title: Timișoara

text: Radio Timișoara, a public station, is part of Radio România Regional, the network of local and regional public radios of the Romanian Radio Broadcasting Company. The idea of building a radio station in Timișoara was advanced for the first time in July 1930. The first broadcast of Radio Timișoara dates from 5 May 1955, with Andrei Dângă and Emilia Culea as broadcasters. Today, Radio Timișoara broadcasts in 10 languages on four frequencies that cover a large part of the counties in western Romania. West City Radio has been broadcasting since 1995, when it received the first broadcasting license in western Romania. The station is addressed to an audience aged between 24 and 48 years. Another local private radio station is Radio Europa Nova, founded in July 1995. Its broadcasting area covers around the city.


title: Timișoara

text: In recent years, numerous local stations of some national stations have appeared, such as Digi FM, Europa FM, Virgin Radio, Radio Impuls, Radio ZU, RFI România, Pro FM, Kiss FM, Radio Guerrilla, etc.


title: Timișoara

text: TVR Timișoara is one of the four territorial studios of the Romanian Television Society. It broadcasts since 17 October 1994 and covers the western part of Romania (Timiș, Arad, Caraș-Severin and Hunedoara counties), as well as the Romanian communities in Vojvodina (Serbia) and southeastern Hungary. TVR Timișoara is a member of CIRCOM Regional and has collaborated over the years with regional public televisions in Novi Sad (Serbia), Szeged (Hungary) and Uzhgorod (Ukraine). Teleuniversitatea (Teleuniversity) has the status of a department within the Polytechnic University, obtaining a broadcasting license in 1994. Teleuniversitatea is a television station with educational objectives, which operates on a non-profit basis, without a budget allocation. TV Europa Nova is the only local private television station. It first aired on 1 May 1994.


title: Timișoara

text: Timișoara hosts two general consulates (Germany and Serbia) and 14 honorary consulates (Austria, Bulgaria, the Czech Republic, Estonia, France, Italy, Moldova, the Netherlands, North Macedonia, Peru, South Korea, Spain, Sweden and Tunisia).


title: Floyd Collins

text: William Floyd Collins (July 20, 1887 – February 13, 1925) was an American cave explorer, principally in a region of Kentucky that houses hundreds of miles of interconnected caves, today a part of Mammoth Cave National Park, the longest known cave system in the world.


title: Floyd Collins

text: In the early 20th century, in an era known as the Kentucky Cave Wars, spelunkers and property owners entered into bitter competition to exploit the bounty of caves for commercial profit from tourists, who paid to see the caves. In 1917 and 1918, Collins discovered and commercialized Great Crystal Cave in the Flint Ridge Cave System, but the cave was remote and visitors were few. Collins had an ambition to find another cave he could open to the public closer to the main roads, and entered into an agreement with a neighbor to open up Sand Cave, a small cave on the neighbor's property.


title: Floyd Collins

text: On January 30, 1925, while working to enlarge the small passage in Sand Cave, Collins became trapped in a narrow crawlway below ground. The rescue operation to save him became a national media sensation and one of the first major news stories to be reported using the new technology of broadcast radio. After four days, during which rescuers were able to bring water and food to Collins, a rock collapse in the cave closed the entrance passageway, stranding him inside, except for voice contact, for more than two weeks. Collins died of thirst and hunger compounded by exposure through hypothermia after being isolated for fourteen days, and three days before a rescue shaft reached his position. Collins' body was recovered two months later.


title: Floyd Collins

text: Although Collins was an unknown figure for most of his lifetime, the fame he gained from the rescue efforts and his death led to him being memorialized on his tombstone as the "Greatest Cave Explorer Ever Known".


title: Floyd Collins

text: , on the Collins family farm, located approximately east of Mammoth Cave near the Green River in Kentucky. He was the third child of Leonidas "Lee" Collins and Martha Jane Burnett, who gave birth to eight children: Elizabeth (died at three months of age), James "Jim", Floyd, Annie, Andy Lee, Marshall, Nellie, and Homer. Floyd began entering caves by himself at the age of six in search of Native American artifacts to sell to tourists at the Mammoth Cave Hotel. In 1910 Floyd discovered his first cave, Donkey's Cave, on the Collins farm. In 1912, Edmund Turner, a geologist, hired Floyd to show him caves of the region. Consequently, Turner and Floyd assisted with the discovery of Dossey's Dome Cave in 1912 and Great Onyx Cave in 1915. Later in 1915, Floyd's mother passed away due to tuberculosis and Lee Collins married a Mammoth Cave guide's widow, Serilda Jane "Miss Jane" Buckingham.


title: Floyd Collins

text: In September 1917, while climbing up a bluff on the Collins farm, Floyd noticed cool air coming from a hole in the ground. Upon widening the hole, he was able to drop down into a cavity that was part of a passage blocked by breakdown. In December 1917, after further excavation of the breakdown, Floyd discovered the sinkhole entrance to what he would later name "Great Crystal Cave." Lee Collins deeded Floyd a half interest in the cave and they immediately decided to commercialize it. After tremendous preparation by the entire family, the transformed show cave was opened to tourists in April 1918. However, the cave attracted a low number of tourists due to its remote location.


title: Floyd Collins

text: Collins hoped to find another entrance to the Mammoth Cave or possibly an unknown cave along the road to Mammoth Cave and draw more visitors and greater profits. He made an agreement with three farmers, who owned land closer to the main highway. If he found a cave, they would form a business partnership and share in the responsibilities of operating this tourist attraction. Working alone, within three weeks, he had explored and expanded a hole that would later be called "Sand Cave" by the news media. On January 30, 1925, after several hours of work, Collins managed to squeeze through several narrow passageways; he claimed he had discovered a large grotto chamber, though this was never verified. Because his lamp was dying, he had to leave quickly before losing all light to the chamber, but became trapped in a small passage on his way out. Collins accidentally knocked over his lamp, putting out the light, and was caught by a rock that fell from the cave ceiling, pinning his left leg. He was trapped from the entrance.


title: Floyd Collins

text: After he was found the next day by his younger brother, crackers were sent to him and an electric light was run down the passage to provide him lighting and some warmth. Collins survived for more than a week while rescue efforts were organized. On February 4, the cave passage collapsed in two places. Rescue leaders, led by Henry St. George Tucker Carmichael, determined the cave impassable and too dangerous and began to dig a shaft to reach the chamber behind Collins. The shaft and subsequent lateral tunnel intersected the cave just above Collins, but when he was finally reached on Monday, February 16, by miner Ed Brenner, he was "cold and apparently dead." Having been appointed as the members of a coroner's jury, Floyd's friend, Johnnie Gerald, a few other acquaintances of Floyd, were allowed to go into the lateral tunnel and positively identify the body. Dr. William Hazlett and Captain C.E. Francis, National Guard medical officer, were then unsuccessful in an attempt to reach the body but Brenner went in front of them to the body and was able to follow their examination instructions for the official death declaration to be made. It was estimated Floyd had been dead for three to five days, with February 13 the most likely date. Because he could not be reached from behind, the rescuers could not free his leg. Carmichael decided that Floyd's body would be left in place and the shaft would be filled with debris. After being allowed to enter the shaft, Skeets Miller and another reporter corroborated Carmichael's claim that it would be too dangerous to retrieve the body.


title: Floyd Collins

text: Newspaper reporter William Burke "Skeets" Miller from "The Courier-Journal" in Louisville reported on the rescue efforts from the scene. Miller, of small stature, was able to remove a lot of earth from around Collins. He also interviewed Collins in the cave, receiving a Pulitzer Prize for his coverage and playing a part in Collins' attempted rescue. Miller's reports were distributed by telegraph and were printed by newspapers across the country and abroad, and the rescue attempts were followed by regular news bulletins on the new medium of broadcast radio (the first broadcast radio station KDKA having been established in 1920). Shortly after the media arrived, the publicity drew crowds of tourists to the site, at one point numbering in the tens of thousands. Collins' neighbors sold hamburgers for 25 cents. Other vendors set up stands to sell food and souvenirs, creating a circus-like atmosphere. The Sand Cave rescue attempt grew to become the third-biggest media event between the world wars. (The biggest media events of that time both involved Charles Lindbergh—the trans-Atlantic flight and his son's kidnapping—and Lindbergh actually had a minor role in the Sand Cave rescue, too, having been hired to fly photographic negatives from the scene for a newspaper.) Since the nearest telegraph station was in Cave City, some miles from the cave, two amateur radio operators with the callsigns 9BRK and 9CHG provided the link to pass messages to the authorities and the press.


title: Floyd Collins

text: With Collins's body remaining in the cave, funeral services were held on the surface. Homer Collins was not pleased with Sand Cave as his brother's grave, and two months later, he and some friends reopened the shaft. They dug a new tunnel to the opposite side of the cave passage and recovered Floyd Collins' remains on April 23, 1925. The body was taken that day to Cave City for embalming at J.T. Geralds and Brothers funeral home. Following a 2-day visitation at the funeral home, on April 26, 1925, his body was transported to the Collins family farm and buried on the hillside over Great Crystal Cave, which Lee Collins renamed "Floyd Collins' Crystal Cave." In 1927, Lee Collins sold the homestead and cave to Dr. Harry Thomas, dentist and owner of Mammoth Onyx Cave and Hidden River Cave. The new owner placed Collins' body in a glass-topped coffin and exhibited it in Crystal Cave for many years. On the night of March 18–19, 1929, the body was stolen. The body was later recovered, having been found in a nearby field, but the injured left leg was missing. After this desecration, the remains were kept in a secluded portion of Crystal Cave in a chained casket. In 1961, Crystal Cave was purchased by Mammoth Cave National Park and closed to the public. The Collins family had objected to Collins' body being displayed in the cave and, at their request, the National Park Service re-interred him at Mammoth Cave Baptist Church Cemetery, Mammoth Cave, Kentucky in 1989. It took a team of 15 men three days to remove the casket and tombstone from the cave.


title: Floyd Collins

text: Collins' life and death inspired the musical "Floyd Collins" by Adam Guettel and Tina Landau, as well as one film documentary, several books, a museum and many short songs.


title: Floyd Collins

text: In 2006, actor Billy Bob Thornton optioned the film rights to "Trapped! The Story of Floyd Collins" and a screenplay was adapted by Thornton's writing partner, Tom Epperson. However, Thornton's option expired and the film rights were acquired by producer Peter R. J. Deyell in 2011.


title: Floyd Collins

text: John Prine and Mac Wiseman recorded "Death of Floyd Collins" on their 2007 album "Standard Songs for Average People".


title: Floyd Collins

text: Floyd's story is recounted in an hour long YouTube video by "Internet Historian", titled "Man In Cave".


