What effects does parental involvement have on low income families or Annotated Bibliography

What effects does parental involvement have on low income families or Does parental involement have an effect on educational achievement - Annotated Bibliography Example including economic demographics, genetic predispositions, overall intelligence, and social factors, like parental involvement. The latter is a fascinating element. A parent’s active involvement in their children’s schooling can have a profound positive impact. There is however, a balance that needs to be achieved; after all too much parental involvement can be detrimental, depending on how that involvement is applied. The articles reviewed for this discussion allow for a thorough and balanced perspective on the topic. These sources, as a whole, were not particularly difficult to obtain. Google search provided a number of online accessible journal sources, simply, by applying the keywords, â€Å"parental involvement and student achievement.† Combined together these sources give a broader area of research and contributes to understanding of the relevant facts and allow for an unbiased viewpoint to answer the applicable questions of this issue. This article intended to determine how relevant parental involvement, or lack of, truly has on elementary school age children in the 1st, 3rd and 5th grades. The authors propose that, although, the immense amount of research has shown that parental involvement is imperative, hugely impactful, and should be encouraged, most research cannot say with absolutely certainty that involvement effects overall academic achievement.(El Nokali, Bachman & Votruba-Drzal, 2010) There is a definite correlation between less â€Å"bad† classroom behavior due to parental involvement and can aid in social development, but not directly on academic achievement. This article is a very interesting source. It is useful in that it approaches the correlation between parental involvement and academic achievement with a skeptical eye. Parental involvement is important and should be recommended, but it may not be a guarantor that it will ensure a

Blood Alcohol Content Essay Example for Free

Blood Alcohol Content Essay The thought of alcohol being involved in fatal crashes brings about an emotional response. Recently, there has been a movement based on emotion rather than logic to change a certain drinking and driving law. This involves lowering the Blood Alcohol Content (BAC) from 0. 10% to 0. 08% nationwide. However, this attention is misdirected. By looking at my personal experiences, statistics, and current laws, it is clear that there is no need for lowering the BAC. First off, I do not drink. Yet, I’ve had many experiences relating to drinking and driving through my friends. One thing I’ve noticed is that it is extremely hard for people to tell if they are legally drunk or not. Furthermore, I have never heard any of my friends say that they feel that they should drive home because they have only a . 09% BAC. The law has very little effect on how many drinks a person decides to consume. Therefore, lowering the legal drunk limit will not result in people acting more responsible. Supporters of lowering the BAC like Judith Lee Stone in her essay â€Å"YES! † think they are targeting the problem of drunken driving, but the real problem lies within the higher BACs. Ninety three percent of fatal accidents are 0. 10% BAC and above, and half of those ninety three percent have a BAC of 0. 20% and above. The average BAC for fatal accidents is at actually at 0. 17%. This seems like a more logical target for new laws then 0. 08%. Furthermore, Stone asks â€Å"Who would want their children in a car driven by someone who has consumed three, four, or even more beers in an hour† (Stone 46)? I couldn’t agree more. However, this common argument from the pro-0. 08% side is more like a parent responsibility question. They use this to manipulate our emotion by putting an innocent child in an improbable and unrelated situation. She also goes on to state, â€Å"A study at Boston University found that 500 to 600 fewer highway deaths would occur annually if all states adopted 0. 08%† (Stone 47). On the other hand, a similar study at University of North Carolina shows no significant change after their adoption of 0. 08%. Which study is correct? Most likely, both have some truthfulness. It could be either way depending on the state. The lowering of the Blood Alcohol Content percentage law is unnecessary and useless. Nevertheless, some states have already moved to the 0. 08%, and we hear the argument: â€Å"It makes no sense for a driver to be legally drunk in one state but not in another† (Stone 46). To that, I ask a couple questions of my own. Why can I carry a concealed gun in one state and not another? Why is it that I can drive a certain speed in one state, but a different speed in another? The response to those questions and Stone’s statement is all of the above are state laws. At this point, the federal government seems to get confused. In October 2000, congress passed a law that uses the states’ money against them. It asserts that if a state doesn’t lower its BAC percentage to 0. 08% by 2003, it will lose two percent of its highway money. States that don’t like the law will be forced to vote for it because they are desperate for highway construction money. Strings shouldn’t be attached to this money. What are lost in all of this are the current laws for drunk driving. Driving while impaired is already illegal whether the person tests 0. 04% or 0. 10%. Courts can use alcohol test of 0. 04% and higher as evidence of impairment. It’s at 0. 10% where a person is legally drunk and cannot legally operate a vehicle. Therefore, it’s not as if people who test 0. 08% are going unpunished like the other side would have you believe. In conclusion, anybody who picks out one particular aspect and says that it is not working hasn’t looked that the whole problem. The president for the Insurance Institute for Highway Safety, Brian O’ Neill, says that he’d rather see resources directed toward enforcing existing drunken driving laws. Hopefully, with more education, more awareness, and more enforcement we can successfully reduce drinking and driving fatalities. Bibliography Stone, Judith Lee. Yes!. Reading and Writing Short Arguments. Ed. William Vesterman. Mountain View, California: Mayfield Publishing Company, 2000. 46-47. Word Count: 702.

