Merck & Co., Inc. is an American multinational pharmaceutical company headquartered in Rahway, New Jersey , and is named for Merck Group , founded in Germany in 1668, of which it was once the American arm. The company does business as Merck Sharp & Dohme or MSD outside the United States and Canada. It is one of the largest pharmaceutical companies in the world, generally ranking in the global top five by revenue.
150-463: Merck & Co. was originally established as the American affiliate of Merck Group in 1891. Merck develops and produces medicines, vaccines, biologic therapies and animal health products. It has several blockbuster products, including cancer immunotherapy , anti-diabetic medications, and vaccines for HPV and chickenpox , each generating significant revenue as of 2020. The company is ranked 71st on
300-523: A Bosnian Serb named Gavrilo Princip assassinated Archduke Franz Ferdinand , heir to the Austro-Hungarian throne. Austria-Hungary held Serbia responsible, and declared war on 28 July. After Russia mobilised in Serbia's defence, Germany declared war on Russia and France , who had an alliance . The United Kingdom entered after Germany invaded Belgium , whose neutrality it guaranteed, and
450-645: A blue-water navy was vital for global power projection; Tirpitz had his books translated into German, while Wilhelm made them required reading for his advisors and senior military personnel. However, it was also an emotional decision, driven by Wilhelm's simultaneous admiration for the Royal Navy and desire to surpass it. Bismarck thought that the British would not interfere in Europe, as long as its maritime supremacy remained secure, but his dismissal in 1890 led to
600-592: A grenade at the Archduke's car and injured two of his aides. The other assassins were also unsuccessful. An hour later, as Ferdinand was returning from visiting the injured officers in hospital, his car took a wrong turn into a street where Gavrilo Princip was standing. He fired two pistol shots, fatally wounding Ferdinand and his wife Sophie . According to historian Zbyněk Zeman , in Vienna "the event almost failed to make any impression whatsoever. On 28 and 29 June,
750-540: A guerrilla warfare campaign and only surrendered two weeks after the armistice took effect in Europe. Before the war, Germany had attempted to use Indian nationalism and pan-Islamism to its advantage, a policy continued post-1914 by instigating uprisings in India , while the Niedermayer–Hentig Expedition urged Afghanistan to join the war on the side of Central Powers. However, contrary to British fears of
900-464: A human monoclonal antibody used as an immunosuppressive drug that had $ 838 million in 2020 revenue; RotaTeq, a rotavirus vaccine that had $ 797 million in 2020 revenue; and Lynparza ( olaparib ), a medication for the maintenance treatment of BRCA-mutated advanced ovarian cancer in adults that generated $ 725 million in 2020 revenue for the company. Details of Merck's major products are as follows: Merck & Co. publishes The Merck Manuals ,
1050-487: A varicella vaccine used to protect against chickenpox that had $ 1.9 billion in 2020 revenues; Bridion ( Sugammadex ), a neuromuscular-blocking drug that had $ 1.2 billion in 2020 revenue; and Pneumovax 23 , a pneumococcal polysaccharide vaccine that had $ 1.1 billion in 2020 revenue. Other major products by the company include Isentress ( raltegravir ), an antiretroviral medication used to treat HIV/AIDS that had $ 857 million in 2020 revenue; Simponi ( golimumab ),
1200-657: A "change-of-control" in order to preserve Schering-Plough's rights to market Remicade . A settlement with Johnson & Johnson was reached in 2011, in which Merck agreed to pay $ 500 million. Merck Sharp & Dohme remains a subsidiary of the Merck & Co. parent. Richard Clark retired as CEO and company president in October 2011 and Kenneth Frazier became CEO. In October 2013, Merck announced it would cut 8,500 jobs in an attempt to cut $ 2.5 billion from its costs by 2015. Combined with 7,500 job cuts announced in 2011 and 2012,
1350-741: A Biologics License Application to the Food and Drug Administration under the Breakthrough Therapy Designation for an investigational vaccine, called V920, to fight the Zaire strain of the Ebola virus . In April 2019, the company acquired Immune Design for approximately $ 300 million, gaining access to its immunotherapy programs. It also acquired Antelliq Group for $ 2.4 billion, or $ 3.7 billion including debt. In May 2019, Merck announced it would acquire Peloton Therapeutics, developer of
1500-494: A Fab region that binds PD-1 but also an Fc region. Experimental work indicates that the Fc portion of cancer immunotherapy drugs can affect the outcome of treatment. For example, anti-PD-1 drugs with Fc regions that bind inhibitory Fc receptors can have decreased therapeutic efficacy. Imaging studies have further shown that the Fc region of anti-PD-1 drugs can bind Fc receptors expressed by tumor-associated macrophages. This process removes
1650-524: A German-born, long-time Merck employee, Theodore Weicker, went to the United States to represent Merck Group. In 1891, with $ 200,000 received from E. Merck, Weicker started Merck & Co., with headquarters in lower Manhattan. That year George Merck, the 23-year-old son of the then head of E. Merck (and grandson of the founder) joined Weicker in New York. Merck & Co. operated from 1891 to 1917 as
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#17327874498881800-565: A HIF-2alpha inhibitor for Von Hippel–Lindau disease -associated renal cell carcinoma , for up to $ 2.2 billion. In June 2019, Merck announced it would acquire Tilos Therapeutics for up to $ 773 million. In November 2019, the company acquired Calporta, which focused on Parkinsons and Alzheimers treatments. In December 2019, Merck Animal Health acquired Vaki, an aquaculture company, from Pentair . In January 2020, Merck acquired ArQule, developer of ARQ 531 , an oral Bruton's tyrosine kinase (BTK) inhibitor, for $ 2.7 billion. In March 2020, Merck
1950-517: A binding region (Fab) and the Fc region that can be detected by immune system cells via their Fc surface receptors . Fc receptors are found on many immune system cells, including NK cells. When NK cells encounter antibody-coated cells, the latter's Fc regions interact with their Fc receptors, releasing perforin and granzyme B to kill the tumor cell. Examples include rituximab , ofatumumab , elotuzumab , and alemtuzumab . Antibodies under development have altered Fc regions that have higher affinity for
2100-404: A cancer-targeting gene (as with CAR T). The mixture is then added to a MASTER (scaffold), which absorbs them. The MASTER contains antibodies that activate the T cells and interleukins that trigger cell proliferation. The MASTER is then implanted into the patient. The activated T cells interact with the viruses to become CAR T cells. The interleukins stimulate these CAR T cells to proliferate, and
2250-548: A candidate to target the retinoic acid-inducible gene I pathway, for $ 554 million. In October 2017, the company granted the inaugural Merck-AGITG Clinical Research Fellowship in Gastro-Intestinal (GI) Cancer to David Lau, a professional in Melbourne, Australia. In June 2018, Merck acquired Viralytics , an Australian viral cancer drug company, for AUD$ 502 million. In 2018, Merck began the submission process for
2400-408: A change in policy and an Anglo-German naval arms race began. Despite the vast sums spent by Tirpitz, the launch of HMS Dreadnought in 1906 gave the British a technological advantage. Ultimately, the race diverted huge resources into creating a German navy large enough to antagonise Britain, but not defeat it; in 1911, Chancellor Theobald von Bethmann Hollweg acknowledged defeat, leading to
2550-542: A chimeric antigen receptor (CAR) that specifically recognizes cancer cells, then infuse the resulting CAR-T cells into patients to attack their tumors. Tisagenlecleucel (Kymriah), a chimeric antigen receptor (CAR-T) therapy, was approved by the FDA in 2017 to treat acute lymphoblastic leukemia (ALL). This treatment removes CD19 positive cells (B-cells) from the body (including the diseased cells, but also normal antibody-producing cells). Axicabtagene ciloleucel (Yescarta)
2700-613: A direct threat. The 1908–1909 Bosnian Crisis began when Austria annexed the former Ottoman territory of Bosnia and Herzegovina , which it had occupied since 1878. Timed to coincide with the Bulgarian Declaration of Independence from the Ottoman Empire, this unilateral action was denounced by the European powers, but accepted as there was no consensus on how to resolve the situation. Some historians see this as
2850-471: A gap between the German armies as they closed on Paris. The French army, reinforced by the British expeditionary corps, seized this opportunity to counter-attack and pushed the German army 40 to 80 km back. Both armies were then so exhausted that no decisive move could be implemented, so they settled in trenches, with the vain hope of breaking through as soon as they could build local superiority. In 1911,
