History.

Plans were initially announced by First Wisconsin National Bank to construct a new headquarters building on August 21, 1969. Although no architectural designs were complete at the time of its announcement, bank officials indicated it would rise at least 40 stories. On March 18, 1971, bank officials unveiled the final design as a 42-story, skyscraper, encompassing a full block fronting on East Wisconsin Avenue. Designed by James DeStefano of the Chicago office of Skidmore, Owings & Merrill, with Fitzhugh Scott Architects of Milwaukee serving as an associate planner for the project, the name of the tower was announced as the First Wisconsin Center.  The building was topped-out on August 29, 1972, with the installing of the final steel beam atop the tower. Along with bank officials, mayor Henry Maier, county executive John Doyne, and Wisconsin governor Patrick Lucey attended the ceremony.  Near the end of construction in 1973, two fatalities occurred at the work site. In May, a foreman died after being struck by a dump truck. In July, one worker died and four others were injured when a derrick used in installing a aluminum panel broke free and fell 41 floors to the ground.  The building was initially occupied on September 4, 1973, and celebrated its official opening on October 6, 1973.

First Wisconsin Center.

While still under construction in September 1972, a group of local developers responsible for the neighboring Juneau Square development filed suit against First Wisconsin. The $138 million suit alleged the bank acted in a "monopolistic" manner to control office development, in an effort to derail the plaintiffs proposed 25-story office tower project on a property adjacent to the First Wisconsin Center. After several years of litigation, the suit finally went to trial in May 1976. The following October, the court found First Wisconsin guilty and awarded the plaintiffs $6 million in damages that was then tripled to $18 million due to federal laws on damages awarded to antitrust suits. First Wisconsin appealed the ruling, and in August 1977, a federal court ruled the case be retried due to the complexity of the original trial, along with the plaintiffs being allowed more time and the admission of hearsay testimony. Upon appeal, in June 1978 the court ruled in favor of First Wisconsin in clearing the company of all charges.  After remaining under the ownership of First Wisconsin since its opening, in June 1987 it was announced the tower would be purchased for $195 million by the Dallas development company Trammell Crow. At the time of the announced sale, Trammell Crow unveiled plans to construct a 50-story tower southeast of the First Wisconsin Center in overtaking it as the state's tallest building. It has since remained unbuilt. The sale was completed in January 1988 with Trammell Crow paying $195 million for the complex, only to subsequently sell it to an investment partnership for $220.9 million.

Firstar Center.

In December 1988, First Wisconsin changed its name to Firstar Corporation as its operations expanded beyond the state of Wisconsin. In May 1992 the First Wisconsin brand was dropped and all retail banking operations were unified under the name Firstar Bank. As a result, on September 14, 1992, the building was renamed the Firstar Center. In 1996, a $1.2 million skywalk was constructed over Van Buren Street to connect the tower with the neighboring Lewis Center. The addition was funded in part by the city of Milwaukee as an economic development project as Firstar had significant operations in both the tower and neighboring Lewis Center.  In 1998, the ownership partnership of The Equitable Life Assurance Society of the United States, the State of Wisconsin Investment Board, and the California Public Employees' Retirement System (CalPERS) decided to place the center on the market. The following November Star Banc Corporation of Cincinnati announced the re-purchase of the tower into company hands for $200 million at the time of their purchase of Firstar.

U.S. Bank Center.

In October 2000, Firstar Corporation announced its purchase of U.S. Bancorp and stated the new company would take the U.S. Bank moniker. The Firstar-U.S. Bancorp merger was approved in February 2001, and on May 3, 2002, the Firstar Center became the U.S. Bank Center when the rebranding was completed in Wisconsin. In April 2008, a panel in the Center's adjacent parking garage fell and crushed a car. As a result of this incident, the building owners decided to tear down the garage constructed in 1973 and replace it with a six-story, precast concrete garage. The 1,000 parking space garage opened in June 2010.  The windows on the U.S. Bank Center are sometimes used to display lighted messages, during significant events in Milwaukee. In 2003, the letters "HD", for Harley Davidson, were displayed during HarleyFest to signify their 100th anniversary. In 2005, the letters "UWM", for University of Wisconsin–Milwaukee, were displayed during their Milwaukee Panthers men's basketball team's "Sweet Sixteen" run in the 2005 NCAA Men's Division I Basketball Tournament. The visible trusses at the top of the building near the U.S. Bank sign are also sometimes lit in germane colors to signify events such as holidays. In the week leading up to the NFC Championship Game they were lit in green and yellow in tribute to the Green Bay Packers. This was done again during the week leading up to the Packers appearance against the Chicago Bears in the on January 16, 2011 in Chicago, Illinois.

Architecture.

Located on East Wisconsin Avenue in Downtown, Milwaukee, Wisconsin, U.S. Bank Center comprises a 42-story, office tower designed by Bruce Graham and James DeStefano of the Chicago office of Skidmore, Owings & Merrill. The U.S. Bank Center covers a full block, between North Cass and Van Buren Streets, and East Michigan Street and East Wisconsin Avenue. The tower features a steel frame sheathed with a white aluminum and glass facade.  Structurally, U.S. Bank Center uses a belt truss system engineered by both Graham and Fazlur Rahman Khan. Using elements similar to those used in one of Khan's prior works (the BHP House, since renamed 140 William Street, in Melbourne, Australia), the three diagonal belt trusses provide for a dramatic contrast with the vertical facade in serving both structural and aesthetic purposes.  The U.S. Bank Center's exterior was left unchanged from its completion in 1973, through the 1999 merger with Mercantile Bancorporation. At that time, Firstar announced that signs would be attached to the top of the building. Critics argued the green advertising signs on all four sides of the building's top story, in place of the original aluminum elements that were subsequently recycled, disrupted the look of the building's signature diagonal trusses. By 2002, the signs were replaced with opaque, white ones to reflect the merger with U.S. Bancorp. In 2013, they were replaced with blue, energy-saving LED signs..

Peregrine falcons.

In July 1987, a hacking box was installed outside the 41st floor to allow peregrine falcons to nest as part of the Wisconsin Department of Natural Resources (DNR) Peregrine Falcon Recovery Plan. The plan was initiated in an effort to reintroduce peregrines within Wisconsin as their whole population in the state were killed off due to the widespread use of DDT in agriculture following World War II. The location atop the building was chosen as it created an environment where the birds were less susceptible to disease and their natural predators. One year after the project was initiated, a pair of peregrine chicks were hatched atop the tower. The hatchlings were the first born in the wild within Wisconsin since the 1960s. Since the launch of the program in 1987, 67 falcons have fledged from the hacking box atop the tower.

Observation deck.

The building was constructed with an observation deck on the 41st floor. Visitors were initially allowed to visit it, and it was the site for several years of the New Year's Eve event "Firstar Eve", though it was closed for all intents and purposes by 1991 because the firm Foley & Lardner did not want members of the public walking through their offices. In 2011, the observation deck was again opened to the public during the first Doors Open Milwaukee event, and has remained open subsequent years.

U.S. Bank Center is a skyscraper located in downtown Milwaukee, Wisconsin, noted for being the tallest building in the state of Wisconsin, and the tallest building between Chicago and Minneapolis. Standing and 42 stories tall, the building has a floor area of and it surpassed the Milwaukee City Hall as the tallest building in both the city and the state. Topped off August 29, 1972, and completed in 1973, it was the headquarters for what eventually became Firstar Corporation from 1973 to 2001. The building was designed by Colombian-Peruvian architect Bruce Graham with James DeStefano of Skidmore, Owings & Merrill, and engineered by Bangladeshi-American structural engineer Fazlur Rahman Khan., the building is home to the headquarters of Foley & Lardner, Robert W. Baird & Company, Sensient Technologies Corporation, and is the Milwaukee office for U.S. Bank, IBM, and CBRE.

Das U.S. Bank Center (ehemals "First Wisconsin Center" und "Firstar Center") ist ein Wolkenkratzer in Downtown Milwaukee. Als die endgültige Höhe von 183,2 Metern (601 ft) erreicht wurde, ist es das höchste Gebäude im US-Bundesstaat Wisconsin. Bis 2001 war es der Hauptsitz der Firstar Company, später von U.S. Bancorp aufgekauft. Bruce Graham und James DeStefano von SOM entwarfen das Gebäude in Zusammenarbeit mit Fitzhugh Scott. Heute betreiben U.S. Bancorp und IBM Büros im Gebäude. Außerdem dient es als Hauptsitz zahlreicher kleinerer, regionaler Unternehmen.


