Targeted Drug Delivery for Sex Dependent Cancers

Targeted Drug Delivery for Sex Dependent Cancers Occurring cancer in any part of the human body such as lung, kidney, skin and etc. has a different incidence ratio between men and women. sex dependent cancers have seen just in male or female which is dependent to sex hormones and specific sex organs such as prostate cancer in male and Ovary and endometrial cancers in female, breast cancer is seen in both sex with 5% incidence in male. Despite of a self-explaining differentiation between the sex organs, since these organs functions are regulated by same hypothalamic gonadotropin-releasing hormone similarities in cell signaling and pathways via molecular interactions are highlighted for cancer studies and targeted therapy. Targeted drug delivery for sex dependent cancers has been studied for many years, but exploring similarities of sex-dependent cancers targeting could provide an opportunity for future targeted drug delivery of these cancers simultaneous effects analysis. Breast Cancer: Breast cancer (BC) is the most common cancer and cause of death among women worldwide during the past decades. To improve diagnosis, therapy and prevention of BC, molecular developments provide various techniques for scientist to study and differentiate BC cell lines as well as observe different phenotype of BC. They classified BC to three main subtypes: estrogen/progesterone receptor (ER) positive, epidermal growth factor receptor (HER2) positive, and triple negative breast cancer (TNBC). Estrogen/progesterone receptor (ER) positive: In BC subtypes of ER+, the overexpression of estrogen receptors on breast cells and nucleus membranes cause the over uptake of estrogen [1]. Many studies showed that estrogen receptors could be targeted for anti-cancer delivery to breast cells. Some estrogen receptor targeted drugs now use in clinical therapy like tamoxifen from the family of SERMs (selective estrogen receptor modulators) which are competitive agonist of the estrogen receptor [2]. Arimidex, Fareston (Toremifene), Anastrozole, Exemestane, anastrozole, letrozole [3], [4],[5]  Fulvestrant [6]  are now in market. Other estrogen receptor targeted drug is a family of aromatase Inhibitors (AI) that suspend the estrogen production. The third-generation aromatase inhibitors are classified into irreversible steroidal inhibitors and they have shown high potential to replace tamoxifen in postmenopausal women such as Exemestane, anastrozole, letrozole[2,4 ,5]. SERDs (selective estrogen receptor down-regulators) is another estrogen targeted that only drug with FDA approved is fulvestrant on the name of Faslodex used in metastatic hormone positive breast cancer [6]. HER2 positive: This breast cancer subtype is referred to overexpression of erbB2 (HER2) from the epidermal growth factor receptor family on breast cells membranes [7]. Anti HER2 agent has studied for targeted therapy of this subtype. Recombinant humanized monoclonal antibodies such as trastuzumab and pertuzumab are widely used for HER2 positive breast cancer and any other HER2 positive cancers [8],  [9],  [10]. Some monoclonal antibodies are under further clinical trials studies like ertumaxomab and margetuximab  [11]  .Her2 Vaccine is now under further studies [11]. Triple Negative breast cancer (TNBC): These subtype tumors do not express receptors for estrogen or progesterone and not overexpress the HER2 receptor. TNBC is a malignant cancer with the high rate of incidence in younger age and it grows faster with the high potential of metastasis in early stage while it is unlikely to be seen on annual mammogram [12]. Not only patients with TNBC almost show poor prognosis compare to other subtypes, but also during therapy they are at the higher risk of relapse, metastasis, and survival [13]. Since the clinical trial of some designed drug were not successful, no commercialized drug and therapy for this subtype still exists. Endometrial Cancer: Endometrial Cancer (EC) begins in the uterus cells of the endometrium layer. Mostly surgery including hysterectomy (removal of the uterus) and removal of ovaries and lymph nodes is the only way to cure the EC if biopsies show that cancer has not spread, no other treatment is needed. According to clinic pathological characteristics, EC is classified to two subtype. Estrogen-dependent endometrioid and estrogen-independent non-endometrioid carcinoma. [14],  [15]. Estrogen-independent EC shows p53 and p16 mutations, overexpression of HER2 and E-cadherin loss [16]. Most of the diagnosed EC tumor are estrogen-dependent that express estrogen receptor and hormonal therapy with progestron is a primary line [17]. Since EC Type I express estrogen receptor the like ER+ BC mentioned previously, targeted therapies for EC are SERM, AI and GnRH inhibitors. Tamoxifen (as SERM) and anastrazole (as AI) commonly used. Anti-angiogenesis drugs are efficiently used for EC like Aflibercept, Abitrexate (Methotrexate) is an only trial drug for EC. Prostate Cancer: Prostate cancer is derived from the specific epithelial of secondary sex organs. Todays, the prostate cancer strategies of treatment is mostly based on suppressing testosterone level by anti-androgenic, gonadorelin agonist or antagonists [18]. Despite of the unknown active mutation in oncogenic pathways in prostate cancers subsets, some molecules express specifically in prostate epithelial cells which have been studied as therapeutic targets including; cell surface prostate-specific membrane antigen (PSMA), the secreted protease prostate-specific antigen (PSA), and the enzyme prostatic acid phosphatase (PAP). PSMA targeting: PSMA is an integral cell surface membrane protein and specifically over-expressed in advanced prostate cancers. PSMA has been studied in phase II trial as a targeted therapy via monoclonal antibody (J591) conjugated with radio and chemical compounds [19]. PSA: The prostate-specific antigen (PSA) mostly use as an indicator for primary diagnosis of prostate cancer. Gonadorelin antagonists