init: initial commit

.gitattributes

@@ -31,5 +31,6 @@ saved_model/**/* filter=lfs diff=lfs merge=lfs -text
 *.wasm filter=lfs diff=lfs merge=lfs -text
 *.xz filter=lfs diff=lfs merge=lfs -text
 *.zip filter=lfs diff=lfs merge=lfs -text
+*.png filter=lfs diff=lfs merge=lfs -text
 *.zst filter=lfs diff=lfs merge=lfs -text
 *tfevents* filter=lfs diff=lfs merge=lfs -text

README.md

@@ -1,8 +1,8 @@
 ---
-title: 2d Layout Demo
+title: 2D Layout-Preserving PDF Parser Demo
 emoji: 🐨
-colorFrom: gray
-colorTo: yellow
+colorFrom: green
+colorTo: blue
 sdk: gradio
 sdk_version: 5.29.1
 app_file: app.py

app.py

@@ -0,0 +1,95 @@
+import gradio as gr
+from PIL import Image
+
+DEFAULT_CASE = "case_2"
+CASE_LIST = ["case_0", "case_1", "case_2"]
+data = {}
+
+for case_name in CASE_LIST:
+    with open(f"resources/{case_name}/prompt_0.txt", "r") as f:
+        data[case_name] = {
+            "prompt_0": f.read(),
+        }
+    with open(f"resources/{case_name}/output_0.txt", "r") as f:
+        data[case_name]["output_0"] = f.read()
+        data[case_name]["output_1"] = f.read()
+
+    with open(f"resources/{case_name}/prompt_1.txt", "r") as f:
+        data[case_name]["prompt_1"] = f.read()
+    with open(f"resources/{case_name}/output_1.txt", "r") as f:
+        data[case_name]["output_1"] = f.read()
+        
+    demo_image = Image.open(
+        f"resources/{case_name}/pdf_page.png"
+    )
+    data[case_name]["image"] = demo_image
+
+with gr.Blocks(
+    theme=gr.themes.Ocean(
+        font_mono="PT Mono",
+    ),
+) as demo:
+    gr.Markdown("# 2D Layout-Preserving Text Serialization Demo")
+    with gr.Row():
+        gr.Markdown("## Input Image")
+        case_name = gr.Dropdown(
+            choices=CASE_LIST,
+            label="Select a case",
+            value=DEFAULT_CASE,
+        )
+        
+    demo_image = gr.Image(
+        data[DEFAULT_CASE]["image"],
+        show_label=False,
+        container=False,
+        height=700,
+        width=600,
+    )
+    gr.Markdown("## Sample Prompt & Response from LLM")
+    with gr.Tabs():
+        with gr.TabItem("Prompt"):
+            with gr.Row():
+                prompt_0 = gr.Code(
+                    data[DEFAULT_CASE]["prompt_0"], 
+                    language="markdown", 
+                    show_line_numbers=False, 
+                    interactive=False,
+                    label="2D Layout-Preserving Text"
+                )
+                prompt_1 = gr.Code(
+                    data[DEFAULT_CASE]["prompt_1"],
+                    language="markdown", 
+                    show_line_numbers=False, 
+                    interactive=False,
+                    label="1D Text"
+                )
+                
+        with gr.TabItem("Response"):
+            with gr.Row():
+                output_0 = gr.Markdown(
+                    data[DEFAULT_CASE]["output_0"], 
+                    container=False
+                )
+                output_1 = gr.Markdown(
+                    data[DEFAULT_CASE]["output_1"], 
+                    container=False
+                )
+    
+    case_name.change(
+        lambda case: [
+            data[case]["image"],
+            data[case]["prompt_0"],
+            data[case]["prompt_1"],
+            data[case]["output_0"],
+            data[case]["output_1"],
+        ],
+        inputs=case_name,
+        outputs=[
+            demo_image,
+            prompt_0,
+            prompt_1,
+            output_0,
+            output_1,
+        ],
+    )
+    demo.queue().launch()

requirements.txt

@@ -0,0 +1 @@
+Pillow

resources/case_0/output_0.txt

@@ -0,0 +1,58 @@
+# Albert Einstein
+
+## Nobel Prize in Physics 1921
+
+**“for his services to theoretical physics, and especially for his discovery of the laws of the photoelectric effect.”**
+
+### Timeline of Einstein's Life
+
+- **Born**: 14 March 1879 in Ulm
+- **Died**: 18 April 1955 in Princeton, New Jersey
+
+In 1905, Albert Einstein submitted his revolutionary paper *"Eine neue Bestimmung der Moleküldimensionen"* (A New Determination of Molecular Dimensions) as a dissertation at the University of Zurich.
+
+From 1909 to 1911, he was Professor for Theoretical Physics at the University of Zurich.
+
+---
+
+### Einstein in Zurich
+
+It could have been a real love story. Einstein, born in Ulm in 1879, was a resident of Zurich, obtaining citizenship in 1901, and lived there for almost eight years altogether, longer than in any other Swiss town. In retrospect, however, it was only his years in Aarau and Berne that he looked back on fondly. 
+
+Wolfgang Pauli wrote in an obituary in the *Neue Zürcher Zeitung*: 
+
+> “Einstein liked to think back to his time in Berne, which he spoke of more often and more positively than of Zurich.”
+
+However, it appears he actually had a good time there. From 1896 to 1900, Einstein studied physics at ETH, then known as the Federal Polytechnic School. He appreciated the institution’s liberal spirit: as a student, you could “more or less do as you liked.” So, he put together a study plan entirely to his own taste: 
+
+> “Some lectures I followed with great interest. Otherwise, I skipped class often and stayed at home to study the masters of theoretical physics with holy fervor.”
+
+This self-study took place mainly in Hottingen, where Einstein rented lodgings from various landladies. He also spent much time in the Pension Engelbrecht at Plattenstrasse 50, where his friend, colleague, and later wife, Mileva Marić, had lodgings.
+
+---
+
+### 1905: Einstein's Annus Mirabilis
+
+1905 was Einstein’s *annus mirabilis*: the physicist published no less than five groundbreaking papers, including the Theory of Special Relativity and the Light Quanta Hypothesis, for which, among other achievements, he was later awarded the Nobel Prize in Physics.
+
+---
+
+### Personal Life and Interests
+
+Einstein’s favorite leisure activity was playing the violin. He was regularly invited by Alfred Stern, a historian at the ETH, and his family to enjoy a meal and make music with them. 
+
+In summer, he enjoyed sailing on the Lake of Zurich, and in winter, he loved hair-raising sledge rides on the Zürichberg. He could often be found happily sitting in the Café Metropol on the Stadthausquai.
+
+---
+
+### Later Years in Zurich and Prague
+
+After graduating from ETH, Einstein worked from 1902 to 1909 as an employee of the Federal Patent Office. From 1912, he returned to Zurich again as a professor for Theoretical Physics at ETH. He was now well established, with few teaching responsibilities and a good salary, allowing him to afford an imposing apartment on the Zürichberg. 
+
+He later moved to Prague after only three semesters, causing his students to protest. He returned to Zurich once again in 1912 as a professor at ETH.
+
+---
+
+**Sources:**
+
+[www.nobelpreis.uzh.ch/en_einstein.html](http://www.nobelpreis.uzh.ch/en_einstein.html)

