document_title: Piper Chapman

question_text: why is piper in jail in orange is the new black

text: Piper Chapman

text: Basis[edit]

text: A Boston-bred Smith College grad,[2] Kerman got involved in a relationship with an international drug smuggler.[1] Chapman's girlfriend Alex Vause is based on Catherine Cleary Wolters, whom Kerman met in approximately 1991 in Northampton, Massachusetts.[2] Eventually, 24-year-old Kerman flew a suitcase of money from the United States to Belgium for a West African drug lord and was named five years later as part of the drug ring.[1] In fact, as part of her plea bargain, she has declared that she made three overseas trips on behalf of the drug ring.[3] After breaking up with Wolters, Kerman met Larry Smith and got engaged before being charged by the feds in 1998 and striking a deal. She spent 13 months in a Danbury, Connecticut women's prison, FCI Danbury.[2] Kerman actually had a six-year delay between being sentenced to prison and entering prison in 2004. The show is based on Kerman's 2010 book Orange Is the New Black: My Year in a Women's Prison about her year in a minimum security federal women's prison.[1] Chapman's fiance, Larry Bloom, is based on Kerman's real life boyfriend and eventual husband, Larry Smith.[4]

text: Jenji Kohan had initially considered casting Katie Holmes but decided against it since Holmes had too many commitments. Ultimately Kohan cast Taylor Schilling.[5]

text: Fictional background[edit]

text: This section needs additional citations for verification. Please help improve this article by adding citations to reliable sources. Unsourced material may be challenged and removed. (June 2017) (Learn how and when to remove this template message)

text: Chapman is a 31-year-old WASP who is sentenced to 15 months in prison for carrying a bag of drug-money ($50,000) to Belgium for her girlfriend, Alex.[6] Prior to prison, Chapman owned an artisanal bath soap business in Brooklyn. She comes from a wealthy family, and was a debutante as a teenager.[7] She is originally from Connecticut. Chapman is bisexual, and in college was in a relationship with Alex Vause (Laura Prepon), a drug smuggler. 10 years prior to the series' beginning, she carried drug money from Colombia to Belgium with Vause. Eventually, Chapman grew disenchanted with Vause's lifestyle and broke up with her. She then began dating Larry Bloom (Jason Biggs), to whom she got engaged.

text: Piper is one of very few emphatically atheist inmates and one of few such characters on US television. She responds to a request that she baptise herself by saying that she cannot pretend to believe in a god, saying that while it might make her happier if she believed in a religion, she "needs it to be true", and instead looks to science to explain the world. In another episode, when confronted on the subject again, she clarifies that "I've always thought agnostic was a sort of cop-out... If I had to label it I'd say that I'm a secular humanist."

text: Storylines[edit]

text: Season 1[edit]

text: Chapman is sentenced to 15 months in Litchfield Prison for Criminal conspiracy and Money laundering;[8] Vause had been arrested and named her as an accomplice in order to reduce her sentence. On her first day, Chapman gets felt up by guard George "Pornstache" Mendez (Pablo Schreiber) and unintentionally offends prison matriarch Red (Kate Mulgrew), who runs the prison cafeteria. Red starves Chapman to make an example of her, and the other inmates are too intimidated to help except for Crazy Eyes (Uzo Aduba). Nonetheless, Chapman resists Crazy Eyes' subsequent advances, and makes amends with Red by making her lotion to help her back. She befriends Nicky Nichols (Natasha Lyonne), who becomes her confidante and protector. She also discovers Vause is sentenced to the same prison.

text: Chapman is assigned to the prison electrical workshop and accidentally steals a screwdriver. Her cellmate Miss Claudette (Michelle Hurst) helps her evade the guards' searches. In order to ingratiate herself with the other inmates, Chapman offers to review their appeal letters.

text: Although Bloom learns that Vause was the informant who gave Chapman up, he does not share this information with her. Chapman then rekindles her relationship with Vause. Meanwhile, Bloom, an aspiring writer, publishes a story about Chapman's incarceration that paints unflattering portraits of her fellow inmates and the prison staff. The article earns Chapman the ire of both the guards and the other prisoners, and puts a severe strain on her already fading relationship with Bloom.

text: Chapman is elected to the prison council, but finds that the only change she is able to make is to get the track reopened for Janae Watson (Vicky Jeudy) who was put in solitary confinement during the screwdriver incident. Chapman makes an enemy of Tiffany "Pennsatucky" Doggett (Taryn Manning), who wanted her spot on the council. Doggett tells inmate counselor Sam Healy (Michael J. Harney) about Chapman and Vause's relationship; Healy punishes her by putting her in solitary confinement and telling Bloom about the affair. Bloom gets back at Chapman by doing an interview on NPR that casts Litchfield in a harsh light, which makes her even more unpopular. During an angry phone call, Bloom reveals that Vause informed on her. Vause asks Chapman to choose between her and Bloom. Chapman chooses Bloom, but Vause breaks them up and spurns Chapman. When Doggett attacks Chapman with a shiv, Chapman finally snaps and beats her to a pulp.[9][10]

text: Season 2[edit]

text: After spending a month in solitary confinement, Chapman is flown to Chicago to serve as a witness against the drug kingpin who had been Vause's boss.[11] There, she spends time in a maximum security prison with dangerous inmates who menace her daily.[12] Also in episode 1, "Thirsty Bird", we see Chapman as a young girl (Clare Foley) in a flashback, discovering that her father is cheating on her mother. Vause persuades Chapman to commit perjury in order to keep them safe from the drug lord, but ultimately cuts a deal to testify against her former boss in return for early release; she then leaves Chapman to suffer the consequences of her perjured testimony alone. In episode 3, "Hugs Can Be Deceiving", we find out that Crazy Eyes had run outside and knocked Chapman unconscious after she had beaten up Doggett at the end of season 1. In episode 6, "You Also Have a Pizza", Chapman starts a prison newsletter, and makes a deal with a reporter to investigate the financial goings on at the prison. She eventually uncovers evidence that assistant warden Natalie Figueroa (Alysia Reiner) has been embezzling from the prison.[11] To keep her quiet, Figueroa arranges for Chapman to be transferred to a facility in Virginia. When she gives prison administrator Joe Caputo (Nick Sandow) the evidence implicating Figueroa, however, he cancels her transfer, and gives the warden the incriminating information, resulting in Figueroa's resignation.

text: Chapman gets a furlough to go to her grandmother's funeral. At home in New York City, she realizes that Larry has lost interest in her, and soon learns that he has fallen in love with her best friend, Polly Harper (Maria Dizzia). Chapman is furious at first, but eventually agrees to give them her blessing in return for telling Vause's parole officer that Vause is trying to break her parole, which lands her back in prison.[13]

text: Season 3[edit]

text: Chapman begins a business selling used panties to people outside of Litchfield, enlisting her brother Cal as her middleman. Chapman begins a romantic relationship with an Australian prisoner, Stella. After Stella steals Chapman's money, she plants contraband in Stella's bunk and orchestrates her being sent to the maximum security unit in retaliation the day before Stella's release date.