can suppress testosterone and PSA, by then Degarelix (Firmagon) is now using for treatment in prostate cancer patients. ARN-509 antiandrogen is only used for prostate cancer with high level of PSA indication. PAP: Prostatic acid phosphatase (PAP) is an enzyme produced by prostate and the amount increased in prostate cancer cells. In clinical studies PAP mostly used as an antigen for anti-tumor vaccines [20]. Ovarian Cancer: Ovarian Cancer is a 5th cause of cancer related death among women worldwide [21].Ovarian cancer has not yet been classified. It is poor diagnosed in stage I and in stage II,III,IV diagnosed by metastasis to other organs  [22]. Surgery and aggressive chemotherapy are currently the only way to treat the ovarian cancer. Many studies on targeted therapy for ovarian cancer by nano-carriers are undergoing. Although, in market there is nano-carriers like liposome that carried chemotherapeutic agents like doxorubicin; DOXIL (Doxorubicin Hydrochloride Liposome), Evacet (Doxorubicin Hydrochloride Liposome) [23]. Novel Targeted therapy: As previously has been mentioned, these cancers are mostly depended on sex hormones level, HER2 expression and other individual molecular marker indications. Almost all chemotherapy regiment have cytotoxic effect on non-cancer cells and caused the chemotherapy side effects. If these chemotherapy regiment could be conjugated with marker to specific targets of cancer cells the result would be cytotoxicity of drug just for cancer cells and no more side effects for healthy cells. This conjugation can be followed by protein based interactions like antigen- antibody mechanism or ligand-receptor affinity. Today novel therapeutical aims are trying to conjugate monoclonal antibodies with drugs which is called antibody-drug conjugated (ADC). Other novel targeted therapy is to conjugate the peptide or protein with drug (PDC). Both ADC and PCD are the subtype of protein drug conjugated approach. The result of covalent conjugation of drug with antibody or peptide is another novel strategy of prod rug in which after delivered to cells would be cleaved by an enzyme and release active drug [24]. For targeted drug delivery for any drugs two main subjects should be considered; Carrier and Targets: Carriers: Antibody: In past decades, targeted drug delivery has been improved by development of antibodies against any identified targeted antigen. Not only antibodies can induce uptake of conjugated drug in targeted cells, but also they can enhance the role of complement-dependant cytotoxicity system to invade targeted cells. The potential of making almost any antigen as a target is an interesting properties of ADCs, however, just few of the human antibodies have shown a longer proper half-lives like IgG1, IgG2, and IgG4. Nearly 40 monoclonal antibodies (mAb) have been approved and develop not only for cancer but also for some autoimmune disease [25]. While antibodies have shown low loading capacity of drug, on molecule of antibodies are capable to conjugate with less than 3 molecules of drug, for improve ADCs efficacy drug should be highly potent. As mentioned previously, HER2 is overexpressed in breast, prostate, ovarian and endometrial cancer that the anti-HER2 antibody can be used for targeted drug delivery. Antibody-drug conjugates (ADC) for HER2 positive is a conjugation of trastuzumab as an antibody and emtansine as cytotoxic compound and commercialized as TDM1. Other cytotoxic compound in conjugation with antibody is under further studies and clinical trial process like defucosylated trastuzumab [26],[27]. Lapatinib is commercialized drug from the family of Receptor tyrosine kinase inhibitors (RTKI) that target the intracellular binding site of HER and EGFR family [28]. In breast cancer antibodies of Anti-LIV1 mAb (hIgG1), Anti-GPNMB mAb (hIgG2), Anti-cripto mAb (hIgG1) in conjugation with drug Auristatin E and DM4 (maytansine) are now clinical Phase I. Anti-HER2 mAb (hIgG1) in conjugation with Emtansine-DM1 (maytansine) has been approved in early 2013 and used for metastatic breast cancer. Anti-TROP-2 mAb (mIgG1) in conjugation with SN-38 (irinotecan metabolite) is under further studies for triple negative breast cancer in Phase II clinical [29]. In prostate cancer Anti-PSMA mAb (hIgG1) in conjugation with Auristatin E (auristatin) is still on phase I clinical [30]. IgG1 ADC targets Folate receptor is in Phase 1 studies for ovarian cancer [31]. Protein/Peptide-drug conjugated (PDC): Proteins are sequences of amino acids with 3D or 4D structures that have vital responsibility in all alive cells. Protein has been studied as a carrier for drug due to its stability, longer half-life, biodegradability and easy modification for carry drug with no effect on its desirable function [32]. Protein which are widely used as for drug delivery are Transferrin and Albumin [33], Zein [34],  Elastin and Gelatine  [35], Gliadin and Legumin [36]. The conjugation of albumin with methotrexate has been studied preclinical for many cancers but it had shown effect on just bone and prostate cancer [37]. Conjugation of transferrin with N-alkylisatin derivatives had shown 10 times more efficient on breast cancer tumor in vivo [38]  and also conjugation with Artemisinin shown high toxicity for breast cancer in rat [39]. Gelatin conjugation with Gallic acid has been studied on prostate cancer [40]. Abraxane is an albumin conjugated with paclitaxel in phase I trial for metastatic breast cancer, prostate and ovarian cancer [41]. Peptide usually refers to a sequence of amino acids (up to 50) with just up to secondary structure [42]. Peptide ligand can be used for targeted receptors. However, peptides have short half-life and poor stability in serum as they can be degraded by protease, but peptides are smaller than antibodies and can easily penetrate the targeted cells and overcome biological barriers that the result would be the fast uptake of drug by targeted cells and also peptides have shown high drug loading potential  [43]. Acyclic RGD4C as peptide c(Cys-Phe-Cys-Asp-Gly-Arg-Cys-Asp-Cys) in conjugation with doxorubicin has been shown higher antitumor activity on metastatic breast cancer in vivo than doxorubicin alone [44]. Targets: Gonadotropin hormone receptor targeting: The overexpression of luteinizing hormone releasing hormone (LHRH) receptors has been well reported on many cancer tumors specially breast, ovary, endometrial and prostate cancer [45],[46]. LHRH analog is widely used as a supplementary drug in order to bind to the LHRH receptor [47]. LHRH agonist induce downregulation of LHRH and suppress sex steroid hormone. While, LHRH antagonist block the LHRH receptors and suppress LHRH and sex steroid releasing immediately [48],[49].  