Table of contents
  1. Story
  2. Slides
    1. NLM-Semantic Medline Data Science Data Publication Commons
      1. Slide 1 NLM-Semantic Medline Data Science Data Publication Commons
      2. Slide 2 Overview
      3. Slide 3 National Library of Medicine's Web Site
      4. Slide 4 Definitions for the National Library of Medicine's Permanence Levels
      5. Slide 5 Data Mining
      6. Slide 6 Databases, Resources & APIs
      7. Slide 7 NLM-SemMed Data Science Data Publication: Database Linked Data Spreadsheet
      8. Slide 8 Broad Subject Terms for Indexed Journals
      9. Slide 9 NLM-SemMed Data Science Data Publication: Broad Subject Terms Linked Data Spreadsheet
      10. Slide 10 NLM-SemMed Data Science Data Publication: SpotfireData Commons
      11. Slide 11 NLM-SemMed Data Science Data Publication: LOINC Big Data
      12. Slide 12 NLM-SemMed Data Science Data Publication: LOINC Big Data in Spotfire
      13. Slide 13 NLM-SemMed Data Science Data Publication: MindTouch Knowledge Base
      14. Slide 14 Conclusions and Recommendations
    2. NIh: Data Science & BD2K
      1. Slide 1 NIH: Data Science & BD2K
      2. Slide 2 NIH Big Data to Knowledge
      3. Slide 3 The Commons 1
      4. Slide 4 The Commons 2
      5. Slide 5 Data and Tool Resources at NIH
      6. Slide 6 BD2K & The Commons
    3. National Library of Medicine Working Group – Interim Briefing about the Final Report
      1. Slide 1 National Library of Medicine Working Group – Interim Briefing about the Final Report
      2. Slide 2 The Context 1
      3. Slide 3 The Context 2
      4. Slide 4 The Context 3
      5. Slide 5 The Context 4
      6. Slide 6 Today's Focus
      7. Slide 7 Report
      8. Slide 8 Charge to the NLM Working Group
      9. Slide 9 Charge: Assess How NLM Should 1
      10. Slide 10 Charge: Assess How NLM Should 2
      11. Slide 11 Charge: Assess How NLM Should 3
      12. Slide 12 NLM Working Group Membership
      13. Slide 13 Deliberative (and Rapid) Process
      14. Slide 14 Listen and Learn from Community
      15. Slide 15 Observations 1
      16. Slide 16 Observations 2
      17. Slide 17 What We Heard... 1
      18. Slide 18 What We Heard... 2
      19. Slide 19 Resources
      20. Slide 20 Observations: NLM has Challenges 1
      21. Slide 21 Observations: NLM has Challenges 2
      22. Slide 22 Recommendations
      23. Slide 23 Recommendations #1: 'General Scope' 1
      24. Slide 24 Recommendations #1: 'General Scope' 2
      25. Slide 25 Recommendations #1: 'General Scope' 3
      26. Slide 26 Recommendations #1: 'General Scope' 4
      27. Slide 27 Recommendations #1: 'General Scope' 5
      28. Slide 28 Recommendations #2: 'Open Science' 1
      29. Slide 29 Recommendations #2: 'Open Science' 2
      30. Slide 30 Recommendations #2: 'Open Science' 3
      31. Slide 31 Recommendations #2: 'Open Science' 4
      32. Slide 32 Recommendations #2: 'Open Science' 5
      33. Slide 33 Recommendation #3: 'Data Science' 1
      34. Slide 34 Recommendation #3: 'Data Science' 2
      35. Slide 35 Recommendation #3: 'Data Science' 3
      36. Slide 36 Recommendation #3: 'Data Science' 4
      37. Slide 37 Recommendation #3: 'Data Science' 5
      38. Slide 38 Recommendation #4: 'Training' 1
      39. Slide 39 Recommendation #4: 'Training' 2
      40. Slide 40 Recommendation #4: 'Training' 3
      41. Slide 41 Recommendation #5: 'History' 1
      42. Slide 42 Recommendation #5: 'History' 2
      43. Slide 43 Recommendation #5: 'History' 3
      44. Slide 44 Recommendation #6: "Further Evaluation' 1
      45. Slide 45 Recommendation #6: "Further Evaluation' 2
      46. Slide 46 Concluding Remarks
      47. Slide 47 A Robust NLM is Vital 1
      48. Slide 48 A Robust NLM is Vital 2
      49. Slide 49 Questions?
    4. Using Semantic MEDLINE to Explore Glucan Research
      1. Slide 1 Using Semantic MEDLINE to Explore Glucan Research
      2. Slide 2 Web Application: Semantic Medline
      3. Slide 3 SemRep
      4. Slide 4 Semantic Predication
      5. Slide 5 ​Semantic Medline Overview
      6. Slide 6 SemMed: Semantic Predications
      7. Slide 7 Research on Glucans
      8. Slide 8 Predicational Overview
      9. Slide 9 AUGMENTS Immunologic Function
      10. Slide 10 PubMed Document 1
      11. Slide 11 Tumor cells, malignant LOCATION_OF
      12. Slide 12 PubMed Document 2
      13. Slide 13 TREATS Neoplasms
      14. Slide 14 PubMed Document 3
  3. Spotfire Dashboard
    1. ​NLM Semantic Medline Data Science Data Publication 1
    2. NIH Data Publication 1
  4. Research Notes
    1. 110th Meeting of the Advisory Committee to the Director (ACD)