text: Season 4[edit]

text: Chapman continues her panty business but finds herself in competition with a group of Dominicans led by Maria Ruiz. When Chapman aligns herself with a gang of white supremacists and plants contraband in Maria's bunk, Maria retaliates by kidnapping her and having her branded with a swastika.[14]

text: Critical commentary[edit]

text: According to Todd VanDerWerff of Vox Media's Vox.com Chapman was a character with "tricky contradictions and likability issues".[15] In reviewing season 1, Matthew Wolfson Slant Magazine describes Chapman as "a familiar vessel through which to comprehend prison's unfamiliar terrain".[16] Over the course of the first season, the show becomes less focused on Chapman, according to James Poniewozik of Time.[17] The Boston Globe describes Chapman's assimilation into prison as a display of "Martha Stewart-like efforts to survive".[7] At the time of the Golden Globe Award nomination, Entertainment Weekly described Chapman in prison as a woman who was "totally out of her element" and said that the role was dichotomous with demands to "vacillate between being sympathy-worthy and trying fans’ patience with Chapman’s entitlement".[18] Tom Meltzer of The Guardian wrote "Chapman's romantic and rebellious re-awakening drives the show, but it is the ensemble that kept us coming back for more".[19]

text: By season 2, Piper remained a main character of an ensemble cast but not the central character according to IGN's Matt Fowler.[20] Liz Raftery of TV Guide says "There's a lot going on in Season 2 of Netflix's Orange Is the New Black, and very little of it has to do with Piper Chapman".[21] Rob Sheffield of Rolling Stone considered that the show's ensemble focus has turned Piper into "dead weight" and "nobody would argue that an early parole for her would hurt the show".[22] As he reviewed season 2, The Huffington Post Canada entertainment editor Chris Jancelewicz, opined that "Schilling's deadpan expressions and snap comedic timing help us empathize and grow to love her" as her character became more understandable.[23] Alicia Lutes of MTV wrote that as of Season 2 the show is about Piper understanding herself and her capabilities better "even if those abilities put her further in the muck" and not about her possible reformation.[24]

text: Sarene Leeds of The Wall Street Journal stated that in Season 3 Piper changed from being "a gangsta wannabe into a dangerous villain that is not to be crossed" after planting contraband in girlfriend Stella's bed to get her sent to the maximum security unit in retaliation for Stella stealing from her; Leeds argued that the change "is a necessary plot device to keep things interesting" even though she did not like the new version of Piper.[25] Drew Millard of Vice wrote that Season 3 Piper went "completely off the deep end" and changed "into the most unlikable version of herself", making her "deadweight on a show that was at first strictly about her."[26] Kerman stated that even though she still found the series to be entertaining, she could no longer relate to Piper Chapman.[27] Sadie Gennis of TV Guide also suggested removing Chapman from the show.[28]

text: Schilling has been nominated for awards in both comedy and drama categories: Outstanding Lead Actress in a Comedy Series at the 66th Primetime Emmy Awards and Best Actress – Television Series Drama at the 71st Golden Globe Awards and won Best Actress – Television Series Musical or Comedy at the 18th Satellite Awards for her season 1 performance.[29][30][31] Her season 2 performance earned a 72nd Golden Globe Awards nomination for Best Actress – Television Series Musical or Comedy,[32] and a 19th Satellite Awards nomination for Best Actress – Television Series Musical or Comedy.[33] Her season 3 performance won Best Actress – Television Series Musical or Comedy at the 20th Satellite Awards.[34]


document_title: List of United States men's national soccer team managers

question_text: who is the us mens national team coach

question_tokens: who is the us mens national team coach

root

text: The role of the United States men's national soccer team manager was first established in 1916 with the appointment of Thomas Cahill. Thirty-five men have since occupied the position.

tag: p

text: The following tables include various statistics for managers of the United States men's national soccer team (featuring matches, wins, losses, ties, goals for, goals against and goal differential along with goals for average and goals against average) from the team's inception in 1916 through the June 9, 2018 game with France.

text: Category items in bold represent leader based on a minimum of 18 matches

tag: ul

text: All-Time Record: 291-148-248

text: Head coaches[edit]

text:
Managers

Years

Matches

Wins

Draws

Losses

Win %

GF

GA

GD

AGF

AGA

World Cup  appearances

CONCACAF Gold Cup Titles

 Dave Sarachan[1]
[2]

2017–2018

6

2

3

1

58.33%

7

4

3

1.17

0.67

 Bruce Arena [3]
[4][5][6]

1998–2006, 2016–2017

148

81

35

32

66.55%

243

111

132

1.64

0.75

2002, 2006

2002, 2005, 2017

 Jürgen Klinsmann [7][8][9]

2011–2016

98

55

16

27

64.29%

178

109

69

1.82

1.11

2014

2013

 Bob Bradley [10][11]

2006–2011

80

43

12

25

61.25%

134

97

37

1.68

1.21

2010

2007

 Steve Sampson [12][13][14][15]

1995–1998

62

26

14

22

53.23%

83

69

14

1.34

1.11

1998

 Bora Milutinović [16][17][18]

1991–1995

96

30

31

35

47.40%

116

110

6

1.21

1.15

1994

1991

  John Kowalski [19]

1991

2

1

1

0

75.00%

4

2

2

2.00

1.00

 Bob Gansler [20][21]

1982, 1989–1991

37

15

6

16

48.65%

43

41

2

1.16

1.11

1990

 Lothar Osiander

1986–1988

18

4

5

9

36.11%

12

21

-9

0.67

1.17

 Alkis Panagoulias [22][23]

1983–1985

18

6

7

5

52.78%

19

21

-2

1.06

1.17

  Walt Chyzowych [24][25]

1976–1980

32

8

10

14

40.63%

26

50

-24

0.81

1.56

  Manfred Schellscheidt

1975

3

0

0

3

0.00%

1

11

-10

0.33

3.67

 Al Miller [26]

1975

2

0

0

2

0.00%

0

11

-11

0.00

5.50

 Dettmar Cramer [27][28][29]

1974

2

0

0

2

0.00%

1

4

-3

0.50

2.00

 Gordon Bradley

1973

5

0

0

5

0.00%

1

9

-8

0.20

1.80

 Gene Chyzowych

1973

5

3

0

2

60.00%

4

5

-1

0.80

1.80

 Max Wosniak

1973

2

0

0

2

00.00%

0

8

-8

0.00

4.00

 Bob Kehoe [30]

1971–1972

4

0

1

3

12.50%

6

10

-4

1.50

2.50

 Gordon Jago [31]

1969

2

0

0

2

0.00%

0

3

-3

0.00

1.50

 Phil Woosnam

1968

9

4

1

4

50.00%

22

22

0

2.44

2.44

 John Herberger

1964

1

0

0

1

0.00%

0

10

-10

0.00

10.00

 Jim Reed

1959–1961

4

0

1

3

12.50%

4

16

-12

1.00

4.00

 George Meyer

1957, 1965

8

1

2

5

25.00%

9

26

-17

1.13

3.25

 Jimmy Mills

1956

1

0

0

1

0.00%

1

9

-8

1.00

9.00

 Ernő Schwarz

1953–1955

6

2

0

4

33.33%

12

18

-6

2.00

3.00

 John Wood

1952

2

0

0

2

0.00%

0

14

-14

0.00

7.00

 Bill Jeffrey

1949–1952

3

1

0

2

33.33%

4

8

-4

1.33

2.67

1950

 Walter Giesler

1948–1949

8

1

1

6

18.75%

8

44

-36

1.00

5.50

 Andrew Brown

1947

2

0

0

2

0.00%

2

10

-8

1.00

5.00

 Bill Lloyd

1937

3

0

0

3

0.00%

6

19

-13

2.00

6.33

 Elmer Schroeder

1936

1

0

0

1

0.00%

0

1

-1

0.00

1.00

 David Gould

1934

2

1

0

1

50.00%

5

9

-4

2.50

4.50

1934

 Robert Millar

1929–1933

4

2

0

2

50.00%

10

10

0

2.50

2.50

1930

 George Burford

1924, 1928

6

2

1

3

41.67%

10

22

-12

1.67

3.67

 Nat Agar

1925–1926

3

2

0

1

66.67%

12

4

8

4.00

1.33

 Thomas Cahill

1916

2

1

1

0

75.00%

4

3

1

2.00

1.50

tag: table

text:
Sources:
USMNT All-Time Scores – SoccerOverThere.com.
USA national football team
United States men's national soccer team results


document_title: List of Phoenix Suns seasons

question_text: when was the last time phoenix suns were in the playoffs

text: List of Phoenix Suns seasons

text: Table key[edit]

text:
AMVP
All-Star Game Most Valuable Player

COY
Coach of the Year

Finish
Final position in league or division standings

GB
Games behind first-place team in division[a]