Prostate cancer drug in market like Degarelix (Firmagon) (ANTAGONISTS), Lupron, Leuprolide Acetate, Zoladex (Goserelin Acetate) are LHRH analog [50]. LHRH and its analogue as a peptide with a sequence of 10 amino acids have been studied as a targeted drug carrier. AEZS-108 (formerly known as AN-152) is an LHRH agonist conjugation with doxorubin which is shown anti-cancer activity in phase II clinical trial of gynaecological cancers and a promising result for prostate cancer [51]. LHRH also has been studied for carry cisplatin encapsulated in dextran nano-particle to breast cancer cells [52]. Compound uptake via an interaction between LHRH and its receptor and then endocytosis by cell membrane. As normal cells with no overexpression of LHRH receptor could not uptake the drug, side effects of toxic drug significantly has been reduced36. Growth factor targeting: Growth factor refers to substances that stimulate cells proliferation and differentiation by binding to their receptors which is tyrosine kinase activate other cell pathways. Epidermal growth factor (EGF) and vascular endothelial growth factor (VEGF) and their receptors are two class of growth factors that have been studied for targeted therapy: Angiogenic pathway targeting: In all cancers, tumor growth and metastasis depend on angiogenesis pathway which activated by vascular endothelial growth factors. VEGF family and their receptors (VEGFR) have been studied for inhibition of tomur growth and metastasis as their overexpression had been seen in most of the malignant cancers [53]. The stimulation of VEGF not only induces cells mitosis and abort apoptosis, but also caused the chemotherapy and radiotherapy resistance [54]. On the other hand, chemotherapy and radiotherapy could induce VEGF in tumor cells [55]. Hereby, today anti-VEGF drug have been added to chemotherapy regiment. Ovarian cancer cell lines has shown overexpress of VEGFR as well as breast cancer cell line like MDA-MB-453, and MDA-MB-231,T-47D,and MCF7  [56]. Studies on triple negative breast cancer cell lines; MDA-MB-453; have shown that overexpression of VEGF protected cancer cells from apoptosis and improved cell mitosis and invasion [57]. Treatment of MDA-MB-453 and MDA-MB-231 with anti-sense oligonucleotide inhibition of VEGF has shown over 50% decrease in invasion by Martigel assay [58]. Targeting VEGF has been studied in Phase I and II clinical by designing monoclonal anti-body directly against VEGF that shown suppressing metastasis relapsed in patients with breast cancer [59],  [60],  [61]. Now, Bevacizumab (Avastin ®) is a monoclonal anti-body that bind to VEGF that has studied in phase III trial for metastasis breast cancer. Successful result has been released in phase III trial studies E2100, AVADO, RIBBON-1 that have Bevacizumab as a supplement and chemotherapy regiment like paclitaxel, docetaxel, anthracycline-based as a first line treatment respectively  [62],  [63],  [64]. Epidermal growth factor targeting: Epidermal growth factor (EGF) is a factor that induce cell growth, proliferation, differentiation, and survival by binding to its receptor (EGFR) with tyrosine kinase activity. The EGFR from ErbB family (also known as HER) has shown overexpression in cell surface of many cancers, especially breast, prostate, and ovarian cancer. HER2 is a receptor with three domains of extracellular for ligand, transmembrane domain, and cytoplasmic domain with tyrosine kinase activity. The excess of HER2 on cell membrane and high tyrosine kinase activities induce the downstream signalling pathways like PI3K/AKT/mTOR as well as JAK/STAT pathways which suppress apoptosis and promote proliferation and survival. HER2 is overexpressed in 15-30% of invasive breast cancers [65],  [66],  [67]. Cetuximab (Erbitux) and panitumumab (Vectibix) are the two most advanced monoclonal anti-bodies targeting the extracellular domain of the receptor and inhibit ligand-receptor interaction and tyrosine kinase activity [68],  [69]. But an abnormal form of HER2 which has the lack of extracellular domain, known as P95, is still active but resistance to drug and antibodies that target the extracellular domain[70]. Antibody-drug conjugates (ADC) for HER2 positive is a conjugation of trastuzumab as an antibody and emtansine as cytotoxic compound and commercialized as TDM1. 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How Far Does Luck Explain the Rise and Fall of Napoleon Bonaparte Essay

