Leadership In Ancient Civilizations Essays - Iulii,

Leadership in Ancient Civilizations Leadership in Ancient Civilizations During the period of the Roman Republic and the Roman Empire, different leaders exhibited different styles of leadership and employed different political strategies. In addition, these leaders came to power and maintained their control in their own unique ways. Each leader seemed to have his own agenda, which set the tone for that era. Five prominent leaders of this time period were Agricola, Augustus, Julius Caesar, and the brothers Tiberius and Gaius Gracchus. The point to be made with respect to these particular men is related to the obvious correlation between the nature of a leader's agenda and the impact of his reign. In the end, a ruler's fate was dependent not on his agenda, but on style and strategy with which he pushed his agenda. Those leaders whose methods were completely altruistic were heralded as great leaders, while those with devious and/or unethical methods of pushing their agendas were hastily assassinated. First consider Tiberius Gracchus. It is imperative to analyze his style of leadership and his political strategies. During his term as tribune, Tiberius' major goal was to pass a land reform bill. This bill was biased toward the masses. Tiberius tried fairly and squarely to gain the support of the Roman senate, but this effort was to no avail. Tiberius then resorted to unfavorable tactics when he impeached another tribune, Octavius, the major opponent of Tiberius' bill. Thus Tiberius willingly destroyed the long-held and quite favored notion of an immune tribune. However, this is what the common people wanted. Tiberius' big mistake was blatantly opposing, thus disrespecting the Roman senate. As a result, the senate assassinated Tiberius. The lesson to be learned here is not that Tiberius' agenda was constructed out of self-interest or greed. Tiberius simply wanted to help the common people. However, Tiberius' methods were not proper for that time in that place. And it is probable that Tiberius could easily have been persuaded to compromise. Thus, Tiberius' downfall was not his agenda, but his style and political strategy. A different example of the same principle is summed up with the story of Tiberius' younger brother, Gaius Gracchus. Gaius worked not to appease the senate, but to appease the people. Although this seems quite noble of him, it was still a mistake to oppose the senate. Granted, this notion is counter-intuitive. One would expect that the senate is supposed to help the people, and since Gaius was helping the people, the senate should favor him. One would also expect that because it was the common people and not the senate that elected him, that he should have unwavering loyalty to the people. However, one must not look at the situation with a 1990's, American, free will and liberty, democratic eyes. Rome was not a democracy. The senate commanded respect, and to disregard the senate, whether the people were in favor of you or not, was not a wise thing to do. Thus, Gaius was also assassinated, like his brother, by the senate. It does not seem fair that Gaius was killed, but such is life, and had Gaius employed a more "senate-friendly" strategy of passing his laws, it is probable that his fate would not have been what it was. One final example of this is Julius Caesar. Caesar was a warlord and a dictator, but if one can look past that, as ridiculous as it sounds, then one would also notice that Caesar did a lot of good for Rome. As dictator, Caesar saw to a series of rapid reforms in many areas of Roman life. He scaled down his large army by settling many of his soldiers in newly founded colonies and extended Roman civilization into some of the provinces. His most lasting reform was one by which we still regulate our lives ? the establishment of a calendar based on the old Egyptian reckoning of 365 days, with one day added every fourth year. This "Julian" calendar lasted until 1582. Then, there were those leaders whose style of leadership and political strategy fit perfectly into the framework of society, such that they were considered to be great leaders. These leaders were Agricola and Augustus. Agricola was an army commander for most of his relatively long life. He was regarded to be one of the best men anywhere, and he was revered by all. Yet, being an army commander does require some killing and punishing. Let's be real. How is it that Agricola was, by the nature of his profession, a killer, yet was so respected, while Tiberius and Gaius strove to help people, and were assassinated? The answer

English words spelled