Mechanisms drug resistance to cancer chemotherapy

Mechanisms drug resistance to cancer chemotherapy Introduction Cancer is one of the major causes of death in the developed world and statistics show that one in three people will be diagnosed with cancer during their lifetime [1]. Cancers are malignant tumours and can be distinguished from normal cells by four characteristics; uncontrolled proliferation, dedifferentiation and loss of function, invasiveness, and ability to metastasise [2]. These characteristics are caused by altered gene expression, as a result of genetic mutations that inactivate tumour suppressor genes and / or activate oncogenes. Most cancer chemotherapeutic drugs affect only one characteristic aspect, which is uncontrolled proliferation [3]. In many cases the antiproloferation action is caused by damage to DNA, which initiates apoptosis and cell death [4]. As their main target is cell division, they affect all rapidly dividing cells, including normal cells. This produces general toxic effects, such as myelosuppression, alopecia, damage to gastrointestinal epithelium, sterility and severe nausea and vomiting. Besides the toxic effects of chemotherapy, another major problem is chemoresistance [5]. Resistance to chemotherapy is when the cancer cells do not respond to the drugs. It can be inherented, as a genetic mutation, or it can be acquired, as a cellular response to drug exposure. Mechanisms of resistance include: increased efflux or decreased influx of cytotoxic drugs; insufficient activation of the drug; increased inactivation of the drug; increased concentration of target enzyme; rapid repair of DNA lesions; or mutations in various genes. When patients develop resistance, multiple drugs with different pathways of entry and different cellular targets are used. However, cancer cells can become multidrug resistant, a phenomenon due to cells expressing mechanisms that cause simultaneous resistance to many different, structurally and functionally, unrelated drugs [6]. Multidrug resistance, generally, results from over expression of ATP-dependent efflux pumps [5]. These pumps have broad drug specificity and belong to a family of ATP-binding cassette (ABC) transporters, of which P-glycoprotein (PGP) is one of the most important members. Increased drug efflux, via these transporters, lowers intracellular drug concentration, allowing cancer cells to escape the toxic effects of the drugs. PGP inhibitors are being developed to overcome multidrug resistance and two that have reached clinical trials are varapamil, a calcium channel blocker, and cyclosporin A, an immunosuppressant [7]. The remainder of this review will focus on the different chemotherapeutic agents currently being used for the treatment of cancer and their mechanism of action. Also the main mechanism of resistance to these drugs will be explored, particularly focusing on the role of P-glycoprotein and how it can be modulated to reverse drug resistance. Drugs used in cancer chemotherapy Drugs used in the treatment of cancer are summarised in table 2. They are grouped into: cytotoxic drugs, which preferentially but not exclusively target rapidly dividing cancer cells; hormone therapy, which is a more specific form of treatment used for tumours derived from hormone sensitive tissues; and miscellaneous agents, which include a number of recently developed drugs such as monoclonal antibodies. Cytotoxic drugs Cytotoxic drugs can be further divided into the following; alkylating agents, which act by forming covalent bonds with DNA and impeding replication; antimetabolites, which block one or more of the metabolic pathways involved in DNA synthesis; cytotoxic antibiotics, which are of microbial origin and prevent cell division by directly acting on DNA; and plant derivertives, which affect microtubule function and hence the formation of the mitotic spindle. Alkylating agents Alkylating agents form carbonium ions, which are highly reactive and interact instantaneously with nucleophilic sites such as N7 of guanine in DNA [8]. They are bifunctional, which means they have two alkylating groups, and can cause intra- or inter-chain cross-linking between DNA strands. This prevents strand separation for DNA synthesis or transcription. They can also cause base mispairing between strands, which interferes with the progression of the replication fork [3]. These actions block DNA synthesis, causing a block at G2 phase and subsequently apoptotic cell death. Alkylating agents currently being used in chemotherapy primarily belong to the following families: nitrogen mustards (Cyclophosphamide, Chlorambucil, Melphalan, Ifosfamide, Busulfan); nitrosoureas (Carmustine, Lomustine, Fotemustine); aziridines (Thiotepa); Dacarbazine and platinum compounds (Cisplatin, Carboplatin, Oxaliplatin) [9]. Nitrogen mustards, nitrosoureas and aziridines are believed to kill tumour cells by inducing DNA inter-strand cross-links, while platinum compounds induce intra- and inter-strand cross-links, as well as DNA-protein cross-links under certain circumstances [8]. Resistance to these drugs can develop as a result of cancer cells rapidly repairing drug induced lesions [10], which will be discussed in detail later. Antimetabolites Antimetabolites interfere with the metabolic pathways involved in DNA synthesis. An example of an antimetabolite is Methotrexate, which is a folate antagonist [11]. Folates are essential for the synthesis of purine nucleotides and thymidylate, which in turn are essential for DNA synthesis and cell division. Folates are actively taken up into cells by the reduced folate carrier (RFC), where they are converted to polyglutamates. Polyglutamate folates are then reduced to tetrahydrofolate (FH4) by the enzyme dihydrofolate reductase (DHFR). Methotrexate exerts its action by being taken up into cells by the follate carrier, and like folate being converted to the polyglutamate form. It has a higher affinity for DHFR than the endogenous folate and thus inhibits the enzyme, depleting intracellular FH4, and therefore hindering DNA synthesis. Another example of an antimetabolite is Fluorouracil, which is a pyrimidine analogue [12]. It interferes with DTMP synthesis by forming a ternary complex with thymidylate synthetase (TS); the enzyme that produces DTMP. DTMP is required for the synthesis of DNA and purines, so the irreversible inhibition of the enzyme by fluorouracil results in is inhibition of DNA but not RNA or protein synthesis. Fludarabine is a purine analogue, which is another group of antimetabolites [13]. It is metabolised to its triphosphate form, which inhibits DNA polymerase. As well as the general side effects associated with chemotherapy, patients may develop resistance to antimetabolites; due to a decreased amount of drug uptake [14] or altered