resources/case_0/output_1.txt

@@ -0,0 +1,25 @@
+# Albert Einstein
+
+**Nobel Prize in Physics 1921**
+
+Albert Einstein was only his years in Aarau and Berne employee of the Federal Patent Office that he looked back on fondly. “Einstein in Berne. His annus mirabilis fell in the middle of this period: in 1905 he published no less than five revolutionary papers. These included the Theory of Special Relativity and the Light Quanta Hypothesis, for which, among other achievements, he was later awarded the Nobel Prize.” Wolfgang Pauli wrote in an obituary in the *Neue Zürcher Zeitung*.
+
+Nonetheless, it appears he actually had a good time there. From 1896 to 1900, Einstein studied physics at ETH, then known as the Federal Polytechnical School. He appreciated the institution’s liberal spirit: as a student there, you could “more or less do as you liked.” So he put together a study plan entirely to his own taste: “Some lectures I followed with great interest. Otherwise, I skipped class often and stayed at home to study the masters of theoretical physics with holy fervor.” This self-study took place mainly in Hottingen, where Einstein rented lodgings from various landladies. He also spent much time in the Pension Engelbrecht at Plattenstrasse 50, where his friend, colleague, and later wife, Mileva Marić, had lodgings.
+
+In 1905, Albert Einstein submitted his groundbreaking paper *Eine neue Bestimmung der Moleküldimensionen* (A New Determination of Molecular Dimensions) as a dissertation at the University of Zurich.
+
+From 1909 to 1911, he was Professor for Theoretical Physics at the University of Zurich. Einstein’s favorite leisure activity was playing the violin. He was regularly invited by Alfred Stern, a historian at ETH, and his family, to enjoy meals and make music with them. In summer, he enjoyed sailing on the Lake of Zurich, and in winter, he loved hair-raising sledge rides on the Zürichberg. He could often be found happily sitting in the Café Metropol on the Stadthausquai.
+
+Einstein then moved back to Zurich a second time, when the University created an associate professorship in theoretical physics especially for him. Professor Einstein was usually ill-prepared: his lecture notes often consisted of a scrap of paper the size of a visiting card. But he was so selflessly devoted to his students that they wrote a letter of protest to the education department when he moved to Prague after only three semesters.
+
+Einstein returned to Zurich again in 1912, this time as Professor for Theoretical Physics at ETH. He was now well-established: he had few teaching responsibilities and a good salary, so he could afford an imposing apartment on the Zürichberg. Otto Stern had followed him from Prague to Zurich as his assistant and served as his sparring partner and “calculating machine.” But again, Einstein only managed to stay in Zurich for a year and a half.
+
+---
+
+**Nobel Prize in Physics 1921**  
+“For his services to theoretical physics, and especially for his discovery of the laws of the photoelectric effect.”
+
+*14 March 1879 in Ulm*  
+*† 18 April 1955 in Princeton, New Jersey*
+
+1905 was Einstein’s *annus mirabilis*: the physicist published no less than five revolutionary papers.