English Words Spelled with 3-letter /Ä «/ English Words Spelled with 3-letter /Ä «/ English Words Spelled with 3-letter /Ä «/ By Maeve Maddox Among several ways to spell the long i sound in English is the 3-letter combination -igh- as in sight [sÄ «t]. The spelling reflects an earlier pronunciation in which the gh represented a sound made with the soft palate, rather like the ch heard in German ich. The -igh- spelling has persisted in English because it occurs in a small group of high frequency one-syllable words. Its easy to tolerate an apparently difficult spelling when one sees it frequently. Most of the -igh- words end with the /t/ sound and spelling. Exceptions are high, nigh, and sigh, in which igh represents the final sound. The other most common -igh- words are: bright from O.E. beorht, byrht fight from O.E. feohtan flight from O.E. flyht knight from OE cniht, cneoht light from O.E. leï ¿ ¼oht might from O.E. meahte, mihte night from O.E. niht right from O.E. riht sight from O.E. sihth The word delight has come to be grouped with the -igh- words because of association with the word light. Etymologically speaking, delight belongs with sprite and spite. All three words come from the French. delight from Old French delit, deleit, from delitier, deleitier sprite from Old French esprit spite shortened from despite which comes from Old French despit In the 16th century, sprite was often spelled spright and spite was spelled spight. Since then, theyve reverted to spellngs closer to their origins, probably because they are not in such frequent use as delight. In case you havent come across the word sprite as anything but a brand name, Ill define it: A sprite is an other-worldly creature, like an elf or a fairy. The word derives from the same source as spirit, but spirit has a more serious connotation than sprite. A sprite plays tricks. Want to improve your English in five minutes a day? Get a subscription and start receiving our writing tips and exercises daily! Keep learning! Browse the Spelling category, check our popular posts, or choose a related post below:When to use "on" and when to use "in"The Possessive ApostropheEspecially vs. Specially

Business Ethics Master Essay Example | Topics and Well Written Essays - 2000 words

Business Ethics Master - Essay Example Unfortunately, fast food can only be delivered fast if it is fried. This is because frying food in oil is the fastest way of cooking something, especially meat, which is preferred by most people. Secondly, fatty food tastes better. Fat itself has a lot of taste. The real magic of fried food tasting so good is not in the hands of the chef. There is no real secret ingredient. The only ingredient which everyone loves in their fast food is fat. This fat however has caused a bit of a dilemma though because even though it tastes excellent, it is full of saturated hydrogen compounds which are very difficult for our body to break down and digest properly. Hence, our body doesn't digest them when it's confronted with such large amounts of it. It merely deposits it in convenient places in our body, hence leading to obesity. Now this would have been relatively fine if it was only happening to the very busy Mr. Businessman. But the truth is, fast food has become the very thing to have at mealtim es. It's become not a thing to have just when you are running late, but as the only meal no matter who you are and which meal of the day you are having. Careless parents give their children loads of cash without bothering to ask where it is being spent, either on pornography, drugs or fast food. Hence children have become dependent upon it and fat being so tasty has become sort of an addiction for these children and they have completely switched from eating proper meals to eating fast foods whenever they feel hungry. In fact, marketing of such products have become so good and so persuasive that young employees and entrepreneurs are also on the same path. So who can blame the children They are only doing what they see going on around them. No warning, no label and not the tiniest hint of the truth. Marketing of fast food is going on so ferociously that for many marketing companies, the account of a corporate giant has become the swan song of the company which was once up in rompers. Ethical Theories The bottom line for every big cheese is always is that whatever they are doing is not unethical. Big corporations put a lot of effort and even more money in trying to make everything they do seem ethical, even if it involves tearing families apart and nailing small children on the wall. Utilitarianism This is one of the theories of ethics with a contrasting opinion of itself. It basically says that man is allowed to do anything as long as it is "for the greater good"1. This means that on one hand it's ok for scientists to make human clones then chop them up into pieces for their organs because apparently they will not be accepted into society as they are completely alienated from our experiences of life and they would come under better use if their organs are used to save "real" humans. On the other hand however, killing these clones might promote a feeling of neglecting the value of human life and our children who will grow up seeing this inhumane treatment will learn to value human life even less than the scientists and political figures do at present. Applying this to our topic, it is good for McDonalds to promote their Big Mac and for KFC to promote their version of packaged fat because they are serving the society by saving

Research hitlers Paper Example | Topics and Well Written Essays - 500 words