concentration of target enzymes [15], which will be discussed later. Cytotoxic antibiotics Cytotoxic antibiotics, such as the anthracyclines (Doxorubicin, Idarubicin, Daunorubicin, Epirubicin, Aclarubicin, Mitoxantrone) bind to DNA and inhibit both DNA and RNA synthesis [16]. Their main cytotoxic action is mediated through an inhibitory effect on topoisomerase II, the activity of which is markedly increased in proliferating cells. During DNA replication, reversible swivelling needs to take place around the replication fork in order to prevent the daughter DNA molecule becoming inextricably entangled during mitotic segregation [17]. The swivel is produced by topoisomerase II, which nicks both DNA strands and subsequently reseals the breaks. Doxorubicin intercalates in the DNA, and its effect is in essence, to stabilise the DNA-topoisomerase II complex after the strands have been nicked, thus halting the process at this point [18]. Dactinomycin is also a cytotoxic antibiotic, which intercalates in the minor groove of DNA, interfering with the movement of RNA polymerase along the gene and thus preventing transcription [19]. Bleomycins are a group of metal-chelating glycopeptide antibiotics that degrade preformed DNA, causing chain fragmentation and release of free bases [20]. This action is thought to involve chelation of ferrous iron and interaction with oxygen, resulting in the oxidation of iron and generation of superoxide and/or hydroxyl radicals. They are most effective in the G2 phase of the cell cycle and mitosis, but are also active against non-dividing cells, that is cells in the G0 phase. This class of drugs cause resistance by altered activity of topoisomerase II, aswell as reduced uptake of the drugs [21]. Plant derivatives One sub group of plant derivatives is the vinca alkaloids, which includes Vincristine, Vinblastine, Vindesine and Vinorelbine [22]. They bind to tubulin and inhibit its polymerisation into microtubules. This prevents spindle formation in dividing cells, which causes arrest at metaphase. They also inhibit other cellular activities that involve microtubules, such as leucocyte phagocytosis, chemotaxis and axonal transport in neurons. They are relatively non-toxic in comparison to the previously mentioned cytotoxic drugs. Another group of plant derivatives is the taxanes, which include Paclitaxel and Docetaxel [23]. They act on microtubules by stabilising them, in effect freezing them in the polymerised state, which achieves a similar effect to that of the vinca alkaloids. Campothecins is another group of plant derivatives and include Irinotecan and Topotecan [24]. They bind to and inhibit topoisomerase I; high levels of which occur throughout the cell cycle. Hormone therapy Tumours derived from hormone sensitive tissues may be hormone dependent [25]. This is due to the presence of steroid receptors in the malignant cells. Their growth can be inhibited by agents with apposing actions, hormone antagonists or drugs that inhibit the endogenous hormone synthesis. The most important group of drugs used to treat cancer are the steroids, namely the glucocorticoids (Prednisolone and Dexamethasone), oestrogens (Diethylstilbestrol and Ethinyloestradiol) and gonadotrophin-releasing hormone analogues (Octreotide and Lanreotide), as well as agents that antagonise hormone action (Tamoxifen, Toremifene and Fulvestrant). Such drugs rarely act as a cure but do mitigate the symptoms of the cancer and thus play an important part in the clinical management of sex-hormone-dependant tumours. Miscellaneous agents Crisantaspase Crisantaspase is a preparation of the enzyme asparaginase and therefore, like asparaginase, can break down asparagine to aspartic acid and ammonia [26]. It is active against tumour cells, such as those of acute lymphoblastic leukaemia, which have lost the capacity to synthesise asparagine and therefore require an exogenous source. As most normal body cells are able to synthesise asparagine, the drug has a fairly selective action and very little suppressive effect on the bone marrow, the mucosa of the gastrointestinal tract or hair follicles. Monoclonal Antibodies Antibodies are immunoglobulins that react with defined target proteins expressed on cancer cells. This activates the hosts immune response, which kills cancer cells by complement-mediated lysis or by killer cells. Monoclonal antibodies can also attach to and activate growth factor receptors on cancer cells, thus inhibiting the survival pathway and promoting apoptosis. Rituximab is a monoclonal antibody that is licensed (in combination with other chemotherapeutic agents) for treatment of certain types of lymphomas [27]. It lysis B lymphocytes by binding to the calcium- channel forming CD20 protein and activating completment. It also sensitises resistant cells to other chemotherapeutic drugs. Trastuzumab (Herceptin) is a humanised murine monoclonal antibody that binds to a protein termed HER2 (the human epithelial growth factor receptor 2); a receptor with integral tyrosine kinase activity [28]. It induces the host immune response as well as inducing the cell cycle inhibitors p21 and p27. Imatinib Mesylate Imatinib is an inhibitor of signalling pathway kinases [29]. It inhibits the platelet-derived growth factor (PDGF); a receptor tyrosine kinase, and the Bcr/Abl kinase; a cytoplasmic kinase. These are considered to be unique factors in the pathogenesis of chronic myeloid leukaemias. Imatinib is licensed for the treatment of this tumour when it has proved to be resistant to other therapeutic strategies, as well as for the treatment of some gastrointestinal tumours that are not susceptible to surgery. Resistance to Anticancer Drugs As mentioned previously patients can develop resistance to many chemotherapeutic agents. This can be caused by a number of mechanisms, which are summarised in figure 1. A decrease in the amount of drug taken up by the cell Resistance can develop as a result of decreased drug uptake. This can be due to the loss of transporter function, for example RFC [30]. Decreased influx of Methotrexate in tumour cells has been widely associated with decreased RFC gene expression. Down-regulation of the transporter protein is due to alterations in the transcription and translation factors. Transcriptional factors, such as the Sp1 family, CREB (cyclic AMP-response element binding protein) and p53, regulate RFC gene expression [31]. Therefore loss of function of these transcription factors cause silencing of the RFC gene, which results in reduced protein level. Also post-translational modifications of transcription factors alter phosphorylation patterns, which abolishes Sp1 and CREB function thereby resulting in loss of RFC gene expression and subsequently resistance [32]. Mutations in the human RFC gene can also