Losses
Number of regular season losses

EOY
Executive of the Year

JWKC
J. Walter Kennedy Citizenship

MVP
Most Valuable Player

ROY
Rookie of the Year

SMOY
Sixth Man of the Year

SPOR
Sportmanship Award

Wins
Number of regular season wins

Win%
Winning percentage

text: Seasons[edit]

text: Note: Statistics are correct as of the 2016–17 season.

text:
NBA Champions

Conference champions

Division champions

Playoff berth

text:
Season

League

Conference

Finish

Division

Finish

Wins

Losses

Win%

GB

Playoffs

Awards[4]

1968–69
NBA
—
—
Western
7th
16
66
.195
7001390000000000000♠39

1969–70
NBA
—
—
Western
3rd
39
43
.476
7000900000000000000♠9
Lost Division Semifinals (Lakers) 4–3[8]

1970–71
NBA
Western
5th
Midwest
3rd
48
34
.585
7001180000000000000♠18

1971–72
NBA
Western
5th
Midwest
3rd
49
33
.598
7001140000000000000♠14

1972–73
NBA
Western
6th
Pacific
3rd
38
44
.463
7001220000000000000♠22

1973–74
NBA
Western
8th
Pacific
4th
30
52
.366
7001170000000000000♠17

1974–75
NBA
Western
8th
Pacific
4th
32
50
.390
7001160000000000000♠16

1975–76
NBA
Western
3rd
Pacific
3rd
42
40
.512
7001170000000000000♠17
Won Conference Semifinals (SuperSonics) 4–2 Won Conference Finals (Warriors) 4–3 Lost NBA Finals (Celtics) 4–2[9]
Alvan Adams (ROY)

1976–77
NBA
Western
10th
Pacific
5th
34
48
.415
7001190000000000000♠19

1977–78
NBA
Western
3rd
Pacific
2nd
49
33
.598
7000900000000000000♠9
Lost First Round (Bucks) 2–0[10]
Walter Davis (ROY)

1978–79
NBA
Western
3rd
Pacific
2nd
50
32
.610
7000200000000000000♠2
Won First Round (Trail Blazers) 2–1 Won Conference Semifinals (Kings) 4–1 Lost Conference Finals (SuperSonics) 4–3[11]

1979–80
NBA
Western
4th
Pacific
3rd
55
27
.671
7000500000000000000♠5
Won First Round (Kings) 2–1 Lost Conference Semifinals (Lakers) 4–1[12]

1980–81
NBA
Western
1st
Pacific
1st
57
25
.695
—
Lost Conference Semifinals (Kings) 4–3[13]

1981–82
NBA
Western
5th
Pacific
3rd
46
36
.561
7001110000000000000♠11
Won First Round (Nuggets) 2–1  Lost Conference Semifinals (Lakers) 4–0[14]

1982–83
NBA
Western
3rd
Pacific
2nd
53
29
.646
7000500000000000000♠5
Lost First Round (Nuggets) 2–1[15]

1983–84
NBA
Western
6th
Pacific
4th
41
41
.500
7001130000000000000♠13
Won First Round (Trail Blazers) 3–2 Won Conference Semifinals (Jazz) 4–2  Lost Conference Finals (Lakers) 4–2[16]

1984–85
NBA
Western
8th
Pacific
3rd
36
46
.439
7001260000000000000♠26
Lost First Round (Lakers) 3–0[17]

1985–86
NBA
Western
9th
Pacific
3rd
32
50
.390
7001300000000000000♠30

1986–87
NBA
Western
9th
Pacific
5th
36
46
.439
7001290000000000000♠29

1987–88
NBA
Western
9th
Pacific
4th
28
54
.341
7001340000000000000♠34

1988–89
NBA
Western
3rd
Pacific
2nd
55
27
.671
7000200000000000000♠2
Won First Round (Nuggets) 3–0 Won Conference Semifinals (Warriors) 4–1 Lost Conference Finals (Lakers) 4–0[18]
Kevin Johnson (MIP)Cotton Fitzsimmons (COY)Eddie Johnson (SMOY)

1989–90
NBA
Western
5th
Pacific
3rd
54
28
.659
7000900000000000000♠9
Won First Round (Jazz) 3–2  Won Conference Semifinals (Lakers) 4–1 Lost Conference Finals (Trail Blazers) 4–2[19]

1990–91
NBA
Western
4th
Pacific
3rd
55
27
.671
7000800000000000000♠8
Lost First Round (Jazz) 3–1[20]
Kevin Johnson (JWKC)

1991–92
NBA
Western
4th
Pacific
3rd
53
29
.646
7000400000000000000♠4
Won First Round (Spurs) 3–0  Lost Conference Semifinals (Trail Blazers) 4–1[21]

1992–93
NBA
Western
1st
Pacific
1st
62
20
.756
—
Won First Round (Lakers) 3–2  Won Conference Semifinals (Spurs) 4–2 Won Conference Finals (SuperSonics) 4–3 Lost NBA Finals (Bulls) 4–2[22]
Charles Barkley (MVP)

1993–94
NBA
Western
3rd
Pacific
2nd
56
26
.683
7000700000000000000♠7
Won First Round (Warriors) 3–0 Lost Conference Semifinals (Rockets) 4–3[23]

1994–95
NBA
Western
2nd
Pacific
1st
59
23
.720
—
Won First Round (Trail Blazers) 3–0 Lost Conference Semifinals (Rockets) 4–3[24]

1995–96
NBA
Western
7th
Pacific
4th
41
41
.500
7001230000000000000♠23
Lost First Round (Spurs) 3–1[25]

1996–97
NBA
Western
7th
Pacific
4th
40
42
.488
7001170000000000000♠17
Lost First Round (SuperSonics) 3–2[26]

1997–98
NBA
Western
4th
Pacific
3rd
56
26
.683
7000500000000000000♠5
Lost First Round (Spurs) 3–1[27]
Danny Manning (SMOY)

1998–99[b]
NBA
Western
7th
Pacific
3rd
27
23
.540
7000800000000000000♠8
Lost First Round (Trail Blazers) 3–0[28]

1999–00
NBA
Western
5th
Pacific
3rd
53
29
.646
7001140000000000000♠14
Won First Round (Spurs) 3–1  Lost Conference Semifinals (Lakers) 4–1[29]
Rodney Rogers (SMOY)

2000–01
NBA
Western
6th
Pacific
3rd
51
31
.623
7000500000000000000♠5
Lost First Round (Kings) 3–1[30]

2001–02
NBA
Western
10th
Pacific
6th
36
46
.439
7001250000000000000♠25

2002–03
NBA
Western
8th
Pacific
4th
44
38
.537
7001150000000000000♠15
Lost First Round (Spurs) 4–2[31]
Amar'e Stoudemire (ROY)

2003–04
NBA
Western
13th
Pacific
6th
29
53
.354
7001270000000000000♠27

2004–05
NBA
Western
1st
Pacific
1st
62
20
.756
—
Won First Round (Grizzlies) 4–0 Won Conference Semifinals (Mavericks) 4–2  Lost Conference Finals (Spurs) 4–1[32]
Steve Nash (MVP)Mike D'Antoni (COY)

2005–06
NBA
Western
2nd
Pacific
1st
54
28
.659
—
Won First Round (Lakers) 4–3 Won Conference Semifinals (Clippers) 4–3 Lost Conference Finals (Mavericks) 4–2[33]
Steve Nash (MVP)Boris Diaw (MIP)

2006–07
NBA
Western
2nd
Pacific
1st
61
21
.744
—
Won First Round (Lakers) 4–1 Lost Conference Semifinals (Spurs) 4–2[34]
Leandro Barbosa (SMOY)Steve Nash (JWKC)