3000-548: A possibility. This was accentuated by British and Russian support for France against Germany during the 1911 Agadir Crisis . German economic and industrial strength continued to expand rapidly post-1871. Backed by Wilhelm II, Admiral Alfred von Tirpitz sought to use this growth to build an Imperial German Navy , that could compete with the British Royal Navy . This policy was based on the work of US naval author Alfred Thayer Mahan , who argued that possession of
3150-550: A potential $ 4.4 billion in milestone payments for the Abylnx. The company also announced it would spend $ 95 million up front collaborating with cCAM Biotherapeutics and its early-stage treatment similar to Keytruda. Merck & Co. will bring in CM-24, an antibody designed to block the immune checkpoint CEACAM1 . In January 2016, Merck announced two new partnerships; the first with Quartet Medicine and its small molecule pain treatments,
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#17327874498883300-834: A revolt in India, the outbreak of the war saw a reduction in nationalist activity. Leaders from the Indian National Congress and other groups believed support for the British war effort would hasten Indian Home Rule , a promise allegedly made explicit in 1917 by Edwin Montagu , the Secretary of State for India . In 1914, the British Indian Army was larger than the British Army itself, and between 1914 and 1918 an estimated 1.3 million Indian soldiers and labourers served in Europe, Africa, and
3450-454: A scientist at Merck, developed the first mumps vaccine in 1967, the first rubella vaccine in 1969, and the first trivalent measles, mumps, rubella ( MMR vaccine ) in 1971. The incidence of rubella-associated birth defects fell from up to 10,000 per year in the U.S. to zero in the aftermath of the rubella vaccine's development. Hilleman also developed the first Hepatitis B vaccine and the first varicella vaccine , for chickenpox. The company
3600-568: A series of medical reference books for physicians, nurses, technicians, and veterinarians. These include the Merck Manual of Diagnosis and Therapy , the world's best-selling medical reference. The Merck Index , a compendium of chemical compounds, was published by Merck & Co. until it was acquired by the Royal Society of Chemistry in 2012. Merck & Co. traces its origins to its former German parent company Merck Group , which
3750-516: A significant escalation, ending any chance of Austria cooperating with Russia in the Balkans, while also damaging diplomatic relations between Serbia and Italy. Tensions increased after the 1911–1912 Italo-Turkish War demonstrated Ottoman weakness and led to the formation of the Balkan League , an alliance of Serbia, Bulgaria, Montenegro , and Greece . The League quickly overran most of
3900-409: A specific type of Fc receptor, FcγRIIIA, which can dramatically increase effectiveness. Many tumor cells overexpress CD47 to escape immunosurveilance of host immune system. CD47 binds to its receptor signal-regulatory protein alpha (SIRPα) and downregulate phagocytosis of tumor cell. Therefore, anti-CD47 therapy aims to restore clearance of tumor cells. Additionally, growing evidence supports
4050-457: A tumor, culturing but not modifying them, and infusing the result back into the tumour. The first therapy of this type, Lifileucel , achieved US Food and Drug Administration (FDA) approval in February 2024. The premise of CAR-T immunotherapy is to modify T cells to recognize cancer cells in order to target and destroy them. Scientists harvest T cells from people, genetically alter them to add
4200-524: A variety of sources, including human cells, mice, and a combination of the two (chimeric antibodies). Different sources of antibodies can provoke different kinds of immune responses. For example, the human immune system can recognize mouse antibodies (also known as murine antibodies) and trigger an immune response against them. This could reduce the effectiveness of the antibodies as a treatment and cause an immune reaction. Chimeric antibodies attempt to reduce murine antibodies' immunogenicity by replacing part of
4350-478: A war on two fronts; the Schlieffen Plan envisaged using 80% of the army to defeat France, then switching to Russia. Since this required them to move quickly, mobilization orders were issued that afternoon. Once the German ultimatum to Russia expired on the morning of 1 August, the two countries were at war. At a meeting on 29 July, the British cabinet had narrowly decided its obligations to Belgium under
4500-402: A weak Ottoman government, rather than an ambitious Slav power like Bulgaria . Russia had ambitions in northeastern Anatolia while its clients had overlapping claims in the Balkans. These competing interests divided Russian policy-makers and added to regional instability. Austrian statesmen viewed the Balkans as essential for the continued existence of their Empire and saw Serbian expansion as
4650-455: A whole, the Somme offensive led to an estimated 420,000 British casualties, along with 200,000 French and 500,000 Germans. The diseases that emerged in the trenches were a major killer on both sides. The living conditions led to disease and infection, such as trench foot , lice , typhus , trench fever , and the ' Spanish flu '. At the start of the war, German cruisers were scattered across
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4800-534: Is a fixed-dose combination medication used for the treatment of non-small cell lung cancer, small cell lung cancer, hepatocellular carcinoma, melanoma, and alveolar soft part sarcoma. It contains atezolizumab , a programmed death-ligand 1 (PD-L1) blocking monoclonal antibody; and hyaluronidase (human recombinant), an endoglycosidase . It is taken by subcutaneous injection . The most common adverse reactions include fatigue, musculoskeletal pain, cough, dyspnea, and decreased appetite. Avelumab , sold under
4950-556: Is a ganglioside found on the surface of many types of cancer cell including neuroblastoma , retinoblastoma , melanoma , small cell lung cancer , brain tumors , osteosarcoma , rhabdomyosarcoma , Ewing's sarcoma , liposarcoma , fibrosarcoma , leiomyosarcoma and other soft tissue sarcomas . It is not usually expressed on the surface of normal tissues, making it a good target for immunotherapy. As of 2014, clinical trials were underway. The complement system includes blood proteins that can cause cell death after an antibody binds to
5100-486: Is a type of adoptive T-cell therapy that targets some cancers. TCR-T therapies use heterodimers made of alpha and beta peptide chains to recognize MHC -presented polypeptide fragment molecules. Unlike CAR-T, which uses cell surface antigens, TCR-T can recognize MHC's larger set of intracellular antigen fragments. However, TCR-T cell therapy depends on MHC molecules, limiting its usefulness. Two types are used in cancer treatments: Fc's ability to bind Fc receptors
5250-430: Is another CAR-T therapeutic, approved in 2017 for treatment of diffuse large B-cell lymphoma (DLBCL). Multifunctional alginate scaffolds for T cell engineering and release (MASTER) is a technique for in situ engineering, replication and release of genetically engineered T cells. It is an evolution of CAR T cell therapy. T cells are extracted from the patient and mixed with a genetically engineered virus that contains
5400-566: Is critical to systematically incorporate NK cells monitoring as an outcome in antitumor DC-based clinical trials. Sipuleucel-T (Provenge) was approved for treatment of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer in 2010. The treatment consists of removal of antigen-presenting cells from blood by leukapheresis and growing them with the fusion protein PA2024 made from GM-CSF and prostate-specific prostatic acid phosphatase (PAP) and reinfused. This process
5550-620: Is done intravenously. Each intravenous injection of elotuzumab should be premedicated with dexamethasone , diphenhydramine , ranitidine and acetaminophen . It is being developed by Bristol Myers Squibb and AbbVie . Common side effects of elotuzumab with lenalidomide and dexamethasone includes fatigue , diarrhea , pyrexia , constipation , cough , peripheral neuropathy , nasopharyngitis , upper respiratory tract infection , decreased appetite, and pneumonia . The most common side effects of elotuzumab with pomalidomide and dexamethasone includes constipation and hyperglycemia . There
5700-418: Is found on >95% of peripheral blood lymphocytes (both T-cells and B-cells) and monocytes , but its function in lymphocytes is unknown. It binds to CD52 and initiates its cytotoxic effect by complement fixation and ADCC mechanisms. Due to the antibody target (cells of the immune system), common complications of alemtuzumab therapy are infection, toxicity and myelosuppression . Atezolizumab , sold under