title: Floyd Collins

text: Black Stone Cherry recorded the song Ghost of Floyd Collins on their 2008 album Folklore and Superstition


title: Maneka Gandhi

text: Maneka Sanjay Gandhi (also spelled Menaka; "née" Anand) (born 26 August 1956) is an Indian politician, animal rights activist, and environmentalist. She is a member of the Lok Sabha, the lower house of the Indian parliament and a member of the Bharatiya Janata Party (BJP). She is the widow of Indian politician Sanjay Gandhi. She has been a minister in four governments, most recently in Narendra Modi's government from May 2014 to May 2019. Gandhi inspired many individuals towards social entrepreneurship for example TreeAndHumanKnot in August 2020 which triggered it become a nationwide movement to plant fruit trees by couples.


title: Maneka Gandhi

text: Maneka Anand was born on 26 August 1956 in Delhi, India into a Sikh family. Her father was Indian Army officer Lt. Col. Tarlochan Singh Anand and her mother was Amteshwar Anand, daughter of Sir Datar Singh. She was educated at The Lawrence School, Sanawar and later at Lady Shri Ram College for Women. She subsequently studied German at Jawaharlal Nehru University, New Delhi.


title: Maneka Gandhi

text: Maneka first met Sanjay Gandhi in 1973 at a cocktail party thrown by her uncle, Major-General Kapur, to celebrate the forthcoming marriage of his son. Maneka married Gandhi, the son of the Prime Minister Indira Gandhi, one year later on 23 September 1974.


title: Maneka Gandhi

text: The Emergency of 1975–77 saw the rise of Sanjay into politics and Maneka was seen with him almost every time on his tours as she helped him in campaigns. It is often said that during the Emergency, Sanjay had total control over his mother (Indira) and that the government was run by the PMH (Prime Minister House) rather than the PMO (Prime Minister Office).


title: Maneka Gandhi

text: Maneka Gandhi founded the news magazine "Surya" which later played a key role in promotion of the Congress party after its defeat in the 1977 election following the Emergency.


title: Maneka Gandhi

text: Gandhi went to court to fight an attempt by the government in power at the time to confiscate her passport and won a landmark decision on personal liberty. In the case of "Maneka Gandhi v Union of India", the court found that "Democracy is based essentially on free debate and open discussion, for that is the only corrective of government action in a democratic setup."


title: Maneka Gandhi

text: In 1980, Gandhi gave birth to a son, Feroze, named after his paternal grandfather. Her mother-in-law added the name Varun. Gandhi was just twenty-three years old, and her son just 100 days old, when her husband died in an air crash.


title: Maneka Gandhi

text: Maneka's relationship with Indira Gandhi gradually disintegrated after Sanjay's death and they would continually argue with one another. Maneka was eventually forced out of 1, Safdarjung Road, the prime minister's residence, after a fallout with Indira. She founded the Rashtriya Sanjay Manch along with Akbar Ahmad. The party primarily focused on youth empowerment and employment. It won four out of five seats in the Elections in Andhra Pradesh.


title: Maneka Gandhi

text: Gandhi published "The Complete Book of Muslim and Parsi Names", in recognition of her husband's Zoroastrian faith.


title: Maneka Gandhi

text: Gandhi contested the Amethi constituency from Uttar Pradesh for the 1984 general election for the Lok Sabha, but lost to Rajiv Gandhi. In 1988, she joined V. P. Singh's Janata Dal Party and became the General Secretary. In the 1989 Indian general election, Gandhi won her first election to Parliament and became a Minister of State as the Minister for Environment.


title: Maneka Gandhi

text: Gandhi is an environmentalist and animal rights leader in India. She has earned international awards and acclaim. She was appointed chairwoman of the Committee for the Purpose of Control and Supervision of Experiments on Animals (CPCSEA) in 1995. Under her direction, CPCSEA members carried unannounced inspections of laboratories where animals are used for scientific research were conducted.


title: Maneka Gandhi

text: Gandhi has filed Public Interest Litigations that have achieved the replacement of the municipal killing of homeless dogs with a sterilisation programme (Animal Birth Control programs, commonly abbreviated as ABCs), the unregulated sale of airguns and a ban on mobile or travelling zoos. She currently chairs the Jury of International Energy Globe Foundation which meets annually in Austria to award the best environmental innovations of the year. She is a member of the Eurosolar Board and the Wuppertal Institute, Germany.


title: Maneka Gandhi

text: Gandhi started the organisation "People for Animals" in 1992 and it is the largest organisation for animal rights/welfare in India. Gandhi is also a patron of International Animal Rescue. While she is not a vegan, she has advocated this lifestyle on ethical and health grounds. She also anchored the weekly television program "Heads and Tails", highlighting the suffering meted out to animals due to their commercial exploitation. She has also authored a book under the same title. Her other books were about Indian people names. She is a cast member for the documentary "A Delicate Balance".


title: Maneka Gandhi

text: In June 2021, She has called up a veterinarian threatening to cancel his license for a allegedly botched up amputation surgery of a dog. Despite a veterinarian was trying to make her aware of situation- that he has exercised all due care during surgery and it was a ferocious dog which has torn up bandage and surgical wound after surgery, she has hurled abusive and unparliamentary words. The call was recorded and was made viral in all social media. All veterinary associations have condemned and protested her behavior.


title: Maneka Gandhi

text: In June 2017, during a Facebook Live session, she commented that men do not commit suicide. She received negative responses to the comment and spent the rest of the chat answering questions related to this, with chatters pointing out that 68% of the suicide cases reported in India were committed by men.


title: Maneka Gandhi

text: In January 2021, Deepika Narayan Bharadwaj came forward with an audio tape where Maneka Gandhi was allegedly berating a man for hitting a dog, and was threatening to file sexual harassment cases against him. The man on the tape claimed that it was in self defense, as the dog had bitten his daughter.


title: Maneka Gandhi

text: In March 2017, she said that an early curfew for girls in hostels helped young women control their "hormonal outbursts" and received a backlash for the comment.


title: Maneka Gandhi

text: In 2016, she stated that she was against the criminalization of marital rape and received a heavy backlash for the comment.


title: Maneka Gandhi

text: Police in Kerala booked Gandhi the basis of complaints against her for promoting hatred by levelling accusations coated with communal overtones for a death of a pregnant elephant, against residents in the Muslim-majority district of Malappuram in June 2020. While the elephant died in Mannarcad, Palakkad district, nearly 90 km from Malappuram, BJP leaders including Gandhi targeted the only Muslim-majority district of Kerala. She said: “It’s a murder. Malappuram is famous for such incidents, it’s India’s most violent district. For instance, they throw poison on roads so that 300–400 birds & dogs die at one time”. The incident was used by many right-wingers to proliferate anti-Muslim resentment and to demonize the community. A multitude of hateful messages towards Malappuram and its people accompanied her remarks, triggering enraged responses. She was charged with adding communal color to an animal-related issue that would otherwise be constrained within the Department of Forests. A group calling themselves Kerala Cyber Warriors briefly hacked Maneka Gandhi's website, People for Animals, India.


title: Maneka Gandhi

text: Gandhi hosted "Maneka's Ark", an environmental talk show which aired on the Indian national public broadcaster Doorarshan's DD National channel in the 1990s. She had earlier hosted "Heads & Tails", an animal rights show, on the same channel.


title: Dominic Solanke

text: Dominic Ayodele Solanke-Mitchell (born 14 September 1997), known as Dominic Solanke, is an English professional footballer who plays as a striker for side AFC Bournemouth. He made one appearance for the English national team in 2017.


title: Dominic Solanke

text: Solanke started his career with Chelsea, making his first-team debut in October 2014. He spent the 2015–16 season on loan with Vitesse in the Eredivisie. He signed for Liverpool in July 2017, making 27 appearances before joining AFC Bournemouth in January 2019.


title: Dominic Solanke

text: Solanke has represented England at all youth, under-21 and senior levels. He has won the 2014 UEFA European Under-17 Championship and the 2017 FIFA U-20 World Cup with his country and received the Golden Ball award for best player in the latter tournament.


title: Dominic Solanke

text: Solanke was born in Reading, Berkshire to a Nigerian Yoruba father and an English mother. He attended Brighton Hill Community College in Basingstoke.


title: Dominic Solanke

text: Solanke started his career with Chelsea in 2004 in their under-eight team. During the 2013–14 season, Solanke scored 20 goals in 25 appearances for the under-18 team. On 6 May 2014, he scored two late goals as Chelsea came from two goals down to beat local rivals Fulham 7–6 on aggregate in the FA Youth Cup Final. On 29 July 2014, José Mourinho stated a belief that he should blame himself were Solanke not to become a senior England international under his management, and indicated that the player would train with the first-team squad during the 2014–15 season.


title: Dominic Solanke

text: Solanke signed his first professional contract with Chelsea in September 2014. Due to the injury of Diego Costa, Solanke was named on the bench for a Premier League match against Crystal Palace on 18 October 2014. Three days later, he made his first-team debut as a substitute for Oscar in the 73rd minute of a 6–0 win over NK Maribor in the UEFA Champions League. This made him the youngest player to debut in the UEFA Champions League for Chelsea.


title: Dominic Solanke

text: He finished as top scorer in the group stages of the UEFA Youth League after scoring a hat-trick in the final group stage match against Sporting CP. On 10 April 2015, Solanke scored two goals in the semi-final of the 2014–15 UEFA Youth League against A.S. Roma to send Chelsea into the final. He scored in the 3–2 win over Shakhtar Donetsk in the UEFA Youth League final, ending the tournament with 12 goals in nine appearances as Chelsea won the title. On 20 April 2015, Solanke scored a late goal to give the team side a 3–1 win in the first leg of the FA Youth Cup final against Manchester City. He played in the 2–1 win in the second leg, as Chelsea won the final 5–2 on aggregate. On 7 May 2015, Solanke reached 41 goals for the season after scoring a hat-trick in a 4–3 victory over Liverpool U21. He was awarded the inaugural Chelsea Academy Player of the Year award for the 2014–15 season.


title: Dominic Solanke

text: On 4 August 2015, Solanke joined Eredivisie club Vitesse on a season-long loan to gain first-team experience. After getting approval from FIFA to play in the Netherlands, he made his debut on 23 August 2015, coming off the bench in the 79th minute against Feyenoord, the match ending in a 2–0 defeat for Vitesse. A week later, Solanke scored his first goal in a 4–1 victory over SC Cambuur after coming off the bench with 15 minutes to go. He ended the season with seven goals in 25 appearances, just three behind top scorer Valeri Qazaishvili and one behind runner-up Milot Rashica.