      1. Thursday, June 11, 2015
      2. Friday, June 12, 2015
  5. Policy Makers: Future of NLM - Report
    1. Report
      1. Executive Summary
      2. Introduction
      3. Process for Deliberations
      4. Summary of Observations
      5. Recommendations
        1. RECOMMENDATION #1
        2. RECOMMENDATION #2
        3. RECOMMENDATION #3
        4. RECOMMENDATION #4
        5. RECOMMENDATION # 5
        6. RECOMMENDATION #6
      6. Concluding Remarks
      7. References
        1. 1
        2. 2
        3. 3
      8. Appendix A Roster
        1. Members
        2. Ex Officio Members
        3. Executive Secretary
      9. Appendix B NLM Consultations
      10. Appendix C Request for Information
        1. Purpose
        2. Background
        3. Information Requested
        4. How to Submit a Response
        5. Inquiries
  6. Public: NLM MedlinePlus
    1. NIH MedlinePlus-The Magazine
      1. Help Out For Health!
    2. Spring 2015 Issue: Volume 10 Number 1
      1. Feature: Celiac Disease
        1. How long did it take you to get your condition diagnosed?
        2. What were your thoughts when you were told you had celiac disease?
        3. How difficult has it been to eliminate your intake of gluten?
        4. Have you found inspiration from others who have celiac disease?
        5. What advice do you have for others who have been diagnosed with celiac disease?
      2. What is Celiac disease?
        1. Fast Facts
        2. How common is celiac disease?
        3. What other health problems do people with celiac disease have?
      3. Symptoms, Diagnosis & Treatment
        1. What are some of the symptoms of celiac disease?
        2. Why are celiac disease symptoms so varied?
        3. How is celiac disease diagnosed?
          1. Blood Tests
          2. Intestinal Biopsy
          3. Dermatitis Herpetiformis
          4. Screening
        4. How is celiac disease treated?
      4. Four Inches and Seven Pounds
        1. Hope through Research
      5. Learning to Live Well with Celiac Disease
        1. Find Out More
      6. Living Gluten Free
        1. Allowed Foods
        2. Foods to Avoid
  7. Researcher
    1. Press Release
      1. Youngevity (YGYI) Announces Acquisition of Restart Your Life
    2. Slides
      1. Slide 1 Glucan
      2. Slide 2 Leukemia & Lymphoma Journal Article
      3. Slide 3 This what you would see if you had really good eyes…or an electron microscope
      4. Slide 4 The phagocytosis of bacteria or phagocytosis of synthetic microspheres is often used for glucan evaluation
      5. Slide 5 The PAC MAN of the immune system in various states
      6. Slide 6 Demonstration of Oral Uptake of Yeast Beta 1,3-D Glucan 1
      7. Slide 7 Demonstration of Oral Uptake of Yeast Beta 1,3-D Glucan 2
      8. Slide 8 effects of two weeks of treatment with different glucans on size of tumors
      9. Slide 9 Long-term effect of orally-given glucans on secretion of IL-2 by spleen cells
      10. Slide 10 Glucan-induced recovery of bone marrow after irradiation of mice
      11. Slide 11 Effect of long-term feeding with individual glucans on blood cholesterol levels in experimentally-induced hypercholesterolemia
      12. Slide 12 Feeding with glucan can control the experimentally-induced hyperglycemia
      13. Slide 13 Effects of various glucans on ear swelling
      14. Slide 14 Glucan in diet reduces supression of immunity caused by mercury
      15. Slide 15 Effects of different glucans on immunosuppression caused by immunotoxic agents
      16. Slide 16 Glucan stimulates the wound healing of human skin cells