2007–08
NBA
Western
6th
Pacific
2nd
55
27
.671
7000200000000000000♠2
Lost First Round (Spurs) 4–1[35]
Grant Hill (SPOR)

2008–09
NBA
Western
9th
Pacific
2nd
46
36
.561
7001190000000000000♠19

Shaquille O'Neal (AMVP)

2009–10
NBA
Western
3rd
Pacific
2nd
54
28
.659
7000300000000000000♠3
Won First Round (Trail Blazers) 4–2 Won Conference Semifinals (Spurs) 4–0 Lost Conference Finals (Lakers) 4–2[36]
Grant Hill (SPOR)

2010–11
NBA
Western
10th
Pacific
2nd
40
42
.488
7001170000000000000♠17

2011–12 [c]
NBA
Western
10th
Pacific
3rd
33
33
.500
7001170000000000000♠17

2012–13
NBA
Western
15th
Pacific
5th
25
57
.305
7001320000000000000♠32

2013–14
NBA
Western
9th
Pacific
3rd
48
34
.585
7000900000000000000♠9

Goran Dragić (MIP)

2014–15
NBA
Western
10th
Pacific
3rd
39
43
.476
7001280000000000000♠28

2015–16
NBA
Western
14th
Pacific
4th
23
59
.280
7001500000000000000♠50

2016–17
NBA
Western
15th
Pacific
5th
24
58
.293
7001430000000000000♠43

2017–18
NBA
Western
15th
Pacific
5th
21
61
.256
7001370000000000000♠37

text: All-time records[edit]

text:
Statistic

Wins

Losses

Win%

Regular season record (1968–2018)

2,167

1,885

.535

Postseason record (1968–2018)

133

141

.485

All-time regular and post-season record (1968–2017)

2,300

2,026

.532

text: Notes[edit]

text:
a  This is determined by adding the absolute difference in wins between the leading team and the team of interest to the absolute difference in losses between the two teams, and dividing by two.
b  Because of a lockout, the season did not start until February 5, 1999, and all 29 teams played a shortened 50-game regular season schedule.[37]
c  Because of a lockout, the season did not start until December 25, 2011, and all thirty teams played a shortened 66-game regular season schedule.


document_title: Gene therapy

question_text: first clinical gene therapy was done for the treatment of

question_tokens: first clinical gene therapy was done for the treatment of

text: Gene therapy

text: Background[edit]

text: Gene therapy was conceptualized in 1972, by authors who urged caution before commencing human gene therapy studies.

text: The first attempt, an unsuccessful one, at gene therapy (as well as the first case of medical transfer of foreign genes into humans not counting organ transplantation) was performed by Martin Cline on 10 July 1980.[6][7] Cline claimed that one of the genes in his patients was active six months later, though he never published this data or had it verified[8] and even if he is correct, it's unlikely it produced any significant beneficial effects treating beta-thalassemia.

text: After extensive research on animals throughout the 1980s and a 1989 bacterial gene tagging trial on humans, the first gene therapy widely accepted as a success was demonstrated in a trial that started on 14 September 1990, when Ashi DeSilva was treated for ADA-SCID.[9]

text: The first somatic treatment that produced a permanent genetic change was performed in 1993.[citation needed]

text: Gene therapy is a way to fix a genetic problem at its source. The polymers are either translated into proteins, interfere with target gene expression, or possibly correct genetic mutations.

text: The most common form uses DNA that encodes a functional, therapeutic gene to replace a mutated gene.  The polymer molecule is packaged within a "vector", which carries the molecule inside cells.

text: Early clinical failures led to dismissals of gene therapy. Clinical successes since 2006 regained researchers' attention, although as of  2014[update], it was still largely an experimental technique.[10] These include treatment of retinal diseases Leber's congenital amaurosis[11][12][13][14] and choroideremia,[15] X-linked SCID,[16] ADA-SCID,[17][18] adrenoleukodystrophy,[19] chronic lymphocytic leukemia (CLL),[20] acute lymphocytic leukemia (ALL),[21] multiple myeloma,[22] haemophilia,[18] and Parkinson's disease.[23] Between 2013 and April 2014, US companies invested over $600 million in the field.[24]

text:
The first commercial gene therapy, Gendicine, was approved in China in 2003 for the treatment of certain cancers.[25] In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of  peripheral artery disease, including critical limb ischemia.[26]
In 2012 Glybera, a treatment for a rare inherited disorder, became the first treatment to be approved for clinical use in either Europe or the United States after its endorsement by the European Commission.[10][27]

text: Approaches[edit]

text: Following early advances in genetic engineering of bacteria, cells, and small animals, scientists started considering how to apply it to medicine. Two main approaches were considered – replacing or disrupting defective genes.[28]  Scientists focused on diseases caused by single-gene defects, such as cystic fibrosis, haemophilia, muscular dystrophy, thalassemia, and sickle cell anemia. Glybera treats one such disease, caused by a defect in lipoprotein lipase.[27]

text: DNA must be administered, reach the damaged cells, enter the cell and either express or disrupt a protein.[29] Multiple delivery techniques have been explored. The initial approach incorporated DNA into an engineered virus to deliver the DNA into a chromosome.[30][31] Naked DNA approaches have also been explored, especially in the context of vaccine development.[32]

text: Generally, efforts focused on administering a gene that causes a needed protein to be expressed. More recently, increased understanding of nuclease function has led to more direct DNA editing, using techniques such as zinc finger nucleases and CRISPR. The vector incorporates genes into chromosomes. The expressed nucleases then knock out and replace genes in the chromosome. As of  2014[update] these approaches involve removing cells from patients, editing a chromosome and returning the transformed cells to patients.[33]

text: Gene editing is a potential approach to alter the human genome to treat genetic diseases,[34] viral diseases,[35] and cancer.[36]  As of  2016[update] these approaches were still years from being medicine.[37][38]

text: Cell types[edit]

text: Gene therapy may be classified into two types:

text: Somatic[edit]

text: In somatic cell gene therapy (SCGT), the therapeutic genes are transferred into any cell other than a gamete, germ cell, gametocyte, or undifferentiated stem cell. Any such modifications affect the individual patient only, and are not inherited by offspring. Somatic gene therapy represents mainstream basic and clinical research, in which therapeutic DNA (either integrated in the genome or as an external episome or plasmid) is used to treat disease.

text: Over 600 clinical trials utilizing SCGT are underway[when?] in the US. Most focus on severe genetic disorders, including immunodeficiencies, haemophilia, thalassaemia, and cystic fibrosis. Such single gene disorders are good candidates for somatic cell therapy. The complete correction of a genetic disorder or the replacement of multiple genes is not yet possible. Only a few of the trials are in the advanced stages.[39]

text: Germline[edit]

text: In germline gene therapy (GGT), germ cells (sperm or egg cells) are modified by the introduction of functional genes into their genomes. Modifying a germ cell causes all the organism's cells to contain the modified gene. The change is therefore heritable and passed on to later generations. Australia, Canada, Germany, Israel, Switzerland, and the Netherlands[40] prohibit GGT for application in human beings, for technical and ethical reasons, including insufficient knowledge about possible risks to future generations[40] and higher risks versus SCGT.[41]  The US has no federal controls specifically addressing human genetic modification (beyond FDA regulations for therapies in general).[40][42][43][44]

text: Vectors[edit]

text: The delivery of DNA into cells can be accomplished by multiple methods. The two major classes are recombinant viruses (sometimes called biological nanoparticles or viral vectors) and naked DNA or DNA complexes (non-viral methods).

