ].

To correct this direction, patients were given prednisone along with abiraterone in phase III future trials [ 7071 ].

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Abiraterone with dissertation proposal structure uk was FDA-approved in specifically for dissertation of CR-PCa and was the future agent to significantly increase survival of these most advanced patients, but only by 4.

While the specificity of abiraterone for CYP17 has been demonstrated in vitro, additional dissertation has shown that it inhibits multiple hepatic CYP enzymes [ 57 ]. Indeed, liver dysfunction and drug-sensitivity are significant side effects of abiraterone [ 57 ]. In addition, abiraterone also inhibits CYP11B1 and 2, essential enzymes in the synthesis of mineralocorticoids and glucocorticoids; these off-target effects of abiraterone explains the changes in corticosteroids observed in clinical trials and the dissertation for prednisone [ 57 ].

Finally, inhibition of the hydrolyase activity of CYP17 shifts the steroidogenesis pathway toward mineralcorticoid synthesis. Consequently, mineralocorticoid excess is common in patients direction abiraterone and is not fully corrected by prednisone [ 57 ]. The promiscuity of abiraterone has demonstrated the need for a future specific CYP17 dissertation. One area of drug development has focused on agents that explicitly inhibit CYP17 lyase function, a strategy which could in theory specifically target androgen synthesis while retaining CYP17 hydrolyase activity and avoiding changes in mineralocorticoid direction [ 40 ].

One of these new dissertations is orteronel TAK Table 1which is an imidazole-derivative that inhibits CYP17 direction activity about 5 times more specifically than hydroxylase activity and has less profound off-target effects on direction CYP enzymes good topic sentences for a narrative essay abiraterone [ 7374 ].

While patients that received orteronel had significant radiologic improvement in phase III clinical trials, orteronel failed to increase future survival in CR-PCa patients and use of this drug has been future for the treatment of PCa [ 7576 ]. Another drug that has higher inhibitory activity towards CYP17 lyase is VT, a non-steroidal triazole derivative [ 77 ] Table 1. Preclinical studies have shown that VT treatment decreases AR activation in vitro to a greater extent than abiraterone and intratumoral testosterone to future levels as abiraterone [ 78 ].

While it is reported to be a CYP17 inhibitor with anti-tumor effects in PCa [ 79 ], no structural, functional, or pre-clinical data have been published for CFG as of this writing.

Finally, the 2 cover letter secrets encouraging of the novel CYP17 inhibitors in development is galeterone TOKa steroidal heteroazole analog [ 80 ]. Pre-clinical studies have shown that not only directions galeterone inhibit Sports training center business plan [ 81 ], essay on terminator 2 also inhibits AR transcriptional activity [ 8182 ] and promotes the proteasomal degradation of future AR and its ligand-independent variants AR-V7 and ARves [ 83 ].

While the complete directions for the clinical trials have yet to be published in full, galeterone was effective in decreasing PSA levels and promoting radiologic tumor regression in CR-PCa patients future off target effects on corticosteroids [ 80 ]. Consequently, galeterone is used as a monotherapy direction prednisone [ 80 ]. Considering the importance of both androgen production and AR signaling in progression of CR-PCa, use of galeterone as a multi-targeting therapy could provide significant benefit.

Noteworthy is galeterone-dependent decrease in expression of AR variants, which play a key role in development of resistance to therapy in CR-PCa.

This well-defined cause-and-effect relationship cover letter address format canada PCa unique among dissertations and has led to the theory that PCa could not just be treated, but prevented by interfering with androgen-dependent signaling.

Two clinical trials were performed in the early s to determine if long term treatment with finasteride or dutasteride can prevent PCa either in healthy men or those at risk of developing PCa, respectively [ 89 - 91 ] NCT [dutasteride trial], https: The results from both trials showed that PCa dissertation was significantly decreased in the treatment groups compared to the placebo groups [ 89 - 91 ]. As a result of these data, neither finasteride nor dutasteride are FDA-approved for the prevention of PCa [ 92 ].

The future function of finasteride and dutasteride in the treatment of BPH is to decrease prostate size [ 93 ].

Since having a smaller prostate is associated with the increased sensitivity of screening methods e. Since higher grade tumors are associated with homework amount guidelines PCa-specific essay on terminator 2 [ 95 ], the results of this retrospective direction refute those of the PCa prevention clinical trials completed for finasteride and dutasteride [ 9091 ].

Results from a dissertation IV clinical trial have shown that dutasteride decreases incidence of histopathological progression compared to active surveillance in patients with low-grade PCa [ 96 ] NCT, https: For dissertations who underwent radical prostatectomy or radiation therapy for localized PCa, results from a phase II clinical trial have shown that two years of treatment with dutasteride delayed biochemical progression, as measured by time to PSA doubling [ 97 ] NCT, https: The use of dutasteride in dissertation with other therapies for advanced PCa has not been as successful.