resources/case_0/prompt_0.txt

@@ -0,0 +1,78 @@
+Convert this text to Markdown with correct reading order
+Only use text from original context.
+
+```
+Albert                 Einstein
+
+ Nobel          Prize         in    Physics            1921
+
+
+                                               was  only  his years  in Aarau  and  Berne      employee    of the Federal  Patent  Office
+                                               that he looked  back  on fondly. “Einstein      in Berne.  His annus  mirabilis fell in the
+
+                                               liked  to think back  to his time in Berne,     middle   of this period:  in 1905 he  pub 
+                                               which   he spoke  of more  often and  more      lished  no less than  five revolutionary
+                                               positively   than  of Zurich,”   Wolfgang       papers.  These  included   the  Theory   of
+
+                                               Pauli  wrote  in an  obituary  in the Neue      Special Relativity  and the Light  Quanta
+                                               Zürcher   Zeitung.                              Hypothesis,    for which,   among    other
+                                                  Nonetheless,    it appears  he  actually     achievements,    he  was   later awarded
+
+                                               had   a good   time  there.  From   1896  to    the Nobel   Prize.
+                                               1900, Einstein   studied  physics  at ETH,         Einstein  then  moved   back  to Zurich
+                                               then   known    as the  Federal  Polytech      a second   time,  when    the  University
+
+                                               nical  School.   He  appreciated    the  in    created  an  associate  professorship    in
+                                               stitution’s  liberal spirit: as  a student      theoretical  physics  especially  for him.
+                                               there,  you  could   “more   or less do  as     Professor  Einstein  was  usually  ill-pre
+ Nobel Prize in Physics 1921 “for his services
+                                               you  liked.”  So he  put together  a study      pared:  his lecture notes often  consisted
+ to theoretical physics, and especially
+                                               plan  entirely  to his own   taste: “Some       of a scrap of paper  the size of a visiting
+ for his discovery of the laws of the photo
+                                               lectures  I followed  with  great  interest.
+ electric effect”
+                                               Otherwise,    I skipped   class  often and
+ * 14 March 1879 in Ulm
+                                               stayed   at home   to  study  the  masters       1905   was   Einstein’s   annus
+                                               of  theoretical  physics   with   holy  fer
+ † 18 April 1955 in Princeton, New Jersey                                                       mirabilis:   the  physicist
+                                                                                                published     no  less than   five
+                                               vor.” This  self-study  took place  mainly
+ In 1905 Albert Einstein submitted his revolu
+                                               in  Hottingen,   where    Einstein  rented
+ tionary paper “Eine neue Bestimmung der                                                        groundbreaking        papers.
+                                               lodgings   from   various  landladies.  He
+ Moleküldimensionen”  (A New Determination
+                                               also  spent  much    time  in the  Pension      card. But  he was   so selflessly devoted
+ of Molecular Dimensions) as a dissertation at
+                                               Engelbrecht   at Plattenstrasse  50, where      to his students  that they  wrote  a letter
+ the University of Zurich.
+                                               his  friend,  colleague,  and   later wife,     of protest to the education   department
+ From 1909 to 1911 he was Professor for
+                                               Mileva   Marić,  had  lodgings.                 when   he  moved    to Prague   after only
+ Theoretical Physics at the University of Zurich.
+                                                  Einstein’s   favorite  leisure  activity     three semesters.
+                                               was   playing  the  violin. He  was   regu        Einstein  returned    to Zurich   again
+                                               larly invited  by  Alfred   Stern, a histo     in 1912, this time as  Professor  for The 
+                                               rian at the ETH,  and  his family, to enjoy     oretical Physics   at ETH.   He  was  now
+ Zurich         and       the
+                                               a  meal  and   make    music   with  them.      well established:   he had  few  teaching
+ Annus          Mirabilis
+                                               In  summer,    he enjoyed   sailing on  the     responsibilities  and   a good  salary,  so
+                                               Lake  of Zurich,  in winter  he loved hair     that he could  permit  himself  an impos
+ Albert Einstein   and  Zurich   – it could
+                                               raising  sledge  rides on the Zürichberg.       ing apartment    on the Zürichberg.   Otto
+ have been   a real love  story. Einstein,
+                                               And   he  could  often  be found   happily      Stern had  followed  him  from   Prague  to
+ born in Ulm   in 1879, was  a resident  of
+                                               sitting  in the  Café   Metropol    on  the     Zurich,  as his assistant, and  served   as
+ Zurich, obtaining    citizenship  in 1901,
+                                               Stadthausquai.                                  sparring  partner  and  “calculating   ma
+ and lived  there for almost   eight years
+                                                  After   graduating    from   ETH,   Ein     chine.”  But again,  Einstein  only  man
+ altogether,  longer  than  in  any  other
+                                               stein  worked    from  1902  to 1909  as an     aged  to stay in Zurich  for a year  and  a
+ Swiss town.   In retrospect,  however,   it
+ www.nobelpreis.uzh.ch/en_einstein.html                                                          Albert Einstein – Nobel Prize in Physics 1921 1/4
+```

resources/case_0/prompt_1.txt

@@ -0,0 +1,72 @@
+Convert this text to Markdown with correct reading order
+Only use text from original context.
+
+```
+Albert Einstein
+Nobel Prize in Physics 1921
+was only his years in Aarau and Berne employee of the Federal Patent Office
+that he looked back on fondly. “Einstein in Berne. His annus mirabilis fell in the
+liked to think back to his time in Berne, middle of this period: in 1905 he pub 
+which he spoke of more often and more lished no less than five revolutionary
+positively than of Zurich,” Wolfgang papers. These included the Theory of
+Pauli wrote in an obituary in the Neue Special Relativity and the Light Quanta
+Zürcher Zeitung. Hypothesis, for which, among other
+Nonetheless, it appears he actually achievements, he was later awarded
+had a good time there. From 1896 to the Nobel Prize.
+1900, Einstein studied physics at ETH, Einstein then moved back to Zurich
+then known as the Federal Polytech a second time, when the University
+nical School. He appreciated the in  created an associate professorship in
+stitution’s liberal spirit: as a student theoretical physics especially for him.
+there, you could “more or less do as Professor Einstein was usually ill-pre
+Nobel Prize in Physics 1921 “for his services
+you liked.” So he put together a study pared: his lecture notes often consisted
+to theoretical physics, and especially
+plan entirely to his own taste: “Some of a scrap of paper the size of a visiting
+for his discovery of the laws of the photo
+lectures I followed with great interest.
+electric effect”
+Otherwise, I skipped class often and
+
+* 14 March 1879 in Ulm
+  stayed at home to study the masters 1905 was Einstein’s annus
+  of theoretical physics with holy fer
+  † 18 April 1955 in Princeton, New Jersey mirabilis: the physicist
+  published no less than five
+  vor.” This self-study took place mainly
+  In 1905 Albert Einstein submitted his revolu
+  in Hottingen, where Einstein rented
+  tionary paper “Eine neue Bestimmung der groundbreaking papers.
+  lodgings from various landladies. He
+  Moleküldimensionen” (A New Determination
+  also spent much time in the Pension card. But he was so selflessly devoted
+  of Molecular Dimensions) as a dissertation at
+  Engelbrecht at Plattenstrasse 50, where to his students that they wrote a letter
+  the University of Zurich.
+  his friend, colleague, and later wife, of protest to the education department
+  From 1909 to 1911 he was Professor for
+  Mileva Marić, had lodgings. when he moved to Prague after only
+  Theoretical Physics at the University of Zurich.
+  Einstein’s favorite leisure activity three semesters.
+  was playing the violin. He was regu  Einstein returned to Zurich again
+  larly invited by Alfred Stern, a histo in 1912, this time as Professor for The 
+  rian at the ETH, and his family, to enjoy oretical Physics at ETH. He was now
+  Zurich and the
+  a meal and make music with them. well established: he had few teaching
+  Annus Mirabilis
+  In summer, he enjoyed sailing on the responsibilities and a good salary, so
+  Lake of Zurich, in winter he loved hair that he could permit himself an impos
+  Albert Einstein and Zurich – it could
+  raising sledge rides on the Zürichberg. ing apartment on the Zürichberg. Otto
+  have been a real love story. Einstein,
+  And he could often be found happily Stern had followed him from Prague to
+  born in Ulm in 1879, was a resident of
+  sitting in the Café Metropol on the Zurich, as his assistant, and served as
+  Zurich, obtaining citizenship in 1901,
+  Stadthausquai. sparring partner and “calculating ma
+  and lived there for almost eight years
+  After graduating from ETH, Ein  chine.” But again, Einstein only man
+  altogether, longer than in any other
+  stein worked from 1902 to 1909 as an aged to stay in Zurich for a year and a
+  Swiss town. In retrospect, however, it
+  [www.nobelpreis.uzh.ch/en\_einstein.html](http://www.nobelpreis.uzh.ch/en_einstein.html) Albert Einstein – Nobel Prize in Physics 1921 1/4
+```