How far does luck explain the rise and fall of Napoleon Bonaparte? Napoleon Bonaparte like many others rose to prominence during the turbulent times of the French revolution- he was therefore lucky to have been born at such a time in to justify his advancing position. However his reputation as a skilled tactician and strategist enabled him to initially capitalize on the reforms of the French Revolution to improve the lives of French citizens. Napoleon Bonaparte emerged as an important figure for re-establishing order in France and initially gained the trust and support of his countrymen, winning many great military victories against the nations of Europe. But over time, Napoleon’s lust for power overcame his good economic, political and military accomplishments, and his transformation into a selfish dictator led to his fall. To say he was unlucky at this point is an understatement. Napoleon’s upbringing is one that could be considered unconventional (at first) for a successful ruler of France. Napoleon was the son of a middle class Corsican family, at a time when Corsica had not even been French for long. Being formerly subject to Genoa, the Corsican people did not speak French but a dialect of Italian. They were, and are, a fiercely independent Mediterranean people, with a Mediterranean temperament. Napoleon was always self-conscious about his humble origins and provincial background. He came from a mediocre family and went to a mediocre military academy, where his schoolmates made fun of his thick Corsican accent. Despite this however he was lucky in a sense that his noble background afforded him more opportunities than were available to a normal Corsican at the time. In January 1779, Napoleon was enrolled at a religious school in Autun, mainland France, to learn French. In May he was admitted to a military academy at Brienne-le-Chateau. He excelled in various subjects including mathematics and was viewed by one examiner as a candidate for an â€Å"excellent sailor†. Napoleon was the first Corsican to graduate from the Ecole Militaire, a testament to his intellectual abilities in the field. Of course his application to maths determined his specialisation as an artillery officer. This can be considered a stroke of luck in his favour, – one of many that he benefited from – inasmuch as the artillery was the most prestigious branch of the army under the old regime. But the biggest stroke of luck Napoleon had was to be born when he was – in the age of the French Revolution. Napoleon, like many others, was made by the Revolution. The Revolution turned the whole world upside down and presented an ambitious young man (he was always ambitious – a consequence of his resentment at his inferior status) with new and vast opportunities. Looking again at the perspective of Napoleon’s capabilities as a man rather than his luck during his ascension we must also consider his fluidity. Despite his early one sidedness and his view of himself as a devout Corsican, he was ostracized by his countrymen when trying to attempt to instil himself as the head of the Corsican national government. The Corsican nationalists were inclined to reactionary and monarchist ideas and distrustful of the ideals of the Revolution. They were also distrustful of Napoleon, who had the misfortune of being seen as a Corsican provincial to the French and a French interloper to the Corsicans. Rejected by his compatriots, Napoleon abandoned all his nationalist ideals. He later became transformed from an ardent Corsican patriot to a fervent advocate of French centralism. In a sense it was luck that Napoleon now saw France as an area would he could advance to power, but there nothing surprising about this sudden turnabout. Napoleon never had any fixed principles about anything, except his own advancement. His early Republican sympathies may have been genuine but they were certainly tempered with a heavy dose of opportunism. He specialised in currying favour with his superiors in order to climb the ladder of careerist advancement. When it was advantageous to appear as a Jacobin, he donned the tricolour, but later he swung against the Jacobins with equal alacrity when their star waned. Napoleon’s big opportunity came in 1794 at the siege of Toulon. This key Mediterranean port had declared for the English and allowed British forces to occupy it. England was the real bulwark of reaction and bankrolled the wars against revolutionary France that others fought. Napoleon saw his chance to make a mark and did so by conspicuous bravery and a high degree of skill in the use of artillery, which decided the battle in France’s favour. His rapid rise to fame and success had begun. His next big military success came with the invasion of Italy in the strategic campaign against Austria. It was at this point Napoleon demonstrated excellent qualities as a tactician and a politician. Napoleon vetoed the idea of the Directory atheists to march on Rome and dethrone the Pope as he reasoned this would create a power vacuum which would be exploited by the Kingdom of Naples. Instead, in March 1797, Bonaparte led his army into Austria and forced it to negotiate peace. The resulting Treaty of Leoben gave France control of most of northern Italy and the Low Countries, and a secret clause promised the Republic of Venice to Austria. Bonaparte marched on Venice and forced its surrender, ending 1,100 years of independence; he also authorised the French to loot treasures such as the Horses of Saint Mark. His application of conventional military ideas to real-world situations effected his military triumphs, such as creative use of artillery as a mobile force to support his infantry. He referred to his tactics thus: â€Å"I have fought sixty battles and I have learned nothing which I did not know at the beginning. Look at Caesar; he fought the first like the last. † His decision to record his exploits through two newspapers he founded for the army and circulation in France earned him wide critical acclaim. But again he was known to sacrifice military glory in favour of preserving his position, as shown by negotiations in Austria and the treaty of Campio Formio in response to Barras and the French republican allies in control of the French government becoming dependent on Bonaparte following the Coup of 18 Fructidor in order to depose the French royalists who feared Napoleon was becoming a dictator. It was not unlucky that this happened, as Napoleon handled the situation effectively and was able to continue his quest for power. His capacity as a strategist in military campaign against nations hostile to France continued to shine when he conceived an expedition into Egypt in order to seize it and thereby undermine Britain’s access to it’s trade interests in India. Although this invasion failed, mostly due to his loss in the battle of the Nile against Horatio Nelson, Napoleon- unlike his later years was able