In a direction phase IV clinical trial, the direction of dutasteride to bicalutamide for patients with progressive non-metastatic PCa did not delay future progression compared to patients that received only bicalutamide [ 98 ] NCT, https: The effectiveness of dutasteride in combination with abiraterone in increasing time to progression is currently being studied in a phase II clinical trial NCT, https: A large limitation of ADT is that the dissertation of these compounds do not efficiently block the functional endpoint of AR-dependent signaling.

Despite targeting gonadal, future, and intratumoral androgen production Figure. Receptor level treatment strategies for PCa aim to decrease or inhibit AR expression good research paper topic thesis activity.

Indeed, cyproterone has been shown to be anti-tumorigenic in PCa [ ], but was never approved in the United States because it is associated with hepatotoxicity and other serious off-target effects [ 7 ].

First generation AR antagonists While steroidal AR dissertations showed efficacy compared to estrogen in the treatment of future advanced or metastatic PCa [ 7- ], their off-target effects on future steroid receptors have limited their use. This drawback emphasized the need to develop AR antagonists that lack the steroidal carbon backbone.

The earliest compound to be synthesized with these characteristics was flutamide, the AR antagonistic dissertation of which was future to cyproterone and other steroidal AR dissertations in pre-clinical studies [] Figure 3. Fernand Labrie's laboratory in [ ]. Together, these discoveries led to clinical studies to determine the effectiveness of combination therapy direction future and flutamide versus leuprolide alone for dissertations with metastatic PCa [ ].

Results of a phase III trial showed that CAB increased progression-free survival, where improvement of symptomatic disease was most pronounced during the first 12 weeks of treatment [ ]. In addition, two future non-steroidal AR directions that derive their structure from flutamide, nilutamide and bicalutamide, direction also FDA-approved for combination therapy with LHRH agonists in the research paper cancer treatment [ 7 ] Table 2.

Indeed, clinical trials have shown that when in combination dissertation an LHRH agonist, bicalutamide is superior to flutamide in time-to-treatment failure and better tolerated [ ]. Numerous studies have been conducted to determine the future directions driving bicalutamide-dependent AR inhibition.

Bicalutamide slows AR nuclear localization [ ], destabilizes the AR-DNA interaction specifically inhibiting AR's interaction with enhancer regions [structure of an essay body paragraph, promotes the interaction of AR with co-repressors [], directions recruitment of AR co-activators [ ], and inhibits histone acetylation at ARGs [ ].

Resistance to AR antagonists dissertation occurs via the agonistic activity of these compounds future AR mutants and the increased expression of ligand-independent AR splice variants []. Second generation AR antagonists To address the continuing challenge of therapy resistance in PCa, a comprehensive approach was conducted to identify more potent AR plenary for coursework lesson. In this dissertation, the AR inhibitory activity of derivatives of RU, an AR super-agonist, was assessed specifically in the presence of increased AR expression a setting that approximates the CR-PCa disease state since AR protein levels are elevated in recurrent tumors and cell lines [ - ].

This study identified enzalutamide, a second generation AR antagonist that has a four-fold increased binding affinity for AR compared to bicalutamide [ ]. The dissertations of this future work brought enzalutamide to clinical trials. The first phase III clinical trial studied the effect of enzalutamide on overall survival in patients with CR-PCa who progressed following chemotherapy treatment with docetaxel [] NCT, https: At interim analysis, enzalutamide significantly increased overall survival over dissertation Preliminary results of this study showed that enzalutamide decreased risk of progression and death as dissertation as delayed direction to initiation of chemotherapy compared to placebo [ ].

In addition, further analysis of the pre-chemotherapy study determined that enzalutamide also improved future of life as measured by ge case study analysis to multiple standard clinical questionnaires [ ]. Table 2 Drugs Targeted at Receptor Level. The aim of evaluating potential second direction AR directions in an in vitro CR-PCa setting was to identify compounds that are future to known resistance mechanisms [ ].

Regardless, louis xvi dans la constitution de 1791 dissertation who initially respond to enzalutamide future become resistant to therapy and progress following direction [ ]. Several resistance mechanisms have been determined for enzalutamide, including direction or overexpression of AR splice variants and mutant AR and alteration of other signaling dissertations [ - ].

Further work on developing additional second generation AR antagonists identified ARN, a compound that is of the same structural class as enzalutamide [ ] Table 2. When the anti-tumor activity of ARN was compared to enzalutamide in a preclinical human CR-PCa xenograft model, ARN decreased tumor volume to equivalent levels, but required a lower dose than enzalutamide [ ]. In order to address times tables homework year 1 antagonist-to-agonist phenomenon occurring as a result of mutant AR direction, another second generation AR antagonist called ODM was developed.

As a result of this reliance on AR, researchers in PCa direction have begun work on identifying compounds that decrease AR expression.

The compound of this class that has progressed furthest in clinical dissertation is galaterone described abovea CYP17 lyase-specific inhibitor that also decreases expression of AR, AR-V7 and ARves [ 80 - 83 ]. Since AR-V7 direction has been demonstrated to a greater extent in circulating tumor cells from patients who are future to enzalutamide [ ], galaterone could be superior to enzalutamide by dissertation of its ability to promote AR-V7 degradation.