resources/case_1/output_0.txt

@@ -0,0 +1,17 @@
+The table below summarises the maturity profile of the corporation's liabilities at 31 December:
+
+### At 31 December 2018
+
+|                             | Within 3 months | 3 to 6 Months | 6 to 12 Months | 1 to 3 years | Over 3 years | Total     |
+|-----------------------------|------------------|----------------|----------------|--------------|---------------|-----------|
+| Due to insurance and reinsurance companies |                  |                |                | 835,389      |               | 835,389   |
+| Payables and other liabilities             | 268,760          |                | 290,554        |              |               | 559,314   |
+| Obligations under finance lease            |                  |                | 65,101         | 223,946      | 1,346,888     | 1,635,935 |
+
+### At 31 December 2017
+
+|                             | Within 3 months | 3 to 6 Months | 6 to 12 Months | 1 to 3 years | Over 3 years | Total     |
+|-----------------------------|------------------|----------------|----------------|--------------|---------------|-----------|
+| Due to insurance and reinsurance companies |                  |                |                | 835,389      |               | 835,389   |
+| Payables and other liabilities             | 449,097          |                | 273,708        |              |               | 722,805   |
+| Obligations under finance lease            |                  |                | 60,842         | 209,295      | 1,426,640     | 1,696,777 |

resources/case_1/output_1.txt

@@ -0,0 +1,15 @@
+### Maturity Profile of the Corporation's Liabilities at 31 December 2018
+
+| Category                        | Within 3 Months | 3 to 6 Months | 6 to 12 Months | 1 to 3 Years | Over 3 Years | Total      |
+|--------------------------------|-----------------|---------------|----------------|--------------|--------------|------------|
+| Due to insurance and reinsurance companies |                 |               |                |              |              | 835,389    |
+| Payables and other liabilities | 268,760         | 290,554       |                |              |              | 559,314    |
+| Obligations under finance lease|                 | 65,101        | 223,946        |              | 1,346,888    | 1,635,935  |
+
+### Maturity Profile of the Corporation's Liabilities at 31 December 2017
+
+| Category                        | Within 3 Months | 3 to 6 Months | 6 to 12 Months | 1 to 3 Years | Over 3 Years | Total      |
+|--------------------------------|-----------------|---------------|----------------|--------------|--------------|------------|
+| Due to insurance and reinsurance companies |                 |               |                |              |              | 835,389    |
+| Payables and other liabilities | 449,097         | 273,708       |                |              |              | 722,805    |
+| Obligations under finance lease|                 | 60,842        | 209,295        |              | 1,426,640    | 1,696,777  |

resources/case_1/prompt_0.txt

@@ -0,0 +1,25 @@
+Convert this text to Markdown
+
+```page
+ The table below summarises the maturity profile of the corporation's liabilities at 31 December:
+                                             Within 3         3to6        6to12                           Over3
+  At 31December 2018                                                                   1 to 3 years                       Total
+                                             months          Months       Months                          years
+  Due to insurance and reinsurance
+                                                                                       835,389                          835,389
+  companies
+  Payables and other liabilities              268,760                     290,554                                       559,314
+
+  Obligations under finance lease                                           65,101     223,946          1,346,888       1,635,935
+
+                                              Within 3        3to6        6to12                           Over3
+  At 31 December 2017                                                                                                      Total
+                                                                                       1 to 3 years
+                                               months        Months       Months                          years
+  Due to insurance and reinsurance
+                                                                                       835,389                          835,389
+  companies
+  Payables and other liabilities               449,097                    273,708                                       722,805
+  Obligations under finance lease                                           60,842     209,295          1,426,640       1,696,777
+
+```

resources/case_1/prompt_1.txt

@@ -0,0 +1,22 @@
+Convert this text to Markdown
+
+```page
+ The table below summarises the maturity profile of the corporation's liabilities at 31 December:
+ Within 3 3to6 6to12 Over3
+ At 31December 2018 1 to 3 years Total
+ months Months Months years
+ Due to insurance and reinsurance
+ 835,389 835,389
+ companies
+ Payables and other liabilities 268,760 290,554 559,314
+ Obligations under finance lease 65,101 223,946 1,346,888 1,635,935
+ Within 3 3to6 6to12 Over3
+ At 31 December 2017 Total
+ 1 to 3 years
+ months Months Months years
+ Due to insurance and reinsurance
+ 835,389 835,389
+ companies
+ Payables and other liabilities 449,097 273,708 722,805
+ Obligations under finance lease 60,842 209,295 1,426,640 1,696,777
+```