Mission, members, and offices.

US operation.

In January 2010, SIFMA announced that it had hired the law firm Sidley Austin to consider filing a lawsuit challenging the Obama administration's banking levy. But an attorney familiar with the matter said: "I suspect SIFMA got out ahead of its key members." One person with a large bank said SIFMA had not consulted the bank about its position, and that it was "wildly premature" to pursue legal action.  In October 2010, CEO Tim Ryan announced the organization's opposition in the residential real estate market to a "system wide moratorium on all foreclosures," reacting to problems and pullbacks in the market by a number of SIFMA members, saying a moratorium "would be catastrophic." Financial writer Felix Salmon drew attention to the position, terming it "unhelpful," detailing it as "bizarre" and "sad,... an inchoate and unhelpful blast of opposition... [without] constructive solutions" proposed.

Political giving and lobbying.

"SIFMA's political action committees (PACs) gave more than $1 million during the 2006 election season, putting the organization in the top 25 of all PACs. Its combined $8.5 million in spending on federal lobbying last year placed it in the top 30. The financial-services industry is the biggest corporate player in national politics. Only organized labor donates more money to candidates for federal offices."

Senior management.

Kenneth E. Bentson, a former U.S. Congressman, is SIFMA's CEO & President. In 2014, he also replaced Simon Lewis, CEO of the Association of Financial Markets in Europe (AFME), as the CEO of Global Financial Markets Association (GFMA), the umbrella group for AFME, ASIFMA, and SIFMA. ASIFMA is the Asian Securities Industry and Financial Markets Association.  T. Timothy Ryan, Jr., was previously SIFMA's CEO & President. He took the position after pulling his name from consideration for a United States Treasury Department international policy advisor position in April 2007, after problems were noted concerning Ryan's financial portfolio, and Ryan refused to take certain steps demanded by the Treasury Department's ethics lawyers. SIFMA's other senior management consists of Kenneth E. Bentsen (EVP, Public Policy and Advocacy), Ileane F. Rosenthal (EVP, Global Communications & Member Engagement), Randy Snook (EVP), and Ira Hammerman (Senior Managing Director & General Counsel).,  In August 2008, SIFMA hired Michael Paese, former Deputy Staff Director of the Committee on Financial Services of the House of Representatives, as EVP, Global Advocacy; eight months later Paese left SIFMA to become director of government affairs at Goldman Sachs. Scott DeFife, who had reported to Paese, left SIFMA in December 2009.  After the 2006 merger which created SIFMA, the organization had a co-CEO structure, with the SIA's Marc E. Lackritz and BMA's Micah S. Green filling the positions. As a 2007 report summarized it, "Lackritz [then 60] ha[d] been a friend, colleague and mentor of Green's [then 49] for two decades." However, with slower-than-hoped-for integration of the merged organization's operations, and with questions about the handling of executive loans by BMA, Green resigned abruptly that year and Lackritz assumed the role of sole CEO. Nine months later, Lackritz retired and Ryan was named CEO.

Board of directors.

SIFMA's Chairman of the Board is Blythe Masters (Head of Global Commodities, JPMorgan Chase), and Vice Chair is Bernard Beal (CEO of M.R. Beal & Company). Other directors include Samir Assaf (HSBC Bank plc), Shigesuki Kashiwagi (Nomura Holdings America Inc.) and Sallie Krawcheck (former Chairman and CEO, Citi Global Wealth Management), among others.  Peter Madoff, brother of fraudster and "money manager" Bernard L. Madoff, and chief compliance officer and senior managing director of the Madoff investment advisor and broker dealer businesses, stepped down from the SIFMA Board of Directors in December 2008. On June 29, 2012, Peter Madoff pleaded guilty to conspiracy and falsifying records and agreed to serve 10 years in prison.  The Madoff family had long-standing ties to SIFMA. Bernard Madoff served on the Board of Directors of the Securities Industry Association, a precursor of SIFMA, and Peter Madoff served two terms as a member of SIFMA’s Board of Directors. From 2000 until 2008, the Madoffs brothers donated $56,000 directly to SIFMA, and paid additional money as sponsors of industry meetings. Bernard Madoff's niece Shana Madoff was a member of the Executive Committee of SIFMA's Compliance and Legal Division, but resigned shortly after Madoff's arrest.

Finances.

In 2007 SIFMA had $105 million in both revenues and expenses. SIFMA's highest-paid officers that year were Donald Kittel (then CFO), $2.1 million, Marc Lackritz (then president & CEO), $1.5 million, and Randolph Snook (SMD), $1.1 million.  SIFMA's highest-paid officer in 2008 was its new president and CEO Tim Ryan (at approximately $2 million, for January–October). Ryan had been hired to replace Lackritz in January 2008, at a 43% ($600,000) higher level of compensation, for less than a full year. In related news,Ryan wrote in a "USA Today" editorial in August 2009 that compensation practices at financial services firms should align with long-term, not short-term, performance.  SIFMA's top-three highest-paid officers in the fiscal year ending October 31, 2009 were CEO Tim Ryan at $2.43 million, Executive Vice President Randolph Snook at $1.04 million, and General Counsel Ira Hammerman at $777,000. SIFMA received total revenue that year of $75 million, had total expenses of $82 million, and finished the year with a fund balance of $40 million. In 2011, Ryan's compensation was the highest among the leaders of 22 self-regulatory, dealer, governmental, and other groups in the municipal bond market, at $3.0 million.  CEO Tim Ryan earned $2.51 million base compensation (and $2.89 million total compensation) for the fiscal year ended October 31, 2012, more than the compensation of any of the officials heading the other 20 self-regulatory, industry, government, and other municipal securities-related groups. His compensation was far higher than that of the Securities and Exchange Commission Chairman Mary Jo White, who earned $165,300. Executive Vice President Ken Bentsen received a total of $1.12 million, and Randy Snook received $1.04 million.

The Securities Industry and Financial Markets Association (SIFMA) is a United States industry trade group representing securities firms, banks, and asset management companies. SIFMA was formed on November 1, 2006, from the merger of the Bond Market Association and the Securities Industry Association. It has offices in New York City and Washington, D.C.

Die Securities Industry and Financial Markets Association (SIFMA, deutsch: "Wertpapier-Industrie- und Finanzmarkt-Vereinigung") ist ein US-amerikanischer Wirtschaftsverband, der seit 2006 die Interessen von Banken, Finanzdienstleistern und Vermögensverwaltungen vertritt. SIFMA ging aus der Bond Market Association und der Securities Industry Association hervor. Nach der Finanzkrise ab 2007 werden noch Büros in Washington, D.C. und New York City betrieben.


Early life.

Born in Mayfield, Kentucky, Mayes was educated at Norton's English and Classical School in Tennessee, Paducah District Methodist College in Kentucky and Vanderbilt University, class of 1881, where he was a member of Phi Delta Theta. He practiced law in Kentucky in 1881 as a partner in the law firm Park and Mayes and in Texas from 1882 to 1886, serving as county attorney of Brown County, Texas from 1882 to 1883. He received an honorary doctorate of laws from Daniel Baker College in 1914.  Mayes purchased weekly newspapers in Brownwood, Texas in the 1880s and began the daily "Brownwood Bulletin" newspaper in 1900, which he published until 1914. He and his brother, H.F. Mayes, founded one of the earliest newspaper chains, owning Texas papers in Brady, Stephenville, Santa Anna, May, Ballinger and Dalhart. The "Brownwood Bulletin" was the first newspaper in Texas to not be officially linked to the state Democratic party, instead opting to be independently Democratic (supportive of the party in general, but critical when warranted).

Politics.