title: Dominic Solanke

text: After rejecting many loan offers from several clubs, Solanke was retained as Chelsea's third-choice striker behind Diego Costa and Michy Batshuayi for the first half of the 2016–17 season. On 23 August 2016, he was involved in Chelsea's matchday squad for the first time since returning from his loan at Vitesse, for their EFL Cup home tie against Bristol Rovers. He remained as an unused substitute in Chelsea's 3–2 victory. In February 2017, Chelsea manager Antonio Conte confirmed that it was likely that Solanke would leave the club in the summer upon the expiry of his contract.


title: Dominic Solanke

text: On 30 May 2017, Solanke agreed to sign for Premier League club Liverpool on 1 July upon the expiration of his Chelsea contract. He was officially confirmed as a Liverpool player on 10 July 2017, with Liverpool expected to pay a tribunal-set fee of around £3 million. He made his debut for the club on 16 August 2017, coming on as a substitute for Roberto Firmino in a 2–1 UEFA Champions League first-leg win over Hoffenheim. His first Premier League start for Liverpool came on 30 November in a 3–0 win over Stoke City at the Bet365 Stadium. He scored his first Liverpool goal on 13 May 2018, the final day of the 2017–18 season, in the 4–0 home victory against Brighton & Hove Albion.


title: Dominic Solanke

text: Solanke signed for fellow Premier League club AFC Bournemouth on 4 January 2019 on a long-term contract for an undisclosed fee, reported by "BBC Sport" as £19 million. He made his debut on 2 February in a 2–0 away loss against Cardiff City in the league.


title: Dominic Solanke

text: Solanke scored his first and second Premier League goals for Bournemouth in his 39th league appearance on 12 July 2020, a 4–1 win over Leicester City. He then netted in Bournemouth's 3–1 victory at Everton on the final day of the league season but it was not enough to save the club from relegation to the Championship.


title: Dominic Solanke

text: Solanke scored fifteen goals in the Championship during the 2020–21 season, finishing as the club’s joint top goal scorer in the league along with Arnaut Danjuma.


title: Dominic Solanke

text: Solanke has represented England at all youth levels. In May 2014, Solanke was part of the under-17 team that won the 2014 UEFA European Under-17 Championship. He was the tournament's joint top scorer with four goals in four appearances, a brace against Turkey, a goal in the semi-final secured a place in the final, and England's goal in the final.


title: Dominic Solanke

text: In January 2015, Solanke was named the England Men's Youth Player of the Year for 2014. In March 2015, Solanke collected his trophy and was invited to train with the senior England squad. He was named in the under-19 squad for the 2016 UEFA European Under-19 Championship.


title: Dominic Solanke

text: Solanke was named in the under-20 squad for the 2017 FIFA U-20 World Cup. He scored four goals in the tournament; in the quarter-final, he scored the only goal against Mexico as England advanced into the semi-final, and scored twice in the semi-final as England beat Italy 3–1 to reach the final. Solanke started as England beat Venezuela 1–0 in the final. Solanke was awarded the Golden Ball as the player of the tournament.


title: Dominic Solanke

text: Solanke was called up by the senior team for the first time in November 2017 for a friendly against Brazil at Wembley Stadium. He came on as a 75th-minute substitute in a 0–0 draw.


title: Dominic Solanke

text: On 27 May 2019, Solanke was included in England's 23-man squad for the 2019 UEFA European Under-21 Championship.


title: Dominic Solanke

text: Solanke primarily plays as a striker, although can also operate as either an attacking midfielder or a winger. Former Chelsea striker Tore André Flo has said that Solanke "works really hard", has "got very good physique" and "a great touch on the ball". He went on to say: "He's quick but often what impresses me the most is when he looks like he's lost the ball, he somehow manages to get out with the ball, no matter how tight the situation is or how difficult it looks".


title: Siegfried Line

text: The Siegfried Line, known in German as the Westwall, was a German defensive line built during the 1930s (started 1936) opposite the French Maginot Line. It stretched more than ; from Kleve on the border with the Netherlands, along the western border of Nazi Germany, to the town of Weil am Rhein on the border with Switzerland – and featured more than 18,000 bunkers, tunnels and tank traps.


title: Siegfried Line

text: From September 1944 to March 1945 the Siegfried Line was subjected to a large-scale Allied offensive.


title: Siegfried Line

text: The official name for the German defensive line construction program before and during the Second World War that collectively came to be known as the "Westwall" (and "Siegfried Line" in English) changed several times during the late 1930s reflecting areas of progress.


title: Siegfried Line

text: These programmes were all pushed forward with the highest priority, putting a heavy demand on the available resources.


title: Siegfried Line

text: The origin of the name "Westwall" is unknown, but it appeared in popular use from the middle of 1939; there is a record of Hitler sending an Order of the Day to the soldiers and the workers at the "Westwall" on 20 May 1939.


title: Siegfried Line

text: The Siegfried Line at the start of the Second World War had serious weaknesses. German General Alfred Jodl said after the war that it was "little better than a building site in 1939", and when Field Marshal Gerd von Rundstedt inspected the line, the weak construction and insufficient weapons caused him to laugh. Despite France's declaration of war on Germany at the beginning of the Second World War, there was no major combat at the Siegfried Line at the start of the campaign in the west, except for a minor offensive by the French. Instead, both sides remained stuck in the so-called Phoney War, where neither side attacked the other and both stayed in their safe positions.


title: Siegfried Line

text: The Reich Ministry of Public Enlightenment and Propaganda drew foreign attention to the unfinished Westwall, in several instances showcasing incomplete or test positions to portray the project finished and ready for action. During the Battle of France, French forces made minor attacks against some parts of the line, but the majority was left untested. When the campaign finished, transportable weapons and materials (metal doors for instance) were removed from the Siegfried Line and used in other places such as the Atlantic Wall defences. <nowiki>The concrete sections were left in place in the countryside and soon became completely unfit for defense. </nowiki> The bunkers were instead used for storage.


title: Siegfried Line

text: With the D-Day landings in Normandy on 6 June 1944, war in the west broke out once more. On 24 August 1944, Hitler gave a directive for renewed construction on the Siegfried Line. 20,000 forced labourers and members of the "Reichsarbeitsdienst" ("Reich" Labour Service), most of whom were 14–16-year-old boys, attempted to re-equip the line for defence purposes. Local people were also called in to carry out this kind of work, mostly building anti-tank ditches.


title: Siegfried Line

text: Even during construction, it was becoming clear that the bunkers could not withstand the newly developed armour-piercing weapons. At the same time as the reactivation of the Siegfried Line, small concrete "Tobruks" were built along the borders of the occupied area. These bunkers were mostly dugouts for single soldiers.


title: Siegfried Line

text: In August 1944, the first clashes took place on the Siegfried Line; the section of the line where most fighting took place was the Hürtgenwald (Hürtgen Forest) area in the Eifel, southeast of Aachen. The Aachen Gap was the logical route into Germany's Rhineland and a main industrial area, and was therefore where the Germans concentrated their defence.


title: Siegfried Line

text: The Americans committed an estimated 120,000 troops plus reinforcements to the Battle of Hürtgen Forest. The battle in this heavily forested area claimed the lives of 24,000 American soldiers plus 9,000 so-called nonbattle casualties—those evacuated because of fatigue, exposure, accidents and disease. The German death toll is not documented. After the Battle of Hürtgen Forest, the Battle of the Bulge began, starting in the area south of the Hürtgenwald, between Monschau and the Luxembourgish town of Echternach. This offensive was a last-ditch attempt by the Germans to reverse the course of the war in the West. German loss of life and material was severe and the effort failed. There were serious clashes along other parts of the Siegfried Line and soldiers in many bunkers refused to surrender, often fighting to the death. By early 1945 the last Siegfried Line bunkers had fallen at the Saar and Hunsrück.


title: Siegfried Line

text: The British 21st Army Group also attacked the Siegfried Line. This army group included US formations and the resulting fighting brought total US losses to approximately 68,000. In addition, the First Army incurred over 50,000 non-battle casualties and the Ninth Army over 20,000. This brings the overall cost of the Siegfried Line Campaign, in US personnel, close to 140,000.


title: Siegfried Line

text: In North Rhine Westphalia, about thirty bunkers still remain; most of the rest were either destroyed with explosives or covered with earth. Tank traps still exist in many areas; in the Eifel, they run over several kilometres. Zweibrücken Air Base was built on top of the Siegfried Line. When the base was still open, the remnants of several old bunkers could be seen in the tree line near the base's main gate. Another bunker was outside the base perimeter fence near the base hospital. Once the base was closed, workers, digging up the base's fuel tanks, discovered lost bunkers buried below the tanks.


title: Siegfried Line

text: Since 1997, with the motto "The value of the unpleasant as a memorial" ("Der Denkmalswert des Unerfreulichen"), an effort has been made to preserve the remains of the Siegfried Line as a historical monument. This was intended to stop reactionary fascist groups from using the Siegfried Line for propaganda purposes.


title: Siegfried Line

text: At the same time, state funding was still being provided to destroy the remains of the Siegfried Line. For this reason, emergency archaeological digs took place whenever any part of the line was removed, for example for road building. Archaeological activity was not able to stop the destruction of these sections but furthered scientific knowledge and revealed details of the line's construction.


title: Siegfried Line

text: Nature conservationists consider the remains of the Siegfried Line valuable as a chain of biotopes where, thanks to its size, rare animals and plants can take refuge and reproduce. This effect is magnified because the concrete ruins cannot be used for agricultural or forestry purposes.


title: Siegfried Line

text: Small bunkers with thick walls were set up with three embrasures towards the front. Sleeping accommodations were hammocks. In exposed positions, similar small bunkers were erected with small round armoured "lookout" sections on the roofs. The programme was carried out by the Border Watch ("Grenzwacht"), a small military troop activated in the Rhineland immediately after the region was re-militarised by Germany after having been de-militarised following the First World War.


title: Siegfried Line

text: The Limes Programme began in 1938 following an order by Hitler to strengthen fortifications on the western German border. "Limes" refers to the former borders of the Roman Empire; the cover story for the programme was that it was an archaeological study.


title: Siegfried Line

text: Its Type 10 bunkers were more strongly constructed than the earlier border fortifications. These had thick ceilings and walls. A total of 3,471 were built along the entire length of the Siegfried Line. They featured a central room or shelter for 10–12 men with a stepped embrasure facing backwards and a combat section higher. This elevated section had embrasures at the front and sides for machine guns. More embrasures were provided for riflemen, and the entire structure was constructed so as to be safe against poison gas.


title: Siegfried Line

text: Heating was from a safety oven, the chimney of which was covered with a thick grating. Space was tight, with about per soldier, who was given a sleeping-place and a stool; the commanding officer had a chair. Surviving examples still retain signs warning "Walls have ears" and "Lights out when embrasures are open!"