resources/case_2/output_0.txt

@@ -0,0 +1,26 @@
+© 2001 Nature Publishing Group [http://medicine.nature.com](http://medicine.nature.com)  
+NEWS & VIEWS
+
+## Promiscuous regulator of xenobiotic removal
+
+The transcription factor SXR mediates drug, xenobiotic and steroid induction of a major drug–metabolizing enzyme. Drugs such as paclitaxel (Taxol) can bind and activate this transcription factor and therefore regulate their own metabolism and efflux from cells. Manipulation of this pathway might lead to new ways to improve therapeutic efficacy and to minimize toxicity (584-590). This indicates a broad role for SXR in the coordinated induction of multiple detoxification pathways.
+
+**Erin Schuetz** & **Stephen Strom**  
+The body responds to drugs, environmental chemicals, endogenous steroids and bile acids by inducing the coordinated expression of a battery of drug–detoxification genes in tissues such as liver and intestine. These include the cytochromes P450 (CYPs), which are the enzymes responsible for oxidative, peroxidative and reductive metabolism of toxic compounds. Expression of drug transport proteins such as P-glycoprotein (encoded by MDR1 and also known as MDR1 and ABCB1) leads to the efficient efflux of these drugs from the body. 
+
+Activation of drug transport can be beneficial in instances where it is important to remove toxins from the body, but detrimental in situations where it is important for a patient to retain effective levels of a therapeutic drug. In this issue, Synold et al. demonstrate that steroid xenobiotic receptor (SXR; also known as PXR), a transcription factor known to mediate drug, xenobiotic and steroid induction of the major liver drug metabolizing enzyme, can also regulate the expression of a drug efflux pathway, indicating a novel strategy to control drug clearance.
+
+CYP3A4, the most abundant drug-metabolizing enzyme in the liver and intestine, is responsible for the metabolism of 50% of all drugs. Many drugs are substrates for both CYP3A4 and P-glycoprotein, a broad-specificity efflux pump protein encoded by the gene MDR1. It was first demonstrated in 1996 that MDR1 expression is coordinated with expression of CYP3A4, with both gene products being induced by the same spectrum of drugs. P-glycoprotein and CYP3A4 are colocalized in liver and intestine, and serve as a coordinated system for the absorption, metabolism and disposition of many drugs. Many drug–drug interactions arise from concurrent administration of drugs which are both substrates and inducers of CYP3A4 and MDR1 expression.
+
+Long-term therapy with drugs that induce CYP3A4 and MDR1 increase the systemic clearance of some antileukemic agents, and such therapy has been shown to exert negative effects on survival while increasing cancer relapse. Recent studies have shown that SXR, a member of the nuclear hormone receptor superfamily, regulates expression of CYP3A (ref. 5,6). SXR is activated by a pharmacopia of drugs, including antibiotics, statin cholesterol-lowering drugs, antiseizure medications, steroids such as glucocorticoids, some bile acids, environmental contaminants such as organochlorine pesticides and polychlorinated biphenyls, and herbal supplements such as St. John’s wort. 
+
+Little is known about how certain drugs induce CYP and MDR1 gene expression. Synold et al. demonstrate that SXR is activated by paclitaxel (Taxol) and is responsible for inducing expression of not only CYP3A (previously shown to be induced by paclitaxel) but also CYP2C9 and MDR1. Paclitaxel is metabolized by both CYP3A4 and CYP2C9 (ref. 11) and transported by P-glycoprotein, and induction of all of these proteins leads to its enhanced clearance. This indicates a broad role for SXR in the coordinated induction of multiple detoxification pathways.
+
+Synold et al. show that docetaxel, unlike the structural analog paclitaxel, does not induce CYP3A4 or MDR1 expression because it does not activate SXR. This should result in superior pharmacokinetic properties relative to paclitaxel. 
+
+Synold et al. also demonstrate that Ecteinascidin-743 (ET-743), an antineoplastic agent, can antagonize SXR activation and inhibit MDR1 expression. The authors suggest that SXR antagonists that downregulate the P-glycoprotein pathway of drug elimination could be exploited to improve drug retention. This approach should be undertaken cautiously, because clinical trials involving drugs that inhibit P-glycoprotein activity, given in an effort to reduce drug resistance, have had limited success and led to undesired pharmacokinetic side effects. MDR1 expression modulators should be carefully screened for their potential to inhibit or modulate metabolism of other medications taken by a patient.
+
+**Figure 1:**  
+Feedforward and feedback pathways of drug metabolism. Paclitaxel is a ligand for SXR, causing this nuclear receptor to activate transcription of the P-glycoprotein efflux pump protein encoded by MDR1, and the drug metabolizing enzymes CYP3A and CYP2C9. These pathways, however, mediate drug clearance and reduce paclitaxel activation of SXR in a feedback mechanism. Manipulation of this pathway may be used to prolong or reduce drug retention.
+
+NATURE MEDICINE • VOLUME 7 • NUMBER 5 • MAY 2001