Mayes was elected Lieutenant Governor of Texas in 1912 despite not campaigning for the position. While Lt. Governor, Mayes played a notable role in the controversy surrounding the Daughters of the Republic of Texas' custodianship of the Alamo Mission in San Antonio, siding with Clara Driscoll over Adina De Zavala to demolish most of the remaining portions of the site's long barracks. He made this decision while governor Oscar Colquitt had left the state on business. This event became known as the "Second Battle of the Alamo."  In September 1913, the University of Texas offered him a position as chair of an as-yet created School of Journalism. However, Mayes declined, and immediately thereafter announced he was running for the office of Governor on a platform of statewide prohibition and local option. He was initially considered to be a favorite, but withdrew after Thomas Ball consolidated prohibitionist support, who in turn lost the nomination to James E. Ferguson. Later in life he also served as executive vice president of the Texas Centennial Committee of 1936.  After failing to gain the Democratic nomination for Governor, Mayes resigned from office, founded, and became dean of the University of Texas School of Journalism at the insistence of University President and friend Sidney Edward Mezes.

Journalism.

Mayes founded the University of Texas School of Journalism in 1914 and was its dean until 1926. As dean, he founded "The Texas Journalist", a student run newspaper. In 1916, he was one of seven faculty members targeted for firing by Texas governor James E. Ferguson, who found them objectionable.  The complaints against Mayes, who had been one of Ferguson's chief rivals for the 1914 Democratic gubernatorial nomination (along with prohibitionist congressman Thomas Henry Ball), stemmed from negative editorials against Ferguson that the "Brownwood Bulletin" published while Mayes still owned half of the company. Ferguson was quoted saying that the "Bulletin" had "skinned me from hell to breakfast." However, Mayes maintained that he was out of the state when these editorials - editorials that were widely reprinted throughout the state in the ensuing controversy - were written and approved by others and that he no longer had a financial stake in the business dealings of the "Bulletin". Although Mayes was exonerated by the board of regents, he was later dismissed by the university in 1917 in a 4-3 vote. However, the dismissal was reversed and he was fully reinstated as dean and Ferguson was eventually impeached by the Texas Legislature. Later, Governor Ma Ferguson succeeded where her husband had not, and was able to remove funding for the School of Journalism entirely, effectively abolishing its programs.  He served as president of the Texas Press Association in 1899–90 and was elected without opposition president of the National Editorial Association in 1908. He was elected vice-president of the American Association of Journalism Teachers in 1916 and president of the Association of American Schools and Departments of Journalism in 1920–21. After retiring from the school and from public life, he published a book entitled "Texas Empire Builders of 1936." In 1940, shortly after his death, the University of Texas acquired his 80-volume library on the history of journalism in Texas.

Personal life.

Mayes had seven children: four from Jessie Ware, whom he married in 1886, and three from his second wife, Anna Marshall, whom he married in 1900 after his first wife's death the year before. Mayes is buried in Greenleaf Cemetery in Brownwood.  His son William Harding Mayes Jr. was a print journalist who worked for the "Brownwood Bulletin", was editor of the "Ranger Times" and Harlingen, Texas's "The Valley Morning Star".  His son Wendell Wise Mayes was initially a print journalist, working for the "Parlier Progress" in Parlier, California and later for the "Fresno Bee". He was later elected mayor of the Texas cities of Center (1925–1928) and Brownwood (1939–1951), where he owned and ran the KBWD radio station as part of a larger broadcasting chain. In 1939, he was appointed by Governor James Allred to serve on the executive committee of the Texas Big Bend Park Association, which created Big Bend National Park. He later served as chairman of the Texas State Parks Board, as a member of the Brown County Hospital Authority, and chairman of the board of regents of Texas Women's University. Dorothy Evans Mayes, wife of Wendell Wise Mayes, was a noted Texan artist. Howard Payne University's Department of Art's gallery is named in their memory. Their son, Wendell Wise Mayes Jr., is a prominent diabetes philanthropist and radio journalist.  His daughter from his second marriage, Isabelle Mayes Hale, was a noted Texas artist. His son from his second marriage, Robert Chappell Mayes, was also a notable Texas journalist working in Edinburg, Texas at the "Edinburg Review" and served as news editor of the "San Antonio Express News" until his retirement in 1977. Anna Elizabeth Morris Mayes, wife of Robert, was also a Texas journalist, working in Gonzales, Texas, Houston, and San Antonio.

William Harding Mayes (May 20, 1861 – June 26, 1939) was Lieutenant Governor of the U.S. state of Texas (1913–1914), a newspaperman who published the "Brownwood Bulletin" and founder of the University of Texas journalism school.

William Harding Mayes (* 20. Mai 1861 in Mayfield, Kentucky; † 26. Juni 1939 in Austin, Texas) war ein US-amerikanischer Politiker. Zwischen 1913 und 1915 war er Vizegouverneur des Bundesstaates Texas.


Professional career.

De Nicoloa progressed through the youth ranks of Pallacanestro Vigodarzere (with stints at Virtus Padova and Petrarca Padova), a team coached by his father. Moving to Benetton Treviso in 2008, he won the under-19 national title with the side at the end of his first season. He made his debut in the Serie A on 12 October 2009, playing a little less than seven minutes per game over the rest of the season. The youngster was then loaned to lower league side Lago Maggiore the next season, returning in 2011. His second season with Treviso saw him collect 16.5 minutes of playing time per game, for 3.5 points and 1.1 assist. De Nicolao moved to fellow Serie A side Cimberio Varese in 2012, gradually increasing his minutes and statistical output over the next two seasons, he was nominated for the Serie A best player under 22 award for 2012-13, finishing third. After a season in the second division Serie A2 with Tezenis Verona, posting 10.3 points and a league-best 6.4 assists per game, De Nicolao joined Grissin Bon Reggio Emilia in 2015.  In May 2018, De Nicolao won the FIBA Europe Cup championship with Reyer Venezia. He re-signed with Reyer Venezia for two seasons with a third year option on June 18, 2020.

International career.

De Nicolao played with Italian representative sides in each age group from the Under-16's to the Under-18's through to the Under-20's. With the latter, he earned a silver medal at the 2011 European Championship, posting 11 points and 9 boards in the final.  He made his fully fledged debut for the senior national team in July 2014.

Andrea De Nicolao (born 21 August 1991) is an Italian professional basketball player who plays for Reyer Venezia of the Italian Lega Basket Serie A (LBA).

Andrea De Nicolao (21. August 1991 in Camposampiero, Venetien) ist ein italienischer Basketballspieler. De Nicolao wurde mit der italienischen U20-Juniorenauswahl 2011 Vize-Europameister und spielte als professioneller Spieler bislang ausschließlich für italienische Vereinsmannschaften. Seit dem Sommer 2014 bestritt De Nicolao auch für die italienische Herrenauswahl Länderspiele.


Triathlon at the 2014 Commonwealth Games

Format.

The Triathlon events at the XX Commonwealth Games were conducted under the ITU Competition Rules and in accordance with the Commonwealth Games Federation (CGF) Constitution.  The men's and women's individual events were at distance - swim, cycle, and a run. The competitions took place as single events between all competitors with no heats.  The mixed relay was contested at the Commonwealth Games for the first time. This event was contested by teams of two men and two women who each complete a 250m swim, 6 km bike and 1600m run leg before passing on to the next athlete in the team. Race order: women-man-women-man.

Competition venue.

On the south eastern edge of Glasgow, Strathclyde Country Park provided an excellent venue for Triathlon. This attractive course, using the loch for swimming and the surrounding network of roads and paths for the cycling and running phases, was already an established national triathlon venue.  Individual race course  swim course – 1,500m. The swim took place in the Strathclyde Loch on a course consisting of two laps of 750m.  bike course – 40 km. The bike course consisted of five laps of an 8 km course.  run course – 10 km. The run course consisted of three laps of 3.33 km each and used part of the bike course.  Mixed Relay course  swim course – 250m. The swim took place in the Strathclyde Loch on a course consisting of one lap.  bike course – 6 km. The bike course consisted of one lap of a 6 km course.  run course – 1.6 km. The run course consisted of two laps.

References.

"Glasgow 2014 Triathlon Events at Strathclyde Park". Triathlonscotland.org. 21 July 2014

The Triathlon competitions at the 2014 Commonwealth Games, in Glasgow, were held in Strathclyde Country Park. The men's and women's individual events were held on Thursday 24 July and women's triathlon was the first medal event of the Games. Mixed team relay was held on Saturday 26 July for the first time ever in major multi-sport Games. Marisol Casado, ITU President and IOC member, commented: "We are delighted the Glasgow 2014 Organising Committee has embraced the Triathlon Mixed Relay. Triathlon is on currently on a high in the United Kingdom, and the Mixed Relay will offer an extra opportunity for the people of Glasgow to watch another thrilling and unpredictable event live on their city streets."