decrease drug influx. Jensen et al (1998) have reported a mutation that causes marked changes in the kinetic properties of RFC mediated transport of folates [14]. The structurally altered RFC was functionally characterized by a 9- and 31-fold increased affinity for transport of reduced folate cofactors and folic acid, respectively. This allowed the accumulation of intracellular folates, which sustained cell growth and DNA replication, allowing cancer cells to escape the cytotoxic effects of antifolate drugs. Altered concentration of target enzyme Increased expression of target enzyme is a common mechanism of acquired resistance. For example Methotrexate resistance can develop as a result of DHFR gene amplification and subsequent enzyme overexpression [15]. Gene amplification is thought to occur as a consequent of antifolate inhibitors binding to DHFR, which causes a conformational change that alters the translational autoregulatary negative feedback mechanism, wherein DHFR protein specifically interacts with its own mRNA and negatively controls translational efficiency. The drug concentration will be limited to the dose administered, which will not be able to block the additional enzyme that is synthesised, resulting in cancer cells overcoming the inhibitory effect of the drug. Insufficient activation of the drug Some drugs require metabolic activation to manifest their antitumour activity for example Cytarabine has to undergo catalytic conversion, by the action of deoxycytidine kinase, to an active form [33]. So under expression or mutation of this drug-metabolising enzyme can reduce drug efficacy and cause resistance. Another example of resistance due to insufficient activation of the drug is Mercaptopurine, which is a prodrug [34]. Mercaptopurine is activated by hypoxanthine guanine phosphoribosyl transferase (HGPRT) and mutations that reduce the activity of this enzyme will allow the cancer cells to escape the toxic effects of the drug. Increase in inactivation Resistant to Mercatopurine can also develop as a result of increased inactivation of the drug [35]. The mechanism behind this is thiopurine s-methyltransferase (TPMT), which inactivates Mercaptopurine and thereby prevents the formation of the active drug. Mutations in the TPMT gene will alter its activity and may cause resistance. Rapid repair of drug-induced lesions Patients can develop resistance as a result of cancer cells recognizing DNA lesions and rapidly initiating repair pathways [9]. This is the main cause of resistance to alkylating agents as their mechanism of action is DNA damage There are several repair pathways and include the Direct Repair (DR) pathway, Base Excision Repair (BER) pathway, Nucleotide Excision Repair (NER) pathway, Homologous Recombination (HR) pathway and Non-Homologous End Joining (NHEJ) pathway. The DR pathway is mainly mediated by the DNA repair protein: O6-alkylguanine DNA alkyltransferase (AGT) [36]. AGT transfers the alkyl adducts from the nucleotides to the cysteine residue within its active site, independently from other proteins and without causing DNA strand breaks. The BER pathway recognizes and accurately removes bases that have been damaged by alkylation [37]. A damaged base is removed by a damage-specific DNA glycosylase, leading to the formation of a potentially cytotoxic apurinic or apirimidinic site intermediate. This is then processed by an AP endonuclease (APE1), which generates a strand break that is further processed by Poly ADP-Ribose Polymerase (PARP), DNA polymerase b (Polb) and ligase III to restore the damage. The NER pathway deals with the repair of bulky DNA lesions formed by DNA-alkylating agents such as Cisplatin, which distort the DNA double helix and block DNA replication and transcription [38]. Two major mechanisms of DNA repair have been recognized in this pathway: the transcription-coupled repair, which specifically targets at and removes lesions that block the progression of RNA polymerase II, and the global genome repair, which deals with lesions in the rest of the genome. Generally, nucleotide repair is a complex multi-step process that sequentially deploys a group of proteins to reorganize the lesion, remove the damage, and support new DNA synthesis. The HR and NHEJ pathways are involved in the repair of DNA double strand breaks, commonly considered to be the most lethal of all DNA lesions. Double strand breaks are induced by chemotherapeutic agents such Bleomycin, and Etoposide. In the HR pathway, ATM (ataxia talagiectasia mutated kinase) and its related ATR proteins sense the severe DNA lesions, and are mobilized to phosphorylate a wide range of substrate proteins [39]. Also a number of regulatory proteins, including BRCA1, BRCA2 and p53, are recruited to coordinate the DNA repair. The NHEJ pathway involves the alignment of the broken ends followed by recruitment and activation of the DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and DNA ligase IV to complete the ligation step [40]. Mutations Mutations in various genes can give rise to resistant target molecules, for example the p53 gene [41]. The p53 protein is an important regulator of the cell cycle and is sensitive to any DNA damage caused during replication. Following DNA damage it will normally induce G1 arrest and/or apoptosis to prevent the production of defective cells. Mutations in this gene will cause the loss of p53 function, which will allow cells with damaged DNA to continue replicating, resulting in resistance to DNA damaging drugs. Other genes, such as h-ras and bcl-2/bax, involved in the apoptotic pathway, have also been implicated in resistance [42]. Resistance due to mutations in genes will affect a wide range of anticancer drugs as all cells contain the same genetic material. It also potentially increases the proportion of surviving mutant cells, which leads to greater tumour heterogeneity. Increased expression of efflux pumps Resistance to natural hydrophobic drugs, such as vinca alkaloids and taxanes, as well as the cytotoxic antibiotics, such as anthracyclines and Dactinomycin, occurs due to the over expression of ATP-dependent efflux pumps in cancer cells [5]. These pumps belong to a family of ATP-binding cassette (ABC) transporters, which are divided into eight distinct subfamilies, shown in table 1. Of these subfamilies PGP, also known as MDR1, has a broad drug specificity, which explains the cross-resistance to several chemically unrelated compounds. It is a multidrug efflux pump that has 12 transmembrane regions, which bind hydrophobic drug substrates that are either neutral or positively charged [6]. It also has two ATP-binding sites, as hydrolysis of two ATP molecules are needed for the transport one drug molecule [43]. Binding of substrate to the transmembrane regions stimulates the ATPase