title: Siegfried Line

text: The Aachen-Saar programme bunkers were similar to those of the Limes programme: Type 107 double MG casemates with concrete walls up to thick. One difference was that there were no embrasures at the front, only at the sides of the bunkers. Embrasures were only built at the front in special cases and were then protected with heavy metal doors. This construction phase included the towns of Aachen and Saarbrücken, which were initially west of the Limes Programme defence line.


title: Siegfried Line

text: The Western Air Defence Zone ("Luftverteidigungszone West" or "LVZ West") continued parallel to the two other lines toward the east, and consisted mainly of concrete "flak" foundations. Scattered MG 42 and MG 34 emplacements added additional defence against both air and land targets. Flak turrets were designed to force enemy planes to fly higher, thus decreasing the accuracy of their bombing. These towers were protected at close range by bunkers from the Limes and Aachen-Saar programmes.


title: Siegfried Line

text: The Geldern Emplacement lengthened the Siegfried Line northwards as far as Kleve on the Rhine, and was built after the start of the Second World War. The Siegfried Line originally ended in the north near Brüggen in the Viersen district. The primary constructions were unarmed dugouts, but their extremely strong concrete design afforded excellent protection to the occupants. For camouflage they were often built near farms.


title: Siegfried Line

text: Standard construction elements such as large Regelbau bunkers, smaller concrete "pillboxes", and "dragon's teeth" anti-tank obstacles were built as part of each construction phase, sometimes by the thousands. Frequently vertical steel rods would be interspersed between the teeth. This standardisation was the most effective use of scarce raw materials, transport and workers, but proved an ineffective tank barrier as US bulldozers simply pushed dirt bridges over these devices.


title: Siegfried Line

text: "Dragon's teeth" tank traps were also known as "Höcker" in German ('humps' or 'pimples' in English) because of their shape. These blocks of reinforced concrete stand in several rows on a single foundation. There are two typical sorts of barrier: Type 1938 with four rows of teeth getting higher toward the back, and Type 1939 with five rows of such teeth. Many other irregular lines of teeth were also built. Another design of tank obstacle, known as the Czech hedgehog, was made by welding together several bars of steel in such a way that any tank rolling over it would get stuck and possibly damaged. If the contour of the land allowed it, water-filled ditches were dug instead of tank traps. Examples of this kind of defence are those north of Aachen near Geilenkirchen.


title: Siegfried Line

text: The early fortifications were mostly built by private firms, but the private sector was unable to provide the number of workers needed for the programmes that followed; this gap was filled by the Todt Organisation. With this organisation's help, huge numbers of forced labourers – up to 500,000 at a time – worked on the Siegfried Line. Transport of materials and workers from all across Germany was managed by the "Deutsche Reichsbahn" railway company, which took advantage of the well-developed strategic railway lines built on Germany's western border in World War I.


title: Siegfried Line

text: Working conditions were highly dangerous. For example, the most primitive means had to be used to handle and assemble extremely heavy armour plating, weighing up to .


title: Siegfried Line

text: Life on the building site and after work was monotonous, and many people gave up and left. Most workers received the West Wall Medal for their service.


title: Siegfried Line

text: German propaganda, both at home and abroad, repeatedly portrayed the Westwall during its construction as an unbreachable bulwark. At the start of the war, the opposing troops remained behind their own defence lines.


title: Siegfried Line

text: As a morale booster for British troops marching off to France, the Siegfried Line was the subject of a popular song: "We're Going to Hang out the Washing on the Siegfried Line".


title: Siegfried Line

text: A French version by Ray Ventura (""On ira pendre notre linge sur la ligne Siegfried"") met a great success during the Phoney War ("Drôle de guerre").


title: Siegfried Line

text: When asked about the Siegfried Line, General George S. Patton reportedly said "Fixed fortifications are monuments to man's stupidity."


title: Nicholle Tom

text: Nicholle Marie Tom is an American actress. She is best known for her roles as Ryce Newton in "Beethoven" (1992), "Beethoven's 2nd" (1993), "Beethoven" (1994–1995), and as Maggie Sheffield on "The Nanny". She is also known for voicing Supergirl in the DC Animated Universe.


title: Nicholle Tom

text: Tom has a twin brother, David Tom, best known for his role as Billy Abbott on "The Young and the Restless", and an older sister, Heather Tom, who is best known for her roles as Katie Logan on "The Bold and The Beautiful" and as Victoria Newman on "The Young and the Restless" from 1990-2003.


title: Nicholle Tom

text: In 1992, Tom played the small role of Scott Scanlon's sister, Sue, on "Beverly Hills, 90210". In 1992 and 1993, she played Ryce Newton in the successful family movies "Beethoven" and "Beethoven's 2nd". She reprised her role as the voice of Ryce in the cartoon spinoff.


title: Nicholle Tom

text: Tom was a member of the cast of "Jim Henson Presents Mother Goose Stories" in 1997-98. From 1998 to 2006, she provided the voice for Supergirl in the DC Animated Universe.


title: Nicholle Tom

text: In 2000, she played Sarah Bryann in the Fox Family television film, "Ice Angel", and played Tracy in "Panic". In 2001, she portrayed a teen reporter, Cassie, in "The Princess Diaries".


title: Nicholle Tom

text: In 2006, she co-starred in the IFC original "The Minor Accomplishments of Jackie Woodman" as Tara, an underling at a film production company. Tom played a small role in "Loose Ends", the September 20, 2007 episode of "Burn Notice".


title: Nicholle Tom

text: In March 2008, she starred in the Lifetime movie, "Her Only Child", that premiered on March 22, 2008. She guest-starred alongside brother David, who played her character's brother in "Damaged", the April 2, 2008, episode of "Criminal Minds". She guest-starred on the May 4, 2008, episode of "Cold Case".


title: Nicholle Tom

text: She competes on the twenty-fourth season of "Worst Cooks in America", the show's seventh celebrity edition titled "Thats So 90s", airing in April and May 2022.


title: Nicholle Tom

text: Tom reprised her role as Kara Kent / Supergirl for the "" dark ride at Warner Bros. Movie World in Australia as well as the seven "" dark rides across Six Flags theme parks in the United States and Mexico.


title: Charles Kushner

text: Charles Kushner (born May 16, 1954) is an American real estate developer, former federal inmate, and disbarred former attorney. He founded Kushner Companies in 1985.


title: Charles Kushner

text: In 2005, he was convicted of illegal campaign contributions, tax evasion, and witness tampering and was sentenced to two years imprisonment, which he served in the Federal Prison Camp, Montgomery. As a convicted felon he was also disbarred in three states. He later received a federal pardon issued by President Donald Trump on December 23, 2020.


title: Charles Kushner

text: His son Jared Kushner is the husband of Ivanka Trump and son-in-law of former President Donald Trump, during whose presidential administration he served as senior advisor from 2017 to 2021. He has 3 other children including Joshua Kushner and he is the father-in-law of Karlie Kloss.


title: Charles Kushner

text: Charles Kushner was born on May 16, 1954, to Joseph Berkowitz and Rae Kushner, Jewish Holocaust survivors born in eastern Poland who came to America from the USSR in 1949. At birth, he was named Chanan, after a maternal uncle who died in a concentration camp during the Holocaust. He grew up in Elizabeth, New Jersey, with his elder brother Murray Kushner and sister Esther Schulder. His father worked as a construction worker, builder, and real estate investor. Kushner graduated from the Hofstra University School of Law in 1979.


title: Charles Kushner

text: In 1985, he began managing his father's portfolio of 4,000 New Jersey apartments. He founded Kushner Companies – headquartered in Florham Park, New Jersey – and became its chairman. In 1999, he won the Ernst & Young New Jersey Entrepreneur of the Year award. At the time, Kushner Companies had grown to more than 10,000 residential apartments, a homebuilding business, commercial and industrial properties, and a community bank.


title: Charles Kushner

text: On June 30, 2004, Kushner was fined $508,900 by the Federal Election Commission for contributing to Democratic political campaigns in the names of his partnerships when he lacked authorization to do so. In 2005, following an investigation by the U.S. Attorney's Office for the District of New Jersey, U.S. Attorney Chris Christie negotiated a plea agreement with him, under which he pleaded guilty to 18 counts of illegal campaign contributions, tax evasion, and witness tampering. The witness-tampering charge arose from Kushner's act of retaliation against William Schulder, his sister Esther's husband, who was cooperating with federal investigators against Kushner. Kushner hired a prostitute he knew to seduce his brother-in-law, arranged to record a sexual encounter between the two, and had the tape sent to his sister. He was sentenced to two years in prison. He served 14 months at Federal Prison Camp, Montgomery in Alabama before being sent to a halfway house in Newark, New Jersey, to complete his sentence. He was released from prison on August 25, 2006.


title: Charles Kushner

text: As a convicted felon, he was also disbarred and prohibited from practicing law in New Jersey, New York, and Pennsylvania.


title: Charles Kushner

text: In her book "Too Much and Never Enough" President Trump's niece Mary L. Trump wrote that Charles Kushner had given a speech in which he claimed that Ivanka Trump had only made herself worthy of inclusion in his family by committing to convert to Judaism, which Mary Trump found "a bit rich" given Kushner's own past as a convicted felon.


title: Charles Kushner

text: Kushner received a federal pardon on December 23, 2020, by his son's father-in-law, Donald Trump, citing his record of "reform" and "charity."


title: Charles Kushner

text: After being released from prison, Kushner shifted his business activities from New Jersey to New York City. In early 2007, Kushner Companies bought the 666 Fifth Avenue building in Manhattan for $1.8 billion. In August 2018, Brookfield Properties signed a 99-year lease for the property, paying $1.286 billion and effectively taking full ownership of the building.


title: Charles Kushner

text: As of the end of 2016, Kushner and his family were estimated to have a net worth of $1.8 billion. He has employed two fellow inmates he became acquainted with in prison.


title: Charles Kushner

text: Charles Kushner met personally with Harvard's president and in 1998 donated $2.5 million to Harvard. His son, Jared, was then beginning his senior year of high school where he was not a particularly good student with test scores below Ivy League standards. Jared Kushner was admitted to the Harvard freshman class of 1999.


title: Charles Kushner

text: Before 2016, Kushner was a donor to the Democratic Party. He serves on the boards of Touro College, Stern College for Women, Rabbinical College of America, and the United Jewish Communities. Kushner has made other donations to Harvard University, Stern College, and United Cerebral Palsy. He donated to the Seryl and Charles Kushner Maternity Unit at St. Barnabas Medical Center in Livingston, New Jersey. He contributed to the funding of two schools, Joseph Kushner Hebrew Academy and Rae Kushner Yeshiva High School, also in Livingston, and named them after his parents. Kushner Hall is a building that is named after him on the Hofstra University campus. The campus of Jerusalem's Shaare Zedek Medical Center is named the "Seryl and Charles Kushner Campus" in honor of their donation of $20 million.