to take defeat well, speeding up the retreat by poisoning plague stricken men- this supposed act of fratricide was deemed necessary by his supporters given the continued harassment of stragglers by Ottoman forces, and indeed those left behind alive were tortured and beheaded by the Ottomans. Back in Egypt, on 25 July, Bonaparte defeated an Ottoman amphibious invasion at Abukir. The coup of Brumaire in 1799 while being the main event for Napoleon’s ascension to ruler of France largely defines how far his luck went in his rise to power. The reasons for General Bonaparte’s coup may have lain more in his defeats than by his victories. In November 1799, France was suffering the effects of military reverses brought on by Bonaparte’s adventurism in theMiddle East. The looming threat of opportunistic invasion by the Second Coalition had provoked internal unrest, with Bonaparte stuck in Egypt. When he returned he stormed into the chambers escorted by grenadiers. At this point his ineptitude at speechmaking failed to impressed the dissolutioned directory, and he was heckled out and even assaulted at the council of Five Hundred. It was only by the intervention of his brother Lucien that he was spared great injury or death, and lucien’s skill at organising the troops to expel the violent deputies from the chamber shouting â€Å"kick ‘em all out! † and dispersing the council. This spelled the end of the directory and the establishment of the consulate. Napoleon had hoped that the his French empire would last for centuries, but the reality was much more disconcerting. His downfall however was not so much attributed to bad luck as it was his ego and complacency due to his earlier military successes. Two main things contributed to his downfall, Economics and Military failure. In the Treaty of Tilset, Napoleon established the continental system which basically was a boycott of selling and buying of goods with the British. He realized that England depended heavily on other countries to buy from and sell to. However Napoleon underestimated the fact that England could trade with the U.  S and controlled India (even though he tried to stop British Trade with India in his invasion of Egypt) and was not limited to Prussia, Russia and Austria. The continental system did not hurt England as much as he had hoped, but it hurt other countries because they loved English goods and got them any way they could. This was also just another reason for the Austrians, Prussians and Russians to rebel against him. Napoleon tended to try and get his way in negotiations by shouting at those who didn’t agree with him, and on one occasion physically assaulted an Austrian diplomat who disagreed with his demands. Napoleon believed military dominance was sufficient to impose his will on Europe, but this necessitated constantly keeping a large army in the field, which strained French finances and alienated the ordinary population of Europe, as French troops lived off the country when campaigning or stationed abroad. His failure to compromise through diplomacy after military victories meant he was never able to consolidate his gains long term and confirm them through any prolonged period of subsequent peace. Napoleon was never accepted as ‘one of them’ by other European rulers. His practice of dethroning monarchs and replacing them with members of his own family, who had no right to them and who were certainly no better as rulers, scared all other European monarchs, who were afraid they might be next. Napoleon didn’t really understand seapower, nor its importance and how to use it effectively. The French navy got few resources-manpower and money being directed mainly to the army. This left the French fleet underequipped, undermanned, and undertrained, which led to a drop in morale and its easy defeat in battle. No attempt was made to rebuild the French fleet after Trafalgar, global naval supremacy being left wholly in British hands. Napoleon didn’t realize that this would have long term economic effects as well as military ones. In the Treaty of Tilset, Napoleon established the continental system which basically was a boycott of selling and buying of goods with the British. He realized that England depended heavily on other countries to buy from and sell to. However Napoleon in a moment of political ineptitude underestimated that though was that England could trade with the U.  S and and controlled India (even though he tried to stop British Trade with India in his invasion of Egypt) and was not limited to Prussia, Russia and Austria. The continental system did not hurt England as much as he had hoped, but it hurt other countries because they loved English goods and got them any way they could. This was also just another reason for the Austrians, Prussians and Russians to rebel against him. Instead of crippling the British economy, it crippled that of much of Europe. Britain had responded with Orders in Council, a close blockade of Europe’s major ports that cut off all foreign seaborne trade to continental Europe. This impoverished many people, denied Europe’s aristocracy luxury goods, and led to endemic smuggling that undermined the economy of France and other European states. When Napoleon created the Continental System, Portugal refused to comply with a treaty that would severely weaken its trade. Promptly, the French marched in with their armies and overran Spain and Portugal. The Spanish people feared that the Catholic Church would be thrown aside by the French, causing unrest. In addition, Napoleon further humiliated the Spanish by deposing their king, to whom the Spaniards were loyal, instead putting his brother on the throne. This was the spark that would set off the true Peninsular War with constant guerrilla warfare that would end with Napoleon losing 300,000 troops by 1813, after 5 years of fighting. Harsh treatment of the population, in particular atrocities committed by French troops against any resistance by the peasantry, led to a opular Spanish uprising against French occupation