activity of PGP, causing a conformational change that releases substrate to the extracellular space. Hydrol ysis at the second ATP site is required to re-set the transporter so that it can bind substrate again, completing one catalytic cycle. Increased expression of the PGP transporter in cancer cells increases the amount of catalytic cycles that occur, which increases the amount of drug effluxed [5]. This lowers the intracellular drug concentration below a cell-killing threshold, which results in resistance. Not all multidrug-resistant cancer cells express PGP. Resistance in these cells was discovered to be linked with the expression of the multidrug-resistance-associated protein 1 (MRP1) [44]. MRP1 is similar to PGP in structure (table 1) but, unlike PGP, it recognizes neutral and negatively charged hydrophobic natural products, and transports glutathione and other conjugates of these drugs, or, in some cases, such as for Vincristine, co-transports unconjugated glutathione. Some anticancer drugs, such as Mitoxantrone, are poor substrates for PGP and MRP1. Mitoxantrone resistance is due to a more distant member of the ABC transporter family, MXR (Mitoxantrone-resistance gene) [45]. This transporter is thought to be a homodimer of two half-transporters, each containing an ATP-binding domain at the amino-terminal end of the molecule and six transmembrane segments (table 1). Resistance can also develop as a result of increased expression of ABC transporters in the apical membrane of the gastrointestinal tract [46]. ABC transporters play a key physiological role, where they extrude toxins thus forming a protective mechanism and a first line of defense. Increased expression of these transporters decreases drug uptake and therefore decrease drug bioavailability. Examples of chemotherapeutic agents that develop resistance by this mechanism include antimetabolites, such as Methotrexate and Fluorouracil, and alkylating agents, such as Cisplatin. Also water-soluble drugs that piggyback on transporters and carriers or enter by means of endocytosis can fail to accumulate as they will not be able to enter the body. Additionally, PGP actively secretes intravenously administered drugs into the gastrointestinal tract [47]. Resistance due to increased levels of PGP transporters in the gastrointestinal tract is illustrated by MDR1a/MDR1b-knockout mice, which have shown to have increased tissue concentrations of PGP substrates. Studies have also shown increased tissue absorption of PGP substrates, following oral administration, when co-administered with a PGP inhibitor. Reversal of drug resistance in cancer Ways to overcome multidrug resistance due to the over expression of ABC transporters are being researched. Some of the main approaches include developing PGP inhibitors, antibodies against the PGP transporter, antisense oligonucleotides and liposome-encapsulated drugs. Drugs that can reverse multidrug resistance, such as PGP inhibitors, could be useful interventions to improve bioavailability, by increasing oral uptake of anticancer drugs and decreasing drug excretion, thereby reducing dosing requirements [7]. Two inhibitors that are used in the laboratory and in clinical trials that attempted to reverse drug resistance are the calcium channel blocker, verapamil and, the immunosuppressant, cyclosporin A. Another method that can be used to inhibit PGP is by competitive inhibition [48]. PGP binds many different hydrophobic compounds so any drug that interacts with the substrate-binding region is likely to be a competitive inhibitor of other drugs. Thus, two drugs that are transported by PGP will compete for this transport, resulting in increased oral absorption of both, decreased excretion, and redistribution. This kind of drug interaction can be used to inhibit the multidrug transporter, when the inhibitor drug has little or no other pharmacologic e ffect. Monoclonal antibodies (MAbs) against PGP have been used to kill multidrug resistant cells [49]. MAbs are of therapeutic use as they can activate the immune response, which results in complement mediated lysis or antibody dependent cellular cytotoxicity of the cells. An example of a MAb is MRK-16, which has shown selective toxicity towards tumours that are over expressing PGP. Molecules, which are normally involved in signal transduction on T and B cells can also be targeted for antibody therapy [50]. Such molecules include CD19, which is a membrane receptor involved in signal transduction and potentiates the response of B cells to antigens. MAbs directed against CD19 can induce cell-cycle arrest due to negative growth signals that cross-link immunoglobulin M and CD19. Antisense drugs work by down regulating gene expression [51]. This occurs by sequence-specific blinding of either DNA or RNA, which inhibits transcription or translation, respectively. Different antisense-oligodeoxynucleotides have been reported to chemosensitize resistant tumour cells to anticancer drugs through down regulation of PGP expression and thus increasing the intracellular accumulation of anticancer drugs in the cancer cells. The efficiency of a synthetic oligodeoxynucleotide (ODN) in regulating gene expression in living cells depends on its thermodynamic stability, resistance toward nucleases and cellular uptake [52]. A number of studies indicate that a synthetic ODN coupled with a DNA intercalator such as acridine, naphthyl imide, psoralen or pyrene might act to increase stability. Novel drug delivery systems such as liposome-encapsulated drugs have also been developed to overcome multidrug resistance [53]. Liposome formulations contain a small fraction of polyethylene glycol (PEG)-derivatised phospholipid, which has been shown to dramatically alter the pharmacokinetic properties of certain anticancer drugs. These pharmacokinetic alterations include long elimination half-life and small volume of distribution. Another formulation developed to bypass PGP transporters is anionic liposomes, which are internalised by certain cells and are able to provide drug release in intracellular compartments. Conclusion Cancer is prevalent in the western world and much research is dedicated to produce effective chemotherapy. Current chemotherapy includes alkylating agents, antimetabolites, cytotoxic antibiotics, plant derivertives, hormone therapy and monoclonal antibodies. However the efficacy of these chemptherapeutic agents is limited to patients developing multidrug resistance. This is mainly due to the over expression of ABC transporters, particularly the PGP transporter, as they have broad drug specificity so can bind many structurally unrelated drugs [5]. Techniques to reverse multidrug resistance are being developed and include co-administration of PGP inhibitors, which prevent the binding of anticancer