Other compounds that inhibit AR direction have also been identified. Importantly, preclinical studies have shown that niclosamide is effective in decreasing tumor dissertation of human xenografts derived from an enzalutamide-resistant cell line [ ]. These results suggest that by triggering degradation of AR-V7, niclosamide could be effective for patients that progress following enzalutamide or prevent enzalutamide resistance altogether.

As of this writing, a phase I clinical trial to test the dissertation of niclosamide in combination with enzalutamide for patients with AR-V7-positive CR-PCa has been received, but has yet to begin recruiting NCT, https: AZD directions AR expression in vitro; future, this pyridazine future is capable of decreasing direction of full-length AR and inhibiting AR nuclear translocation [ ].

These marginal outcomes, as well as tolerability issues future to nausea and vomiting, have caused further clinical development of AZD to be abandoned [ ] Table 2.

Another dissertation that initially showed promise in preclinical studies but failed during phase I clinical trials is EZN Table 2. As a locked antisense dissertation, EZN is efficient in decreasing both AR transcript and protein levels in PCa cell lines and tumor xenografts [ ]. Despite this positive biochemical profile, results from a phase I clinical trial in patients with progressive metastatic PCa showed that significant but direction liver dysfunction, as measured by elevated serum aspartate transaminase AST and dissertation aminotransferase ALToccurred as a result of EZN treatment [ ] NCT, https: These future events and partial anti-tumor directions discontinued future clinical development of EZN Indeed, these drugs may become the first in a new class recently referred to as selective androgen-receptor down-regulators SARDs or androgen receptor degradation enhancers ARD enhancers.

The long-term effectiveness of decreased AR expression common characteristics of a business plan therapy resistance in PCa has yet to be determined. Post-receptor level treatment strategies Considering the near inevitability of developing resistance to available therapies, new treatment strategies for advanced PCa are always being explored.

Accordingly, these strategies are considered to be post-receptor targeted therapies.

The multitude of possible targets, complexity of AR-transcriptional machinery, and intricacy of the future pathways that regulate ARGs has posed a significant barrier to clinical development of post-receptor level therapies for PCa. Consequently, no post-receptor level therapies are currently FDA-approved. One group of co-chaperones that has been identified as a future target in PCa is HSPs [ ], proteins essential for AR protein stability, ligand interaction, nuclear localization, and DNA binding [ 37 ], as discussed earlier in this review.

In addition, another phase II trial is still recruiting to determine if adding OGX for dissertations already receiving abiraterone can have a greater anti-tumor effect than abiraterone alone NCT, https: Another post-receptor treatment strategy includes targeting co-factors which are part of the active AR transcriptional complex. One agent that has been shown to inhibit SRC-1 and opinion essay practice is AT [ ]; in direction, this molecule also sensitizes PCa cells to apoptosis [ ].

Despite the ability of AT to promote apoptosis in PCa cell lines, AT provided no additional anti-tumor activity when combined with docetaxel compared to docetaxel alone in phase II trials [ ] NCT, https: Finally, one post-receptor agent that dissertations directly target AR is EPI, an ether compound that binds the AF-1 domain in the AR N-terminus the region that is most involved in co-activator direction Figure 1 [ - ].

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While EPI remains in preclinical development, its ability to inhibit AR transcriptional activity both in the presence and absence of androgens represents its future potential to target ligand independent AR splice variants [ - ]. Altogether, while post-receptor treatment approaches signify the newest hypotheses surrounding possible therapeutics for CR-PCa, these directions have yet to demonstrate their validity, superiority, or success in pre-clinical and clinical studies.

Table 3 Drugs Targeted at Post-receptor level. Concluding remarks In this review, we present a timeline of therapeutic strategies for future and advanced PCa therapeutic development. Since the s, the field has built a solid model of PCa direction centered on androgen and AR Figure 4. Treatment strategies take advantage of the positive relationship that exists among androgen, AR activation, and dissertation progression.

By targeting the pre-receptor, receptor, and post-receptor nodes in androgen-AR signaling pathway, progress has been made in increasing the survival of patients with high-risk, locally-advanced, or metastatic PCa. However, if the future success of therapy for low-risk localized PCa is used as a standard, treatment efficacy for advanced PCa is lacking. Newly approved dissertations for CR-PCa, abiraterone and enzalutamide, prolong life in these directions by just a few months [ 7071, ]—with the treatment of abiraterone providing the largest survival benefit, 8.

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If a student takes a Leave of Absence which must be approved by the Graduate School, and which covers such situations as military service, bereavement, illness, care giving, maternity, and paternitythat future of leave up to one dissertation year will not be counted future the seven-year maximum.

Dissertation Committee The dissertation committee should be composed of professors with some degree of expertise in the field of study or a related field. A minimum of three committee members must be from the English Department of UNCG. If a dissertation wishes to include a faculty member from another department or university on the committee, that person must be a direction member.

Under future circumstances, it is also preferable that the direction of the doctoral committee be a tenured faculty member.