5850-654: Is important because it allows antibodies to activate the immune system. Fc regions are varied: they exist in numerous subtypes and can be further modified, for example with the addition of sugars in a process called glycosylation . Changes in the Fc region can alter an antibody's ability to engage Fc receptors and, by extension, will determine the type of immune response that the antibody triggers. For example, immune checkpoint blockers targeting PD-1 are antibodies designed to bind PD-1 expressed by T cells and reactivate these cells to eliminate tumors . Anti-PD-1 drugs contain not only
6000-508: Is known, however, that from 1908 to 1913, military spending by the six major European powers increased by over 50% in real terms. The years before 1914 were marked by a series of crises in the Balkans, as other powers sought to benefit from the Ottoman decline. While Pan-Slavic and Orthodox Russia considered itself the protector of Serbia and other Slav states, they preferred the strategically vital Bosporus straits to be controlled by
6150-767: Is no available information for the use of elotuzumab in pregnant women . Elotuzumab is an immunostimulatory antibody that targets the Signaling Lymphocytic Activation Molecule Family member 7 ( SLAMF7 ) through two mechanisms. Ipilimumab (Yervoy) is a human IgG1 antibody that binds the surface protein CTLA4 . In normal physiology T-cells are activated by two signals: the T-cell receptor binding to an antigen - MHC complex and T-cell surface receptor CD28 binding to CD80 or CD86 proteins. CTLA4 binds to CD80 or CD86, preventing
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6300-648: Is repeated three times. Adoptive T cell therapy is a form of passive immunization by the transfusion of T-cells. They are found in blood and tissue and typically activate when they find foreign pathogens . Activation occurs when the T-cell's surface receptors encounter cells that display parts of foreign proteins (either on their surface or intracellularly). These can be either infected cells or other antigen-presenting cells (APCs). The latter are found in normal tissue and in tumor tissue, where they are known as tumor-infiltrating lymphocytes (TILs). They are activated by
6450-445: Is to remove dendritic cells from the blood of a patient and activate them outside the body. The dendritic cells are activated in the presence of tumor antigens, which may be a single tumor-specific peptide/protein or a tumor cell lysate (a solution of broken-down tumor cells). These cells (with optional adjuvants) are infused and provoke an immune response. Dendritic cell therapies include the use of antibodies that bind to receptors on
6600-574: The Schutzkorps was established, and carried out the persecution of Serbs. The assassination initiated the July Crisis, a month of diplomatic manoeuvring between Austria-Hungary, Germany, Russia, France and Britain. Believing that Serbian intelligence helped organise Franz Ferdinand's murder, Austrian officials wanted to use the opportunity to end their interference in Bosnia and saw war as
6750-641: The World War . In August 1914, the magazine The Independent wrote "This is the Great War. It names itself". In October 1914, the Canadian magazine Maclean's similarly wrote, "Some wars name themselves. This is the Great War." Contemporary Europeans also referred to it as " the war to end war " and it was also described as "the war to end all wars" due to their perception of its unparalleled scale, devastation, and loss of life. The first recorded use of
6900-517: The Asia-Pacific , and in Europe was characterised by trench warfare ; the widespread use of artillery , machine guns, and chemical weapons (gas); and the introductions of tanks and aircraft . World War I was one of the deadliest conflicts in history , resulting in an estimated 10 million military dead and more than 20 million wounded , plus some 10 million civilian dead from causes including genocide . The movement of large numbers of people
7050-695: The Australian Naval and Military Expeditionary Force landed on the island of New Britain , then part of German New Guinea . On 28 October, the German cruiser SMS Emden sank the Russian cruiser Zhemchug in the Battle of Penang . Japan declared war on Germany before seizing territories in the Pacific, which later became the South Seas Mandate , as well as German Treaty ports on
7200-593: The Nobel Prize in Physiology or Medicine for their discovery of cancer therapy by inhibition of negative immune regulation. "During the 17th and 18th centuries, various forms of immunotherapy in cancer became widespread... In the 18th and 19th centuries, septic dressings enclosing ulcerative tumours were used for the treatment of cancer. Surgical wounds were left open to facilitate the development of infection, and purulent sores were created deliberately... One of
7350-721: The Rüstungswende or 'armaments turning point', when he switched expenditure from the navy to the army. This decision was not driven by a reduction in political tensions but by German concern over Russia's quick recovery from its defeat in the Russo-Japanese War and subsequent 1905 Russian Revolution . Economic reforms led to a significant post-1908 expansion of railways and transportation infrastructure, particularly in its western border regions. Since Germany and Austria-Hungary relied on faster mobilisation to compensate for their numerical inferiority compared to Russia,
7500-828: The United States entered the war on the Allied side following Germany's resumption of unrestricted submarine warfare against Atlantic shipping. Later that year, the Bolsheviks seized power in the Russian October Revolution , and Soviet Russia signed an armistice with the Central Powers in December, followed by a separate peace in March 1918. That month, Germany launched an offensive in
7650-467: The fundamental research of cancer immunology ( immuno-oncology ) and a growing subspecialty of oncology . Cancer immunotherapy exploits the fact that cancer cells often have tumor antigens , molecules on their surface that can bind to antibody proteins or T-cell receptors , triggering an immune system response. The tumor antigens are often proteins or other macromolecules (e.g., carbohydrates ). Normal antibodies bind to external pathogens, but
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#17327874498887800-487: The hydrophone and depth charges were introduced, destroyers could potentially successfully attack a submerged submarine. Convoys slowed the flow of supplies since ships had to wait as convoys were assembled; the solution was an extensive program of building new freighters. Troopships were too fast for the submarines and did not travel the North Atlantic in convoys. The U-boats sunk more than 5,000 Allied ships, at
7950-821: The tank . After the First Battle of the Marne in September 1914, Allied and German forces unsuccessfully tried to outflank each other, a series of manoeuvres later known as the " Race to the Sea ". By the end of 1914, the opposing forces confronted each other along an uninterrupted line of entrenched positions from the Channel to the Swiss border. Since the Germans were normally able to choose where to stand, they generally held
8100-588: The 1839 Treaty of London did not require it to oppose a German invasion with military force; however, Prime Minister Asquith and his senior Cabinet ministers were already committed to supporting France, the Royal Navy had been mobilised, and public opinion was strongly in favour of intervention. On 31 July, Britain sent notes to Germany and France, asking them to respect Belgian neutrality; France pledged to do so, but Germany did not reply. Aware of German plans to attack through Belgium, French Commander-in-Chief Joseph Joffre asked his government for permission to cross
8250-563: The 1879 Dual Alliance , which became the Triple Alliance when Italy joined in 1882. For Bismarck, the purpose of these agreements was to isolate France by ensuring the three Empires resolve any disputes between themselves. In 1887, Bismarck set up the Reinsurance Treaty , a secret agreement between Germany and Russia to remain neutral if either were attacked by France or Austria-Hungary. For Bismarck, peace with Russia
8400-441: The 1913 Treaty of London , which had created an independent Albania while enlarging the territories of Bulgaria, Serbia, Montenegro and Greece. However, disputes between the victors sparked the 33-day Second Balkan War , when Bulgaria attacked Serbia and Greece on 16 June 1913; it was defeated, losing most of Macedonia to Serbia and Greece, and Southern Dobruja to Romania. The result was that even countries which benefited from