forces in 1808. A British army sent to Portugal invaded Spain in support of the uprising,and its operations in conjunction with Spanish guerrillas caused the so called â€Å"Spanish ulcer† which diverted troops and resources away from Napoleon’s main army and forced France into a war on 2 fronts. But possibly the greatest blunder of Napoleon was his decision to invade Russia. Under pressure from important nobles who were losing money, the Tzar withdrew from the Continental System. Napoleon determined to invade Russia in 1812 so as to force Russia back in. ossibly due to his inflated ego in becoming the superior leader and incessant wanting of more land, he was convinced that Moscow was the heart of Russia and was determined to march there directly and take control. Napoleon was overconfident in that he allowed himself only nine weeks to defeat Russia and return to Italy and so did not provide cold weather gear for his soldiers nor frost nails for his horses. At the point of his expedition he was initially unlucky that the Russian army did not decide to fight face to face, although their initial retreat and the Russian Autumn inticed Napoleon too much, and he was lured deeper into Russia. The Russians instead implemented a scorched earth policy, destroying and burning anything worthy of supply and nourishment for Napoleon’s men, stretching the French emperor’s supply lines still further and demoralising his army. When the French and Russians finally met head on at the Battle of Borodino on 7 September, it was the largest and bloodiest single-day action of the Napoleonic Wars; it involved more than 250,000 soldiers and resulted in at least 70,000 casualties. The French captured the battlefield, but failed to destroy the Russian army. Moreover, the French could not replace their losses whereas the Russians could replace theirs. Napoleon was caught out by the Russian tactics, but could not adapt to them effectively due to his overreliance on previous tried and tested techniques, thinking he could still win the war on his standard strategy, he was badly wrong. Napoleon entered Moscow on September 14, after the Russian Army had again retreated. But by then the Russians had largely evacuated the city and even released criminals from the prisons to inconvenience the French; furthermore, the governor, Count Fyodor Rostopchin, ordered the city to be burnt. Alexander I refused to capitulate and the peace talks that Napoleon initiated failed. In October, with no clear sign of victory in sight, Napoleon began his disastrous Great Retreat from Moscow, during the usual autumn Russian mud season. Napoleon at this point found himself amongst a disorganised militant force that could only retreat via a single route easily blocked by the Russian army thanks to inadequate maps and intelligence gathered on the Russian geography and Topography: the aforementioned mud made the retreat slow and bloody, with better clothed Cossack troops able to strike with impunity against the confused French army. In the following weeks, the Grande Armee underwent catastrophic blows from the onset of the Russian Winter, the lack of supplies and constant guerilla warfare by Russian peasants and irregular troops. When the remnants of Napoleon’s army crossed the Berezina River in November, only 27,000 fit soldiers remained; the Grand Armee had lost some 380,000 men dead and 100,000 captured. Napoleon then abandoned his men and returned to Paris to protect his position as Emperor and to prepare to resist the advancing Russians. This disaster encouraged the formation of the Sixth Coalition, Prussia and Austria quickly joining Russia and Britain in arms against Napoleon. The strain of fighting a multi front war became apparent to him The Peninsular War (known to the French as the Spanish ulcer) combined with the Russian disaster of 1812 to weaken him so much that he was exiled, for the first time. When he returned in the Hundred Days, Napoleon’s downfall was that he did have so much power. He promised peace to the other European Powers if they let him have the throne. However, no-one could bear to see the man who once ruled most of Europe in power again, so it was off to war. This conflict led to Waterloo, and his final exile. In conclusion it was a combination of luck based on skill and merit that allowed Napoleon to ascend to power from such a foreign position leading the French to establish great military successes In his early years. The great French military leader Napoleon Bonaparte had initially capitalized on the reforms of the French Revolution to improve the lives of French citizens. However his focus on conquering Europe had eventually overridden his economic and military accomplishments. His previous successes exacerbated his ego to the point at which he became complacent with his standard tactics both on the battlefield and in the council. A sequence of poor diplomacy and belief that he could hold the European countries together by sheer force led to European countries rising in vengeance, such as the Spanish ulcer. Napoleon’s failure o deal with these threats and subsequent failing to enforce the ill fated continental system meant his empire was being dismantled piece by piece. Another reason for his downfall was his war tactic of constant Napoleonic Warfare. His main goal was to completely destroy the enemies army to the point where they no longer had the men to fight. But, this also caused heavy causualities on his side. Also, during his Invasion of Russia, he was hurt by the infamous Russian winters. When he retreated from Russia, almost all of his men got left behind (along with Michael Ney) and were completely annihilated by the enemy forces. After this, he suffered because of his army, or lack thereof. The resultant strain of fighting a multi front war against the united European forces was more failure of effective leadership than simple bad luck. Although he successfully returned from exile in the Hundred Days, his military defeat at Waterloo was the final nail in his coffin.