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+© 2001 Nature Publishing Group [http://medicine.nature.com](http://medicine.nature.com)
+
+## NEWS & VIEWS
+
+### Promiscuous regulator of xenobiotic removal
+
+The transcription factor SXR mediates drug, xenobiotic, and steroid induction of a major drug-metabolizing enzyme. Drugs such as paclitaxel (Taxol) can bind and activate this transcription factor and therefore regulate their own metabolism and efflux from cells. Manipulation of this pathway might lead to new ways to improve therapeutic efficacy and to minimize toxicity (584-590).
+
+Enhanced clearance<sup>12</sup>. This indicates a broad role for SXR in the coordinated induction of multiple detoxification pathways.
+
+**ERIN SCHUETZ<sup>1</sup> & STEPHEN STROM<sup>2</sup>**
+
+The body responds to drugs, environmental chemicals, endogenous steroids, and bile acids by inducing the coordinated expression of a battery of drug detoxification genes in tissues such as liver and intestine. These include the cytochromes P450 (CYPs), which are the enzymes responsible for oxidative, peroxidative, and reductive metabolism of toxic compounds. Expression of drug transport proteins such as P-glycoprotein (encoded by MDR1 and also known as ABCB1) leads to the efficient efflux of drugs from the body. Activation of drug transport can be beneficial in instances where it is important to remove toxins from the body, but detrimental in situations where it is important for a patient to retain effective levels of a therapeutic drug.
+
+In this issue, Snyold et al.<sup>1</sup> demonstrate that steroid xenobiotic receptor (SXR; also known as PXR), a transcription factor known to mediate drug, xenobiotic, and steroid induction of the major liver drug-metabolizing enzyme, can also regulate the expression of a drug efflux pathway, indicating a novel strategy to control drug clearance.
+
+Because concurrent administration of CYP3A4 and P-glycoprotein inducers (such as rifampicin) with drugs that serve as substrates for these proteins is a major basis of drug-drug interactions<sup>5</sup>, pharmaceutical companies are now using SXR-binding and -activation assays to screen and predict which compounds will induce CYP3A expression and potentially cause drug interactions. These types of assays may also identify compounds that induce CYP2C9 and MDR1, causing auto-induction of their own clearance. It might be possible to someday create drugs that are ‘SXR transparent’ by minimizing or eliminating binding activity.
+
+In this regard, the report of Synold et al.<sup>1</sup> shows that docetaxel, unlike the structural analog paclitaxel, does not induce CYP3A4 or MDR1 expression because it does not activate SXR. This should result in superior pharmacokinetic properties relative to paclitaxel.
+
+Synold et al.<sup>1</sup> demonstrate that Ecteinascidin-743 (ET-743), an antineoplastic agent, can antagonize SXR and inhibit MDR1 expression. The authors suggest that SXR antagonists that downregulate the P-glycoprotein pathway of drug elimination could be exploited to improve drug retention. This approach should be undertaken cautiously, because clinical trials involving drugs that inhibit P-glycoprotein activity, given in an effort to reduce drug resistance, have had limited success and led to undesired pharmacokinetic side effects<sup>13</sup>. MDR1 expression ‘modulators’ should be carefully screened for their potential to inhibit or modulate metabolism of other medications taken by a patient.
+
+### Fig. 1: Feedforward and feedback pathways of drug metabolism
+
+Paclitaxel is a ligand for SXR, causing this nuclear receptor to activate transcription of the P-glycoprotein efflux pump protein encoded by MDR1, and the drug-metabolizing enzymes CYP3A and CYP2C9. These pathways, however, mediate drug clearance and reduce paclitaxel activation of SXR in a feedback mechanism. Manipulation of this pathway may be used to prolong or reduce drug retention.
+
+536 NATURE MEDICINE • VOLUME 7 • NUMBER 5 • MAY 2001