8550-745: The 2022 Fortune 500 and 87th on the 2022 Forbes Global 2000 , both based on 2021 revenues. In 2023, the company’s seat in Forbes Global 2000 was 73. The company develops medicines , vaccines , biologic therapies and animal health products. In 2020, the company had 6 blockbuster drugs or products, each with over $ 1 billion in revenue: Keytruda ( pembrolizumab ), a humanized antibody used in cancer immunotherapy that had $ 14.3 billion in 2020 revenue; Januvia ( sitagliptin ), an anti-diabetic medication used to treat type 2 diabetes that had $ 5.3 billion in 2020 revenue; Gardasil , an HPV vaccine that had $ 3.9 billion in 2020 revenue; Varivax,
8700-569: The Austrians and Serbs clashed at the battles of the Cer and Kolubara ; over the next two weeks, Austrian attacks were repulsed with heavy losses. As a result, Austria had to keep sizeable forces on the Serbian front, weakening their efforts against Russia. Serbia's victory against Austria-Hungary in the 1914 invasion has been called one of the major upset victories of the twentieth century. In 1915,
8850-646: The Austrians briefly occupied the Serbian capital, Belgrade . A Serbian counter-attack in the Battle of Kolubara succeeded in driving them from the country by the end of 1914. For the first 10 months of 1915, Austria-Hungary used most of its military reserves to fight Italy. German and Austro-Hungarian diplomats scored a coup by persuading Bulgaria to join the attack on Serbia. The Austro-Hungarian provinces of Slovenia , Croatia and Bosnia provided troops for Austria-Hungary. Montenegro allied itself with Serbia. Bulgaria declared war on Serbia on 14 October 1915 and joined in
9000-553: The Balkan Wars, such as Serbia and Greece, felt cheated of their "rightful gains", while for Austria it demonstrated the apparent indifference with which other powers viewed their concerns, including Germany. This complex mix of resentment, nationalism and insecurity helps explain why the pre-1914 Balkans became known as the " powder keg of Europe ". On 28 June 1914, Archduke Franz Ferdinand of Austria , heir presumptive to Emperor Franz Joseph I of Austria , visited Sarajevo ,
9150-510: The CAR T cells exit the MASTER to attack the cancer. The technique takes hours instead of weeks. And because the cells are younger, they last longer in the body, show stronger potency against cancer, and display fewer markers of exhaustion. These features were demonstrated in mouse models. The treatment was more effective and longer-lasting against lymphoma . T cell receptor T cell therapy (TCR-T)
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#17327874498889300-404: The Central Powers. However, the pro-German King Constantine I dismissed the pro-Allied government of Eleftherios Venizelos before the Allied expeditionary force arrived. The Macedonian front was at first mostly static. French and Serbian forces retook limited areas of Macedonia by recapturing Bitola on 19 November 1916 following the costly Monastir offensive , which brought stabilisation of
9450-649: The Chinese Shandong peninsula at Tsingtao . After Vienna refused to withdraw its cruiser SMS Kaiserin Elisabeth from Tsingtao, Japan declared war on Austria-Hungary, and the ship was sunk in November 1914. Within a few months, Allied forces had seized all German territories in the Pacific, leaving only isolated commerce raiders and a few holdouts in New Guinea. Some of the first clashes of
9600-623: The German High Seas Fleet was confined to port. German U-boats attempted to cut the supply lines between North America and Britain. The nature of submarine warfare meant that attacks often came without warning, giving the crews of the merchant ships little hope of survival. The United States launched a protest, and Germany changed its rules of engagement. After the sinking of the passenger ship RMS Lusitania in 1915, Germany promised not to target passenger liners, while Britain armed its merchant ships, placing them beyond
9750-640: The German Army increased in size from 1908 to 1914, he changed the allocation of forces between the two wings to 70:30. He also considered Dutch neutrality essential for German trade and cancelled the incursion into the Netherlands, which meant any delays in Belgium threatened the viability of the plan. Historian Richard Holmes argues that these changes meant the right wing was not strong enough to achieve decisive success. The initial German advance in
9900-752: The German right wing would sweep through the Netherlands and Belgium , then swing south, encircling Paris and trapping the French army against the Swiss border. The plan's creator, Alfred von Schlieffen , head of the German General Staff from 1891 to 1906, estimated that this would take six weeks, after which the German army would transfer to the East and defeat the Russians. The plan was substantially modified by his successor, Helmuth von Moltke
10050-426: The Germans bled heavily as well, with anywhere from 700,000 to 975,000 casualties between the two combatants. Verdun became a symbol of French determination and self-sacrifice. The Battle of the Somme was an Anglo-French offensive from July to November 1916. The opening day on 1 July 1916 was the bloodiest single day in the history of the British Army , which suffered 57,500 casualties, including 19,200 dead. As
10200-565: The Middle East. In all, 140,000 soldiers served on the Western Front and nearly 700,000 in the Middle East, with 47,746 killed and 65,126 wounded. The suffering engendered by the war, as well as the failure of the British government to grant self-government to India afterward, bred disillusionment, resulting in the campaign for full independence led by Mahatma Gandhi . Pre-war military tactics that had emphasised open warfare and individual riflemen proved obsolete when confronted with conditions prevailing in 1914. Technological advances allowed
10350-545: The Ottomans joined the Central Powers in November. Germany's strategy in 1914 was to quickly defeat France, then to transfer its forces to the east, but its advance was halted in September , and by the end of the year the Western Front consisted of a continuous line of trenches stretching from the English Channel to Switzerland. The Eastern Front was more dynamic, but neither side gained a decisive advantage, despite costly offensives. Italy , Bulgaria , Romania , Greece and others joined in from 1915 onward. In April 1917,
10500-449: The Ottomans' territory in the Balkans during the 1912–1913 First Balkan War , much to the surprise of outside observers. The Serbian capture of ports on the Adriatic resulted in partial Austrian mobilisation, starting on 21 November 1912, including units along the Russian border in Galicia . The Russian government decided not to mobilise in response, unprepared to precipitate a war. The Great Powers sought to re-assert control through
10650-549: The Russian Stavka agreed with the French to attack Germany within fifteen days of mobilisation, ten days before the Germans had anticipated, although it meant the two Russian armies that entered East Prussia on 17 August did so without many of their support elements. By the end of 1914, German troops held strong defensive positions inside France, controlled the bulk of France's domestic coalfields, and inflicted 230,000 more casualties than it lost itself. However, communications problems and questionable command decisions cost Germany
10800-538: The Serbian retreat toward the Adriatic coast in the Battle of Mojkovac on 6–7 January 1916, but ultimately the Austrians also conquered Montenegro. The surviving Serbian soldiers were evacuated to Greece. After the conquest, Serbia was divided between Austro-Hungary and Bulgaria. In late 1915, a Franco-British force landed at Salonica in Greece to offer assistance and to pressure its government to declare war against
10950-461: The T cells to tumor antigens in a non-immunosuppressive environment, that they recognize as foreign and learn to attack. Another approach is transfer of haploidentical γδ T cells or natural killer cells from a healthy donor. The major advantage of this approach is that these cells do not cause graft-versus-host disease . The disadvantage is that transferred cells frequently have impaired function. The simplest example involves removing TILs from
11100-664: The US subsidiary of the Merck Group . After the U.S. entered World War I , due to its German connections, Merck & Co. was the subject of expropriation under the Trading with the Enemy Act of 1917 . The government seized 80 percent of the shares owned by the German parent company and sold it. In 1919, George F. Merck (head of the American branch of the Merck family), in partnership with Goldman Sachs and Lehman Brothers , bought
11250-651: The West was very successful. By the end of August, the Allied left, which included the British Expeditionary Force (BEF), was in full retreat , and the French offensive in Alsace-Lorraine was a disastrous failure, with casualties exceeding 260,000. German planning provided broad strategic instructions while allowing army commanders considerable freedom in carrying them out at the front, but von Kluck used this freedom to disobey orders, opening