Hitlers - Research Paper Example The fact that some Jews at birth is not at all associated with genetics. The only other way to become a Jew is conversion so this should not be a surprise that there are Jews with blue eyes and blonde hair. This is surprising to me as it is very contradictory to what he actually did. He interfered with the lives of the Jews because of his belief in a perfect race. He strongly desired a â€Å"perfect race† and by attempting to do this, he has killed about seventy million Jewish people during his rule in Germany, believing that, â€Å"we [Germans] shall regain our health only by eliminating the Jews.† By â€Å"decontaminating† Germany, Hitler was one step ahead in achieving his ideal â€Å"super race.† Therefore, I definitely disagree with this quote because he did the exact opposite of what he just said. During both World War I and II, Europe’s economy and Asia’s economy was going extremely downhill. There was so much destruction. However, the United States, although it interfered in wars of other countries, the country in itself did not face a drastic decline of the economy. Therefore, I strongly agree with this quote, considering the situation and condition of the worldwide economy during the time. National socialism, or Nazism, was a unique fascist ideology practiced in Germany during the 1st and 2nd World War. I partly agree with this quote, as Hitler did not force Nazism on anybody, except the Jews. The Germans inspired by Hitler and with the same goal to bring Germany back to power, joined Hitler. Together, they were the ones who fervently desired to help Germany get back on its feet after World War I and the great worldwide Great Depression. I personally disagree with this quote of Hitler. Again, it is very contradictory to the reality. Being a war leader was against his will, but it was his very will that turned him into a war leader not just in Germany, but he was a war leader that was known throughout the world. In fact,

Art of the renaissance Essay Example | Topics and Well Written Essays - 750 words

Art of the renaissance - Essay Example I am trying to persuade one of my patrons to support these young men and so it was a fortunate coincidence that allowed me to come and view your works at the same time. I very much enjoyed my visit to that quaint little corner of the city behind the Cathedral of San Marco. It was most interesting to see the new works that Fra Angelico is doing for the monks there and I do believe that they will soon be finished. I don’t expect you will be permitted to view them, my dear, because the monks will hardly be prepared to open their doors to even one so beautiful as you, on the grounds that you are a women and hence forbidden to enter their hallowed rooms. I do assure you, however, that Fra Angelico’s frescoes are magnificent and truly a masterpiece worthy of this fine city of ours. I happened to meet him when I was coming out of the tavern, and he says that there has never been a more glorious time or place for art than our beloved Florence at the present time. When I told hi m that I was coming to see your paintings, he was most intrigued and informed me that he had indeed spied one or two young women carrying easel and paints and setting out their wares for sale at the marketplace alongside the boys. My how times have changed since my youth! I always have fond memories of your innocence and beauty since the days when I used to visit your father so many years ago. Your mama told me that one day you would be married to young Giovanni and live in that beautiful house by the lagoon. It is so very pleasing to see you all grown up and experimenting with art in your spare time now that you have settled down to married life. I expect that you have very little time for painting now, what with all your wifely duties, and so it is all the more fitting that you should have a chance to hang your paintings in public just for once before you have a family. I must say that I found your paintings delightful in their naive and honest depiction of womanly habits. Your ap preciation of the intricacies of female dress gave me a glimpse of the lady’s dressing room, and I am sure no man could have captured the mood of these scenes quite as well as you have managed it. Of course, there are some technical points that you have yet to learn, but I feel that I can excuse some such faults in your composition because you have not had the benefit of formal tuition in the way that my young Florentine apprentices have had. They will one day astonish us all with their brilliance, because they can match the power of the imagination with the skill acquired through long training at the feet of master artists. But you, my dear, have studied your subject well, and your pictures will no doubt be very useful as gifts to your adoring friends and family who will adorn the walls of their private spaces with your little oeuvres. I was particularly impressed with your copies of the work of Michelangelo. I expect that he will one day be revered across the whole of Europ e, because he captures the spirit of our age so perfectly. You would do well to copy his work more in the future, if you have time to continue your hobby, because he will teach you so many wonderful things about space, and proportion and texture – things that you could have learned about if you had been a man. As it

Oncolytic Virus Therapy for Cancer