Financial Accounting Standards Boards’ Codification Essay

For my role as a staff accountant, I was assigned to research the appropriate accounting for revenue treatment of construction contracts for a client, LabCo. In specific, I was assigned to oversee LabCos’ contract involving a six-axis laser-cutting machine with Halibut Co. After researching and developing a theory based on the Financial Accounting Standards Boards’ Codification, I have concluded that LabCos’ treatment of revenue was reasonable; however, they should have changed revenue recognition principles sooner. In this situation, there are three possible ways they can handle changing their accounting method: Retrospective Application, Change in Accounting Estimate Method, or Change in Estimate Affected by Accounting Principle. The revenue treatment principle for a construction type principle states, â€Å"In accounting for contracts, the basic accounting policy decision is the choice between two generally accepted methods: the percentage-of-completion method including units of delivery and the completed-contract method. The determination of which of the two methods is preferable is based on a careful evaluation of circumstances because the two methods should not be acceptable alternatives for the same circumstances (ASC 605-35-25-1).† LabCo agreed to build a six-axis laser-cutting machine for Halibut. The contract entered into was a fixed price contract. A fixed price contract is, â€Å"An agreement to perform all acts under the contract for a stated price† (ASC 605-35-15-4). LabCo decided to use the percentage of completion method for recognizing income. â€Å"The percentage of completion method recognizes income as work on a contracts progress† (ASC 605-35-25-51). Income recognized shall be that percentage of estimated total income, either: â€Å"That incurred costs to date bear to estimated total costs after giving effect to estimates of costs to complete based on most recent information, or that may be indicated by such other measure of progress toward completion as may be appropriate having due regard to work performed (ASC 605-32-25-52).† It is appropriate to use the percentage of completion method when, â€Å"The ability to make reasonably dependable estimates, which, for purposes of this Subtopic, relates to estimates of the extent of progress toward completion, contract revenues, and contract costs (ASC 605-35-25-56.)† LabCo believed they could correctly estimate the cost to build a laser cutting machine because they had completed similar contracts in the past for Halibut. After the contract went into effect, LabCo experienced difficulties designing and manufacturing the laser cutting machine. They were forced to redo initial designs, outsource engineering costs, and the price of steel used to construct the cutting machine unexpectedly rose. LabCo had to re-estimate their costs to complete the project and concluded that the excess costs would exceed the total fixed fee contract price they negotiated with Halibut. To update their estimated costs, LabCo continued using the percentage of completion method. LabCo appropriately recorded a loss in the period in which they became aware. â€Å"When the current estimates of total contract revenue and contract cost indicate a loss, a provision for the entire loss on the contract shall be made. Provisions for losses shall be made in the period in which they become evident under either the percentage-of-completion method or the completed-contract method (ASC 605-35-25-46.)† LabCo experienced another setback which delayed their process six more months. When the cutting machine was finally complete, they delivered it to Halibut to have it tested. During the final test, the machine failed to meet the specifications of Halibut. LabCo was forced to redesign and fix the various problems with the machine. At this point, LabCos’ chief accounting officer decided to switch to the completed contract method, which says, â€Å"Under the completed-contract method, income is recognized only when a contract is completed or substantially completed. Accordingly, during the period of performance, billings and costs are accumulated on the balance sheet, but no profit or income is recorded before completion or substantial completion of the work (ASC 605-35-25-88).† â€Å"The completed contract method is preferable when lack of dependable estimates or inherent hazards cause forecasts to be doubtful (ASC 605-35-25-90)†, which was the case in the situation. The two methods, percentage of completion and completed contract, are not acceptable alternatives for the same situation (ASC 605-35-25-1). LabCo should have realized after running into unexpected costs the first time that they should have switched to the completed contract method. â€Å"An entity using the percentage-of-completion method as its basic accounting policy shall use the completed-contract method for a single contract or a group of contracts for which reasonably dependable estimates cannot be made or for which inherent hazards make estimates doubtful (ASC 605-35-25-61).