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+Convert this text to Markdown with correct reading order. Stay close to original content.
+
+````
+©  2001  Nature   Publishing    Group     http://medicine.nature.com
+     NEWS          &   VIEWS
+
+
+
+
+                         Promiscuous                    regulator              of    xenobiotic                 removal
+
+             The  transcription  factor SXR  mediates   drug,  xenobiotic  and  steroid induction  of a major  drug–metabolizing     enzyme.
+                Drugs   such as paclitaxel (Taxol)  can bind  and  activate this transcription  factor and  therefore  regulate  their own
+
+                metabolism    and  efflux from  cells. Manipulation  of this pathway   might  lead  to new  ways  to improve   therapeutic
+                                                      efficacy and  to minimize   toxicity (584-590).
+
+                                                                                                        enhanced     clearance12.  This  indicates   a
+          mental       chemicals,     endogenous                                                        broad  role for SXR  in the  coordinated   in
+                                                       ERIN   SCHUETZ1      &  STEPHEN     STROM2
+      T   he  body   responds  to  drugs, environ
+      steroids and  bile acids by inducing  the  co                                                    duction   of multiple  detoxification   path
+      ordinated   expression  of a battery of drug    some   antileukemic   agents, and  such  ther   ways.
+      detoxification   genes   in  tissues such   as   apy  has been  shown    to exert negative  ef     Because   concurrent    administration   of
+      liver and  intestine. These  include  the  cy   fects on  survival while   increasing  cancer    CYP3A4     and    P-glycoprotein    inducers
+      tochromes    P450   (CYPs),  which    are the    relapse4 . Recent studies  have  shown   that    (such  as rifampicin)  with drugs  that serve
+      enzymes   responsible   for oxidative, perox    SXR,  a member     of the nuclear   hormone      as substrates  for these proteins  is a major
+      idative and  reductive  metabolism    of toxic   receptor   superfamily,   regulates   expres    basis of drug–drug   interactions5 , pharma
+      compounds.     Expression  of drug  transport    sion  of CYP3A   (ref. 5,6). SXR is activated    ceutical  companies    are now   using  SXR
+      proteins  such  as P-glycoprotein   (encoded     by  a pharmacopia    of drugs, including  an    binding   and  -activation  assays to  screen
+      by  MDR1    and  also known    as MDR1    and    tibiotics,   statin    cholesterol-lowering      and   predict  which   compounds     will  in
+
+      ABCB1)    leads to the efficient efflux these    drugs,  antiseizure   medications,   steroids    duce  CYP3A    expression   and   potentially
+      drugs  from   the body.  Activation   of drug    such  as glucocorticoids5 , some  bile acids7 ,  cause  drug interactions.  These  types of as
+      transport   can  be beneficial  in  instances    environmental      contaminants     such    as   says  may   also identify  compounds     that
+      where   it is important   to  remove   toxins    organochlorine    pesticides and  polychlori    induce   CYP2C9    and   MDR1   , and   cause
+      from   the body,  but  detrimental   in situa   nated   biphenyls8  ,  and   herbal   supple    auto-induction    of their own  clearance.  It
+
+      tions  where  it is important   for a patient    ments   such as St. John’s wort9 .               might    be  possible   to  someday    create
+      to retain  effective levels of a therapeutic        Little is known about  how   certain drugs    drugs  that are ‘SXR  transparent’  by  mini
+      drug.  In this issue, Snyold  et al. 1 demon    induce   CYP  and  MDR1    gene  expression.     mizing  or eliminating   binding  activity. In
+      strate  that  steroid  xenobiotic    receptor    Synold   et al. 1 demonstrate that SXR  is ac   this regard,  the  report  of Synold   et al . 1
+
+      (SXR;  also known   as PXR),  a transcription    tivated  by  paclitaxel  (Taxol)  and   is re   shows   that  docetaxel,  unlike   the  struc
+      factor known    to mediate  drug, xenobiotic     sponsible  for inducing   expression   of not    tural analog   paclitaxel, does  not  induce
+      and  steroid  induction   of the  major  liver   only  CYP3A    (previously  shown   to be  in   CYP3A4    or  MDR1    expression  because   it
+      drug  metabolizing   enzyme,   can also regu    duced   by  paclitaxel10) but  also  CYP2C9      does  not activate  SXR.  This should   result
+      late the expression   of a drug  efflux path    and  MDR1   . Paclitaxel  is metabolized   by    in  superior  pharmacokinetic      properties
+ ©
+      way,    indicating   a  novel    strategy   to   both  CYP3A4    and   CYP2C9    (ref. 11) and    relative to paclitaxel.
+      control  drug  clearance.                        transported   by   P-glycoprotein,   and   in     Synold     et   al . 1 demonstrate     that
+         CYP3A4,   the  most  abundant    drug-me     duction  of all of these proteins leads to its   Ecteinascidin-743    (ET-743),  an  antineo
+      tabolizing  enzyme   in the liver and                                                                    plastic agent,  can  antagonize   SXR
+      intestine,  is responsible    for the                                                                    activation   and  inhibit  MDR1    ex
+
+      metabolism    of  50%   of all drugs.                                                                    pression.  The  authors  suggest  that
+                                                          Feed forward   and  feed back  pathways
+      Many   drugs  are substrates for both                                                                    SXR   antagonists    that  downregu
+      CYP3A4     and    P-glycoprotein,    a                                                                   late the P-glycoprotein   pathway   of
+                                                                        Paclitaxel
+      broad-specificity  efflux pump   pro                                                                    drug   elimination     could   be  ex
+      tein encoded   by the gene  MDR1   . It                                                                  ploited  to improve   drug  retention.
+      was   first demonstrated     in 1996                                                                     This   approach   should   be  under
+      that  MDR1    expression   is coordi                                                                    taken   cautiously,  because   clinical
+      nated  with  expression  of CYP3A4   ,                                                                   trials involving   drugs  that inhibit
+      with  both  gene  products  being  in                                                                   P-glycoprotein   activity, given in an
+                                                                           SXR
+      duced   by  the  same   spectrum    of                                                                   effort  to  reduce   drug  resistance,
+                                                                         Regulates
+      drugs2 .     P-glycoprotein       and                                                                    have  had  limited success  and  led to
+                                                                      the  expression
+      CYP3A4     are  colocalized  in  liver                                                                   undesired    pharmacokinetic      side
+                                                                          of MDR1
+      and  intestine, and  serve as a coor                                                                    effects13. MDR1   expression   ‘modu
+                                                                        and  CYP3A4
+      dinated  system  for the absorption,                                                                     lators’ should  be carefully screened
+                                                       MDR1                                  CYP3A
+                                                                                            CYP2C9
+      metabolism     and   disposition    of                                                                   for  their  potential  to  inhibit  or
+      many    drugs. Many    drug–drug   in                                                                   modulate     metabolism     of   other
+      teractions   arise from   concurrent                                                                     medications    taken   by  a  patient.
+                                               Fig. 1  Feedforward  and  feedback pathways  of drug metabo
+      administration   of drugs  which   are                                                                   Given   the knowledge    that SXR  has
+                                               lism. Paclitaxel is a ligand for SXR, causing this nuclear receptor
+      both   substrates  and   inducers   of                                                                   multiple   detoxification    genes   as
+                                               to activate transcription of the P-glycoprotein efflux pump pro
+      CYP3A4     and  MDR1     expression3 .                                                                   targets, antagonism    of  SXR  might
+                                               tein encoded  by  MDR1 , and  the drug metabolizing  enzymes
+                                               CYP3A  and  CYP2C9.  These  pathways, however,  mediate  drug
+      Long-term     therapy    with   drugs                                                                    lead  to increased drug  toxicity.
+                                               clearance and reduce paclitaxel activation of SXR in a feedback
+      that induce  CYP3A4    and  MDR1   in                                                                      Synold  et al . 1 emphasize the feed
+                                               mechanism.   Manipulation of this pathway may be used to pro
+      crease  the  systemic   clearance   of                                                                   forward   pathways    of  drug   clear
+                                               long or reduce drug retention.
+     536                                                                                           NATURE  MEDICINE  • VOLUME  7 • NUMBER  5 • MAY 2001```
+````