Oncolytic Virus Therapy for Cancer Abstract Interest of oncolytic virotherapy is mounting from over the past few decades for treating many kinds of malignancies. Despite oncolytic viruses attain many successes in cancer therapeutic era; they all have still challenges in their developments. The interaction between virulence factors of viruses, hosts immune defense system, microenvironments and tumour factors are the hazardous influences in their achievements of novelties. Currently, with the thanks of modern recombinant biotechnology, most of the oncolytic viruses are increasing their tumour selectivity and specificity. On the other hand, they reduce their efficacies on physiologically functioning cells. Furthermore, combinational therapies with traditional anti-cancer treatment regimes have also promising and relevance outcomes. In 2004, Chinese food and drug administration (FDA) approved first oncolytic virus in treatment of head and neck tumours. However, they have some still unsolved obstacles in proper cancer therapy. In m y paper, the current issues and future prospects of the oncolytic viruses are highlighted how to use as therapeutic weapons. Keywords: Oncolytic viruses; Oncolytic virotherapy; Cancer gene therapies; recombinant 1. Introduction Cancer is one of the leading causes of death globally comprising 13% of all deaths (7.6 million deaths) in 2008. Although well established conventional therapies including surgery, radiotherapy and chemotherapy are existed, we still need new therapies and strategic plans. Local therapies such as surgery and radiotherapy have been limited in disseminated tumours. Likewise, chemotherapy has some intolerable adverse effects and sometimes, pre-existing chemo-sensitive tumours are resistance to chemotherapy after prolonged used. Thus, we really need certain promising therapies to handle these problems. Recent years, oncolytic virotherapy is uprising and promising for the various types of cancers. Ideology of virotherapy treating the malignancy has been introduced since early 20th century. However, since early oncolytic viruses were targeted not only tumour cells but also the normal cells, interest in the virotherapy was declined. Therefore, many trials related with such therapy were termi nated during the following decades. Late 1990s, interest of virotherapy was re-active with the advance of modern biotechnology. Today, concern of the virotherapy is high and it has the potential promises as a reasonable cancer treatment by itself or conjunction with other conventional therapies such as surgery, radio and/ or chemotherapy (synergic effect). Advance technology allows the development of oncolytic viruses which only effective on dividing cancer cells but not attack the normal dividing cells. There are generally two types of oncolytic viruses namely non-engineered (naturally occouring) and engineered agents. Both types may destroy the malignant cells without harming the normal cells. Generally, oncolytic viruses only infect and preferentially replicate within the cancer cells followed by lyses these cells. In recent years, many therapeutic virus candidates are emerging and testing their oncolytic prosperities with preclinical and clinical trials. Among them, adenovirus H101 was the first virus approved by C hinese food and drug administration (FDA) in 2004 as the adjuvant oncolytic virotherapy combined with pre-existing conventional chemo- and radiotherapy in the head and neck cancers. 2. Type of oncolytic viruses Oncolytic viruses are principally divided into 4 types according to their mechanisms of action. There are intrinsically tumour selective viruses, virulent gene deleted viruses, promoter inserted viruses and pseudotyped viruses. Genetic modified oncolytic viruses are manipulated whether insertion of the transgenes or deletion of the virulence genes. Naturally occouring tumour selective viruses are the viruses that are not genetically modified, direct targeting on the malignant cells. For instance, New castle disease virus, Vesicular stomatitis virus, Poliovirus and Reovirus are intrinsically tumour selective. However, affectivity is less due to depend on the natural strength of their lytic properties. Virulent gene deleted oncolytic viruses are more popular because their selectivity on target tumours are more specific without infectivity to normal ones. For example, herpes simplex virus, adenovirus, measles virus and vaccinia virus can be modified by deletion of their virulence protein coding genes. In addition, inserting of foreign genetic elements such as promoter region boost tumor specificity and selectivity of oncolytic viruses. Thus, tumour cells allow the replication of these viruses because only tumour cells can activate the promoter region of them. For example, prostate specific antigen (PSA) promoter inserted adenovirus CG7870 applies in prostate cancer and promising results were came out. Pesudotyped oncolytic viruses are modified with ligands which target tumour selective cell surface receptors. Therefore, they solely have their infectivity on malignant cells. (E.g. adenovirus delta 24RGD). Moreover, these viruses may reduce toxicity and dose requirement. 