title: Charles Kushner

text: In August 2015, Kushner donated $100,000 to Donald Trump's Make America Great Again PAC, a super PAC supporting Trump's 2016 campaign for the presidency. Kushner and his wife also hosted a reception for Trump at their Jersey Shore seaside mansion in Long Branch.


title: Bowhead whale

text: The bowhead whale (Balaena mysticetus) is a species of baleen whale belonging to the family Balaenidae and the only living representative of the genus "Balaena". They are the only baleen whale endemic to the Arctic and subarctic waters, and are named after their characteristic massive triangular skull, which they use to break through Arctic ice. Other common names of the species are the Greenland right whale, Arctic whale, and Arviq in aboriginal languages (Inuktitut). American whalemen called them the steeple-top, polar whale, or Russian whale.


title: Bowhead whale

text: Bowheads have the largest mouth of any animal representing almost one-third of the length of the body, the longest baleen plates with a maximum length of and may be the longest-lived mammals, with the ability to reach an age of more than 200 years.


title: Bowhead whale

text: The bowhead was an early whaling target. Their population was severely reduced before a 1966 moratorium was passed to protect the species. Of the five stocks of bowhead populations, three are listed as "endangered", one as "vulnerable", and one as "lower risk, conservation dependent" according to the IUCN Red List. The global population is assessed as of least concern.


title: Bowhead whale

text: Carl Linnaeus named this species in the tenth edition of his "Systema Naturae" (1758). It was seemingly identical to its relatives in the North Atlantic, North Pacific, and Southern Oceans, and as such they were all thought to be a single species, collectively known as the "right whale", and given the binomial name "Balaena mysticetus".


title: Bowhead whale

text: Today, the bowhead whale occupies a monotypic genus, separate from the right whales, as proposed by the work of John Edward Gray in 1821. For the next 180 years, the family Balaenidae was the subject of great taxonometric debate. Authorities have repeatedly recategorized the three populations of right whale plus the bowhead whale, as one, two, three or four species, either in a single genus or in two separate genera. Eventually, it was recognized that bowheads and right whales were different, but there was still no strong consensus as to whether they shared a single genus or two. As recently as 1998, Dale Rice, in his comprehensive and otherwise authoritative classification, "Marine Mammals of the World: Systematics and Distribution", listed just two species: "B. glacialis" (the right whales) and "B. mysticetus" (the bowheads).


title: Bowhead whale

text: Studies in the 2000s finally provided clear evidence that the three living right whale species comprise a phylogenetic lineage, distinct from the bowhead, and that the bowhead and the right whales are rightly classified into two separate genera. The right whales were thus confirmed to be in a separate genus, "Eubalaena". The relationship is shown in the cladogram below:


title: Bowhead whale

text: The earlier fossil record shows no related cetacean after "Morenocetus", found in a South American deposit dating back 23 million years.


title: Bowhead whale

text: An unknown species of right whale, the so-called "Swedenborg whale", which was proposed by Emanuel Swedenborg in the 18th century, was once thought to be a North Atlantic right whale by scientific consensus. Based on later DNA analysis, those fossil bones claimed to be from Swedenborg whales were confirmed to be from bowhead whales.


title: Bowhead whale

text: The bowhead whale has a large, robust, dark-coloured body and a white chin/lower jaw. It has a massive triangular skull, which it uses to break through the Arctic ice to breathe. Inuit hunters have reported bowheads surfacing through of ice. It also possesses a strongly bowed lower jaw and a narrow upper jaw. Its baleen is the longest of that of any whale, at , and is used to strain tiny prey from the water. The bowhead whale has paired blowholes at the highest point of the head, which can spout a blow high. The bowhead's blubber is the thickest of that of any animal, with a maximum of . Unlike most cetaceans, the bowhead does not have a dorsal fin - an adaptation for spending much time under sea-surface ice. Like the sperm whale and other cetaceans, the bowhead whale has a vestigial pelvis that is not connected to the spine.


title: Bowhead whale

text: Bowhead whales are comparable in size to the three species of right whales. According to whaling captain William Scoresby Jr., the longest bowhead he measured was long, while the longest measurement he had ever heard of was of a whale caught at Godhavn, Greenland, in early 1813. He also spoke of one, caught near Spitsbergen around 1800, that was allegedly nearly long. In 1850, an American vessel claimed to have caught a individual in the Western Arctic. Whether these lengths were actually measured is questionable. The longest reliably measured were a male of and a female of , both landed in Alaska. On average, female bowheads are larger than males. The adults would have likely measured in length and in body mass, but larger individuals (like the one claimed in 1850) may weigh up to .


title: Bowhead whale

text: Analysis of hundreds of DNA samples from living whales and from baleen used in vessels, toys, and housing material has shown that Arctic bowhead whales have lost a significant portion of their genetic diversity in the past 500 years. Bowheads originally crossed ice-covered inlets and straits to exchange genes between Atlantic and Pacific populations. This conclusion was derived from analyzing maternal lineage using mitochondrial DNA. Whaling and climatic cooling during the Little Ice Age, from the 16th century to the 19th, is supposed to have reduced the whales' summer habitats, which explains the loss of genetic diversity.


title: Bowhead whale

text: A 2013 discovery has clarified the function of the bowhead's large palatal retial organ. The bulbous ridge of highly vascularized tissue, the corpus cavernosum maxillaris, extends along the centre of the hard plate, forming two large lobes at the rostral palate. The tissue is histologically similar to that of the corpus cavernosum of the mammalian penis. This organ is thought to provide a mechanism of cooling for the whale (which is normally protected from the cold Arctic waters by or more of fat). During physical exertion, the whale must cool itself to prevent hyperthermia (and ultimately brain damage). This organ becomes engorged with blood, and as the whale opens its mouth cold seawater flows over the organ, thus cooling the blood.


title: Bowhead whale

text: The bowhead whale is not a social animal, typically travelling alone or in small pods of up to six. It is able to dive and remain submerged under water for up to an hour. The time spent under water in a single dive is usually limited to 9–18 minutes. The bowhead is not thought to be a deep diver, but can reach a depth down to . It is a slow swimmer, normally travelling around [0.55–1.39 m/s]. When fleeing from danger, it can travel at a speed of []. During periods of feeding, the average swim speed is increased to .


title: Bowhead whale

text: The head of the bowhead whale comprises a third of its body length, creating an enormous feeding apparatus. The bowhead whale is a filter feeder, and feeds by swimming forward with its mouth wide open. It has hundreds of overlapping baleen plates consisting of keratin hanging from each side of the upper jaw. The mouth has a large, upturning lip on the lower jaw that helps to reinforce and hold the baleen plates within the mouth. This also prevents buckling or breakage of the plates from the pressure of the water passing through them as the whale advances. To feed, water is filtered through the fine hairs of keratin of the baleen plates, trapping the prey inside near the tongue where it is then swallowed. The diet consists of mostly zooplankton, which includes copepods, amphipods, and many other crustaceans. About of food are consumed each day. While foraging, bowheads are solitary or occur in groups of two to 10 or more.


title: Bowhead whale

text: Bowhead whales are highly vocal and use low frequency (<1000 Hz) sounds to communicate while travelling, feeding, and socialising. Intense calls for communication and navigation are produced especially during migration season. During breeding season, bowheads make long, complex, variable songs for mating calls. From 2010 through to 2014, near Greenland, 184 distinct songs were recorded from a population of around 300 animals.


title: Bowhead whale

text: Sexual activity occurs between pairs and in boisterous groups of several males and one or two females. Breeding season is observed from March through August; conception is believed to occur primarily in March when song activity is at its highest. Reproduction can begin when a whale is 10 to 15 years old. The gestation period is 13–14 months with females producing a calf once every three to four years. Lactation typically lasts about a year. To survive in the cold water immediately after birth, calves are born with a thick layer of blubber. Within 30 minutes of birth, bowhead calves are able to swim on their own. A newborn calf is typically long, weighs roughly , and grows to within the first year.


title: Bowhead whale

text: Bowhead whales are considered to be the longest-living mammals, living for over 200 years. In May 2007, a specimen caught off the Alaskan coast was discovered with the head of an explosive bomb lance of a model manufactured between 1879 and 1885, so the whale was probably bomb lanced sometime between those years, and its age at the time of death was estimated at between 115 and 130 years. Spurred by this discovery, scientists measured the ages of other bowhead whales; one specimen was estimated to be 211 years old. Other bowhead whales were estimated to be between 135 and 172 years old. This discovery showed the longevity of the bowhead whale is much greater than originally thought. According to researchers at CSIRO, Australia's national science agency, the genome sequence revealed bowhead whales' maximum lifespan to be 268 years.


title: Bowhead whale

text: A greater number of cells present in an organism was once believed to result in greater chances of mutations that cause age-related diseases and cancer. Although the bowhead whale has thousands of times more cells than other mammals, it has a much higher resistance to cancer and aging. In 2015, scientists from the US and UK were able to successfully map the whale's genome. Through comparative analysis, two alleles that could be responsible for the whale's longevity were identified. These two specific gene mutations linked to the bowhead whale's ability to live longer are the "ERCC1" gene and the proliferating cell nuclear antigen ("PCNA") gene. "ERCC1" is linked to DNA repair and increased cancer resistance. "PCNA" is also important in DNA repair. These mutations enable bowhead whales to better repair DNA damage, allowing for greater resistance to cancer. The whale's genome may also reveal physiological adaptations such as having low metabolic rates compared to other mammals. Changes in the gene "UCP1", a gene involved in thermoregulation, can explain differences in the metabolic rates in cells.


title: Bowhead whale

text: The bowhead whale is the only baleen whale to spend its entire life in the Arctic and subarctic waters. The Alaskan population spends the winter months in the southwestern Bering Sea. The group migrates northward in the spring, following openings in the ice, into the Chukchi and Beaufort seas. The whale's range varies depending on climate changes and on the forming/melting of ice.


title: Bowhead whale

text: Historically, bowhead whales' range may have been broader and more southerly than currently thought. Bowheads were abundant around Labrador, Newfoundland (Strait of Belle Isle) and the northern Gulf of St Lawrence until at least the 16th and 17th centuries. It is unclear whether this was due to the colder climate during these periods. Distributions of "Balaena" spp. during the Pleistocene were far more southerly as fossils have been excavated from Italy and North Carolina, thus could have overlapped between those of "Eubalaena" based on those locations.