† LabCo is able to handle this change in of accounting principle in one of the three methods; Retrospective Application, Change in Accounting Estimate, or Change in Accounting Estimate Affected by Accounting Principle. It is clear that the percentage of completion method was not the acceptable alternative because LabCo could not effectively estimate costs. The completed contract method is the preferable method because there was a lack of dependable estimates. LabCos’ decision to switch from percentage of completion to completed contract method is in accordance with FASB Codification because this transition can be handled by the Accounting Staff to apply a retrospective application to the previous year’s financial information. â€Å"The application of a different accounting principle to one or more previously issued financial statements, or to the statement of financial position at the beginning of the current period, as if that principle had always been used, or a change to financial statements of prior accounting periods to present the financial statements of a new reporting entity as if it had existed in those prior years. (ASC 250-10-20)† Since the retrospective application is applied to this situation to show the effect of the change to completed contract method; the estimated contract costs were no longer reliably determinable, therefore, disclosure for the reasons behind this change must be included within the year’s financial statements when the change actually is incurred. The situation can also be handled with a Change in Accounting Estimate approach. When LabCo incurred significant difficulties with the design and manufacturing of the laser machine, they decided to update their estimates used in the percentage of completion method to reflect both the cost overruns incurred as well as the cost overruns expected to be incurred. Handling it with this approach prohibits the retrospective treatment to the situation. It will affect only the period of change and future periods, if the change affects both, in which case it does. â€Å"The effect on income from continuing operations, net income (or other appropriate captions of changes in the applicable net assets or performance indicator), and any related per-share amounts of the current period shall be disclosed for a change in estimate that affects several future periods.† (ASC 250-10-50-4) The final approach that could have handled this situation is the Change in Estimate Affected by a Change in Accounting Principle. Due to LabCo dealing with continued problems with the Halibut contract, and prior estimates adjusted previously during the contract period, it forced the Chief Accountant of LabCo to allow the change in accounting principle from percentage of completion method to completed contract method. LabCo can make this change by it being impossible to determine whether a change in principle or a change in estimate has occurred. â€Å"If it is impracticable to determine the cumulative effect of applying a change in accounting principle to any prior period, the new accounting principle shall be applied as if the change was made prospectively as of the earliest date practicable.† (ASC 250-10-45-7) After much continued research and intellectual thought, we have concluded that the Retrospective Application is not sufficient in this matter because the estimates have been altered drastically; to retrospectively apply the changes this year would distort Net Income figures to the point where timeliness and consistency will no longer apply. The Change in Accounting Estimate would seem sufficient to apply to this situation, but it will not work because a change in estimate cannot be applied retrospectively. Therefore, I have concluded that the best way to handle this issue is the Change in Accounting Estimate affected by the Change in Accounting Principle approach. I have come to this conclusion based on the facts that due to a change in accounting principle and change in accounting estimate both being involved in this situation, and retrospective application not being applicable, the entire effect of the two changes should be applied in a prospective method. This free SWOT analysis shows strengths, weaknesses, opportunities and threats. We cover over 40,000 companies and industries. This SWOT analysis for Labco can provide a competitive advantage. Strengths|

National Security Structure Development in Steven Hook and...

A Summary and Critical Evaluation of the Key Issues In Post-World War II National Security Structure Development Steven Hook and John Spaniers 2012 book titled â€Å"American foreign policy since WWII serves as one of the most important texts that can be used in understanding the underlying complexities on American foreign policies. Like the first readings that are analyzed in class (American Diplomacy by George Kennan and Surprise, Security, and the American Experience by John Lewis Gaddis), this text also brings history into a more understandable context. Aside from being informative and concise in its historical approach, Hook and Spanier also critiques the several flaws and perspectives that occurred in the American foreign policy†¦show more content†¦The concept is also very evident from the choice of opening quote from Hook and Spaniers book. This quote is specifically delivered by George W. Bush for the introduction of the National Security Strategy of the United States of America. In this quote, he mentioned that We [the U.S] seek instead to create a balance of power that favors human freedom... We will actively work to bring the hope of democracy, development, free markets, and free trade to every corner of the world (2002). This quote mirrors the concept of American Exceptionalism in a way that Bush recognizes that the U.S. is a separate country that needs to salvage the remaining nations of the world through foreign policies. In Hook and Spaniers words, [t]hese words capture the global ambitions of an American president who, despite his optimistic tone, was still recovering from the deadliest attacks ever on his country (2012, p.1). The authors also discussed how the negative things that happened to the Bush administration transpired into Obamas government. Among the earliest effects are the threats on the classic American dream of unending prosperity and opportunity (Hook and Spanier, p.1). On the other hand, the book also discussed how American foreign policies and the overall American exp erienced are affected by the prevailing cultural attitudes and beliefs. On the other hand, David Rothkopf book titled Running the world: The inside story of the National Security