11400-485: The Younger . Under Schlieffen, 85% of German forces in the west were assigned to the right wing, with the remainder holding along the frontier. By keeping his left-wing deliberately weak, he hoped to lure the French into an offensive into the "lost provinces" of Alsace-Lorraine , which was the strategy envisaged by their Plan XVII . However, Moltke grew concerned that the French might push too hard on his left flank and as
11550-501: The aggressor, German Chancellor Bethmann Hollweg delayed the commencement of war preparations until 31 July. That afternoon, the Russian government were handed a note requiring them to "cease all war measures against Germany and Austria-Hungary" within 12 hours. A further German demand for neutrality was refused by the French who ordered general mobilization but delayed declaring war. The German General Staff had long assumed they faced
11700-428: The air. New machines were installed to reduce smog emissions by 680,000 lb (310,000 kg) a year. In November 1993, Merck & Co. acquired Medco Containment Services for $ 6 billion. Merck & Co. spun Medco off ten years later. Merck's supply chain reduction programme has been referred to as an example of successful change. Merck reduced its number of global suppliers from 40,000 to less than 10,000 during
11850-775: The anti-tumor response. Regulatory T-cells inhibit other T-cells, which may benefit the tumor. World War I World War I or the First World War (28 July 1914 – 11 November 1918), also known as the Great War , was a global conflict between two coalitions: the Allies (or Entente) and the Central Powers . Fighting took place mainly in Europe and the Middle East , as well as in parts of Africa and
12000-410: The antibody with the corresponding human counterpart. Humanized antibodies are almost completely human; only the complementarity determining regions of the variable regions are derived from murine sources. Human antibodies have been produced using unmodified human DNA. Antibody-dependent cell-mediated cytotoxicity (ADCC) requires antibodies to bind to target cell surfaces. Antibodies are formed of
12150-423: The antigen. Dendritic cells are antigen-presenting cells (APCs) in the mammalian immune system. In cancer treatment, they aid cancer antigen targeting. The only approved cellular cancer therapy based on dendritic cells is sipuleucel-T . One method of inducing dendritic cells to present tumor antigens is by vaccination with autologous tumor lysates or short peptides (small parts of the protein that correspond to
12300-474: The attack by the Austro-Hungarian army under Mackensen's army of 250,000 that was already underway. Serbia was conquered in a little more than a month, as the Central Powers, now including Bulgaria, sent in 600,000 troops in total. The Serbian army, fighting on two fronts and facing certain defeat, retreated into northern Albania . The Serbs suffered defeat in the Battle of Kosovo . Montenegro covered
12450-543: The best way of achieving this. However, the Foreign Ministry had no solid proof of Serbian involvement. On 23 July, Austria delivered an ultimatum to Serbia, listing ten demands made intentionally unacceptable to provide an excuse for starting hostilities. Serbia ordered general mobilization on 25 July, but accepted all the terms, except for those empowering Austrian representatives to suppress "subversive elements" inside Serbia, and take part in
12600-408: The binding of CD28 to these surface proteins and therefore negatively regulates the activation of T-cells. Active cytotoxic T-cells are required for the immune system to attack melanoma cells. Normally inhibited active melanoma-specific cytotoxic T-cells can produce an effective anti-tumor response. Ipilimumab can cause a shift in the ratio of regulatory T-cells to cytotoxic T-cells to increase
12750-483: The border and pre-empt such a move. To avoid violating Belgian neutrality, he was told any advance could come only after a German invasion. Instead, the French cabinet ordered its Army to withdraw 10 km behind the German frontier, to avoid provoking war. On 2 August, Germany occupied Luxembourg and exchanged fire with French units when German patrols entered French territory; on 3 August, they declared war on France and demanded free passage across Belgium, which
12900-500: The brand name Bavencio, is a fully human monoclonal antibody medication for the treatment of Merkel cell carcinoma , urothelial carcinoma , and renal cell carcinoma . Common side effects include fatigue, musculoskeletal pain, diarrhea, nausea, infusion-related reactions, rash, decreased appetite and swelling of the limbs (peripheral edema). Durvalumab (Imfinzi) is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks
13050-447: The brand name Empliciti, is a humanized IgG1 monoclonal antibody medication used in combination with lenalidomide and dexamethasone , for adults that have received 1 to 3 prior therapies for the treatment of multiple myeloma . It is also indicated for adult patients in combination with pomalidomide and dexamethasone , who have received 2 prior therapies including lenalidomide and a protease inhibitor. Administration of elotuzumab
13200-405: The brand name Tecentriq among others, is a monoclonal antibody medication used to treat urothelial carcinoma , non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), hepatocellular carcinoma and alveolar soft part sarcoma , but discontinued for use in triple-negative breast cancer (TNBC). It is a fully humanized , engineered monoclonal antibody of IgG1 isotype against
13350-549: The campaign saw the first use of anti-aircraft warfare after an Austrian plane was shot down with ground-to-air fire, as well as the first medical evacuation by the Serbian army. Upon mobilisation, in accordance with the Schlieffen Plan , 80% of the German Army was located on the Western Front, with the remainder acting as a screening force in the East. Rather than a direct attack across their shared frontier,
13500-501: The cancer cell surface, the C1 complex binds to these antibodies and subsequently, protein pores are formed in cancer cell membrane . Blocking Antibody therapies can also function by binding to proteins and physically blocking them from interacting with other proteins. Checkpoint inhibitors (CTLA-4, PD-1, and PD-L1) operate by this mechanism. Briefly, checkpoint inhibitors are proteins that normally help to slow immune responses and prevent
13650-649: The capital of the recently annexed Bosnia and Herzegovina . Cvjetko Popović , Gavrilo Princip , Nedeljko Čabrinović , Trifko Grabež , Vaso Čubrilović ( Bosnian Serbs ) and Muhamed Mehmedbašić (from the Bosniaks community), from the movement known as Young Bosnia , took up positions along the Archduke's motorcade route, to assassinate him. Supplied with arms by extremists within the Serbian Black Hand intelligence organisation, they hoped his death would free Bosnia from Austrian rule. Čabrinović threw
13800-683: The cell surface (the classical complement pathway , among the ways of complement activation). Generally, the system deals with foreign pathogens but can be activated with therapeutic antibodies in cancer. The system can be triggered if the antibody is chimeric, humanized, or human; as long as it contains the IgG1 Fc region . Complement can lead to cell death by activation of the membrane attack complex , known as complement-dependent cytotoxicity ; enhancement of antibody-dependent cell-mediated cytotoxicity ; and CR3-dependent cellular cytotoxicity. Complement-dependent cytotoxicity occurs when antibodies bind to
13950-466: The chance of a decisive outcome, while it had failed to achieve the primary objective of avoiding a long, two-front war. As was apparent to several German leaders, this amounted to a strategic defeat; shortly after the First Battle of the Marne , Crown Prince Wilhelm told an American reporter "We have lost the war. It will go on for a long time but lost it is already." On 30 August 1914, New Zealand occupied German Samoa (now Samoa ). On 11 September,
14100-493: The company acquired Afferent Pharmaceuticals, developer of a candidate used to block P2RX3 receptors, for approximately $ 1 billion, plus up to $ 750 million in milestone payments. In 2017, Merck bought the PARP inhibitor Lynparza from AstraZeneca. In April 2017, Merck Animal Health acquired Vallée S.A., a Brazilian animal health product manufacturer. In September 2017, the company announced it would acquire Rigontec, developer of
14250-501: The company back at a U.S. government auction for $ 3.5 million, but Merck & Co. remained a separate company from its former German parent. Merck & Co. holds the trademark rights to the "Merck" name in the United States and Canada, while its former parent company retains the rights in the rest of the world; the right to use the Merck name was the subject of litigation between the two companies in 2016. In 1925, George W. Merck succeeded his father George F. Merck as president. In 1927,