Bei den Commonwealth Games 2014 im schottischen Glasgow fanden im Triathlon drei Wettbewerbe statt, je einer für Männer und Frauen und ein weiterer für eine gemischte Staffel.


Approvals and indications.

Melanoma.

Ipilimumab was approved by US FDA in March 2011 to treat patients with late-stage melanoma that has spread or cannot be removed by surgery. It was later approved by the US FDA on October 28, 2015 for stage 3 patients as adjuvant therapy. On February 1, 2012, Health Canada approved ipilimumab for "treatment of unresectable or metastatic melanoma in patients who have failed or do not tolerate other systemic therapy for advanced disease." Ipilimumab was approved in the European Union (EU), for second line treatment of metastatic melanoma in November 2012.

Renal cell carcinoma.

On 16 April 2018, the FDA approved the combination therapy nivolumab and ipilimumab for advanced renal cell carcinoma, both owned by Bristol-Myers Squibb. The recommended dosing is nivolumab (3 mg/kg) followed by ipilimumab (1 mg/kg) weekly every 3 weeks for 4 doses, then nivolumab for 240 mg for every 2 weeks.

Adverse effects.

A major drawback of ipilimumab therapy is its association with severe and potentially fatal immunological adverse effects due to T cell activation and proliferation, occurring in ten to twenty percent of patients. Serious adverse effects include stomach pain, bloating, constipation, diarrhea, fever, trouble breathing, and urinating problems. A "risk evaluation and mitigation strategy" informs prescribers of the potential risks.  Between 5.7 and 9.1% of individuals treated with ipilimumab develop checkpoint inhibitor induced colitis.  Individual cases of severe neurologic disorders following ipilimumab have been observed, including acute inflammatory demyelination polyneuropathy and an ascending motor paralysis, and myasthenia gravis.

Interactions.

The combination of ipilimumab with either leflunomide or vemurafenib may lead to increased hepatotoxicity.  Systemic corticosteroids should be avoided before starting ipilimumab; however, systemic corticosteroids may be used to treat an immune-related adverse reaction that arises from ipilimumab treatment.  Patients taking anticoagulants with ipilimumab should be monitored due to an increased risk of gastrointestinal bleeding.

Mechanism of action.

T lymphocytes can recognize and destroy cancer cells. However, an inhibitory mechanism interrupts this destruction. Ipilimumab turns off this inhibitory mechanism and allows the lymphocytes to continue to destroy cancer cells.  Cancer cells produce antigens, which the immune system can use to identify them. These antigens are recognized by dendritic cells that present the antigens to cytotoxic T lymphocytes (CTLs) in the lymph nodes. The CTLs recognize the cancer cells by those antigens and destroy them. However, along with the antigens, the dendritic cells present an inhibitory signal. That signal binds to a receptor, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), on the CTL and turns off the cytotoxic reaction. This allows the cancer cells to survive.  Ipilimumab binds to CTLA-4, blocking the inhibitory signal, which allows the CTLs to destroy the cancer cells. In 2014 a study indicated that the antibody works by allowing the patients' T cells to target a greater variety of antigens rather than by increasing the number attacking a single antigen.

Identifying patients most likely to respond.

During “cancer immunoediting", tumor cells can produce antigens that provoke a reduced immune response and/or establish an immunosuppressive tumor microenvironment (TME). The latter can arise as a consequence of repeated, ineffective T cell stimulation. This triggers the checkpoint that ipilumumab targets. Many patients do not benefit from treatment, which may be related to reduced mutation load and/or missense point mutation-derived neoantigens. Tumor antigens can either be improperly expressed normal proteins or abnormal proteins with tumor-specific expression. Somatic cancer mutations can produce “nonself” tumor-specific mutant antigens (neoantigens).  Sequencing and epitope prediction algorithms identified neoantigens in mouse tumors that functioned as tumor-specific T cell targets. Neoantigens were recognized by T cells in melanoma patients and were likely the major contributor to positive clinical effects of adoptive cell transfer. Mouse models established that neoantigens were the targets of T cells activated by checkpoint blockade therapy and that synthetic long peptides comprising these neoantigens were effective when administered as vaccines with CTLA-4 and/or PD-1 mAbs. Cancers with higher mutation burdens, and an associated likelihood of expressing neoantigens, appear most likely to respond to checkpoint therapy. In melanoma and certain other cancers, the numbers of mutations and neoantigens correlate with patient response. Increased PD ligand 2 (PD-L2) transcript expression and an immune “cytolytic” gene signature also correlated with neoantigen load and tumor response. CTLA-4 expression was a response indicator, which along with PD-L2 were likely expressed in tumor-infiltrating immune cells. An inflamed TME prior to treatment is also associated with response.  Nearly all neoantigens in one study were patient-specific and most likely reflected mutations that do not directly contribute to tumorigenesis. However, none revealed features or motifs exclusive to responders.

Clinical trial history.

In the 2000s, ipilimumab clinical trials were under way on patients with melanoma, renal cell carcinoma, prostate cancers, urothelial carcinoma and ovarian cancer. By 2007, there were two fully human anti CTLA-4 monoclonal antibodies in advanced clinical trials. Ipilimumab, which is an IgG1 isotype, and tremelimumab (from Pfizer) which is an IgG2 isotype.

Melanoma.

On December 10, 2007, Bristol-Myers Squibb and Medarex released the results of three studies on ipilimumab for melanoma. The three studies tested 487 patients with advanced skin cancer. One of the three studies failed to meet its primary goal of shrinking tumors in at least 10.0% of the study's 155 patients. Side effects included rashes, diarrhea, and hepatitis.  In 2010, a study was presented that showed a median survival of 10 months in advanced melanoma patients treated with ipilimumab, compared with 6.4 months for those treated with, an experimental vaccine (n=676), and 10.1 months for those treated with both the vaccine and ipilimumab. The Phase III clinical studies on the drug were controversial for their unconventional use of a control arm (as opposed to using a placebo or standard treatment). Ipilimumab gained FDA approval in early 2011.

Prostate cancer.

In 2008/09 Medarex performed a phase I/II dose escalation clinical trial of ipilimumab in metastatic hormone-refractory prostate cancer (HRPC). Some of the patients with advanced prostate cancer had their tumors drastically shrink, promoting further trials.  On June 19, 2009, the Mayo Clinic reported two prostate cancer patients involved in a phase II study using MDX-010 therapy who had been told initially that their condition was inoperable but had their tumors shrunk by the drug such that operation was possible and are now cancer-free as a result. This press report however was criticized as premature and somewhat inaccurate. The clinical trials were still at an early stage and were run alongside other treatments – which could have been the real explanation for the tumor shrinkage. It was too early to say whether ipilimumab made any difference.  In 2016, a phase II study using ipilimumab and nivolumab in AR-V7-expressing metastatic castration-resistant prostate cancer was opened. AR-V7 is an androgen receptor splice variant that can be detected in circulating tumor cells of metastatic prostate cancer patients.

Lung cancer.

Medarex ran a phase II trial of ipilimumab in addition to platinum-based chemotherapy (carboplatin) in patients with small cell and non-small cell lung cancer. It was scheduled to run from February 2008 to December 2011.

Bladder cancer.

Early results of a trial in urothelial carcinoma have been reported.

Combination trials.

Advanced melanoma.

To increase response rate and reduce adverse reactions, various drug combinations are being tested.  In 2013 a trial was running that compared ipilimumab alone against ipilimumab in combination with nivolumab. The response rate (tumours shrinking by at least 30%) was 58% for the combination, 44% for nivolumab alone, and 19% for ipilimumab alone. This combination gained FDA approval for melanoma in Oct 2015.  In March 2014, an open-label, randomized, two agent, single center trial started combining ipilimumab with phosphatidylserine-targeting immunotherapy bavituximab for the treatment of advanced melanoma. The number of treated patients in arm A (ipilimumab plus bavituximab) was to be 16, with 8 in arm B (ipilimumab only). The trial was expected to complete in March 2016. Previous, preclinical studies showed that PS targeting antibodies (such as bavituximab) enhance the anti-tumor activity of anti-CTLA-4 and anti-PD-1 antibodies. Tumor growth inhibition correlates with infiltration of immune cells in tumors and induction of adaptive immunity. The combination of these mechanisms promotes strong, localized, anti-tumor responses without the side-effects of systemic immune activation.