text: Viruses[edit]

text: In order to replicate, viruses introduce their genetic material into the host cell, tricking the host's cellular machinery into using it as blueprints for viral proteins. Retroviruses go a stage further by having their genetic material copied into the genome of the host cell.  Scientists exploit this by substituting a virus's genetic material with therapeutic DNA. (The term 'DNA' may be an oversimplification, as some viruses contain RNA, and gene therapy could take this form as well.) A number of viruses have been used for human gene therapy, including retroviruses, adenoviruses, herpes simplex, vaccinia, and adeno-associated virus.[4] Like the genetic material (DNA or RNA) in viruses, therapeutic DNA can be designed to simply serve as a temporary blueprint that is degraded naturally or (at least theoretically) to enter the host's genome, becoming a permanent part of the host's DNA in infected cells.

text: Non-viral[edit]

text: Non-viral methods present certain advantages over viral methods, such as large scale production and low host immunogenicity. However, non-viral methods initially produced lower levels of transfection and gene expression, and thus lower therapeutic efficacy. Later technology remedied this deficiency.[citation needed]

text: Methods for non-viral gene therapy include the injection of naked DNA, electroporation, the gene gun, sonoporation, magnetofection, the use of oligonucleotides, lipoplexes, dendrimers, and inorganic nanoparticles.

text: Hurdles[edit]

text: Some of the unsolved problems include:

text:
Short-lived nature – Before gene therapy can become a permanent cure for a condition, the therapeutic DNA introduced into target cells must remain functional and the cells containing the therapeutic DNA must be stable. Problems with integrating therapeutic DNA into the genome and the rapidly dividing nature of many cells prevent it from achieving long-term benefits. Patients require multiple treatments.
Immune response – Any time a foreign object is introduced into human tissues, the immune system is stimulated to attack the invader. Stimulating the immune system in a way that reduces gene therapy effectiveness is possible. The immune system's enhanced response to viruses that it has seen before reduces the effectiveness to repeated treatments.
Problems with viral vectors – Viral vectors carry the risks of toxicity, inflammatory responses, and gene control and targeting issues.
Multigene disorders – Some commonly occurring disorders, such as heart disease, high blood pressure, Alzheimer's disease, arthritis, and diabetes, are affected by variations in multiple genes, which complicate gene therapy.
Some therapies may breach the Weismann barrier (between soma and germ-line) protecting the testes, potentially modifying the germline, falling afoul of regulations in countries that prohibit the latter practice.[45]
Insertional mutagenesis – If the DNA is integrated in a sensitive spot in the genome, for example in a tumor suppressor gene, the therapy could induce a tumor. This has occurred in clinical trials for X-linked severe combined immunodeficiency (X-SCID) patients, in which hematopoietic stem cells were transduced with a corrective transgene using a retrovirus, and this led to the development of T cell leukemia in 3 of 20 patients.[46][47] One possible solution is to add a functional tumor suppressor gene to the DNA to be integrated. This may be problematic since the longer the DNA is, the harder it is to integrate into cell genomes. CRISPR technology allows researchers to make much more precise genome changes at exact locations.[48]
Cost – Alipogene tiparvovec or Glybera, for example, at a cost of $1.6 million per patient, was reported in 2013 to be the world's most expensive drug.[49][50]

text: Deaths[edit]

text: Three patients' deaths have been reported in gene therapy trials, putting the field under close scrutiny. The first was that of Jesse Gelsinger, who died in 1999 because of immune rejection response.[51] One X-SCID patient died of leukemia in 2003.[9] In 2007, a rheumatoid arthritis patient died from an infection; the subsequent investigation concluded that the death was not related to gene therapy.[52]

text: History[edit]

text: 1970s and earlier[edit]

text: In 1972 Friedmann and Roblin authored a paper in Science titled "Gene therapy for human genetic disease?"[53] Rogers (1970) was cited for proposing that exogenous good DNA be used to replace the defective DNA in those who suffer from genetic defects.[54]

text: In 1984 a retrovirus vector system was designed that could efficiently insert foreign genes into mammalian chromosomes.[55]

text: The first approved gene therapy clinical research in the US took place on 14 September 1990, at the National Institutes of Health (NIH), under the direction of William French Anderson.[56] Four-year-old Ashanti DeSilva received treatment for a genetic defect that left her with ADA-SCID, a severe immune system deficiency. The defective gene of the patient's blood cells was replaced by the functional variant. Ashanti’s immune system was partially restored by the therapy. Production of the missing enzyme was temporarily stimulated, but the new cells with functional genes were not generated. She led a normal life only with the regular injections performed every two months. The effects were successful, but temporary.[57]

text: Cancer gene therapy was introduced in 1992/93 (Trojan et al. 1993).[58] The treatment of glioblastoma multiforme, the malignant brain tumor whose outcome is always fatal, was done using a vector expressing antisense IGF-I RNA (clinical trial approved by NIH protocolno.1602 November 24, 1993,[59] and by the FDA in 1994). This therapy also represents the beginning of cancer immunogene therapy, a treatment which proves to be effective due to the anti-tumor mechanism of IGF-I antisense, which is related to strong immune and apoptotic phenomena.

text: In 1992 Claudio Bordignon, working at the Vita-Salute San Raffaele University, performed the first gene therapy procedure using hematopoietic stem cells as vectors to deliver genes intended to correct hereditary diseases.[60] In 2002 this work led to the publication of the first successful gene therapy treatment for adenosine deaminase deficiency (ADA-SCID). The success of a multi-center trial for treating children with SCID (severe combined immune deficiency or "bubble boy" disease) from 2000 and 2002, was questioned when two of the ten children treated at the trial's Paris center developed a leukemia-like condition. Clinical trials were halted temporarily in 2002, but resumed after regulatory review of the protocol in the US, the United Kingdom, France, Italy, and Germany.[61]

text: In 1993 Andrew Gobea was born with SCID following prenatal genetic screening. Blood was removed from his mother's placenta and umbilical cord immediately after birth, to acquire stem cells. The allele that codes for adenosine deaminase (ADA) was obtained and inserted into a retrovirus. Retroviruses and stem cells were mixed, after which the viruses inserted the gene into the stem cell chromosomes. Stem cells containing the working ADA gene were injected into Andrew's blood. Injections of the ADA enzyme were also given weekly. For four years T cells (white blood cells), produced by stem cells, made ADA enzymes using the ADA gene. After four years more treatment was needed.[62]

text: Jesse Gelsinger's death in 1999 impeded gene therapy research in the US.[63][64] As a result, the FDA suspended several clinical trials pending the reevaluation of ethical and procedural practices.[65]

text: The modified cancer gene therapy strategy of antisense IGF-I RNA (NIH n˚ 1602)[59] using antisense / triple helix anti-IGF-I approach was registered in 2002 by Wiley gene therapy clinical trial - n˚ 635 and 636. The approach has shown promising results in the treatment of six different malignant tumors: glioblastoma, cancers of liver, colon, prostate, uterus, and ovary (Collaborative NATO Science Programme on Gene Therapy USA, France, Poland n˚ LST 980517 conducted by J. Trojan) (Trojan et al., 2012). This anti-gene antisense/triple helix therapy has proven to be efficient, due to the mechanism stopping simultaneously IGF-I expression on translation and transcription levels, strengthening anti-tumor immune and apoptotic phenomena.