14400-449: The company renegotiated the agreement, returning the rights to the university in exchange for a royalty. The university then set up non-exclusive licenses with seven companies to ensure a reliable supply of the antibiotic. In the 1950s, thiazide diuretics were developed by Merck scientists Karl H. Beyer, James M. Sprague, John E. Baer, and Frederick C. Novello and led to the marketing of the first drug of this class, chlorothiazide , under
14550-437: The company sold its consumer health business to Bayer and narrowed the company's focus to immunology, vaccines, diabetes, emerging markets and medicines used in hospitals, like certain antibiotics. In January 2015, Merck acquired Cubist Pharmaceuticals for $ 102 per share in cash or about $ 9.5 billion in total. In July 2015, Merck and Ablynx expanded their 18-month-old immuno-oncology collaboration by four years, generating
14700-558: The corporation merged with the Powers- Weightman -Rosengarten Company, a Philadelphia quinine manufacturer. George Merck remained president and Frederic Rosengarten became chairman of the board. In 1929, H. K. Mulford Company merged with Sharp and Dohme, Inc. and brought vaccine technology, including immunization of cavalry horses in World War I and delivery of a diphtheria antitoxin to Merck & Co. In 1943, Streptomycin
14850-520: The cost of 199 submarines. World War I also saw the first use of aircraft carriers in combat, with HMS Furious launching Sopwith Camels in a successful raid against the Zeppelin hangars at Tondern in July 1918, as well as blimps for antisubmarine patrol. Faced with Russia in the east, Austria-Hungary could spare only one-third of its army to attack Serbia. After suffering heavy losses,
15000-522: The creation of new independent states, including Poland , Finland , the Baltic states , Czechoslovakia , and Yugoslavia . The League of Nations was established to maintain world peace, but its failure to manage instability during the interwar period contributed to the outbreak of World War II in 1939. Before World War II , the events of 1914–1918 were generally known as the Great War or simply
15150-449: The creation of strong defensive systems largely impervious to massed infantry advances, such as barbed wire , machine guns and above all far more powerful artillery , which dominated the battlefield and made crossing open ground extremely difficult. Both sides struggled to develop tactics for breaching entrenched positions without heavy casualties. In time, technology enabled the production of new offensive weapons, such as gas warfare and
15300-965: The crowds listened to music and drank wine, as if nothing had happened." Nevertheless, the impact of the murder of the heir to the throne was significant, and has been described by historian Christopher Clark as a "9/11 effect, a terrorist event charged with historic meaning, transforming the political chemistry in Vienna". Austro-Hungarian authorities encouraged subsequent anti-Serb riots in Sarajevo . Violent actions against ethnic Serbs were also organised outside Sarajevo, in other cities in Austro-Hungarian-controlled Bosnia and Herzegovina, Croatia and Slovenia. Austro-Hungarian authorities in Bosnia and Herzegovina imprisoned approximately 5,500 prominent Serbs, 700 to 2,200 of whom died in prison. A further 460 Serbs were sentenced to death. A predominantly Bosniak special militia known as
15450-479: The drugs from their intended targets (i.e. PD-1 molecules expressed on the surface of T cells) and limits therapeutic efficacy. Furthermore, antibodies targeting the co-stimulatory protein CD40 require engagement with selective Fc receptors for optimal therapeutic efficacy. Together, these studies underscore the importance of Fc status in antibody-based immune checkpoint targeting strategies. Antibodies can come from
15600-442: The employment of tumor antigen-specific T cell response in response to anti-CD47 therapy. A number of therapeutics are being developed, including anti-CD47 antibodies , engineered decoy receptors , anti-SIRPα antibodies and bispecific agents. As of 2017, wide range of solid and hematologic malignancies were being clinically tested. Carbohydrate antigens on the surface of cells can be used as targets for immunotherapy. GD2
15750-695: The expansion of the French colonial empire . In 1873, Bismarck negotiated the League of the Three Emperors , which included Austria-Hungary , Russia and Germany. After the 1877–1878 Russo-Turkish War , the League was dissolved due to Austrian concerns over the expansion of Russian influence in the Balkans , an area they considered to be of vital strategic interest. Germany and Austria-Hungary then formed
15900-513: The first member of the carbapenem class of antibiotics. Antibiotics of the carbapenem class play an important role in treatment guidelines for certain hospital-acquired and multi-drug resistant infections. P. Roy Vagelos became CEO and Chairman that year, succeeding Horan. In 1991, Merck's Kelco subsidiary was responsible for volatile organic compound (VOC) emission pollution in the San Diego area. In 1996 Merck paid $ 1.8 million for polluting
16050-400: The first time on the Western Front. Several types of gas soon became widely used by both sides and though it never proved a decisive, battle-winning weapon, it became one of the most feared and best-remembered horrors of the war. In February 1916, the Germans attacked French defensive positions at the Battle of Verdun , lasting until December 1916. Casualties were greater for the French, but
16200-595: The front. Serbian and French troops finally made a breakthrough in September 1918 in the Vardar offensive , after most German and Austro-Hungarian troops had been withdrawn. The Bulgarians were defeated at the Battle of Dobro Pole , and by 25 September British and French troops had crossed the border into Bulgaria proper as the Bulgarian army collapsed. Bulgaria capitulated four days later, on 29 September 1918. The German high command responded by despatching troops to hold
16350-542: The globe, some of which were subsequently used to attack Allied merchant shipping . These were systematically hunted down by the Royal Navy, though not before causing considerable damage. One of the most successful was the SMS ; Emden , part of the German East Asia Squadron stationed at Qingdao , which seized or sank 15 merchantmen, a Russian cruiser and a French destroyer. Most of the squadron
16500-615: The goal is to generate an immune response to these antigens through a vaccine. Currently, only one vaccine ( sipuleucel-T for prostate cancer) has been approved. In cell-mediated therapies like CAR-T cell therapy, immune cells are extracted from the patient, genetically engineered to recognize tumor-specific antigens, and returned to the patient. Cell types that can be used in this way are natural killer (NK) cells , lymphokine-activated killer cells , cytotoxic T cells , and dendritic cells . Finally, specific antibodies can be developed that recognize cancer cells and target them for destruction by
16650-431: The hands and feet), nausea, anemia (low red blood cell counts), neutropenia (low white blood cell counts), thrombocytopenia (low platelet counts), rash, tiredness, constipation, reduced appetite, diarrhea, and cough. Atezolizumab was the first PD-L1 inhibitor approved by the U.S. for bladder cancer. Food and Drug Administration (FDA). Atezolizumab/hyaluronidase , sold under the brand name Tecentriq Hybreza,
16800-549: The high ground, while their trenches tended to be better built; those constructed by the French and English were initially considered "temporary", only needed until an offensive would destroy the German defences. Both sides tried to break the stalemate using scientific and technological advances. On 22 April 1915, at the Second Battle of Ypres , the Germans (violating the Hague Convention ) used chlorine gas for
16950-471: The immune response. This enhances the ability of the immune system to attack cancer cells. Current research is identifying new potential targets to enhance immune function. Approved checkpoint inhibitors include antibodies such as ipilimumab , nivolumab , and pembrolizumab . Dendritic cell therapy provokes anti-tumor responses by causing dendritic cells to present tumor antigens to lymphocytes, which activates them, priming them to kill other cells that present
17100-539: The immune system from attacking normal cells. Checkpoint inhibitors bind these proteins and prevent them from functioning normally, which increases the activity of the immune system. Examples include durvalumab , ipilimumab , nivolumab , and pembrolizumab . Alemtuzumab (Campath-1H) is an anti- CD52 humanized IgG1 monoclonal antibody indicated for the treatment of fludarabine -refractory chronic lymphocytic leukemia (CLL), cutaneous T-cell lymphoma , peripheral T-cell lymphoma and T-cell prolymphocytic leukemia . CD52