Development.

Following the 1987 cloning of CTLA-4 in mice, its conservation in humans and similarities with CD28 were soon noticed. CD28 at that time was a recently identified "T cell costimulatory" molecule important for T cell activation. Anti-CTLA-4 blockade, the invention that gave rise to ipilimumab, was conceived by Allison and Krummel along with CTLA-4's inhibitory role in T cell activation. They were able to demonstrate that CTLA-4 signaling in T cells inhibited T cell responses. They then injected intact antibodies and demonstrated that CTLA-4 blockade enhanced T cell responses in mice responding to vaccines and to super antigens. Leach, a new postdoctoral fellow, was tasked by Allison with applying these in tumor models. Antibody-treated mice showed significantly less cancer growth than the controls.  Bluestone and Linsley separately studied the similarities between CD28 and CTLA-4. Bluestone's lab published studies, one together with Krummel and Allison, for "in vitro" studies of CTLA-4 function. In collaboration with Mark Jenkins, they were able to see effects of anti-CTLA-4 antibodies "in vivo" in an immunization setting, but did not effectively carry this into tumor biology. Linsley and colleagues had made antibodies against CTLA-4 three years prior to those of Krummel/Allison or Walunas/Bluestone. They concluded that the molecule functioned similarly to CD28 and was a "positive costimulator". They apparently did not pursue CTLA-4 tumor targeting, although BMS licensed the Allison/Leach/Krummel patent through their acquisition of Medarex and the fully humanized antibody MDX010, which later became ipilimumab.

Ipilimumab (trade name Yervoy) is a monoclonal antibody that works to activate the immune system by targeting CTLA-4, a protein receptor that downregulates the immune system.

Ipilimumab (MDX-010; Handelsname "Yervoy") ist ein biotechnologisch hergestellter, vollständig humaner monoklonaler Antikörper, der in der Behandlung von Melanomen, einer aggressiven Form von Hautkrebs, eingesetzt wird. Die Wirkung richtet sich gegen das Protein CTLA-4.


Life on Mars (US-amerikanische Fernsehserie)

Synopsis.

The series centers around Detective Sam Tyler, assigned to the 125th Precinct Detective Squad of the New York City Police Department.  At the show's outset in 2008, he cohabits with his girlfriend who is also his NYPD assigned partner, Detective Maya Daniels. Maya, to Tyler's horror, is kidnapped by a murderer they are investigating. While responding to a radio call as he crosses the street, Tyler is distracted and hit by another responding speeding police car. He regains consciousness in the same spot in the year 1973, dressed in period civilian attire, carrying a period-accurate identity card with his badge, and equipped with a vintage automobile, a 1971 Chevrolet Chevelle — and, astonishingly, he's parked within sight of the Twin Towers of the World Trade Center. He returns to his precinct house to find an unfamiliar early-1970s police squad, with contemporary equipment and culture which he likens to finding himself on a different planet. However, the detectives have been expecting him, thinking that he is a transfer from a place called "Hyde". His disorientation and frequent reference to things from the future brand him as eccentric, being labeled with the nickname "Spaceman", but he becomes a valued member of the squad.  Later on in the series, with Sam supposedly in a coma in 2008, Maya decided to end the relationship.  Several of the show's plots involve Sam looking into earlier versions of his cases from 2008, such as in "Out Here in the Fields" where he discovers the sociopath mentor of a future serial killer, and in "The Simple Secret of the Note in Us All" where Sam has the opportunity to stop a serial killer early in his career. Additional storylines are driven by the conflict between Sam's 2008 values and the more corrupt, almost vigilante-style policing of the era he finds himself in, while others are driven by Sam's discovery of more personal information about his past in this era that radically reshapes his understanding of the life he's left behind. He engages in an ongoing struggle to figure out what has happened to him, torn between his developing relationships in 1973 and his desire to return to 2008.  His 2008 reality frequently intrudes into 1973 through surreal, anachronistic visions and cryptic telephone calls. In one episode he sees a man in a nightclub wearing a Nirvana T-shirt, in several early episodes he sees the face of George W. Bush on the front page of the newspaper, and he frequently sees Mars rover robots following him or attempting to enter his body.  At other times, he also hints at his knowledge of the future to his colleagues; in a discussion of then-President Richard Nixon he confuses them by asserting that Nixon won't be in office much longer, he makes a veiled allusion to the September 11 attacks when advising them against engaging in hate speech, and he uses then-future cultural references as undercover pseudonyms — sometimes giving his name as "Luke Skywalker", "Tom Cruise" or "Sam Bono", and giving Gene and a female companion the undercover names "George and Laura Bush".  At the end of the series, it is revealed that Tyler's 2008 and 1973 realities were "both" fictitious, created by the onboard computer of a spacecraft that is carrying Tyler, Hunt, Norris, Carling, and Skelton on the first ever manned mission to the planet Mars, in 2035. The crew he worked with in 1973 were just virtual reality versions of his fellow spaceship crewmembers. His room number, "2B", is his sleeping unit; his old precinct, "Hyde", and his new precinct, the "125", are based on the name of the spacecraft — "Hyde 125"; his neighbor, Windy, is the name of the computer A.I.; Frank Morgan, an FBI agent in the series, is the Mission Control flight director; in a reversal from her struggle to be taken seriously as a police officer in 1973, Annie Norris is the ship's commander. To sustain the crew, their minds were routinely kept active while asleep using virtual reality "neural stimulation" programs of their own choosing, but Sam's choice of a scenario where he was a police officer c. 2008 was abruptly changed to a 1973 setting by a computer glitch induced by a meteor-storm. The identity of Maya in 2035, however, is left unexplained. In a twist, Gene Hunt in 1973 turns out to be astronaut 'Major Tom' Tyler — Sam's father — in the conclusion. Just as Maria was estranged from Gene in 1973, Sam was estranged from his father until the very end of the series, when he reconciles with his dad before they step out onto the bare ground of the Red Planet. However the final shot shows, not an astronaut boot, but Gene Hunt's signature white loafer taking the first step onto the Martian surface, casting doubt once again onto the ending.

Production.

David E. Kelley was the initial writer and executive producer of the series pilot, but later handed over production responsibilities to others. The executive producers of the show were Josh Appelbaum, André Nemec, and Scott Rosenberg, the producers of the ABC drama "October Road".  After reviewing the pilot episode, ABC ordered an overhaul. Several members of the cast and crew were replaced, with production moved from Los Angeles to New York to allow producers to take advantage of recently enacted local and state tax credits for shows filmed in that state. The setting of the series was also changed from Los Angeles to New York, taking place at the fictional 125th precinct of the New York City Police Department (NYPD).  The script was rewritten, with permission of the original creators, to remove the "unsatisfying" ambiguity of Sam's story in favor of a "mythological element" and "deeper mystery".  The series premiered in North America on October 9, 2008, on ABC, following "Grey's Anatomy". Internationally, it also aired on Global in Canada, on FX in the UK, and on Network Ten in Australia. On November 20, 2008, ABC ordered four additional episodes to the show's original thirteen episodes. After its winter hiatus, the series was shifted to a Wednesday night timeslot on January 28, 2009, following "Lost".  On March 2, 2009, it was announced that ABC would not be ordering a second season. The cancellation decision came early enough to allow producers time to wrap up the show's storyline. The network aired all 17 episodes ordered, with the final episode airing April 1, 2009.

Reception.

Commentary.

In a UK interview with "SFX", Matthew Graham—co-creator of the original "Life on Mars"—was asked his opinion on the US remake. His opinion was "Have you seen it? It beggars belief, doesn't it?" He goes on to speak of how he discussed future "Ashes to Ashes" endings and theories with the US team, stating they thought the UK ending "wasn't extreme enough". He spoke of how strong endings should be there for the viewer to work out, whereas the US ending was like "coming up with something and going 'Hey-hey, you never knew this, but Gene is a Martian!, which he felt was a mistake.

Life on Mars is an American version of a UK science fiction crime drama television series which originally aired on ABC from October 9, 2008 to April 1, 2009. It is an adaptation of the BAFTA-winning original UK series of the same title produced by the BBC. The series was co-produced by Kudos Film and Television, 20th Century Fox Television, and ABC Studios.