text: Sickle-cell disease can be treated in mice.[66] The mice – which have essentially the same defect that causes human cases – used a viral vector to induce production of fetal hemoglobin (HbF), which normally ceases to be produced shortly after birth. In humans, the use of hydroxyurea to stimulate the production of HbF temporarily alleviates sickle cell symptoms. The researchers demonstrated this treatment to be a more permanent means to increase therapeutic HbF production.[67]

text: A new gene therapy approach repaired errors in messenger RNA derived from defective genes. This technique has the potential to treat thalassaemia, cystic fibrosis and some cancers.[68]

text: Researchers created liposomes 25 nanometers across that can carry therapeutic DNA through pores in the nuclear membrane.[69]

text: In 2003 a research team inserted genes into the brain for the first time. They used liposomes coated in a polymer called polyethylene glycol, which unlike viral vectors, are small enough to cross the blood–brain barrier.[70]

text: Short pieces of double-stranded RNA (short, interfering RNAs or siRNAs) are used by cells to degrade RNA of a particular sequence. If a siRNA is designed to match the RNA copied from a faulty gene, then the abnormal protein product of that gene will not be produced.[71]

text: Gendicine is a cancer gene therapy that delivers the tumor suppressor gene p53 using an engineered adenovirus. In 2003, it was approved in China for the treatment of head and neck squamous cell carcinoma.[25]

text: In March researchers announced the successful use of gene therapy to treat two adult patients for X-linked chronic granulomatous disease, a disease which affects myeloid cells and damages the immune system. The study is the first to show that gene therapy can treat the myeloid system.[72]

text: In May a team reported a way to prevent the immune system from rejecting a newly delivered gene.[73] Similar to organ transplantation, gene therapy has been plagued by this problem. The immune system normally recognizes the new gene as foreign and rejects the cells carrying it. The research utilized a newly uncovered network of genes regulated by molecules known as microRNAs. This natural function selectively obscured their therapeutic gene in immune system cells and protected it from discovery. Mice infected with the gene containing an immune-cell microRNA target sequence did not reject the gene.

text: In August scientists successfully treated metastatic melanoma in two patients using killer T cells genetically retargeted to attack the cancer cells.[74]

text: In November researchers reported on the use of VRX496, a gene-based immunotherapy for the treatment of HIV that uses a lentiviral vector to deliver an antisense gene against the HIV envelope. In a phase I clinical trial, five subjects with chronic HIV infection who had failed to respond to at least two antiretroviral regimens were treated. A single intravenous infusion of autologous CD4 T cells genetically modified with VRX496 was well tolerated. All patients had stable or decreased viral load; four of the five patients had stable or increased CD4 T cell counts. All five patients had stable or increased immune response to HIV antigens and other pathogens. This was the first evaluation of a lentiviral vector administered in a US human clinical trial.[75][76]

text: In May researchers announced the first gene therapy trial for inherited retinal disease. The first operation was carried out on a 23-year-old British male, Robert Johnson, in early 2007.[77]

text: Leber's congenital amaurosis is an inherited blinding disease caused by mutations in the RPE65 gene. The results of a small clinical trial in children were published in April.[11] Delivery of recombinant adeno-associated virus (AAV) carrying RPE65 yielded positive results. In May two more groups reported positive results in independent clinical trials using gene therapy to treat the condition. In all three clinical trials, patients recovered functional vision without apparent side-effects.[11][12][13][14]

text: In September researchers were able to give trichromatic vision to squirrel monkeys.[78] In November 2009, researchers halted a fatal genetic disorder called adrenoleukodystrophy in two children using a lentivirus vector to deliver a functioning version of ABCD1, the gene that is mutated in the disorder.[79]

text: An April paper reported that gene therapy addressed achromatopsia (color blindness) in dogs by targeting cone photoreceptors. Cone function and day vision were restored for at least 33 months in two young specimens. The therapy was less efficient for older dogs.[80]

text: In September it was announced that an 18-year-old male patient in France with beta-thalassemia major had been successfully treated.[81] Beta-thalassemia major is an inherited blood disease in which beta haemoglobin is missing and patients are dependent on regular lifelong blood transfusions.[82] The technique used a lentiviral vector to transduce the human ß-globin gene into purified blood and marrow cells obtained from the patient in June 2007.[83] The patient's haemoglobin levels were stable at 9 to 10 g/dL. About a third of the hemoglobin contained the form introduced by the viral vector and blood transfusions were not needed.[83][84] Further clinical trials were planned.[85] Bone marrow transplants are the only cure for thalassemia, but 75% of patients do not find a matching donor.[84]

text: Cancer immunogene therapy using modified antigene, antisense/triple helix approach was introduced in South America in 2010/11 in La Sabana University, Bogota (Ethical Committee 14 December 2010, no P-004-10). Considering the ethical aspect of gene diagnostic and gene therapy targeting IGF-I, the IGF-I expressing tumors i.e. lung and epidermis cancers were treated (Trojan et al. 2016).[86][87]

text: In 2007 and 2008, a man (Timothy Ray Brown) was cured of HIV by repeated hematopoietic stem cell transplantation (see also allogeneic stem cell transplantation, allogeneic bone marrow transplantation, allotransplantation) with double-delta-32 mutation which disables the CCR5 receptor. This cure was accepted by the medical community in 2011.[88] It required complete ablation of existing bone marrow, which is very debilitating.

text: In August two of three subjects of a pilot study were confirmed to have been cured from chronic lymphocytic leukemia (CLL). The therapy used genetically modified T cells to attack cells that expressed the CD19 protein to fight the disease.[20] In 2013, the researchers announced that 26 of 59 patients had achieved complete remission and the original patient had remained tumor-free.[89]

text: Human HGF plasmid DNA therapy of cardiomyocytes is being examined as a potential treatment for coronary artery disease as well as treatment for the damage that occurs to the heart after myocardial infarction.[90][91]

text: In 2011 Neovasculgen was registered in Russia as the first-in-class gene-therapy drug for treatment of peripheral artery disease, including critical limb ischemia; it delivers the gene encoding for VEGF.[92][26] Neovasculogen is a plasmid encoding the CMV promoter and the 165 amino acid form of VEGF.[93][94]

text: The FDA approved Phase 1 clinical trials on thalassemia major patients in the US for 10 participants in July.[95] The study was expected to continue until 2015.[85]

text: In July 2012, the European Medicines Agency recommended approval of a gene therapy treatment for the first time in either Europe or the United States. The treatment used Alipogene tiparvovec (Glybera) to compensate for lipoprotein lipase deficiency, which can cause severe pancreatitis.[96] The recommendation was endorsed by the European Commission in November 2012[10][27][97][98] and commercial rollout began in late 2014.[99]  Alipogene tiparvovec was expected to cost around $1.6 million per treatment in 2012,[100] revised to $1 million in 2015,[101] making it the most expensive medicine in the world at the time.[102]  As of  2016[update], only one person had been treated with drug.[103]

text: In December 2012, it was reported that 10 of 13 patients with multiple myeloma were in remission "or very close to it" three months after being injected with a treatment involving genetically engineered T cells to target proteins NY-ESO-1 and LAGE-1, which exist only on cancerous myeloma cells.[22]

text: In March researchers reported that three of five adult subjects who had acute lymphocytic leukemia (ALL) had been in remission for five months to two years after being treated with genetically modified T cells which attacked cells with CD19 genes on their surface, i.e. all B-cells, cancerous or not. The researchers believed that the patients' immune systems would make normal T-cells and B-cells after a couple of months. They were also given bone marrow. One patient relapsed and died and one died of a blood clot unrelated to the disease.[21]

text: Following encouraging Phase 1 trials, in April, researchers announced they were starting Phase 2 clinical trials (called CUPID2 and SERCA-LVAD) on 250 patients[104] at several hospitals to combat heart disease. The therapy was designed to increase the levels of SERCA2, a protein in heart muscles, improving muscle function.[105] The FDA granted this a Breakthrough Therapy Designation to accelerate the trial and approval process.[106] In 2016 it was reported that no improvement was found from the CUPID 2 trial.[107]

text: In July researchers reported promising results for six children with two severe hereditary diseases had been treated with a partially deactivated lentivirus to replace a faulty gene and after 7–32 months. Three of the children had metachromatic leukodystrophy, which causes children to lose cognitive and motor skills.[108] The other children had Wiskott-Aldrich syndrome, which leaves them to open to infection, autoimmune diseases, and cancer.[109] Follow up trials with gene therapy on another six children with Wiskott-Aldrich syndrome were also reported as promising.[110][111]

text: In October researchers reported that two children born with adenosine deaminase severe combined immunodeficiency disease (ADA-SCID) had been treated with genetically engineered stem cells 18 months previously and that their immune systems were showing signs of full recovery. Another three children were making progress.[18] In 2014 a further 18 children with ADA-SCID were cured by gene therapy.[112] ADA-SCID children have no functioning immune system and are sometimes known as "bubble children."[18]

text: Also in October researchers reported that they had treated six hemophilia sufferers in early 2011 using an adeno-associated virus.  Over two years later all six were producing clotting factor.[18][113]

text: In January researchers reported that six choroideremia patients had been treated with adeno-associated virus with a copy of REP1.  Over a six-month to two-year period all had improved their sight.[114][115] By 2016, 32 patients had been treated with positive results and researchers were hopeful the treatment would be long-lasting.[15] Choroideremia is an inherited genetic eye disease with no approved treatment, leading to loss of sight.