3. Characteristic features of standard oncolytic virus Since viruses can infect not only the malignant cells but also the functioning cells, oncolytic virotherapy is the critical therapy. Hence, safety and efficacy of the virotherapy are considerable issue and still challenging for further improvement. Potential oncolytic viruses are needed to confirm or compare whether they have real ideal characters of oncolytic virus or not. Standard characters of the oncolytic virus stated that (1) they only replicate within tumour with high multiplication rate, not on normal cells (2) less or no infectivity and virulence than their wild types (3) genetically stable so that mutations and recombination with other viruses are minimized for manufacturing and safety issues. DNA virus is more stable than RNA virus (4) can inactivated anytime with antiviral drugs or other mechanisms (5) considerable mass production (commercially available) can be possible with good manufacturing practices. Therefore, for development of virotherapy, all oncolytic viruses sh ould be fulfilled above criteria. Adenovirus and Herpes simplex virus (HSV) have high selectivity and specificity on tumour cells with massive replication rate of 1000 folds in 1st cycle. Besides, they are considerably stable whereas terminate anytime with their respective antiviral therapy (e.g. adenovirus is self-limiting and HSV is treated by acyclovir). 4. Tumour selective mechanism With the knowledge of the malignant cells molecular biology, oncolytic virotherapy can be created to attack the tumour cells selectively. Cancer cells undergo changes ranging from subtle point mutation to chromosomal instability. Inherent tumour selective viruses specifically attack the tumour cells by targeting the specific tumour promoting pathway of the malignant cells such as activated Ras and AKT pathway, defective interferon (IFN) pathway etc. RNA-activated protein kinase (PKR) pathway is a natural process that inhibits viral protein synthesis. Physiologically, interferon (IFN) secreted from infected cells phosphorylates the PKR which subsequent phosphorylates eIF-2ÃŽ ±. Then, phosphorylated eIF-2ÃŽ ± interfere the oncolytic viral protein synthesis that require for their virulence. In contrast, Ras mutation and defective IFN in malignant cells disturbs the PKR pathway and favours the oncolytic virus activity. For instance, herpes simplex virus (HSV) containing neurovirulence gene ÃŽ ³34.5 that binds with intracellular phosphatase and dephosphorylates eIF-2ÃŽ ± allowing replication of HSV in both normal and tumour cells. However, deletion of this gene permits to replicate only in Ras mutated or interferon (IFN) defective cells. Controversially, recent finding suggested that ÃŽ ³34.5 deleted HSV can also replicate in PKR functional malignant cells. It is seen to be defects in PI-3 kinase pathway which favours translation of ÃŽ ³34.5 mutant HSV. Moreover, genetically modified adenovirus (dl331), VAI mutant strain, prefers to replicate only in tumour cells with Ras activation. Similarly, dl331 is also effective in Epstein-Barr virus (EBV) associated tumours such as nasopharyngeal malignancy because Epstein-Barr virus expresses viral associated RNAs (VA RNAs) that defect PKR pathway. Many cancer cells over-express receptors for virus in high level. Thus, exploiting this mechanism, many oncolytic viruses are selectively homed in their specific malignant cells. For example, over-expression of intracellular adhesion molecule 1 (ICAM-1) and decay acceleration factor (DAF) in tumour favours to infect Coxsackie virus A21. Besides, Newcastle disease virus (NDV) binds sialic acid receptors. Alpha virus similarly uses heparin sulphate or ICAM-1 as its receptors. Both of them are highly express in tumor population. Therefore, these viruses are highly concentrated in tumour cells. 5. Immunogenicity of virotherapy Likewise as many other viruses, oncolytic viruses also stimulate and activate the body defense mechanisms including innate as well as adopted immunity. These viruses produce the viral proteins required for their replication within tumour cells. These proteins also stimulate the MHC class I gene to present it on the cellular surface of tumour cells as well as on the normal cells. MHC class I antigen was recognized by cytotoxic T cells (CTLs) or CD8+ cells which may destroy any cells representing MHC I antigens. Therefore, nature immunity allows eliminating both tumour and normal non-dividing cells. So, oncolytic viruses may also destroy normal cells apart from abnormal ones. An immune mechanism on the oncolytic viruses is one of the major constraints for developing modern virotherapy. However, to date, genetically modified viruses can only replicate and lyses p53 mutant cells. They cannot inactivate p53 gene of the normal host cells. p53 is functional and prevent replication of these viruses in the normal host cells. So, they are allowed their functions only in mutant tumour cells. 6. Conversion of oncogenic to oncolytic Many oncogenic viruses are potential to use as oncolytic therapy nowadays after genetically manipulation. Generally, 15-20% of the carcinogenesis is contributed by various kinds of oncogenic viruses such as herpes papilloma virus (HPV), Epstein-Barr virus etc. Reversely, these viruses can be changed to treat the malignancies by exploiting their lytic effects on the dividing cells. One of the classical examples is herpes simplex virus type 2 which is ongoing trials in many tumour cell lines by deleting its oncogenic genes coding thymidilase kinase or ribonucleotide reductase. Therefore, even tumourogenic agents can be used as oncolytic therapy by engineering their oncogenic gene components. 