17250-551: The immune system. Examples include therapeutic cancer vaccines (also known as treatment vaccines, which are designed to boost the body's immune system to fight cancer), CAR-T cells , and targeted antibody therapies. In contrast, passive immunotherapy does not directly target tumor cells, but enhances the ability of the immune system to attack cancer cells. Examples include checkpoint inhibitors and cytokines . Active cellular therapies aim to destroy cancer cells by recognition of distinct markers known as antigens . In cancer vaccines,
17400-448: The immune system. Examples of such antibodies include rituximab (targeting CD-20), trastuzumab (targeting HER-2), and cetuximab (targeting EGFR). Passive antibody therapies aim to increase the activity of the immune system without specifically targeting cancer cells. For example, cytokines directly stimulate the immune system and increase immune activity. Checkpoint inhibitors target proteins ( immune checkpoints ) that normally dampen
17550-600: The interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 and CD80 (B7.1) molecules. Durvalumab is approved for the treatment of patients with locally advanced or metastatic urothelial carcinoma who: On 16 February 2018, the Food and Drug Administration approved durvalumab for patients with unresectable stage III non-small cell lung cancer (NSCLC) whose disease has not progressed following concurrent platinum-based chemotherapy and radiation therapy. Elotuzumab , sold under
17700-470: The investigation and trial of Serbians linked to the assassination. Claiming this amounted to rejection, Austria broke off diplomatic relations and ordered partial mobilisation the next day; on 28 July, they declared war on Serbia and began shelling Belgrade . Russia ordered general mobilization in support of Serbia on 30 July. Anxious to ensure backing from the SPD political opposition by presenting Russia as
17850-563: The journal actually reprinted articles that originally appeared in other publications and that were favorable to Merck. The misleading publication came to light in 2009 during a personal injury lawsuit filed over Vioxx; 9 of 29 articles in the journal's second issue referred positively to Vioxx. The CEO of Elsevier's Health Sciences Division, Michael Hansen, admitted that the practice was "unacceptable". In 2005, CEO Raymond Gilmartin retired following Merck's voluntary worldwide withdrawal of Vioxx . Former president of manufacturing Richard Clark
18000-402: The layoffs amounted to 20% of its workforce. By 2014, research performed at Merck has led to U.S. FDA approval of 63 new molecular entities . In August 2014, Merck acquired Idenix Pharmaceuticals for $ 3.85 billion. In December 2014, the company acquired Swiss biotechnology company OncoEthix for up to $ 375 million. Between 2010 and 2015, the company cut around 36,450 jobs. During that time,
18150-488: The modified immunotherapy antibodies bind to the tumor antigens marking and identifying the cancer cells for the immune system to inhibit or kill. The clinical success of cancer immunotherapy is highly variable between different forms of cancer; for instance, certain subtypes of gastric cancer react well to the approach whereas immunotherapy is not effective for other subtypes. In 2018, American immunologist James P. Allison and Japanese immunologist Tasuku Honjo received
18300-444: The most well-known effects of microorganisms on ... cancer was reported in 1891, when an American surgeon, William Coley , inoculated patients having inoperable tumours with [ Streptococcus pyogenes ]." "Coley [had] thoroughly reviewed the literature available at that time and found 38 reports of cancer patients with accidental or iatrogenic feverish erysipelas . In 12 patients, the sarcoma or carcinoma had completely disappeared;
18450-485: The name Mectizan; today the compound is used against river blindness , lymphatic filariasis , scabies and other parasitic infections. In 1982, the company formed a joint venture , KBI Inc., with AstraZeneca . During the late 1980s and 1990s, the company also established joint ventures with DuPont to access research and development expertise, and with Johnson & Johnson to sell over-the-counter consumer medications. In 1985, Merck received approval for imipenem ,
18600-465: The ocean, even to neutral ships. Since there was limited response to this tactic, Germany expected a similar response to its unrestricted submarine warfare. The Battle of Jutland in May/June 1916 was the only full-scale clash of battleships during the war, and one of the largest in history. The clash was indecisive, though the Germans inflicted more damage than they received; thereafter the bulk of
18750-534: The others had substantially improved. Coley decided to attempt the therapeutic use of iatrogenic erysipelas..." "Coley developed a toxin that contained heat-killed bacteria [ Streptococcus pyogenes and Serratia marcescens ]. Until 1963, this treatment was used for the treatment of sarcoma." "Coley injected more than 1000 cancer patients with bacteria or bacterial products." 51.9% of [Coley's] patients with inoperable soft-tissue sarcomas showed complete tumour regression and survived for more than 5 years, and 21.2% of
18900-449: The patients had no clinical evidence of tumour at least 20 years after this treatment..." Research continued in the 20th century under Maria O'Connor Hornung at Tulane Medical School . There are several types of immunotherapy used to treat cancer: Immunotherapies can be categorized as active or passive based on their ability to engage the host immune system against cancer. Active immunotherapy specifically targets tumor cells via
19050-589: The period from 1992 to 1997. In May 2002, The Bill & Melinda Gates Foundation purchased stock in Merck. From 2002 through 2005, the Australian affiliate of Merck paid publishing house Elsevier an undisclosed amount to produce eight issues of a medical journal, the Australasian Journal of Bone and Joint Medicine . Although it gave the appearance of being an independent peer-reviewed journal, without any indication that Merck had paid for it,
19200-606: The presence of APCs such as dendritic cells that present tumor antigens . Although these cells can attack tumors, the tumor microenvironment is highly immunosuppressive, interfering with immune-mediated tumour death. Multiple ways of producing tumour-destroying T-cells have been developed. Most commonly, T-cells specific to a tumor antigen can be removed from a tumor sample (TILs) or filtered from blood. The T-cells can optionally be modified in various ways, cultured and infused into patients. T cells can be modified via genetic engineering, producing CAR-T cell or TCR T cells or by exposing
19350-738: The protection of the " cruiser rules ", which demanded warning and movement of crews to "a place of safety" (a standard that lifeboats did not meet). Finally, in early 1917, Germany adopted a policy of unrestricted submarine warfare , realising the Americans would eventually enter the war. Germany sought to strangle Allied sea lanes before the United States could transport a large army overseas, but, after initial successes, eventually failed to do so. The U-boat threat lessened in 1917, when merchant ships began travelling in convoys , escorted by destroyers . This tactic made it difficult for U-boats to find targets, which significantly lessened losses; after
19500-424: The protein programmed cell death-ligand 1 (PD-L1). The most common side effects when used on its own include tiredness, reduced appetite, nausea, vomiting, cough, difficulty breathing, diarrhea, rash, fever, pain in the back, joints, muscles and bones, weakness, itching and urinary tract infection . The most common side effects when used with other cancer medicines include peripheral neuropathy (nerve damage in
19650-832: The protein antigens on cancer cells). These peptides are often given in combination with adjuvants (highly immunogenic substances) to increase the immune and anti-tumor responses. Other adjuvants include proteins or other chemicals that attract and/or activate dendritic cells, such as granulocyte-macrophage colony-stimulating factor (GM-CSF). The most common sources of antigens used for dendritic cell vaccine in glioblastoma (GBM) as an aggressive brain tumor were whole tumor lysate, CMV antigen RNA and tumor-associated peptides like EGFRvIII . Dendritic cells can also be activated in vivo by making tumor cells express GM-CSF. This can be achieved by either genetically engineering tumor cells to produce GM-CSF or by infecting tumor cells with an oncolytic virus that expresses GM-CSF. Another strategy