text: In March researchers reported that 12 HIV patients had been treated since 2009 in a trial with a genetically engineered virus with a rare mutation (CCR5 deficiency) known to protect against HIV with promising results.[116][117]

text: Clinical trials of gene therapy for sickle cell disease were started in 2014.[118][119] There is a need for high quality randomised controlled trials assessing the risks and benefits involved with gene therapy for people with sickle cell disease.[120]

text: In February LentiGlobin BB305, a gene therapy treatment undergoing clinical trials for treatment of beta thalassemia gained FDA "breakthrough" status after several patients were able to forgo the frequent blood transfusions usually required to treat the disease.[121]

text: In March researchers delivered a recombinant gene encoding a broadly neutralizing antibody into monkeys infected with simian HIV; the monkeys' cells produced the antibody, which cleared them of HIV. The technique is named immunoprophylaxis by gene transfer (IGT). Animal tests for antibodies to ebola, malaria, influenza, and hepatitis were underway.[122][123]

text: In March, scientists, including an inventor of CRISPR, Jennifer Doudna, urged a worldwide moratorium on germline gene therapy, writing "scientists should avoid even attempting, in lax jurisdictions, germline genome modification for clinical application in humans" until the full implications "are discussed among scientific and governmental organizations".[124][125][126][127]

text: In October, researchers announced that they had treated a baby girl, Layla Richards, with an experimental treatment using donor T-cells genetically engineered using TALEN to attack cancer cells. One year after the treatment she was still free of her cancer (a highly aggressive form of acute lymphoblastic leukaemia [ALL]).[128] Children with highly aggressive ALL normally have a very poor prognosis and Layla's disease had been regarded as terminal before the treatment.[129]

text: In December, scientists of major world academies called for a moratorium on inheritable human genome edits, including those related to CRISPR-Cas9 technologies[130] but that basic research including embryo gene editing should continue.[131]

text: In April the Committee for Medicinal Products for Human Use of the European Medicines Agency endorsed a gene therapy treatment called Strimvelis[132][133] and the European Commission approved it in June.[134] This treats children born with adenosine deaminase deficiency and who have no functioning immune system.  This was the second gene therapy treatment to be approved in Europe.[135]

text: In October, Chinese scientists reported they had started a trial to genetically modify T-cells from 10 adult patients with lung cancer and reinject the modified T-cells back into their bodies to attack the cancer cells.  The T-cells had the PD-1 protein (which stops or slows the immune response) removed using CRISPR-Cas9.[136][137]

text: A 2016 Cochrane systematic review looking at data from four trials on topical cystic fibrosis transmembrane conductance regulator (CFTR) gene therapy does not support its clinical use as a mist inhaled into the lungs to treat cystic fibrosis patients with lung infections. One of the four trials did find weak evidence that liposome-based CFTR gene transfer therapy may lead to a small respiratory improvement for people with CF. This weak evidence is not enough to make a clinical recommendation for routine CFTR gene therapy.[138]

text: In February Kite Pharma announced results from a clinical trial of CAR-T cells in around a hundred people with advanced Non-Hodgkin lymphoma.[139]

text: In March, French scientists reported on clinical research of gene therapy to treat sickle-cell disease.[140]

text: In August, the FDA approved tisagenlecleucel for acute lymphoblastic leukemia.[141]  Tisagenlecleucel is an adoptive cell transfer therapy for B-cell acute lymphoblastic leukemia; T cells from a person with cancer are removed, genetically engineered to make a specific T-cell receptor (a chimeric T cell receptor, or "CAR-T") that reacts to the cancer, and are administered back to the person.  The T cells are engineered to target a protein called CD19 that is common on B cells. This is the first form of gene therapy to be approved in the United States. In October, a similar therapy called axicabtagene ciloleucel was approved for non-Hodgkin lymphoma.[142]

text: In December the results of using an adeno-associated virus with blood clotting factor VIII to treat nine haemophilia A patients were published.  Six of the seven patients on the high dose regime increased the level of the blood clotting VIII to normal levels. The low and medium dose regimes had no effect on the patient's blood clotting levels.[143][144]

text: In December, the FDA approved Luxturna, the first in vivo gene therapy, for the treatment of blindness due to Leber's congenital amaurosis.[145] The price of this treatment was 850,000 US dollars for both eyes.[146][147]

text: Speculative uses[edit]

text: Speculated uses for gene therapy include:

text: Gene doping[edit]

text: Athletes might adopt gene therapy technologies to improve their performance.[148] Gene doping is not known to occur, but multiple gene therapies may have such effects. Kayser et al. argue that gene doping could level the playing field if all athletes receive equal access. Critics claim that any therapeutic intervention for non-therapeutic/enhancement purposes compromises the ethical foundations of medicine and sports.[149]

text: Human genetic engineering[edit]

text: Genetic engineering could be used to cure diseases, but also to change physical appearance, metabolism, and even improve physical capabilities and mental faculties such as memory and intelligence. Ethical claims about germline engineering include beliefs that every fetus has a right to remain genetically unmodified, that parents hold the right to genetically modify their offspring, and that every child has the right to be born free of preventable diseases.[150][151][152] For parents, genetic engineering could be seen as another child enhancement technique to add to diet, exercise, education, training, cosmetics, and plastic surgery.[153][154] Another theorist claims that moral concerns limit but do not prohibit germline engineering.[155]

text: Possible regulatory schemes include a complete ban, provision to everyone, or professional self-regulation. The American Medical Association’s Council on Ethical and Judicial Affairs stated that "genetic interventions to enhance traits should be considered permissible only in severely restricted situations: (1) clear and meaningful benefits to the fetus or child; (2) no trade-off with other characteristics or traits; and (3) equal access to the genetic technology, irrespective of income or other socioeconomic characteristics."[156]

text: As early in the history of biotechnology as 1990, there have been scientists opposed to attempts to modify the human germline using these new tools,[157] and such concerns have continued as technology progressed.[158][159] With the advent of new techniques like CRISPR, in March 2015 a group of scientists urged a worldwide moratorium on clinical use of gene editing technologies to edit the human genome in a way that can be inherited.[124][125][126][127]  In April 2015, researchers sparked controversy when they  reported results of basic research to edit the DNA of non-viable human embryos using CRISPR.[160][161] A committee of the American National Academy of Sciences and National Academy of Medicine gave qualified support to human genome editing in 2017[162][163] once answers have been found to safety and efficiency problems "but only for serious conditions under stringent oversight."[164]

text: Regulations[edit]

text: Regulations covering genetic modification are part of general guidelines about human-involved biomedical research.  There are no international treaties which are legally binding in this area, but there are recommendations for national laws from various bodies.