title: Bowhead whale

text: Generally, five stocks of bowhead whales are recognized: 1) the Western Arctic stock in the Bering, Chukchi, and Beaufort Seas, 2) the Hudson Bay and Foxe Basin stock, 3) the Baffin Bay and Davis Strait stock, 4) the Sea of Okhotsk stock, and 5) the Svalbard-Barents Sea stock. However, recent evidence suggests that the Hudson Bay and Foxe Basin stock and the Baffin Bay and Davis Strait stock should be considered one stock based on genetics and movements of tagged whales.


title: Bowhead whale

text: The Western Arctic bowhead population, also known as the Bering-Chukchi-Beaufort population, has recovered since the commercial harvest of this stock ceased in the early 1900s. A 2019 study estimated that the Western Arctic population was 12,505; although it was lower than the 2011 value of 16,820, the surveyors believed there was no significant decline in 2011-2019 due to the unusual conditions of whale migration and observation in 2019. The yearly growth rate of the Western Arctic bowhead population was 3.7% from 1978 to 2011. These data suggest that the Western Arctic bowhead stock may be near its precommercial whaling level.


title: Bowhead whale

text: Alaskan Natives continue to hunt small numbers of bowhead whales for subsistence purposes. The Alaska Eskimo Whaling Commission co-manages the bowhead subsistence harvest with the National Oceanic and Atmospheric Administration. The Alaskan villages that participate in the bowhead subsistence harvest include Barrow, Point Hope, Point Lay, Wainwright, Nuiqsut, Kaktovik, Gambell, Savoonga, Kivalina, Wales, and Little Diomede. The annual subsistence harvest of the Western Arctic stock has ranged from 14 to 72, amounting to an estimated 0.1-0.5% of the population.


title: Bowhead whale

text: In March 2008, Canada's Department of Fisheries and Oceans stated the previous estimates in the eastern Arctic had undercounted, with a new estimate of 14,400 animals (range 4,800–43,000). These larger numbers correspond to prewhaling estimates, indicating the population has fully recovered. However, if climate change substantially shrinks sea ice, these whales could be threatened by increased shipping traffic.


title: Bowhead whale

text: The status of other populations is less well known. About 1,200 were off West Greenland in 2006, while the Svalbard population may only number in the tens. However, the numbers have been increasing in recent years.


title: Bowhead whale

text: The Hudson Bay – Foxe Basin population is distinct from the Baffin BayDavis Strait group. The original population size of this local group is unclear, but possibly about 500 to 600 whales annually summered in the northwestern part of the bay in the 1860s. It is likely that the number of whales that actually inhabit Hudson Bay is much smaller than the total population size of this group, but reports from local indigenous people indicate that this population is increasing over decades. Larger portions of the bay are used for summering, while wintering is on a smaller scale. Some animals winter in Hudson Strait, most notably north of Igloolik Island and north eastern Hudson Bay. Distribution patterns in these regions are affected by the presence of killer whales, and bowheads can disappear from normal ranges in the presence of atypical numbers of orcas. Increased mortality caused by killer whale attack is a possible outcome of climate change, as reduced ice coverage is expected to result in fewer areas that the bowheads can use for shelter from attack. Whaling grounds in the 19th century stretched from Marble Island to Roes Welcome Sound and to


title: Bowhead whale

text: Distribution within Hudson Bay is mostly restricted to the northwestern part along with Wager Bay, Repulse Bay, Southampton Island (one of two main know summering areas), Frozen Strait, northern Foxe


title: Bowhead whale

text: Basin, and north of Igloolik in summer. Satellite tracking indicates that some portions of the group within the bay do not venture further south than Whale Cove and areas south of Coats and Mansel Islands. Cow – calf pairs and juveniles up to in length make up the majority of summering aggregation in the northern Foxe Basin, while matured males and noncalving females may use the northwestern part of Hudson Bay. Fewer whales also migrate to the west coast of Hudson Bay and Mansel and Ottawa Islands. Bowhead ranges within Hudson Bay are usually considered not to cover southern parts, but at least some whales migrate to locations further south such as Sanikiluaq and Churchill river mouth.


title: Bowhead whale

text: Congregation within Foxe Basin occurs in a well-defined area of north of Igloolik Island to Fury and Hecla Strait and Kapuiviit and Gifford Fiord, and into Gulf of Boothia and Prince Regent Inlet. Northward migrating along western Foxe Basin to eastern side of the basin also occurs in spring.


title: Bowhead whale

text: Not much is known about the endangered Sea of Okhotsk population. To learn more about the population, these mammals have been regularly observed near the Shantar Islands, very close to the shore, such as at Ongachan Bay. Several companies provide whale-watching services, which are mostly land-based. According to Russian scientists, this total population likely does not exceed 400 animals. Scientific research on this population was seldom done before 2009, when researchers studying belugas noticed concentrations of bowheads in the study area. Thus, bowheads in the Sea of Okhotsk were once called "forgotten whales" by researchers. The WWF welcomed the creation of a nature sanctuary in the region


title: Bowhead whale

text: Possibly, vagrants from this population occasionally reach into Asian nations such as off Japan or the Korean Peninsula (although this record might be of a right whale). The first documented report of the species in Japanese waters was of a strayed infant () caught in Osaka Bay on 23 June 1969, and the first living sighting was of a juvenile around Shiretoko Peninsula (the southernmost of ice floe range in the Northern Hemisphere) on 21 to 23 June 2015. Fossils have been excavated on Hokkaido, but it is unclear whether the northern coasts of Japan were once included in seasonal or occasional migration ranges.


title: Bowhead whale

text: Genetic studies suggest Okhotsk population share common ancestry with whales in Bering-Chukchi-Beaufort Seas, and repeated mixings had occurred between whales in the two seas.


title: Bowhead whale

text: The most endangered but historically largest of all bowhead populations is the Svalbard/Spitsbergen population. Occurring normally in Fram Strait, Barents Sea and Severnaya Zemlya along Kara Sea to Laptev Sea and East Siberian Sea regions, these whales were seen in entire coastal regions in European and Russian Arctic, even reaching to Icelandic and Scandinavian coasts and Jan Mayen in Greenland Sea, and west of Cape Farewell and western Greenland coasts. Also, bowheads in this stock were possibly once abundant in areas adjacent to the White Sea region, where few or no animals currently migrate, such as the Kola and Kanin Peninsula. Today, the number of sightings elsewhere is very small, but with increasing regularities with whales having strong regional connections. Whales have also started approaching townships and inhabited areas such as around Longyearbyen. The waters around the marine mammal sanctuary of Franz Josef Land is possibly functioning as the most important habitat for this population.


title: Bowhead whale

text: It is unclear whether this population is a remnant of the historic Svalbard group, recolonized individuals from other stocks, or if a mixing of these two or more stocks has taken place. In 2015, discoveries of the refuge along eastern Greenland where whaling ships could not reach due to ice floes and largest numbers of whales (80–100 individuals) ever sighted between Spitsbergen and Greenland indicate that more whales than previously considered survived whaling periods, and flows from the other populations are possible.


title: Bowhead whale

text: During expeditions by a tour operator 'Arctic Kingdom', a large group of bowheads seemingly involved in courtship activities was discovered in very shallow bays south of Qikiqtarjuaq in 2012. Floating skins and rubbing behaviours at sea bottom indicated possible moulting had taken place. Moulting behaviours had never or seldom been documented for this species before. This area is an important habitat for whales that were observed to be relatively active and to interact with humans positively, or to rest on sea floors. These whales belong to Davis Strait stock.


title: Bowhead whale

text: Isabella Bay in Niginganiq National Wildlife Area is the first wildlife sanctuary in the world to be designed specially for bowhead whales. However, moultings have not been recorded in this area due to environmental factors.


title: Bowhead whale

text: In 1978 the International Whaling Commission (IWC) introduced a hunting strike quota for the Bering-Chukchi-Beaufort Sea (BCB) bowhead. The quota has remained at 67 strikes per year since 1998 and represents about 0.5 percent of BCB population. The population of bowheads in West Greenland and Canada is estimated to be 6,000 and rising, and hunts in this are minimal (<0.001 percent). Both stocks are rising, and the indigenous hunts seem to be self-sustaining.


title: Bowhead whale

text: Killer whales are also known predators. There is no consensus on the number of deaths by killer whales. Bowheads seek the ice and shallow waters' safety when threatened by killer whales. The Inuit have a word for this behavior to give historical context that this is not a new phenomenon. Global warming is increasing the frequency that killer whales are observed in the far north. A once-rare event, killer whales are now seen more frequently.


title: Bowhead whale

text: The bowhead whale has been hunted for blubber, meat, oil, bones, and baleen. Like the right whale, it swims slowly, and floats after death, making it ideal for whaling. Before commercial whaling, they were estimated to number 50,000.


title: Bowhead whale

text: Commercial bowhead whaling began in the 16th century when the Basques killed them as they migrated south through the Strait of Belle Isle in the fall and early winter. In 1611, the first whaling expedition sailed to Spitsbergen. The whaling settlement Smeerenburg was founded on Spitsbergen in 1619. By midcentury, the population(s) there had practically been wiped out, forcing whalers to voyage into the "West Ice"—the pack ice off Greenland's east coast. By 1719, they had reached the Davis Strait, and by the first quarter of the 19th century, Baffin Bay.


title: Bowhead whale

text: In the North Pacific, the first bowheads were taken off the eastern coast of Kamchatka by the Danish whaleship "Neptun", Captain Thomas Sodring, in 1845. In 1847, the first bowheads were caught in the Sea of Okhotsk, and the following year, Captain Thomas Welcome Roys, in the bark "Superior", of Sag Harbor, caught the first bowheads in the Bering Strait region. By 1849, 50 ships were hunting bowheads in each area; in the Bering Strait, 500 whales were killed that year, and that number jumped to more than 2000 in 1850. By 1852, 220 ships were cruising around the Bering Strait region, which killed over 2,600 whales. Between 1854 and 1857, the fleet shifted to the Sea of Okhotsk, where 100–160 ships cruised annually. During 1858–1860, the ships shifted back to the Bering Strait region, where the majority of the fleet cruised during the summer until the early 20th century. An estimated 18,600 bowheads were killed in the Bering Strait region between 1848 and 1914, with 60% of the total being reached within the first two decades. An estimated 18,000 bowheads were killed in the Sea of Okhotsk during 1847–1867, 80% in the first decade.


title: Bowhead whale

text: Bowheads were first taken along the pack ice in the northeastern Sea of Okhotsk, then in Tausk Bay and Northeast Gulf (Shelikhov Gulf). Soon, ships expanded to the west, catching them around Iony Island and then around the Shantar Islands. In the Western Arctic, they mainly caught them in the Anadyr Gulf, the Bering Strait, and around St. Lawrence Island. They later spread to the western Beaufort Sea (1854) and the Mackenzie River delta (1889).