Life on Mars ist eine US-amerikanische Fernsehserie, die von 2008 bis 2009 beim Network ABC ausgestrahlt wurde. Es handelt sich um ein Remake der britischen Serie "Life on Mars – Gefangen in den 70ern".


Early life.

Mihailov was born on 22 May 1964, in Sofia, People's Republic of Bulgaria, and has a twin brother named Boris. The brothers started playing hockey at age 14, and learned on the outdoor Druzhba rink in Sofia. Their father Simeon played hockey until he was 40 years old, and wanted his boys to play as wingers, but Konstantin dreamed of being a goaltender. He innovated equipment for the position by reusing old hockey pants, and constructing a trapper and blocker. He also carried his own tools to fix goaltending equipment, since teams did not have a dedicated equipment manager then. He is credited as being the first Bulgarian to train specifically as a goaltender, and used tennis balls to develop his eye–hand coordination.

Club hockey career.

Mihailov had a lengthy professional ice hockey career mostly in the Bulgarian Hockey League, and two single seasons in Turkey and France. He played with HC Levski Sofia for twenty seasons from 1984 to 2004, which included a brief appearance with the Turkish Istanbul Paten Kulübü for part of the 2002–03 season. He played the 2004–05 season with the Galaxians d'Amneville in the French Ice Hockey Federation Division 2, then returned to Bulgaria. He played with Akademika Sofia from 2005 to 2007, HC Slavia Sofia from 2007 to 2012, HC CSKA Sofia from 2012 to 2014, and with Irbis-Skate Sofia from 2015 to 2019. He was named the best goaltender in the Bulgarian Hockey League during the 1991–92, 2011–12, and 2012–13 seasons; and was also named the best goaltender in Group A of the 2013–14 IIHF Continental Cup.

International career.

Mihailov first represented his country on the international level with the Bulgaria men's national under-18 ice hockey team. During the 1982 IIHF European U18 Championship Group B tournament hosted in Sofia, he was named the best goaltender at the event. He later played for the Bulgaria men's national junior ice hockey team at the 1983 World Junior Ice Hockey Championships, and the 1984 World Junior Ice Hockey Championships.  Mihailov made his debut with the Bulgaria men's national ice hockey team during the 1985 World Ice Hockey Championships Group C tournament in Megève, France. He went on to play in 28 Ice Hockey World Championships with Bulgaria, which concluded with the 2014 IIHF World Championship Division III, at age 49. During this time, he also played in three Winter Olympic Games qualifying tournaments in 2004, 2008, and 2015. Mihailov later said that he played as long he did for the love for the game, and there was nobody as good as him in Bulgaria. His career was extended in 2009, with the unexpected death of his successor, Kiril Vajarov. He was named the best goaltender at both Group C of the 1990 Men's World Ice Hockey Championships, and the 2006 IIHF World Championship Division II. He led Bulgaria to a silver medal at the 2006 IIHF World Championship Division II, a bronze medal at the 2012 IIHF World Championship Division II, and the gold medal at the 2014 IIHF World Championship Division III.  Mihailov also played for the Bulgaria men's national inline hockey team at three IIHF Inline Hockey World Championships, and said that there was "not a big difference between ice hockey and inline hockey". During the European qualification portion of the 2015 IIHF Inline Hockey World Championship Division I, Mihailov was given a standing ovation and was named the event's best goaltender. He was 51 years old at the time, which was his last appearance with the national team.

Later life.

Mihailov became a goaltender coach in Bulgaria after retiring from playing, with the goal of someone having more success than him. He remained active playing amateur hockey, and has a son who played as a professional goaltender.  Mihailov was honored by the IIHF in 2019, as a recipient of the Torriani Award to recognize his international hockey career. The formal ceremony took place on 26 May 2019 at the 2019 Men's World Ice Hockey Championships in Bratislava. The Hockey Hall of Fame considers Mihailov "one of the best goaltenders in the history of Bulgarian hockey".

Konstantin Mihailov (also Mihaylov; ; born 22 May 1964) is a Bulgarian retired ice hockey and roller in-line hockey goaltender. He played in 28 Ice Hockey World Championships with the Bulgaria men's national ice hockey team, and three IIHF Inline Hockey World Championships with the Bulgaria men's national inline hockey team, then retired from international play at age 51. His lengthy international career was recognized by the International Ice Hockey Federation (IIHF) in 2019, as a recipient of the Torriani Award.

Konstantin Michailow (; * 22. Mai 1964) ist ein bulgarischer Eishockeytorwart, der seit 2015 beim SK Irbis-Skate in der bulgarischen Eishockeyliga unter Vertrag steht.


Etymology.

In English translations of Ukrainian texts, the word "vyshyvanka" is a loanword. Same way as kilt speaks about its Scottish origin, or moccasins attribute to American Indians heritage, vyshyvanka proudly defines Ukrainian people.  The term originated from the word "vyshyvka" meaning "stitch patterns".

In Ukraine.

Embroidery.

The embroidery is a fundamental element of the Ukrainian folk costume. Ukrainian vyshyvanka is distinguished by local embroidery features specific to Ukrainian embroidery:  In Ukrainian embroidery, black, red, and white colours are basic, and yellow, blue, and green are supplementary.  On the territory of Ukraine, embroidery existed already in the 5th century B.C, and was a creation of Scythian fine art. Ukraine is famous throughout the world for its highly artistic embroidery. It is important for the embroiderer today to use folk art as a source without altering stitches or colours because every change devalues a piece of embroidery and distorts it.

Artistic Influence.

Other national dresses.

Southern Russian dress, which shows a propensity for bright, polychromatic garments, was most certainly affected by the influence of vividly coloured Ukrainian costume from the significant influx of Ukrainian settlers since the 17th century.

High fashion.

During Paris Fashion Week 2015, Ukrainian fashion designer Vita Kin was featured in "Vogue" magazine and "Harper's Bazaar" for introducing vyshyvankas as modern Bohemian style designs that attracted fashion icons like Anna Dello Russo, Miroslava Duma, and Leandra Medine.  In its US May issue "Vogue" wrote that the vyshyvanka has "made waves far past the Eastern European country". The "Times of London" declared it "this summer's [2016] most sought-after item of clothing", soon following was the "New York Times" who advised readers to stock up on this "top of summer" fashion. French actress Melanie Thierry wore a vyshyvanka at the 2016 Cannes Film Festival. Queen Máxima of the Netherlands wore a vyshyvanka dress when visiting the 2016 Summer Olympics.

Meaning.

Traditional beliefs.

Vyshyvanka is used as a talisman to protect the person wearing it and to tell a story. A geometric pattern weaved in the past by adding red or black threads into the light threads, which was later imitated by embroidery, was believed having the power to protect a person from all harm.

Patriotism.

Archduke Wilhelm of Austria was a Ukrainian patriot who preferred wearing the vyshyvanka and was therefore known in Ukrainian as Vasyl Vyshyvanyi (Basil the Embroidered). The Vyshyvanoho Square was named in his honour in the city of Lviv.  Vyshyvanka and other national symbols became extremely popular in Ukraine following Euromaidan, including in LGBT+ communities signalling their belonging to the nation.

Celebration.

Vyshyvanka Day originated in 2006 at Chernivtsi National University by its student Lesya Voronyuk and gradually became international as the International Day of Vyshyvanka. It is celebrated on the third Thursday of May. It is intended to unite all Ukrainians over the world, regardless of religion, language they speak or their place of residence. It is a flash mob holiday, which is not attached to any public holiday or feast day. On this day many Ukrainians wear vyshyvankas to demonstrate commitment to the idea of national identity and unity and to show their patriotism. State officials, including municipal, court, and the government officials and the head of the state, may take part in celebration.  In 2018, the Appeal Instance of the Ministry of Economic Development and Trade of Ukraine conducted a research and came to the following conclusions:

Vyshyvanka ( or ) is a casual name for the embroidered shirt in Ukrainian and Belarusian national costumes. Ukrainian vyshyvanka is distinguished by local embroidery features specific to Ukrainian embroidery.

Als Wyschywanka (; ; ; zu deutsch: "Stickerei") bezeichnet man traditionelle, ostslawische Stickmuster, die besonders in ukrainischen Regionen verbreitet sind und dort als nationales Kulturgut gesehen werden. Vergleichbare Muster finden sich ebenso in Weißrussland und Russland.


Background.