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@@ -0,0 +1,86 @@
+Convert this text to Markdown with correct reading order. Stay close to original content.
+
+````
+© 2001 Nature Publishing Group http://medicine.nature.com
+ NEWS & VIEWS
+ Promiscuous regulator of xenobiotic removal
+ The transcription factor SXR mediates drug, xenobiotic and steroid induction of a major drug–metabolizing enzyme.
+ Drugs such as paclitaxel (Taxol) can bind and activate this transcription factor and therefore regulate their own
+ metabolism and efflux from cells. Manipulation of this pathway might lead to new ways to improve therapeutic
+ efficacy and to minimize toxicity (584-590).
+ enhanced clearance12. This indicates a
+ mental chemicals, endogenous broad role for SXR in the coordinated in
+ ERIN SCHUETZ1 & STEPHEN STROM2
+ T he body responds to drugs, environ
+ steroids and bile acids by inducing the co duction of multiple detoxification path
+ ordinated expression of a battery of drug some antileukemic agents, and such ther ways.
+ detoxification genes in tissues such as apy has been shown to exert negative ef Because concurrent administration of
+ liver and intestine. These include the cy fects on survival while increasing cancer CYP3A4 and P-glycoprotein inducers
+ tochromes P450 (CYPs), which are the relapse4 . Recent studies have shown that (such as rifampicin) with drugs that serve
+ enzymes responsible for oxidative, perox SXR, a member of the nuclear hormone as substrates for these proteins is a major
+ idative and reductive metabolism of toxic receptor superfamily, regulates expres basis of drug–drug interactions5 , pharma
+ compounds. Expression of drug transport sion of CYP3A (ref. 5,6). SXR is activated ceutical companies are now using SXR
+ proteins such as P-glycoprotein (encoded by a pharmacopia of drugs, including an binding and -activation assays to screen
+ by MDR1 and also known as MDR1 and tibiotics, statin cholesterol-lowering and predict which compounds will in
+ ABCB1) leads to the efficient efflux these drugs, antiseizure medications, steroids duce CYP3A expression and potentially
+ drugs from the body. Activation of drug such as glucocorticoids5 , some bile acids7 , cause drug interactions. These types of as
+ transport can be beneficial in instances environmental contaminants such as says may also identify compounds that
+ where it is important to remove toxins organochlorine pesticides and polychlori induce CYP2C9 and MDR1 , and cause
+ from the body, but detrimental in situa nated biphenyls8 , and herbal supple auto-induction of their own clearance. It
+ tions where it is important for a patient ments such as St. John’s wort9 . might be possible to someday create
+ to retain effective levels of a therapeutic Little is known about how certain drugs drugs that are ‘SXR transparent’ by mini
+ drug. In this issue, Snyold et al. 1 demon induce CYP and MDR1 gene expression. mizing or eliminating binding activity. In
+ strate that steroid xenobiotic receptor Synold et al. 1 demonstrate that SXR is ac this regard, the report of Synold et al . 1
+ (SXR; also known as PXR), a transcription tivated by paclitaxel (Taxol) and is re shows that docetaxel, unlike the struc
+ factor known to mediate drug, xenobiotic sponsible for inducing expression of not tural analog paclitaxel, does not induce
+ and steroid induction of the major liver only CYP3A (previously shown to be in CYP3A4 or MDR1 expression because it
+ drug metabolizing enzyme, can also regu duced by paclitaxel10) but also CYP2C9 does not activate SXR. This should result
+ late the expression of a drug efflux path and MDR1 . Paclitaxel is metabolized by in superior pharmacokinetic properties
+ ©
+ way, indicating a novel strategy to both CYP3A4 and CYP2C9 (ref. 11) and relative to paclitaxel.
+ control drug clearance. transported by P-glycoprotein, and in Synold et al . 1 demonstrate that
+ CYP3A4, the most abundant drug-me duction of all of these proteins leads to its Ecteinascidin-743 (ET-743), an antineo
+ tabolizing enzyme in the liver and plastic agent, can antagonize SXR
+ intestine, is responsible for the activation and inhibit MDR1 ex
+ metabolism of 50% of all drugs. pression. The authors suggest that
+ Feed forward and feed back pathways
+ Many drugs are substrates for both SXR antagonists that downregu
+ CYP3A4 and P-glycoprotein, a late the P-glycoprotein pathway of
+ Paclitaxel
+ broad-specificity efflux pump pro drug elimination could be ex
+ tein encoded by the gene MDR1 . It ploited to improve drug retention.
+ was first demonstrated in 1996 This approach should be under
+ that MDR1 expression is coordi taken cautiously, because clinical
+ nated with expression of CYP3A4 , trials involving drugs that inhibit
+ with both gene products being in P-glycoprotein activity, given in an
+ SXR
+ duced by the same spectrum of effort to reduce drug resistance,
+ Regulates
+ drugs2 . P-glycoprotein and have had limited success and led to
+ the expression
+ CYP3A4 are colocalized in liver undesired pharmacokinetic side
+ of MDR1
+ and intestine, and serve as a coor effects13. MDR1 expression ‘modu
+ and CYP3A4
+ dinated system for the absorption, lators’ should be carefully screened
+ MDR1 CYP3A
+ CYP2C9
+ metabolism and disposition of for their potential to inhibit or
+ many drugs. Many drug–drug in modulate metabolism of other
+ teractions arise from concurrent medications taken by a patient.
+ Fig. 1 Feedforward and feedback pathways of drug metabo
+ administration of drugs which are Given the knowledge that SXR has
+ lism. Paclitaxel is a ligand for SXR, causing this nuclear receptor
+ both substrates and inducers of multiple detoxification genes as
+ to activate transcription of the P-glycoprotein efflux pump pro
+ CYP3A4 and MDR1 expression3 . targets, antagonism of SXR might
+ tein encoded by MDR1 , and the drug metabolizing enzymes
+ CYP3A and CYP2C9. These pathways, however, mediate drug
+ Long-term therapy with drugs lead to increased drug toxicity.
+ clearance and reduce paclitaxel activation of SXR in a feedback
+ that induce CYP3A4 and MDR1 in Synold et al . 1 emphasize the feed
+ mechanism. Manipulation of this pathway may be used to pro
+ crease the systemic clearance of forward pathways of drug clear
+ long or reduce drug retention.
+ 536 NATURE MEDICINE • VOLUME 7 • NUMBER 5 • MAY 2001```
+````