title: Bowhead whale

text: Commercial whaling, the principal cause of the population decline, is over. Bowhead whales are now hunted on a subsistence level by native peoples of North America.


title: Bowhead whale

text: Some Alaska Natives continue by tradition to hunt bowhead and beluga whales on a subsistence level, with low annual bowhead total quotas set by the International Whaling Commission in conjunction with individual village limits set by the Alaska Eskimo Whaling Commission.


title: Bowhead whale

text: This bowhead subsistence hunting occurs during the northward spring migrations based from the ice and from small boats during the returning fall migrations.


title: Bowhead whale

text: The bowhead is listed in Appendix I by CITES. While the global population is thought to be secure, thus assigned "least concern" status, some populations are listed by the National Marine Fisheries Service as "endangered" under the auspices of the United States' Endangered Species Act. The IUCN Red List data are:


title: Bowhead whale

text: The Alaska Department of Fish and Game and the USA government list the bowhead whale as federally endangered.


title: Bowhead whale

text: The bowhead whale is listed in Appendix I of the Convention on the Conservation of Migratory Species of Wild Animals (CMS), as this species has been categorized as being in danger of extinction throughout all or a significant proportion of its range. CMS Parties strive towards strictly protecting these animals, conserving or restoring the places where they live, mitigating obstacles to migration, and controlling other factors that might endanger them.


title: Tamoxifen

text: Tamoxifen, sold under the brand name Nolvadex among others, is a selective estrogen receptor modulator used to prevent breast cancer in women and treat breast cancer in women and men. It is also being studied for other types of cancer. It has been used for Albright syndrome. Tamoxifen is typically taken daily by mouth for five years for breast cancer.


title: Tamoxifen

text: Serious side effects include a small increased risk of uterine cancer, stroke, vision problems, and pulmonary embolism. Common side effects include irregular periods, weight loss, and hot flashes. It may cause harm to the baby if taken during pregnancy or breastfeeding. It is a selective estrogen-receptor modulator (SERM) and works by decreasing the growth of breast cancer cells. It is a member of the triphenylethylene group of compounds.


title: Tamoxifen

text: Tamoxifen was initially made in 1962, by chemist Dora Richardson. It is on the World Health Organization's List of Essential Medicines. Tamoxifen is available as a generic medication. In 2020, it was the 317th most commonly prescribed medication in the United States, with more than 900thousand prescriptions.


title: Tamoxifen

text: Tamoxifen has been used effectively to improve blood flow, reduce uterine contractility and pain in dysmenorrhea patients.


title: Tamoxifen

text: Tamoxifen is used for the treatment of both early and advanced estrogen receptor-positive (ER-positive or ER+) breast cancer in pre- and postmenopausal women. Tamoxifen increases the risk of postmenopausal bleeding, endometrial polyps, hyperplasia, and endometrial cancer; using tamoxifen with an intrauterine system releasing levonorgestrel might increase vaginal bleeding after 1 to 2 years, but reduces somewhat endometrial polyps and hyperplasia, but not necessarily endometrial cancer. Additionally, it is the most common hormone treatment for male breast cancer. It is also approved by the FDA for the prevention of breast cancer in women at high risk of developing the disease. It has been further approved for the reduction of contralateral (in the opposite breast) cancer. The use of tamoxifen is recommended for 10 years.


title: Tamoxifen

text: In 2006, the large STAR clinical study concluded that raloxifene is also effective in reducing the incidence of breast cancer. Updated results after an average of 6.75 years of follow up found that raloxifene retains 76% of tamoxifen's effectiveness in preventing invasive breast cancer, with 45% fewer uterine cancers and 25% fewer blood clots in women taking raloxifene than in women taking tamoxifen.


title: Tamoxifen

text: Tamoxifen is used for ovulation induction to treat infertility in women with anovulatory disorders. It is given at days three to seven of a woman's cycle.


title: Tamoxifen

text: Tamoxifen improves fertility in males with infertility by disinhibiting the hypothalamic–pituitary–gonadal axis (HPG axis) via ER antagonism and thereby increasing the secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH) and increasing testicular testosterone production.


title: Tamoxifen

text: Tamoxifen is used to prevent and treat gynecomastia. It is taken as a preventative measure in small doses, or used at the onset of any symptoms such as nipple soreness or sensitivity. Other medications are taken for similar purposes such as clomifene and the anti-aromatase drugs which are used in order to try to avoid the hormone-related adverse effects.


title: Tamoxifen

text: Tamoxifen is useful in the treatment of peripheral precocious puberty, for instance due to McCune–Albright syndrome, in both girls and boys. It has been found to decrease growth velocity and the rate of bone maturation in girls with precocious puberty, and hence to improve final height in these individuals.


title: Tamoxifen

text: Tamoxifen has a number of contraindications, including known hypersensitivity to tamoxifen or other ingredients, individuals taking concomitant coumarin-type anticoagulant therapy, and women with a history of venous thromboembolism (deep vein thrombosis or pulmonary embolism).


title: Tamoxifen

text: A report in September 2009 from Health and Human Services' Agency for Healthcare Research and Quality suggests that tamoxifen, raloxifene, and tibolone used to treat breast cancer significantly reduce invasive breast cancer in midlife and older women, but also increase the risk of adverse side effects.


title: Tamoxifen

text: Tamoxifen is a selective estrogen receptor modulator (SERM). Even though it is an antagonist in breast tissue it acts as partial agonist on the endometrium and has been linked to endometrial cancer in some women. Therefore, endometrial changes, including cancer, are among tamoxifen's side effects. With time, risk of endometrial cancer may be doubled to quadrupled, which is a reason tamoxifen is typically only used for five years.


title: Tamoxifen

text: The American Cancer Society lists tamoxifen as a known carcinogen, stating that it increases the risk of some types of uterine cancer while lowering the risk of breast cancer recurrence.


title: Tamoxifen

text: Tamoxifen treatment of postmenopausal women is associated with beneficial effects on serum lipid profiles. However, long-term data from clinical trials have failed to demonstrate a cardioprotective effect. For some women, tamoxifen can cause a rapid increase in triglyceride concentration in the blood. In addition, there is an increased risk of thromboembolism especially during and immediately after major surgery or periods of immobility. Use of tamoxifen has been shown to slightly increase risk of deep vein thrombosis, pulmonary embolism, and stroke.


title: Tamoxifen

text: Tamoxifen has been associated with a number of cases of hepatotoxicity. Several different varieties of hepatotoxicity have been reported. Tamoxifen can also precipitate non-alcoholic fatty liver disease in obese and overweight women (not in normal weight women) at an average rate of 40% after a year use with 20 mg/day.


title: Tamoxifen

text: Acute overdose of tamoxifen has not been reported in humans. In dose-ranging studies, tamoxifen was administered at very high doses in women (e.g., 300 mg/m) and was found to produce acute neurotoxicity including tremor, hyperreflexia, unsteady gait, and dizziness. These symptoms occurred within three to five days of therapy and disappeared within two to five days of discontinuation of therapy. No indications of permanent neurotoxicity were observed. QT prolongation was also observed with very high doses of tamoxifen. There is no specific antidote for overdose of tamoxifen. Instead, treatment should be based on symptoms.


title: Tamoxifen

text: Patients with variant forms of the gene CYP2D6 may not receive full benefit from tamoxifen because of too slow metabolism of the tamoxifen prodrug into its active metabolites. On 18 October 2006, the Subcommittee for Clinical Pharmacology recommended relabeling tamoxifen to include information about this gene in the package insert. Certain CYP2D6 variations in breast cancer patients lead to a worse clinical outcome for tamoxifen treatment. Genotyping therefore has the potential for identification of women who have these CYP2D6 phenotypes and for whom the use of tamoxifen is associated with poor outcomes. Recent research has shown that 7–10% of women with breast cancer may not receive the full medical benefit from taking tamoxifen due to their genetic make-up. DNA Drug Safety Testing can examine DNA variations in the CYP2D6 and other important drug processing pathways. More than 20% of all clinically used medications are metabolized by CYP2D6 and knowing the CYP2D6 status of a person can help the doctor with the future selection of medications. Other molecular biomarkers may also be used to select appropriate patients likely to benefit from tamoxifen.


title: Tamoxifen

text: Recent studies suggest that taking the selective serotonin reuptake inhibitors (SSRIs) antidepressants paroxetine (Paxil), fluoxetine (Prozac), and sertraline (Zoloft) can decrease the effectiveness of tamoxifen, as these drugs compete for the CYP2D6 enzyme which is needed to metabolize tamoxifen into its active forms. A U.S. study presented at the American Society of Clinical Oncology's annual meeting in 2009 found that after two years, 7.5% of women who took only tamoxifen had a recurrence, compared with 16% who took either paroxetine, fluoxetine or sertraline, drugs considered to be the most potent CYP2D6 inhibitors. That difference translates to a 120% increase in the risk of breast cancer recurrence. Patients taking the SSRIs Celexa (citalopram), Lexapro (escitalopram), and Luvox (fluvoxamine) did not have an increased risk of recurrence, due to their lack of competitive metabolism for the CYP2D6 enzyme. A newer study demonstrated a clearer and stronger effect from paroxetine in causing the worst outcomes. Patients treated with both paroxetine and tamoxifen have a 67% increased risk of death from breast cancer, from 24% to 91%, depending on the duration of coadministration.


title: Tamoxifen

text: Tamoxifen interacts with certain other antiestrogens. The aromatase inhibitor aminoglutethimide induces the metabolism of tamoxifen. Conversely, the aromatase inhibitor letrozole does not affect the metabolism of tamoxifen. However, tamoxifen induces the metabolism of letrozole and significantly reduces its concentrations.


title: Tamoxifen

text: Tamoxifen acts as a selective estrogen receptor modulator (SERM), or as a partial agonist of the estrogen receptors (ERs). It has mixed estrogenic and antiestrogenic activity, with its profile of effects differing by tissue. For instance, tamoxifen has predominantly antiestrogenic effects in the breasts but predominantly estrogenic effects in the uterus and liver. In breast tissue, tamoxifen acts as an ER antagonist so that transcription of estrogen-responsive genes is inhibited. A beneficial side effect of tamoxifen is that it prevents bone loss by acting as an ER agonist (i.e., mimicking the effects of estrogen) in this cell type. Therefore, by inhibiting osteoclasts, it prevents osteoporosis. When tamoxifen was launched as a drug, it was thought that tamoxifen would act as an ER antagonist in all tissues, including bone, and therefore it was feared that it would contribute to osteoporosis. It was therefore very surprising that the opposite effect was observed clinically. Hence tamoxifen's tissue selective action directly led to the formulation of the concept of SERMs.