7. Novel oncolytic viruses 7.1. Adenovirus Adenovirus is interested in treatment of brain tumour especially in glioma multiforme. This tumour is never metastasized and contributed as single lesion. Moreover, it is almost resistance to systemic therapy because of blood-brain barrier and lack of cell mediated antigen drainage. However, fortunately, oncolytic viruses can replicate and spread within the tumour population since blood brain barrier create immune privileged site. In glioma cells, tumour suppressor gene (Rb) is inactivated and lack of expression. Taking this advantage, genetically modified adenoviruses are constructed by deletion of eight amino acids in Rb binding region of E1A protein. Therefore, they are unable to replicate in the normal cells because viruses cannot inactivate Rb gene of the functioning cells. But they can easily divide within the malignant cells owing to the lack of Rb protein. Additionally, adenoviruses induce autophagy in infected cells (malignant cells) through down-regulation of AKT/TOR pathwa y. Many genetically engineered adenoviruses are still on trials including in vitro and in vivo tests. ONYX-015 (dl1520) is a simple adenovirus lack of E1B 55K protein which do not replicate in the normal cells. So, they only express their functions in p53 mutant cells. In other word, their function does not work in p53 competent cells. Onyx-015 is a first oncolytic virus that has been approved by china FDA to treat the head and neck cancers especially refractory nasopharyngeal cancer combining with standard cisplatin based chemotherapy. Onyx-015 should be given intratumoural or peritumoural injection because of their side effects (e.g. flu-like syndrome). In addition, it showed 50% response rate observed in phase I and II clinical trials of pancreatic cancer. Recent studies found that Onyx-015 replication is not solely dependent on p53 function. Onyx-015 can replicate within some p53 competent cells whereas sometimes, cannot replicate even in mutant p53 cells. It may think to be reliable on E1B 55K independent nuclear late mRNA export of the tumour cells but not in functionally norma l cells. Besides, other co-founding effects should be considered. For example, increasing the temperature (fever, hyperthermia or drugs) promotes replication of E1B deficient adenovirus in the malignant cells rather than normal ones. dl250 mutant strain is engineered by deletion of E1B 19K which is homologue of Bcl-2 and also inhibits pro-apoptotic protein Bax. Functionally, Bcl-2 is the anti-apoptosis protein. Hence, deletion of E1B 19K leads to permit cell death in Bcl-2 over-expressed tumour cells. It may also reduce expression of anti-apoptosis proteins and various growth factors. This type of virus is more potent in anti-tumour activity than dl1520. Delta 24 (dl922-947) adenoviruses are genetically modifying agents which are deleted the gene related with virulence factors and upregulate the transcription elements sensitive to the transcription factors of tumour cells. E.g. Delta-24 is modified by deleting of 24 nucleotides (pRb binding region) in E1A gene so that it is unable to inactivate Rb gene in the normal cells. So, it can only effective in the malignant cells. Now, many studies promise that it has potent anti-tumor effect in glioma. E1A mutants are more superior in oncolysis than E1B strains in vivo and vitro. Besides, Delta-24 RGD is more efficient in treating the low CAR (coxsackie-adenovirus receptor) expression malignant cells such as glioma and bronchogenic carcinoma cells. 7.2. Herpes Simplex virus First herpes simplex virus (dlsptk) as an oncolytic agent is developed in 1991 that is deleted in thymine kinase (TK) genes required for nucleic acid metabolism. Lacking of this gene, Herpes Simplex virus (HSV) lose its ability of replication in the normal cells. Hence, HSV only prefer to infect the tumour cells. HSV is a primarily potential treatment in several paediatric cancers including brain tumours. So far, ÃŽ ³34.5 deleted HSV are tracking on the clinical trials. These all vectors directly target to the tumour cells by deletion of neurovirulant gene ÃŽ ³34.5 (30kb) which is not essential for replication of the malignant cells. G47Δ HSV virus is derived from G207 parent virus. They are constructed by deletion of both copies of ÃŽ ³34.5 gene (1kb) and deletion of 312bp in ICP47 gene increasing oncolyitc efficacy. Also, they promote MHC class I expression in the tumour cells enhancing the immunogenicity of these cells. G207 variant was completed phase I study in glioblastoma multiforme resulting with no serious side-effects. Similarly, HSV 1716 is a genetically engineered variant by manipulating HSV1 stain 17 and deleting both copies of neurovirulent gene, ÃŽ ³34.5. Pilot study has already completed in Metastatic melanoma. NV 1020 (R7020) stain is the chimeric recombinant of HSV 1 and 2 with deleting one copy of ÃŽ ³34.5 gene, UL24 and 56 genes. Originally, it is developed as HSV vaccination. However, recently, it is still ongoing phase II trial on hepatic metastases of colorectal cancer by direct infusion into the hepatic artery. OncoVEXTM is recombinant vector with deletion of ÃŽ ³34.5 gene as well as ICP47. Deletion of ÃŽ ³34.5 reduces intrinsic neuro-pathogenecity of HSV whereas ICP47 deletion restores MHC class I presentation. Additionally, insertion of GM-CSF gene stimulates immune response of the host to the tumour cells. Releasing of GM-CSF promotes recruitment of dendritic cells for tumour specific response. It promotes tumour specific antigen (TSA) expression as well. Thus, OncoVEXTM affects not only on local tumour but on metastases or distant tumours. Currently, OncoVEXTM improved loco-regional control of head and neck cancers combining with chemo-radiotherapy. Intralesional injection of OncoVEX GM-CSF is ongoing phase I trials on cutaneous metastases and melanomas although it has dose related limitation such as injection site inflammation. Another advantage is that it is able to carry large transgenes up to 150kb. It is the main advantage of these viruses using for oncolytic agent although they ma y produce neurotoxity at high doses, difficult cloning and reactivate latent herpes infection which are hidden in the nervous systems (Ganglions). 