drugs the transporter [7], the use of antibodies, which kill cells over expressing the PGP transporter [49], antisense oligonucleotides that down regulate PGP expression [51] and liposome-encapsulated drugs, which alter the pharmacokinetic properties of anticancer drugs [53]. A better understanding of the mechanism by which ABC transporters efflux chemotherapy and further analysis, in clinical trials, of known mechanisms of multidrug resistance would increase the development of agents that reverse multidrug resistance. Also improved imaging techniques used in clinic to screen cancer cells would enhance the ability of practitioners to prescribe individualised treatment according to the patients level of resistance. One approach that can be developed is to produce fluorescent antibodies against all 48 human ABC transporters and use them in conjunction with a specialised fluorescent microscope to monitor the levels of ABC transporters in cancer cells. References Office for National Statistics (2005) Cancer Statistics registrations: registrations of cancer diagnosed in 2006, England. http://www.statistics.gov.uk/downloads/theme_health/MB1-37/MB1_37_2006.pdf [accessed December 2009] Weinberg RA (1996) How Cancer Arises. Scientific American; 275: 42-48 Lawley PD and Phillips DH (1996) DNA adducts from chemotherapeutic agents. Mutation Research; 355: 13-40 This article is not included in your organizations subscription. However, you may be able to access this article under your organizations agreement with ELowenthal RM and Eaton K (1996) Toxicity of Chemotherapy. Hematology/Oncology Clinics of North America; 10: 967-990 Gottesman MM (2002) Mechanisms of cancer drug resistance. Annual Review of Medicine; 53: 615-627 Ambudkar SV, Dey S, Hrycyna CA, Ramachandra M, Pastan I and Gottesman MM (1999) Biochemical, cellular, and pharmacological aspects of the multidrug transporter. Annual Review of Pharmacology and Toxicology; 39: 361-398 Ferry DR, Traunecker H and Kerr DJ (1996) Clinical trials of P-glycoprotein reversal in solid tumours. European Journal of Cancer ; 32A: 1070-1081 Lawley PD and Brookes P (1967) Interstrand cross-linking of DNA by difunctional alkylating agents. Journal of Molecular Biology; 25: 143-160 Zhu Y, Hub J, Hu Y and Liu W (2009) Anti-Tumour Treatment Targeting DNA repair pathways: A novel approach to reduce cancer therapeutic resistance. Cancer Treatment Reviews; 35: 590-596 Bouziane M, Miao F, Ye N, Holmquist G, Chyzak G and OConnor TR (1998) Repair of DNA alkylation damage. Acta Biochim Pol; 45:191-202 Schweitzer BI, Dicker AP and Bertino JR (1990) Dihydrofolate reductase as a therapeutic target. FASEB Journal; 4: 2441-2452 Spiegelman S, Nayaak R, Sawyer R, Stolfi R and Martin D (1980) Potentiation of the antitumor activity of 5-FU by thymidine and its correlation with the formation of (5-FU)RNA. Cancer; 45: 1129-1134 Nabhan C, Gartenhaus RB and Tallman MS (2004) Purine nucleoside analogues and combination therapies in B-cell chronic lymphocytic leukemia: dawn of a new era. Leukemia Research; 28: 429-442 Jansen G, Mauritz R, Drori S, Sprecher H, KathmannI, Bunni M, Priest DG, Noordhuis P, Schornagel JH, Pinedo HM, Peters GJ and Assaraf YG (1998). A structurally altered human reduced folate carrier with increased folic acid transport mediates a novel mechanism of antifolate resistance. Journal of Biological Chemistry; 273: 30189-30198 Tai N, Schmitz JC, Chen TM and Chu E (2004) Characterization of cis-acting regulatory element in the proteincoding region of human dihydrofolate reductase mRNA. Biochemical Journal; 378: 999-1006 Zunino F and Capranico G (1990) DNA topoisomerase II as the primary target of antitumor anthracyclines. Anti-Cancer Drug Design; 5: 307-317 Wang JC (1996) DNA Topoisomerases. Annual Review of Biochemistry; 65: 635-692 Kasahara K, Fujiwara Y, Sugimoto Y, Nishio K, Tamura T, Matsuda T and Saijo N (1992) Determinants of Response to the DNA Topoisomerase II Inhibitors Doxorubicin and Etoposide in Human Lung Cancer Cell Lines. Journal of the National Cancer Institute; 84: 113-118 Chen AY, Yu C, Gatto B, and Liu LF (1993) DNA minor groove-binding ligands: A different class of mammalian DNA topoisomerase I inhibitors. Procedings of the National Academy of Sciences of the USA; 90: 8131-8135 Povirk LF (1996) DNA damage and mutagenesis by radiomimetic DNA-cleaving agents: bleomycin, neocarzi

New Media Artists on the Internet :: Internet Net World Wide Web Media

New Media Artists The enormous success and popularity of the Internet and new media as a whole have changed society in many ways. Artists have begun to use new media to deliver their works. As the artists use new media such as the Internet, the medium in which the work is delivered has become part of the artwork itself. In old media the book in which a story was printed is not part the literary piece of art. Ed Falco’s â€Å"Self-Portrait as Child with Father† and Olia Lialina’s â€Å"My Boyfriend Came Back From The War† are examples of McLuhan's message that the medium is the message. Both artworks are examples of new media art as defined by Lev Manovich in â€Å"The Language of New Media†. The introduction of new media art forms have changed the role of the artist, as the medium of digital art has now become the message itself making the individual ideas, perspectives, and narratives of the artist less important to the artwork as a whole. Marshall McLuhan is one of the first to articulate some of the social consequences of the great technological advances of the 20th Century. In his book â€Å"The Medium is the Message† from 1964 he introduces the idea that with the use of the new media as forms of communication it is the medium itself that is the message and he explains that, â€Å"This is merely to say that the personal and social consequences of any medium†¦result from the new scale that is introduced into our affairs by each extension of ourselves, or by any new technology† (Liu 1). The message will therefore change according to the medium. As we will see with new media art, the message would clearly be different if Ed Falco’s â€Å"Self-Portrait as Child with Father† was read linearly in a traditionally printed book than when experienced in its actual online non-linear presentation. Olia Lialina’s â€Å"My Boyfriend Came Back From The War† is presented similarly as a n online non-linear artwork. These artworks are interactive in the sense that the reader must click on links to read the story, or using a traditional turn the reader must click the link to virtually turn the page. Since there are multiple links at the same time the different pages are read at different times and in different order from reader to reader. It is therefore the case that no two readers of the artworks will have the same experience and opinion about them.