The Seleucid dynasty controlled a developed network of trade with the Indian Subcontinent which had previously existed under the influence of the Achaemenid Empire. The Greek-Ptolemaic dynasty, controlling the western and northern end of other trade routes to Southern Arabia and the Indian Subcontinent, had begun to exploit trading opportunities in the region prior to the Roman involvement but, according to the historian Strabo, the volume of commerce between Indians and the Greeks was not comparable to that of later Indo-Roman trade.  The Periplus Maris Erythraei mentions a time when sea trade between Egypt and the subcontinent did not involve direct sailings. The cargo under these situations was shipped to Aden:  The Ptolemaic dynasty had developed trade with Indian kingdoms using the Red Sea ports. With the establishment of Roman Egypt, the Romans took over and further developed the already existing trade using these ports.  Classical geographers such as Strabo and Pliny the Elder were generally slow to incorporate new information into their works and, from their positions as esteemed scholars, were seemingly prejudiced against lowly merchants and their topographical accounts. Ptolemy's "Geography" represents somewhat of a break from this since he demonstrated an openness to their accounts and would not have been able to chart the Bay of Bengal so accurately had it not been for the input of traders. It is perhaps no surprise then that Marinus and Ptolemy relied on the testimony of a Greek sailor named Alexander for how to reach "Cattigara" (most likely Oc Eo, Vietnam, where Antonine-period Roman artefacts have been discovered) in the "Magnus Sinus" (i.e. Gulf of Thailand and South China Sea) located east of the Golden Chersonese (i.e. Malay Peninsula). In the 1st-century CE "Periplus of the Erythraean Sea", its anonymous Greek-speaking author, a merchant of Roman Egypt, provides such vivid accounts of trade cities in Arabia and India, including travel times from rivers and towns, where to drop anchor, the locations of royal courts, lifestyles of the locals and goods found in their markets, and favorable times of year to sail from Egypt to these places in order to catch the monsoon winds, that it is clear he visited many of these locations.

Early Common Era.

Prior to Roman expansion, the various peoples of the subcontinent had established strong maritime trade with other countries. The dramatic increase in the importance of Indian ports, however, did not occur until the opening of the Red Sea by the Greeks and the Romans' attainment concerning the region’s seasonal monsoons. The first two centuries of the Common Era indicate a marked increase in trade between western India and the Roman east by sea. The expansion of trade was made possible by the stability brought to the region by the Roman Empire from the time of Augustus (r. 27 BCE–14 CE) which allowed for new explorations and the creation of a sound silver and gold coinage..  The west coast of present-day India is mentioned frequently in literature, such as the Periplus of the Erythraean Sea. The area was noted for its strong tidal currents, turbulent waves and rocky sea-beds were dangerous for shipping experience. The anchors of ships would be caught by the waves and quickly detach to capsize the vessel or cause a shipwreck. Stone anchors have been observed near Bet Dwarka, an island situated in the Gulf of Kachchh, from ship lost at sea. Onshore and offshore explorations have been carried out around Bet Dwarka Island since 1983. The finds discovered include lead and stone objects buried in sediment and considered to be anchors due to their axial holes. Though it is unlikely that the remains of the shipwreck’s hull survived, offshore explorations in 2000 and 2001 have yielded seven differently-sized amphoras, two lead anchors, forty-two stone anchors of different types, a supply of potsherds, and a circular lead ingot. The remains of the seven amphoras were of a thick, coarse fabric with a rough surface, which was used for exporting wine and olive oil from the Roman Empire. Archeologists have concluded that most of these were wine amphoras, since olive oil was in less demand in the subcontinent. Since the discoveries at Bet Dwarka are significant for the maritime history of the region, archeologists have researched the resources in India. Despite the unfavorable conditions the island is situated in, the following items have made Bet Dwarka as well as the rest of western India an important place for trade. From Latin literature, Rome imported Indian tigers, rhinoceros, elephants, and serpents to use for circus shows – a method employed as entertainment to prevent riots in Rome. It has been noted in the Periplus that Roman women also wore Indian Ocean pearls and used a supply of herbs, spices, pepper, lyceum, costus, sesame oil and sugar for food. Indigo was used as a color while cotton cloth was used as articles of clothing. Furthermore, the subcontinent exported ebony for fashioned furniture in Rome. The Roman Empire also imported Indian lime, peach, and various other fruits for medicine. Western India, as a result, was the recipient of large amounts of Roman gold during this time.  Since one must sail against the narrow gulfs of western India, special large boats were used and ship development was demanded. At the entrance of the gulf, large ships called trappaga and cotymba helped guide foreign vessels safely to the harbor. These ships were capable of relatively long coastal cruises, and several seals have depicted this type of ship. In each seal, parallel bands were suggested to represent the beams of the ship. In the center of the vessel is a single mast with a tripod base.  Apart from the recent explorations, close trade relations, as well as the development of ship building, were supported by the discovery of several Roman coins. On these coins were depictions of two strongly constructed masted ships. Thus, these depictions of Indian ships, originating from both coins and literature (Pliny and Pluriplus), indicate Indian development in seafaring due to the increase in Indo-Roman commerce. In addition, the silver Roman coins discovered in western India primarily come from the 1st, 2nd, and 5th centuries. These Roman coins also suggest that the Indian peninsula possessed a stable seaborne trade with Rome during 1st and 2nd century AD. Land routes, during the time of Augustus, were also used for Indian embassies to reach Rome.  The discoveries found on Bet Dwarka and on other areas on the western coast of India strongly indicate that there were strong Indo-Roman trade relations during the first two centuries of the Common Era. The 3rd century, however, was the demise of the Indo-Roman trade. The sea-route between Rome and India was shut down, and as a result, the trading reverted to the time prior to Roman expansion and exploration.

Establishment.

The replacement of Greek kingdoms by the Roman empire as the administrator of the eastern Mediterranean basin led to the strengthening of direct maritime trade with the east and the elimination of the taxes extracted previously by the middlemen of various land based trading routes. Strabo's mention of the vast increase in trade following the Roman annexation of Egypt indicates that monsoon was known from his time.  The trade started by Eudoxus of Cyzicus in 130 BCE kept increasing according to Strabo (II.5.12.):  By the time of Augustus up to 120 ships were setting sail every year from Myos Hormos to India. So much gold was used for this trade, and apparently recycled by the Kushan Empire (Kushans) for their own coinage, that Pliny the Elder (NH VI.101) complained about the drain of specie to India:

Trade of exotic animals.

There is evidence of animal trade between Indian Ocean harbours and the Mediterranean. This can be seen in the mosaics and frescoes of the remains of Roman villas in Italy. For example, the Villa del Casale has mosaics depicting the capture of animals in India, Indonesia and Africa. The intercontinental trade of animals was one of the sources of wealth for the owners of the villa. In the Ambulacro della Grande Caccia, the hunting and capture of animals is represented in such detail that it is possible to identify the species. There is a scene that shows a technique to distract a mother tiger with a shimmering ball of glass or mirror in order to take her cubs. Tiger hunting with red ribbons serving as a distraction is also shown. In the mosaic there are also numerous other animals such as rhinoceros, an Indian elephant (recognized from the ears) with his Indian conductor, and the Indian peafowl, and other exotic birds. There are also numerous animals from Africa. Tigers, leopards and Asian and African lions were used in the arenas and circuses. The European lion was already extinct at that time. Probably the last lived in the Balkan Peninsula and were hunted to stock arenas. The birds and monkeys entertained the guests of many villas. Also in the Villa Romana del Tellaro there is a mosaic with a tiger in the jungle attacking a man with Roman clothes, probably a careless hunter. The animals were transported in cages by ship.

Ports.

Roman ports.

The three main Roman ports involved with eastern trade were Arsinoe, Berenice and Myos Hormos. Arsinoe was one of the early trading centers but was soon overshadowed by the more easily accessible Myos Hormos and Berenice.

Arsinoe.

The Ptolemaic dynasty exploited the strategic position of Alexandria to secure trade with the subcontinent. The course of trade with the east then seems to have been first through the harbor of Arsinoe, the present day Suez. The goods from the East African trade were landed at one of the three main Roman ports, Arsinoe, Berenice or Myos Hormos. The Romans repaired and cleared out the silted up canal from the Nile to harbor center of Arsinoe on the Red Sea. This was one of the many efforts the Roman administration had to undertake to divert as much of the trade to the maritime routes as possible.  Arsinoe was eventually overshadowed by the rising prominence of Myos Hormos. The navigation to the northern ports, such as Arsinoe-Clysma, became difficult in comparison to Myos Hormos due to the northern winds in the Gulf of Suez. Venturing to these northern ports presented additional difficulties such as shoals, reefs and treacherous currents.