7.3. Newcastle disease virus Newcastle disease virus (NDV) is paramyxovirus containing single stranded RNA which causes Newcastle disease in avian (birds). Earliest NDV (73-T strain) has been started to use as a clinical trial oncolytic virus for cervical cancer in 1965. Based on their oncolytic properties, NDV is divided into lytic and non-lytic stains. Lytic strains direct lyses the targeted cells. Currently, 2 lytic strains of NDV are ongoing trials which are NDV-HUJ and PV701. Both are naturally occouring live attenuated viruses. As NDV-HUJ strain is a neurotropic virus, it applies in glioblastoma multiforme (GBM). Likewise, NDV-PV701 strain has effect on many types of tumours. Results of their trials have potential promising. One of the advantages of NDV is that it selectively replicates in the tumour cells, not on normal ones. When NDV has also studied in breast cancer patients neoadjuvant with chemotherapy, outcome was desirable with minimal adverse effects including fever, flu-like syndrome, hypotension etc. Occourance and severity of side effects is reduced in subsequent therapy due to development of NDV antibodies in patients serum. On the other hand, non-lytic strains disturb the malignant cell metabolisms leading to allow regression of the tumours. Common non-lytic strains include Ulster stain. NDV damages the malignant cells by either direct lysis of the cells, induction of cytokine production (Interferon, Tumour necrotic factor) or enhance apoptosis including both intrinsic and extrinsic pathways. 72-T stain induces cytokine release while Ulster stain over-expresses the TRAIL receptors on tumour cells surface which may lead to apoptosis. 7.4. Mump virus and Simian virus Mump virus is the first paramyxovirus trying to treat in variety of human malignant cells. Vaccine strain 79 (S79) has potential promising oncolytic virus because S79 can only be infected to the cancer cells but not in normal ones. Studying in nude mice, mump virus demonstrated its tumour inhibition effect significantly. Simian virus is also a rubulavirus and among them, strain 5 can be genetically engineered as an oncolytic virus. This modified strain is able to attack several different cancer cell types significantly. 7.5. Vesicular stomatitis virus Vesicular stomatitis virus (VSV) is only rhabdovirus potentially using in cancer therapy. VSV is a single stranded RNA virus considering for oncolytic therapy. Developing of the recombinant VSV virus in 1995, the role of VSV is amounting in virotherapy. In recent studies, genetically modified replication competent VSV prolonged survival of hapatocellular carcinoma, breast cancer and malignant melanoma. Oncolytic properties of VSV is more effective in type I interferon (IFN) resistance malignant cells. Tumour cells are defect in interferon (IFN) signaling pathways but activated in Ras -ERK pathway. However, VSV can also impact on the normal cells especially in high doses. Thus, early (prophylactic) interferon therapy is required concomitant with VSV virotherapy because interferon appears to prevent the viral replication within the normal cells. Using the advantage of replication within the interferon defect cells, recombinant VSV deltaM51 which is defective in M (matrix) protein (poin t mutation) was constructed. Matrix protein is the regulator protein that increases replication and transcription of the virus but blocks the host cells anti-viral mechanism. Studies showed that VSV deltaM51 strain has beneficial role in glioma cells xenografted nude mice. Furthermore, VSV shutdown the blood supply to the tumour leading to deprivation of oxygen and nutrients which may require for tumour growth. 7.6. Measles Measles as oncolytic therapy is more interesting since there was significant regression of Hodgkins lymphoma after infecting with measles virus. Resent study suggested that recombinant measles virus (Edmonston B strain) showed significant inhibition on xenograft SCID mice with human lymphoma cells. Next, Edmonston B stain specifically attracts CD 46 cell surface receptors that are highly expressed in human mesothelioma cells. Thus, this strain has highly attractive role in treatment of mesothelioma. In addition, engineered measles virus with interferon (IFN) ÃŽ ² gene inhibits tumour angiogenesis rather than parental strain. Despite most of the people previously encountered with measles infection or vaccination in their early life which may cause therapeutic failure, the evidence highlighted that replication of measles virus was taken place even in the immune individuals. It seems to be immunosuppression due to cancer itself or concurrent use of other anti-cancer therapies such as ra diotherapy, and (or) chemotherapy. 