Operations Management assignment Essay

Supply chain management is the coordination of the processes and functions within a business, adopted by most companies in the UK in the late 1990’s. It deals with the internal and external factors that, when dealt with correctly and systematically, can determine a businesses success or failure. A supply chain is the network of activities that delivers a finished product service to the customer. By definition, supply chain management (SCM) is â€Å"the management of the flows of materials from suppliers to customers in order to reduce overall cost and increase responsiveness to the customers† (Reid & Sanders). SCM entails the co-ordination of the movement of good through the supply chain from suppliers to manufacturers to distributors to the final customer. The main aim of SCM is to maximise the efficiency of any given process being carried out by a company; by doing this it is allowing them to try to cut their costs and hopefully keep satisfying their customers’ needs, while at the same time maintaining their competitive position within their market. Supply chain management is seen as more of an â€Å"open system† in contrast to the traditional system used by the majority of companies just 20 years ago. The new â€Å"open system† allows room for change which is greatly needed with the current financial instability of the economy. SCM has evolved over the years and has moulded to suit the ever changing economy. First adopted by the Japanese, in the form of Geba Kai (A meeting of the minds), the now commonly found process is used by a vast amount of companies in the UK. Nowadays, SCM within a business is responsible for a product from when it’s in its raw state to when it’s a finished product, ready for consumption by customers. The chain management that Comfort Company PLC currently uses is a very traditional system, otherwise known as a â€Å"closed system†. This type of management system isolates itself from the other components in the supply chain and therefore only has communication flowing through the companies own system, this is a negative attribute as it prevents the company from getting important and influential information about the state of the other links in their supply chain. When the dynamics of change happened, it forced the breakthrough of a new approach, the â€Å"open system†. The â€Å"open system† made companies a lot more open to operational change and as a result of this it made several managers, whose companies used the closed, more traditional system, view the new approach as a loss of power; this consequently made a lot of companies resist against the change. The new and more flexible â€Å"open system† was adopted firstly by the Japanese in the form of â€Å"Geba Kai†, they were closely flowed by the British who quickly followed them in adopting it. There are still some nations that, even now, rigidly stick to their old ways and use the â€Å"closed system†, two examples of these nations are the Americans and the Germans. Along with the list of positives the company will gain by changing from a traditional chain system to a more formal supply chain management (SCM) system, there are also a few strategic reasons why a company should change to the newer system, reasons that will help them to stay on par with the other business’ within their industry and within the whole business sector. One of these reasons is globalisation. As stated in â€Å"Operations management: Along the supply chain†, Two thirds of today’s businesses operate globally through global markets, global operations, global financing, and global supply chains†. Globalisation means that British companies, such as Comfort Company PLC are going to have to be prepared to compete in markets that are foreign to them and also have foreign competition within their own domestic markets. Companies that adopt, or have already adopted, a formal supply chain management system will have an advantage upon those who havenâ€⠄¢t and will be able to benefit from globalisation. There are many benefits a company would gain from introducing a formal supply chain management system, all fulfilling the wish to supply the customer with good quality products that â€Å"Comfort Company plc† posses, while at the same time giving them an opportunity to maximise their customer satisfaction, manage their supply chain effectively and allow flexibility to their supply chain. By maximising customer satisfaction, â€Å"Comfort Company plc† could asses how well they are meeting their customers needs, while at the same receiving an indication of how well the business is doing in comparison with their competition; both in their market and foreign markets. Having a flexible supply chain would mean that the company would be able to react to change in demand quickly to ensure that they level the demand to their output, this would save them a lot of time, waste and resources if a freak change in demand was to happen. If â€Å"Comfort company plc† did not adopt the formal supply chain management system they would be at risk of loosing a lot of money if an unforeseeable change was to happen, this would give them a disadvantage upon the competition and would lower their competitive advantage. Effective management of a supply chain could open up opportunities for â€Å"Comfort Company plc† to improve many aspects of their production, and potentially save themselves a lot of money. By identifying the unnecessary waste along the supply chain, â€Å"Comfort Company plc† could make the process an easier, cheaper and quicker one for themselves and other links in their supply chain; this would make the chain more productive, co nsequently making the finished product â€Å"better value†. One of the main advantages of a formal supply chain management system, and an excellent attribute a company can have, is an advantage upon your competitors. Defined, competitive advantage is â€Å"an advantage over competition gained by offering consumers greater value, either by means of lower prices or by providing greater benefits and service that justifies higher prices†(Tutor2u.net, 2011). The type of competitive advantages a company such as â€Å"Comfort Company plc† would achieve from a formal SCM system are advantages such as lower costs and operational flexibility. As there are numerous ways of gaining a competitive advantage, the company in question needs to do some research into their market to see how it could be done, they could research the ways in which their successful competition operate and try to adopt some of their approaches. A good example of a company using its formal SCM system to achieve a good competitive advantage is Dell Computer Corporation. â€Å"Quick delivery of customised computers at prices 10-15 percent lower than the industry standard is Dell’s competitive advantage. A customised Dell computer can be en route to the customer within thirty-six hours. This quick response allows Dell to reduce its inventory level to approximately thirteen days of supply. Dell achieves this in part through its warehousing plan. Most of the components Dell uses are warehoused within fifteen minute travel time to an assembly point. Dell does not order components at its Austin, Texas, facility; instead, suppliers restock warehouses as needed, and Dell is only billed for items only after they are shipped. The result is better value for the customer† (Reid & Sanders). There are a few ways â€Å"Comfort Company plc† can gain competitive advantage within their market, such as using tools like business to business (B2B) e-commerce, or adopting one of Dells results gaining approaches and making sure that there components and raw materials for making the products are located a short travel time away from the place of assembly. Being situated on the Crewe Gates industrial park, where many other businesses, some similar to â€Å"Comfort Company plc† no doubt, are situated, there’s sure to be some way that they could find a supplier closer. If this was to succeed they could create a good, strong relationship with the suppliers and build a barrier of trust and communication, this would be a perfect scenario to ensure the links in the supply chain are strong, as the supply chain is â€Å"only as weak and its weakest link† and vice versa. A business to business (B2B) e-commerce is when companies sell to other business, it is the largest segment of e-commerce. If â€Å"Comfort Company plc† were to use business to business (B2B) e-commerce, they could gain potential benefits such as: †¢Lower procurement administrative costs, †¢Better quality because if increased cooperation of between buyers and sellers, especially during the product design and development, †¢Low-cost access to global suppliers, †¢Lower inventory investment due to price transparency and reduced response times (R. Dan Reid, Nada R. Sanders) The