title: Tamoxifen

text: Tamoxifen is a long-acting SERM, with a nuclear retention of the ER–tamoxifen (or metabolite) complex of greater than 48 hours. It has relatively little affinity for the ERs itself and instead acts as a prodrug of active metabolites such as endoxifen (4-hydroxy-"N"-desmethyltamoxifen) and afimoxifene (4-hydroxytamoxifen; 4-OHT). These metabolites have approximately 30 to 100 times greater affinity for the ERs than tamoxifen itself. Per one study, tamoxifen had 7% and 6% of the affinity of estradiol for the ERα and ERβ, respectively, whereas afimoxifene had 178% and 338% of the affinity of estradiol for the ERα and ERβ, respectively. Hence, afimoxifene showed 25-fold higher affinity for the ERα and 56-fold higher affinity for the ERβ than tamoxifen. The antiestrogenic potencies of endoxifen and afimoxifene are very similar. However, endoxifen occurs in much higher concentrations than afimoxifene and is now thought to be the major active form of tamoxifen in the body.


title: Tamoxifen

text: Tamoxifen binds to ER competitively (with respect to the endogenous agonist estrogen) in tumor cells and other tissue targets, producing a nuclear complex that decreases DNA synthesis and inhibits estrogen effects. It is a nonsteroidal agent with potent antiestrogenic properties which compete with estrogen for binding sites in breast and other tissues. Tamoxifen causes cells to remain in the G and G phases of the cell cycle. Because it prevents (pre)cancerous cells from dividing but does not cause cell death, tamoxifen is cytostatic rather than cytocidal. Tamoxifen binds to ER, the ER/tamoxifen complex recruits other proteins known as co-repressors, and the complex then binds to DNA to modulate gene expression. Some of these proteins include NCoR and SMRT. Tamoxifen function can be regulated by a number of different variables including growth factors. Tamoxifen needs to block growth factor proteins such as ErbB2/HER2 because high levels of ErbB2 have been shown to occur in tamoxifen resistant cancers. Tamoxifen seems to require a protein PAX2 for its full anticancer effect. In the presence of high PAX2 expression, the tamoxifen/ER complex is able to suppress the expression of the pro-proliferative ERBB2 protein. In contrast, when AIB-1 expression is higher than PAX2, tamoxifen/ER complex upregulates the expression of ERBB2 resulting in stimulation of breast cancer growth.


title: Tamoxifen

text: Tamoxifen is antigonadotropic in postmenopausal women and partially suppresses levels of the gonadotropins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH) in such women. However, it has progonadotropic effects in premenopausal women and increases estrogen levels by 6-fold in them. Due to the nature of tamoxifen as a competitive ER ligand, this increase in estrogen levels is liable to interfere with the antiestrogenic efficacy of tamoxifen. The effects of tamoxifen on breast cancer Ki-67 expression, sex hormone-binding globulin (SHBG) levels, and IGF-1 levels are dose-dependent across a dosage range of 1 to 20 mg/day in women with breast cancer. Tamoxifen has been found to decrease insulin-like growth factor 1 (IGF-1) levels by 17 to 38% in women and men. Suppression of IGF-1 production in the liver is a well-known action of estrogens and SERMs. A 10 mg/day dosage of tamoxifen is nearly as effective as a 20 mg/day dosage in suppressing IGF-1 levels.


title: Tamoxifen

text: Afimoxifene is an agonist of the G protein-coupled estrogen receptor (GPER) with relatively low affinity. Its affinity for the receptor is in the range of 100 to 1,000 nM, relative to 3 to 6 nM for estradiol.


title: Tamoxifen

text: In addition to its activity as a SERM, afimoxifene binds to both the estrogen-related receptor β and estrogen-related receptor γ and is an antagonist of the estrogen-related receptor γ (ERRγ).


title: Tamoxifen

text: Norendoxifen (4-hydroxy-"N","N"-didesmethyltamoxifen), another active metabolite of tamoxifen, has been found to act as a potent competitive aromatase inhibitor (IC = 90 nM), and may also be involved in the antiestrogenic activity of tamoxifen.


title: Tamoxifen

text: In addition to its activity as a SERM, tamoxifen is a potent and selective protein kinase C inhibitor, and is active in this regard at therapeutic concentrations. This action is thought to underlie the efficacy of tamoxifen in the treatment of bipolar disorder.


title: Tamoxifen

text: Tamoxifen is rapidly and extensively absorbed from the intestines with oral administration. The oral bioavailability of tamoxifen is approximately 100%, which is suggestive of minimal first-pass metabolism in the intestines and liver. Following intake, peak levels of tamoxifen occur after three to seven hours. Steady state levels of tamoxifen are reached typically after 3 to 4 weeks but possibly up to 16 weeks of daily administration. Steady state levels of afimoxifene are achieved after 8 weeks of daily tamoxifen administration. Peak levels of tamoxifen after a single 40 mg oral dose were 65 ng/mL and steady state levels at 20 mg/day were 310 ng/mL. Levels of tamoxifen show clear dose dependency across a dosage range of 1 to 20 mg/day. Endoxifen levels are approximately 5 to 10 times higher than afimoxifene levels, with large interindividual variability. Endoxifen levels have been reported as 10.8 to 15.9 ng/mL at steady state in CYP2D6 normal metabolizers during therapy with 20 mg/day tamoxifen. The most abundant metabolites of tamoxifen in terms of circulating concentrations are "N"-desmethyltamoxifen, "N","N"-didesmethyltamoxifen, ("Z")-endoxifen, and tamoxifen "N"-oxide.


title: Tamoxifen

text: The volume of distribution of tamoxifen is 50 to 60 L/kg and its clearance has been estimated as 1.2 to 5.1 L/hour. High concentrations of tamoxifen have been found in breast, uterus, liver, kidney, lung, pancreas, and ovary tissue in animals and humans. Levels of tamoxifen in the uterus have been found to be 2- to 3-fold higher than in the circulation and in the breasts 10-fold higher than in the circulation. The plasma protein binding of tamoxifen and afimoxifene is greater than 99%. A majority of tamoxifen is bound to albumin. Albumin alone binds 98.8% of tamoxifen while other plasma proteins are not greatly involved.


title: Tamoxifen

text: Tamoxifen is a prodrug and is metabolized in the liver by the cytochrome P450 isoforms CYP3A4, CYP2C9, and CYP2D6 into active metabolites such as endoxifen (4-hydroxy-"N"-desmethyltamoxifen) and afimoxifene (4-hydroxytamoxifen). Conversion of tamoxifen by "N"-demethylation into "N"-desmethyltamoxifen, which is catalyzed primarily by CYP3A4 and CYP3A5, is responsible for approximately 92% of tamoxifen metabolism. Conversely, 4-hydroxylation of tamoxifen into afimoxifene is responsible for only about 7% of tamoxifen metabolism. Following its formation, "N"-desmethyltamoxifen is oxidized into several other metabolites, the most notable of which is endoxifen. Another active metabolite, norendoxifen (4-hydroxy-"N","N"-didesmethyltamoxifen), is formed via "N"-demethylation of endoxifen or 4-hydroxylation of "N","N"-didesmethyltamoxifen. Tamoxifen and its metabolites undergo conjugation, including glucuronidation and sulfation. Tamoxifen may inhibit its own metabolism.


title: Tamoxifen

text: Tamoxifen has a long elimination half-life of typically 5 to 7 days, with a range of 4 to 11 days. Similarly, the half-life of afimoxifene is 14 days. Conversely, the half-life of endoxifen is 50 to 70 hours (2–3 days). The long half-lives of tamoxifen and afimoxifene are attributed to their high plasma protein binding as well as to enterohepatic recirculation. Upon discontinuation of treatment, levels of tamoxifen and its metabolites persist in the circulation for at least 6 weeks. Tamoxifen is excreted in bile and is eliminated in feces, while small amounts are eliminated in urine.


title: Tamoxifen

text: Tamoxifen is a nonsteroidal SERM of the triphenylethylene family and was structurally derived from diethylstilbestrol-like estrogens and antiestrogens such as chlorotrianisene and ethamoxytriphetol. Initially, clomifene was synthesized, and tamoxifen was developed subsequently. Tamoxifen is closely related structurally to other triphenylethylenes, such as clomifene, nafoxidine, ospemifene, toremifene, and numerous others. Other SERMs, like raloxifene, are structurally distinct from tamoxifen and other triphenylethylenes.


title: Tamoxifen

text: In the late 1950s, pharmaceutical companies were actively researching a newly discovered class of anti-estrogen compounds in the hope of developing a morning-after contraceptive pill. Arthur L Walpole was a reproductive endocrinologist who led such a team at the Alderley Park research laboratories of ICI Pharmaceuticals. It was there in 1962 that chemist Dora Richardson first synthesized tamoxifen, back then known as ICI-46,474, when she was looking to create triphenylethylene derivatives for the contraceptive pill project that her team was researching.


title: Tamoxifen

text: This compound was originally created to work as an estrogen inhibitor, but instead was found to stimulate ovulation in participants of the drug testing trial. Walpole and his colleagues filed a UK patent covering this compound in 1962, but patent protection on this compound was repeatedly denied in the US until the 1980s. Tamoxifen did eventually receive marketing approval as a fertility treatment, but the class of compounds never proved useful in human contraception. A link between estrogen and breast cancer had been known for many years, but cancer treatments were not a corporate priority at the time, and Walpole's personal interests were important in keeping support for the compound alive in the face of this and the lack of patent protection. It was only when Walpole threatened to leave his position that corporate decided to allow trials and testing for Tamoxifen as a drug that could be used to treat breast cancer. Without Walpole's effort towards defending the work that his team had done in discovering a possibly revolutionary source for breast cancer treatment, Tamoxifen could have become a discarded or under-researched idea. Walpole's team consisted of Dora Richardson and G.A. Snow, who worked on the chemistry portion of the project, along with G.E. Paget and J.K. Walley, who focused primarily on the biological side.


title: Tamoxifen

text: Tamoxifen is one of three drugs in an anti-angiogenetic protocol developed by Dr. Judah Folkman, a researcher at Children's Hospital at Harvard Medical School in Boston. Folkman discovered in the 1970s that angiogenesis – the growth of new blood vessels – plays a significant role in the development of cancer. Since his discovery, an entirely new field of cancer research has developed. Clinical trials on angiogenesis inhibitors have been underway since 1992 using many different drugs. The Harvard researchers developed a specific protocol for a golden retriever named Navy who was cancer-free after receiving the prescribed cocktail of celecoxib, doxycycline, and tamoxifen – the treatment subsequently became known as the Navy Protocol. Furthermore, tamoxifen treatment alone has been shown to have anti-angiogenetic effects in animal models of cancer which appear to be, at least in part, independent of tamoxifen's ER antagonist properties.