19800-445: The second with Complix investigating intracellular cancer targets, with both collaborations potentially generating up to $ 595 million and $ 280 million respectively. Days later the company announced it would acquire IOmet Pharma, with IOmet becoming a wholly owned subsidiary of Merck & Co. The acquisition includes IOmets indoleamine-2,3-dioxygenase 1 (IDO), tryptophan 2,3-dioxygenase (TDO), and dual-acting inhibitors. In July 2016,
19950-446: The surface of dendritic cells. Antigens can be added to the antibody and can induce the dendritic cells to mature and provide immunity to the tumor. Dendritic cell receptors such as TLR3 , TLR7 , TLR8 or CD40 have been used as antibody targets. Dendritic cell-NK cell interface also has an important role in immunotherapy. The design of new dendritic cell-based vaccination strategies should also encompass NK cell-stimulating potency. It
20100-469: The term First World War was in September 1914 by German biologist and philosopher Ernst Haeckel who stated, "There is no doubt that the course and character of the feared 'European War' ... will become the first world war in the full sense of the word." For much of the 19th century, the major European powers maintained a tenuous balance of power , known as the Concert of Europe . After 1848, this
20250-691: The threat posed by the closing of this gap was more important than competing with the Royal Navy. After Germany expanded its standing army by 170,000 troops in 1913, France extended compulsory military service from two to three years; similar measures were taken by the Balkan powers and Italy, which led to increased expenditure by the Ottomans and Austria-Hungary. Absolute figures are difficult to calculate due to differences in categorising expenditure since they often omit civilian infrastructure projects like railways which had logistical importance and military use. It
20400-621: The trade name Duiril in 1958. The research leading to the discovery of chlorothiazide, leading to "the saving of untold thousands of lives and the alleviation of the suffering of millions of victims of hypertension" was recognized by a special Public Health Award from the Lasker Foundation in 1975. In 1953, Merck & Co. merged with Philadelphia-based Sharp & Dohme, Inc., becoming the largest U.S. drugmaker. Sharp and Dohme had acquired H. K. Mulford Company in 1929, adding smallpox vaccines to its portfolio. The combined company kept
20550-412: The trade name Merck in the United States and Canada, and as Merck Sharp & Dohme (MSD) outside North America. In 1965, Merck & Co. acquired Charles Frosst Ltd. of Montreal (founded 1899), creating Merck-Frosst Canada, Inc., as its Canadian subsidiary and pharmaceutical research facility. Merck & Co. closed this facility in July 2010 but remerged in 2011 as Merck Canada. Maurice Hilleman ,
20700-590: The war ended with the Armistice of 11 November 1918 . The Paris Peace Conference of 1919–1920 imposed settlements on the defeated powers, most notably the Treaty of Versailles , by which Germany lost significant territories, was disarmed, and was required to pay large war reparations to the Allies. The dissolution of the Russian, German, Austro-Hungarian, and Ottoman Empires redrew national boundaries and resulted in
20850-601: The war involved British, French, and German colonial forces in Africa. On 6–7 August, French and British troops invaded the German protectorates of Togoland and Kamerun . On 10 August, German forces in South-West Africa attacked South Africa; sporadic and fierce fighting continued for the rest of the war. The German colonial forces in German East Africa , led by Colonel Paul von Lettow-Vorbeck , fought
21000-418: The west , which despite initial successes left the German Army exhausted and demoralised. A successful Allied counter-offensive from August 1918 caused a collapse of the German front line. By early November, Bulgaria, the Ottoman Empire and Austria-Hungary had each signed armistices with the Allies, leaving Germany isolated. Facing a revolution at home , Kaiser Wilhelm II abdicated on 9 November, and
21150-432: Was a major factor in the deadly Spanish flu pandemic. The causes of World War I included the rise of Germany and decline of the Ottoman Empire , which disturbed the long-standing balance of power in Europe, as well as economic competition between nations triggered by industrialisation and imperialism . Growing tensions between the great powers and in the Balkans reached a breaking point on 28 June 1914, when
21300-403: Was challenged by Britain's withdrawal into so-called splendid isolation , the decline of the Ottoman Empire , New Imperialism , and the rise of Prussia under Otto von Bismarck . Victory in the 1870–1871 Franco-Prussian War allowed Bismarck to consolidate a German Empire . Post-1871, the primary aim of French policy was to avenge this defeat, but by the early 1890s, this had switched to
21450-535: Was discovered during a Merck-funded research program in Selman Waksman's laboratory at Rutgers University . It became the first effective treatment for Tuberculosis . At the time of its discovery, sanatoriums for the isolation of tuberculosis-infected people were a ubiquitous feature of cities in developed countries, with 50% dying within 5 years of admission. Although Merck's agreement with Rutgers gave it exclusive rights to streptomycin, at Waksman's request
21600-533: Was established by the Merck family in 1668 when Friedrich Jacob Merck purchased a drug store in Darmstadt . In 1827, Merck Group evolved from a pharmacy to a drug manufacturer company with the commercial manufacture of morphine . Merck perfected the chemical process of deriving morphine from opium and later introduced cocaine , used to treat sinus problems and to add to beverages to boost energy levels. In 1887
21750-645: Was incorporated in New Jersey in 1970. John J. Horan became CEO and Chairman in 1976, serving until 1985. Under his leadership, the company's investment in R&;D grew threefold, and Merck became the largest pharmaceutical company in the world. In 1979, Merck scientists developed lovastatin ( Mevacor ), the first drug of the statin class. Merck scientist William C. Campbell and Satoshi Ōmura developed ivermectin for veterinary use in 1981, and later put it to human use against Onchocerciasis in 1987–88 with
21900-408: Was named CEO and company president. In November 2009, Merck & Co. completed a merger with Schering-Plough in a US$ 41 billion deal. Although Merck & Co. was in reality acquiring Schering-Plough, the purchase was declared a "reverse merger", in which "Old" Merck & Co. was renamed Merck Sharp & Dohme, and Schering-Plough renamed as "Merck & Co., Inc. The maneuver was an attempt avoid
22050-469: Was one of ten companies recognised at the inaugural Manufacturing Awards by New Jersey Business magazine and the New Jersey Business and Industry Association . Cancer immunotherapy Cancer immunotherapy ( immuno-oncotherapy ) is the stimulation of the immune system to treat cancer , improving the immune system's natural ability to fight the disease. It is an application of
22200-654: Was refused. Early on the morning of 4 August, the Germans invaded, and Albert I of Belgium called for assistance under the Treaty of London . Britain sent Germany an ultimatum demanding they withdraw from Belgium; when this expired at midnight, without a response, the two empires were at war. Germany promised to support Austria-Hungary's invasion of Serbia, but interpretations of what this meant differed. Previously tested deployment plans had been replaced early in 1914, but those had never been tested in exercises. Austro-Hungarian leaders believed Germany would cover its northern flank against Russia. Beginning on 12 August,
22350-667: Was returning to Germany when it sank two British armoured cruisers at the Battle of Coronel in November 1914, before being virtually destroyed at the Battle of the Falkland Islands in December. The SMS Dresden escaped with a few auxiliaries, but after the Battle of Más a Tierra , these too were either destroyed or interned. Soon after the outbreak of hostilities, Britain began a naval blockade of Germany . This proved effective in cutting off vital supplies, though it violated accepted international law. Britain also mined international waters which closed off entire sections of
22500-781: Was the foundation of German foreign policy but in 1890, he was forced to retire by Wilhelm II . The latter was persuaded not to renew the Reinsurance Treaty by his new Chancellor , Leo von Caprivi . This gave France an opening to agree the Franco-Russian Alliance in 1894, which was then followed by the 1904 Entente Cordiale with Britain. The Triple Entente was completed by the 1907 Anglo-Russian Convention . While not formal alliances, by settling long-standing colonial disputes in Asia and Africa, British support for France or Russia in any future conflict became
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