Myos Hormos and Berenice.

Myos Hormos and Berenice appear to have been important ancient trading ports, possibly used by the Pharaonic traders of ancient Egypt and the Ptolemaic dynasty before falling into Roman control.  The site of Berenice, since its discovery by Belzoni (1818), has been equated with the ruins near Ras Banas in Southern Egypt. However, the precise location of Myos Hormos is disputed with the latitude and longitude given in Ptolemy's "Geography" favoring Abu Sha'ar and the accounts given in classical literature and satellite images indicating a probable identification with Quseir el-Quadim at the end of a fortified road from Koptos on the Nile. The Quseir el-Quadim site has further been associated with Myos Hormos following the excavations at el-Zerqa, halfway along the route, which have revealed ostraca leading to the conclusion that the port at the end of this road may have been Myos Hormos.

Major regional ports.

The regional ports of Barbaricum (modern Karachi), Sounagoura (central Bangladesh), Barygaza (Bharuch in Gujarat), Muziris (present day Kodungallur), Korkai, Kaveripattinam and Arikamedu (Tamil Nadu) on the southern tip of present-day India were the main centers of this trade, along with Kodumanal, an inland city. The Periplus Maris Erythraei describes Greco-Roman merchants selling in Barbaricum "thin clothing, figured linens, topaz, coral, storax, frankincense, vessels of glass, silver and gold plate, and a little wine" in exchange for "costus, bdellium, lycium, nard, turquoise, lapis lazuli, Seric skins, cotton cloth, silk yarn, and indigo". In Barygaza, they would buy wheat, rice, sesame oil, cotton and cloth.

Barigaza.

Trade with Barigaza, under the control of the Indo-Scythian Western Satrap Nahapana ("Nambanus"), was especially flourishing:

Muziris.

Muziris is a lost port city on the south-western coast of India which was a major center of trade in the ancient Tamil land between the Chera kingdom and the Roman Empire. Its location is generally identified with modern-day Cranganore (central Kerala). Large hoards of coins and innumerable shards of amphorae found at the town of Pattanam (near Cranganore) have elicited recent archeological interest in finding a probable location of this port city.  According to the Periplus, numerous Greek seamen managed an intense trade with Muziris:

Arikamedu.

The Periplus Maris Erythraei mentions a marketplace named Poduke (ch. 60), which G.W.B. Huntingford identified as possibly being Arikamedu in Tamil Nadu, a centre of early Chola trade (now part of Ariyankuppam), about from the modern Pondicherry. Huntingford further notes that Roman pottery was found at Arikamedu in 1937, and archeological excavations between 1944 and 1949 showed that it was "a trading station to which goods of Roman manufacture were imported during the first half of the 1st century AD".

Cultural exchanges.

The Rome-subcontinental trade also saw several cultural exchanges which had a lasting effect on both the civilizations and others involved in the trade. The Ethiopian kingdom of Aksum was involved in the Indian Ocean trade network and was influenced by Roman culture and Indian architecture. Traces of Indian influences are visible in Roman works of silver and ivory, or in Egyptian cotton and silk fabrics used for sale in Europe. The Indian presence in Alexandria may have influenced the culture but little is known about the manner of this influence. Clement of Alexandria mentions the Buddha in his writings and other Indian religions find mentions in other texts of the period. Han China was perhaps also involved in the Roman trade, with Roman embassies recorded for the years 166, 226, and 284 that allegedly landed in Rinan (Jianzhi) in northern Vietnam, according to Chinese histories. Roman coins and goods such as glasswares and silverwares have been found in China, as well as Roman coins, bracelets, glass beads, a bronze lamp, and Antonine-period medallions in Vietnam, especially at Oc Eo (belonging to the Funan Kingdom). The 1st-century "Periplus" notes how a country called "This", with a great city called "Thinae" (comparable to "Sinae" in Ptolemy's "Geography"), produced silk and exported it to Bactria before it traveled overland to Barygaza in India and down the Ganges River. While Marinus of Tyre and Ptolemy provided vague accounts of the Gulf of Thailand and Southeast Asia, the Alexandrian Greek monk and former merchant Cosmas Indicopleustes, in his "Christian Topography" (c. 550), spoke clearly about China, how to sail there, and how it was involved in the clove trade stretching to Ceylon. Comparing the small amount of Roman coins found in China as opposed to India, Warwick Ball asserts that most of the Chinese silk purchased by the Romans was done so in India, with the land route through ancient Persia playing a secondary role.  Christian and Jewish settlers from Rome continued to live in India long after the decline in bilateral trade. Large hoards of Roman coins have been found throughout India, and especially in the busy maritime trading centers of the south. The Tamilakkam kings reissued Roman coinage in their own name after defacing the coins in order to signify their sovereignty. Mentions of the traders are recorded in the Tamil Sangam literature of India. One such mention reads: "The beautifully built ships of the Yavanas came with gold and returned with pepper, and Muziris resounded with the noise." (from poem no. 149 of 'Akananuru' of Sangam Literature)"

Decline and aftermath.

Roman decline.

Trade declined from the mid-3rd century during a crisis in the Roman Empire, but recovered in the 4th century until the early 7th century, when Khosrow II, Shah of the Sasanian Empire, occupied the Roman parts of the Fertile Crescent and Egypt until being defeated by the Eastern Roman emperor Heraclius at the end of 627, after which the lost territories were returned to the Eastern Romans. Cosmas Indicopleustes ('Cosmas who sailed to India') was a Greek-Egyptian trader, and later monk, who wrote about his trade trips to India and Sri Lanka in the 6th century.

Ravaging of the Gupta Empire by the Huns.

In India, the Alchon Huns' invasions (496–534 CE) are said to have seriously damaged India's trade with Europe and Central Asia. The Gupta Empire had been benefiting greatly from Indo-Roman trade. They had been exporting numerous luxury products such as silk, leather goods, fur, iron products, ivory, pearl or pepper from centers such as Nashik, Prathisthana, Pataliputra and Varanasi. The Huna invasions probably disrupted these trade relations and the tax revenues that came with it. Soon after the invasions, the Gupta Empire, already weakened by these invasions and the rise of local rulers, ended as well. Following the invasions, northern India was left in disarray, with numerous smaller Indian powers emerging after the crumbling of the Guptas.

Arab expansion.

The Arabs, led by 'Amr ibn al-'As, crossed into Egypt in late 639 or early 640 CE. This advance marked the beginning of the Islamic conquest of Egypt. The capture of Alexandria and the rest of the country, brought an end to 670 years of Roman trade with the subcontinent.  Tamil speaking south India turned to Southeast Asia for international trade where Indian culture influenced the native culture to a greater degree than the sketchy impressions made on Rome seen in the adoption of Hinduism and then Buddhism However, knowledge of the Indian subcontinent and its trade was preserved in Byzantine books and it is likely that the court of the emperor still maintained some form of diplomatic relation to the region up until at least the time of Constantine VII, seeking an ally against the rising influence of the Islamic states in the Middle East and Persia, appearing in a work on ceremonies called De Ceremoniis.  The Ottoman Turks conquered Constantinople in the 15th century (1453), marking the beginning of Turkish control over the most direct trade routes between Europe and Asia. The Ottomans initially cut off eastern trade with Europe, leading in turn to the attempt by Europeans to find a sea route around Africa, spurring the European Age of Discovery, and the eventual rise of European Mercantilism and Colonialism.

Indo-Roman trade relations (see also the spice trade and incense road) was trade between the Indian subcontinent and the Roman Empire in Europe and the Mediterranean Sea. Trade through the overland caravan routes via Asia Minor and the Middle East, though at a relative trickle compared to later times, antedated the southern trade route via the Red Sea and monsoons which started around the beginning of the Common Era (CE) following the reign of Augustus and his conquest of Egypt in 30 BCE.

Zwischen dem römischen Reich und dem indischen Subkontinent gab es vielfältige römisch-indische Beziehungen. Von großer Bedeutung war in diesem Zusammenhang der Indienhandel.