text: The Helsinki Declaration (Ethical Principles for Medical Research Involving Human Subjects) was amended by the World Medical Association's General Assembly in 2008. This document provides principles physicians and researchers must consider when involving humans as research subjects. The Statement on Gene Therapy Research initiated by the Human Genome Organization (HUGO) in 2001 provides a legal baseline for all countries. HUGO’s document emphasizes human freedom and adherence to human rights, and offers recommendations for somatic gene therapy, including the importance of recognizing public concerns about such research.[165]

text: United States[edit]

text: No federal legislation lays out protocols or restrictions about human genetic engineering. This subject is governed by overlapping regulations from local and federal agencies, including the Department of Health and Human Services, the FDA and NIH's Recombinant DNA Advisory Committee. Researchers seeking federal funds for an investigational new drug application, (commonly the case for somatic human genetic engineering,) must obey international and federal guidelines for the protection of human subjects.[166]

text: NIH serves as the main gene therapy regulator for federally funded research. Privately funded research is advised to follow these regulations. NIH provides funding for research that develops or enhances genetic engineering techniques and to evaluate the ethics and quality in current research. The NIH maintains a mandatory registry of human genetic engineering research protocols that includes all federally funded projects.

text: An NIH advisory committee published a set of guidelines on gene manipulation.[167] The guidelines discuss lab safety as well as human test subjects and various experimental types that involve genetic changes. Several sections specifically pertain to human genetic engineering, including Section III-C-1. This section describes required review processes and other aspects when seeking approval to begin clinical research involving genetic transfer into a human patient.[168]  The protocol for a gene therapy clinical trial must be approved by the NIH's Recombinant DNA Advisory Committee prior to any clinical trial beginning; this is different from any other kind of clinical trial.[167]

text: As with other kinds of drugs, the FDA regulates the quality and safety of gene therapy products and supervises how these products are used clinically. Therapeutic alteration of the human genome falls under the same regulatory requirements as any other medical treatment. Research involving human subjects, such as clinical trials, must be reviewed and approved by the FDA and an Institutional Review Board.[169][170]

text: Popular culture[edit]

text: Gene therapy is the basis for the plotline of the film I Am Legend[171] and the TV show Will Gene Therapy Change the Human Race?.[172] In 1994, gene therapy was a plot element in The Erlenmeyer Flask, The X-Files' first-season finale. It is also used in Stargate as a means of allowing humans to use Ancient technology.[173]


document_title: Bullet (Hollywood Undead song)

question_text: who sings at the end of bullet by hollywood undead

text: Bullet (Hollywood Undead song)

text: Background and development[edit]

text: "Bullet" was written by Lewis Edwards. The song contains verses by Terrell and Ragan, and a b-section and chorus sung by Terrell.

text: The song was produced, recorded, and mixed by Griffin Boice at the Beat Suite in Hollywood, California.[1]

text: Composition and lyrics[edit]

text: The acoustic guitar pattern repeats throughout the intro and outro, the verse, the pre-chorus and the chorus in a pattern of intro-verse-pre chorus-chorus-verse-pre chorus-outro, with the chord progression being E-B-C#m-A. The chord progression during the pre-chorus is G#m-F#m-E-D#m-C-B, with every chord following a two strum pattern, with the exceptions of C and B, which both follow an eight strum pattern.

text: The lyrics detail a teenage male's trouble with attempted (or successful) suicide. The chorus, which the song opens with, implies past attempts at suicide for the protagonist: "My legs are dangling off the edge, the bottom of the bottle is my only friend. I think I'll slit my wrist again, and I'm gone, gone, gone, gone! My legs are dangling off the edge, a stomach full of pills didn't work again. I put a bullet in my head, and I'm gone, gone, gone, gone!" The protagonist continues in the verses to describe the decomposition of his life, stating that his "two best friends" are "a bottle of pills" and "a bottle of Gin". We then learn he is at the top of a twenty story building, and that the polishing of a bottle is "pushing [me]" off and he describes how asphalt has never "looked so soft". The protagonist begins to express concern that his mother found his suicide note and had called the police. He starts realising he needs to move fast, as he hears "sirens and they're off in the distance" and that he's "more scarred than my wrist is". He states that he's going to purchase a suit, because "when you go to meet God ya know you wanna look nice." The pre-chorus states that "So if I survive then I'll see you tomorrow" and the chorus plays again. Johnny 3 Tears takes the second verse from a third-person point of view of another young man who had an abusive family life. The young man's father had apparently abandoned him, which left his mother guilt-struck, and he had gone astray in a way that is not specified. It is, however, stated that he "Climbed to the roof to see if [you] could fly". This ends the verse, and goes into the pre-chorus and chorus. After the chorus, Petra Christensen sings the outro stated by J-Dog in a Hollywood Undead live cast in January promoting the release for the band's latest album.

text: Remix contest[edit]

text: The band has hosted a remix contest for the songs "Bullet" and "Le Deux". Bullet's remix is hosted on Indaba Music and is chosen by voting majority. One of the top five voted remixes will be picked by the band themselves, and will receive the grand prize of a Cakewalk SONAR X1 Producer, a Cakewalk Z3TA+2 virtual instrument, and a Roland audio interface. The remix will also be featured on an upcoming official remix EP. Five honorable mentions from the top ten remixes will be sent a Hollywood Undead album signed by the members. Submissions for the contest were due by August 24, 2011.[2]

text: Critical reception[edit]

text: The song has received positive reviews from music critics. Rick Florino of Artist Direct had a list of ten reasons readers needed American Tragedy, with number three being the track "Bullet". Florino explains that "Hollywood Undead snap from faint acoustic guitar into cinematic rhyming about suicide. It's as infectious as it is intense." He states that the ending refrain featuring a little girl "is utterly powerful." He also stated that "Bullet" is "the kind of song that could save some kid in the crowd," and closed his review stating that the song is "heart-wrenching genius."[3] In his official review, Florino again referenced "Bullet" stating it was one of "two moments that make [American Tragedy] a classic," stating that "After an acoustic intro, the song tells a potent and poignant tale of longing for suicide. However, it's the sunniest and catchiest tune on American Tragedy" and that the band's genius lies "in that dangerous space between unforgettable and unsettling." He compared Johnny 3 Tears' verse to being as soulful as Jonathan Davis of Korn. The album as a whole garnered five out of five stars.[4]

text: Jeremy Borjon of Revolver described the song as "a disturbingly upbeat song about a man attempting suicide" and included it with several other songs as high points of the album. He gave the album four out of five stars.[5]

text: Richard Solomon of The Minaret stated that the song was in a part of the album that "stayed strong and continued to please", and analyzed it as "an intense song about suicide," and stated that "[t]he lyrics are probably more depressing than most. The twist? It has a melody happier than many songs, an upbeat and almost peppy tempo that's completely at odds with lyrics like, 'I never bought a suit before in my life, but when you go to meet God you know you wanna look nice!' and, 'A stomach full of pills didn't work again. I put a bullet in my head, and I'm gone, gone, gone, gone!'" He later analyzed that "[t]he final verse is different and is sung by what sounds like a little girl and adds to the 'happy' melody, but with the previous lyrics it just makes it even sadder," and stated that "if 'Comin' in Hot' is a successor to 'No. 5,' then this song is the successor to '[sic] My Black Dahlia.'" Solomon gave the album a positive review, granting four and a half out of five stars.[6]

text: Credits and personnel[edit]

text: The credits for "Bullet" are adapted from the liner notes of American Tragedy.[1]

text:
Recorded at: The Beat Suite in Hollywood, California.
Drums recorded at: NRG Studios, North Hollywood, California.

text:
Charlie Scene – clean vocals, rapping, guitar, composer, writer
Johnny 3 Tears – vocals, composer, writer
Johnny 3 Tears's daughter - End Vocals
J-Dog – synthesizers, keyboards, composer, writer
Danny – composer, writer, background vocals
Griffin Boice – production, recording, mixing, guitar, bass guitar, programming, percussion, composer, writer
Sean Curiel – drum recording assistant
Ken Dudley – additional recording
Daren Pfeifer – drums
Petra Christensen – additional vocals