reasons/advantages stated above for changing from a traditional chain system to a formal supply chain management system are in fact more than just small advantages â€Å"Comfort Company plc† could gain, but necessary changed that need to be made if they want to survive the current economical crisis and still have customers/revenue at the end of it. With globalisation growing and the need to satisfy the customers becoming more apparent and diverse, the formal supply chain management system is a necessary system that every business, no matter how small or large, should put into place. The formal SCM system will allow â€Å"Comfort Company plc† to integrate their information systems with their suppliers and customers in an effort to meet their goals and objective while still at the same time doing this in a cost-saving way. With every new system brought into a company, there is the risk of it creating a few problems within the company; this makes the need of a contingency plan much higher. There are a few risks that come along with implementing such a big change to a business so set in its ways like â€Å"Comfort Company plc†, a main one being the possible lack of cooperation from the workforce or managers. When change happens in a workplace the employees can feel threatened and scared and will sometimes rebel against the new change, this could be avoided if the company took a few simple procedures to ensure the workforce are happy with the new system. They should tell the workforce about the new operational plan and get their feedback on it, this will make them feel involved in the change and will hopefully make them feel less alienated. Also, they should sit them down and explain the needs of introducing a formal supply chain management system into the company, and the benefits it would gain by doing so, if they feel it would be benefiting the company, they should feel happier about the change going on. Furthermore, if both of the steps are carried out correctly, it could make them more motivated towards their job as they will feel involved in the company and will hopefully want it to succeed. Another risk of the formal supply chain management system is the potential loss of jobs within the company; this will be because some members of staff will not be needed as a go between for information between suppliers and so on. The redundancies in the company could possibly cause bad feeling between the workforce and the new system and could de-motivate them, possibly leading to a decrease in the effort put in by the workforce; this could potentially lead to a product being of a lower quality. Also, the possible redundancies made will be a negative factor for the economy as there will be a few more unemployed people in the country; this is one of the only major downfalls of the introduction of the formal SCM system. However, there may be members of staff who are close to retirement and could benefit from voluntary redundancy and the benefits that go with it. A negative of that would be that â€Å"Comfort Company plc† may loose some of their staff with the most experience and expertise, potentially making them train up current members of staff to the same quality as the members of staff who left. However, the operations management team at â€Å"Comfort Company plc† will have to put contingency plans in place that cover all of the possible risks, and ways to reduce the risks from happening. There are many needs of introducing a formal supply chain management system into â€Å"Comfort Company plc†, and many advantages it would gain by doing so. While there are also some risks involved, the advantages and needs outweigh them massively as they could potentially provide â€Å"Comfort Company plc† with a competitive advantage, while at the same time reducing their costs and use of resources. Like the traditional chain system currently adopted by â€Å"Comfort Company plc†, the new, more up to date formal supply chain management system will fulfil their wish to supply the customer with good quality products while at the same time saving them resources and money, making them more profitable. The introduction of a formal supply chain management (SCM) system is necessary and â€Å"Comfort Company plc† should definitely strongly consider it. References: †¢Operations Management: An integrated approach (2007) (3rd edition) R. Dan Reid, Nada R. Sanders. Pages 16, 98-105 †¢Operations Management: Along the supply chain (6h edition) Russell & Taylor. Page 9. †¢Tutur2u.net (2011) Competitive advantage (WWW) Available from: http://tutor2u.net/business/strategy/competitive_advantage.htm

If Venerus Implements the Suggested Methodology?

If Venerus implements the suggested methodology, what would be the range of discount rates that AES would use around the world? * 12% discount rate was used for all projects * Venerus felt that this model worked fairly well In 1990s this model of capital budgeting was exported to projects overseas * model became increasingly strained with the expansions in Brazil and Argentina * because hedging key exposures such as regulatory or currency risk was not feasible * the ever-increasing complexity in the financing of international operations is another problem * when subsidiaries’ local currency real exchange rates depreciated, leverage at the subsidiary and holding company level effectively increased, and the subsidiaries struggled to service their foreign currency debt * Venerus’s solution to the problem had to be consistent, transparent, and accessible As a starting point, he considered the 15 representative projects shown in Exhibit 7a and, using the financial data in Ex hibit 7b * he endeavored to derive a weighted average cost of capital (WACC) for each project using a standard methodology: * he endeavored to derive a weighted average cost of capital (WACC) for each project using a standard methodology: WACC=EVre+DVrd1-? In order to calculate each WACC, Venerus knew he would have to measure all of the constituent parts for the 15 projects: * the cost of debt * the target capital structure * the local country tax rates * an appropriate cost of equity Venerus feared the use of a World CAPM might yield artificially low costs of capital.Similarly, Venerus did not advocate the use of a â€Å"Local CAPM† where beta measured the covariance of a project’s returns with a portfolio of local equities. Countries such as Tanzania or Georgia, where AES had projects, did not have any meaningful equity markets or local benchmarks. Still, he knew he had to find a way to capture the country-specific risks in foreign markets. 1. he calculated a cost of debt and cost of equity for each of the 15 projects using U. S. market data 2. he added the difference between the yield on local government bonds and the yield on corresponding U. S. Treasury bonds to both the cost of debt and the cost of equity Summary of WACC Calculations for AES

Lord of the Flies1 essays

Lord of the Flies1 essays The classic novel Lord of the Flies by William Golding is an exciting adventure deep into the nether regions of the mind. The part of the brain that is suppressed by the mundane tasks of modern society. It is a struggle between Ralph and Jack, the boys and the Beast, good and evil. The story takes a look at what would happen if a group of British school boys were to become stranded on an island. At first the boys have good intentions, keep a fire going so that a passing ship can see the smoke and rescue them, however because of the inherent evil of the many the good intentions of the few are quickly passed over for more exciting things. The killing of a pig slowly begins to take over the boys life, and they begin to go about this in a ritualistic way, dancing around the dead animal and chanting. As this thirst for blood begins to spread the group is split into the rational (the fire-watchers) pitted against the irrational (the hunters) (Dick 121). The fear of a mythological beast is perpetuated by the younger members of the groups and they are forced to do something about it. During one of the hunters celebrations around the kill of an animal a fire-watcher stumbles in to try and disband the idea of the monster. Caught of in the rabid frenzy of the dance, thi s fire-watcher suddenly becomes the monster and is brutally slaughtered by the other members of the group. The climax of the novel is when the hunters are confronted by the fire-watchers. The hunters had stole Piggys (one of the fire-watchers) glasses so that they may have a means of making a cooking fire. One of the more vicious hunters roles a boulder off of a cliff, crushing Piggy, and causing the death of yet another rational being. The story concludes with the hunters hunting Ralph (the head and last of the fire-watchers). After lighting half of the island on fire in an attempt to smoke Ralph from his h ...