7.7. Poxvirus Vaccinia virus (VV) is the most potential candidate poxvirus utilized as virotherapy recently. This virus is genetically engineered by deletion of thymidine kinase genes like herpes simplex virus (HSV). For instance, JX-594 strain which is transfected with GM-CSF gene, displayed oncolytic activity in animal models. However, it may rarely affective in the normal cells. Most Vaccinia viruses kill the targeted malignant cells by apoptosis as well as traditional mechanisms. Myxoma virus, another poxvirus, is significantly effective on human glioma cancer cell lines. In addition, rapamycin (immunosuppressant) reinforced its oncolytic efficacy when using combination. 7.8. Togaviruses Togaviruses (Sindbis and Semliki Forest Virus) also show their potential roles in the oncolytic therapy. Sindbis virus (SIN) is an RNA virus that naturally infects human by mosquito bites. This virus binds with its receptors of 65kD (Laminin receptors) which are highly express on the tumor cells (tumour homing property). To take the advantage, Sindbis virus promotes considerably regression of the several tumor cell lines in vitro testing and xenograft SCID mice. In human study, it has promising effect on cervical and ovarian malignancies with minimal or no remarkable adverse effect on normal cells. Next, Semliki Forest Virus (SFV) may inoculate repeatedly without prominent immune response. Togaviruses favour as the oncolytic virotherapy agents due to their high replication rate, broad spectrum of host ranges, increase transgene expression and stable in blood stream. Apart from these viruses, Venezuelan equine encephalitis virus (VEE) is also a replication competent virus which is int eresting in certain circumstance of oncolytic therapy. 7.9. Retrovirus Gamma retrovirus (moloney murine leukemia virus (MoMLV)) may have effect on the tumour cells not in the non-dividing cells. So, it may safe as oncolysis. For instance, when U87 glioma xenografted nude mice were administrated with MoMLV, significant oncolytic result has been reported. These viruses are less effect on normal cells due to lack of nuclear transport of viral genome. Certainly, they cannot replicate well within non-dividing cells. In addition, modified MoMLV viruses expressing HSV thymidine kinase (TK) have synergistic effect on glioblastoma cells combining with ganciclovir (anti-viral agent for HSV). Another retrovirus such as fomy virus has also intrinsic oncolytic property. It is researched recently on glioma implanted nude mice. However, the result is still controversial.

Cocaine :: essays research papers

Cocaine is a drug extracted from the leaves of the coca plant. It is a potent brain stimulant and one of the most powerfully addictive drugs. Cocaine is distributed on the street in two main forms: cocaine hydrochloride is a white crystalline powder that can be snorted or dissolved in water and injected; and "crack" is cocaine hydrochloride that has been processed with ammonia or sodium bicarbonate (baking soda) and water into a freebase cocaine. These chips, chunks, or rocks can be smoked. Cocaine may be used occasionally, daily, or in a variety of compulsive, repeated-use "binges". Regardless of how it is used, cocaine is highly addictive. Crack cocaine and injected cocaine reach the brain quickly and bring an intense and immediate high. Snorted cocaine produces a high more slowly. Cocaine can produce a surge in energy, a feeling of intense pleasure, and increased confidence. The effects of powder cocaine last about 20 minutes, while the effects of "crack" last about 12 minutes. Heavy use of cocaine may produce hallucinations, paranoia, aggression, insomnia, and depression. Cocaine's effects are short lived, and once the drug leaves the brain, the user experiences a "coke crash" that includes depression, irritability, and fatigue. Many people ask is cocaine addictive? Yes. Cocaine can take over your life and cause you to lose interest in everything else. Studies in monkeys have shown that animals will work very hard (press a bar over 10,000 times) for a single injection of cocaine, choose cocaine over food and water, and take cocaine even when this behavior is punished. Animals must have their access to cocaine limited in order not to take toxic or even lethal doses. People addicted to cocaine behave similarly. They will go to great lengths to get cocaine and continue to take it even when it hurts their school or job performance and their relationships with loved ones. Do users develop a tolerance to crack or cocaine? Yes. Users may find they need more and more of the drug to get high. What are the effects of cocaine use? Cocaine stimulates the central nervous system. It acts on the "pleasure centers" of the brain, producing heightened pleasure and increased confidence. Other immediate effects include dilated pupils and elevated blood pressure, heart rate, respiratory rate, and body temperature. The pleasurable effects of powder cocaine last about 20 minutes. Occasional use can cause a stuffy or runny nose, and chronic use can ulcerate the mucous membrane of the nose. Injecting cocaine with contaminated equipment can cause AIDS, hepatitis, and other diseases. Preparation of freebase cocaine, which involves the use of volatile solvents, can result in death or injury from fire or explosion.