      17. Slide 17 Improvement in skin properties after application of glucan in creams
      18. Slide 18 Effect of 14 days of feeding on stress-induced levels of corticosterone
      19. Slide 19 Effects of glucan supplementation of antibody formation in children
      20. Slide 20 Effects of different immunomodulators on phagocytic activity
      21. Slide 21 Effects of various combinations on NK cell activity
      22. Slide 22 Differences in glucan content among different commercial glucans
      23. Slide 23 More glucan does not always mean higher activity as inferior glucans never reach the biological activities of superior glucans
      24. Slide 24 Effects of different combinations on production of IL-2
      25. Slide 25 Effects of resveratrol-vitamin C-glucan combination on antibody response
      26. Slide 26 Effects of resveratrol-vitamin C-glucan combination on phagocytosis in stressed mice
      27. Slide 27 Before and After
      28. Slide 28 Wound Healing
      29. Slide 29 How To Never Run Out of Leads
      30. Slide 30 Acknowledgement
  8. PubMed Search - Glucan
    1. See 1 citation found by title matching your search
    2. Author information
    3. Abstract
    4. Keywords
    5. PubMed Help
  9. Data Scientist: Publication - Leukemia & Lymphoma
    1. Original Article: Clinical
    2. Format Options
    3. Authors
    4. Abstract
    5. Keywords
    6. Agreement
    7. Result
      1. Abstract
      2. Introduction
      3. Methods
      4. Therapy
      5. Response evaluation
      6. Statistical analysis
    8. Results
      1. Table I Patient demographics
      2. Table II Treatment summary
      3. Toxicity
      4. Treatment response
        1. Figure 1. Time to progression
        2. Figure 2. Time to retreatment
    9. Discussion
    10. Acknowledgement
    11. Potential Conflict of Interest
    12. References
      1. 1
      2. 2
      3. 3
      4. 4
      5. 5
      6. 6
      7. 7
      8. 8
      9. 9
      10. 10
      11. 11
      12. 12
      13. 13
      14. 14
      15. 15
      16. 16
      17. 17
      18. 18
    13. Supplementary Material
  10. Semantic Medline
  11. Semantic Insights
  12. Tamr
  13. NEXT

NLM - Semantic Medline Data Science Data Publication

Last modified
Table of contents
  1. Story
  2. Slides
    1. NLM-Semantic Medline Data Science Data Publication Commons
      1. Slide 1 NLM-Semantic Medline Data Science Data Publication Commons
      2. Slide 2 Overview
      3. Slide 3 National Library of Medicine's Web Site
      4. Slide 4 Definitions for the National Library of Medicine's Permanence Levels
      5. Slide 5 Data Mining
      6. Slide 6 Databases, Resources & APIs
      7. Slide 7 NLM-SemMed Data Science Data Publication: Database Linked Data Spreadsheet
      8. Slide 8 Broad Subject Terms for Indexed Journals
      9. Slide 9 NLM-SemMed Data Science Data Publication: Broad Subject Terms Linked Data Spreadsheet
      10. Slide 10 NLM-SemMed Data Science Data Publication: SpotfireData Commons
      11. Slide 11 NLM-SemMed Data Science Data Publication: LOINC Big Data
      12. Slide 12 NLM-SemMed Data Science Data Publication: LOINC Big Data in Spotfire
      13. Slide 13 NLM-SemMed Data Science Data Publication: MindTouch Knowledge Base
      14. Slide 14 Conclusions and Recommendations
    2. NIh: Data Science & BD2K
      1. Slide 1 NIH: Data Science & BD2K
      2. Slide 2 NIH Big Data to Knowledge
      3. Slide 3 The Commons 1
      4. Slide 4 The Commons 2
      5. Slide 5 Data and Tool Resources at NIH
      6. Slide 6 BD2K & The Commons
    3. National Library of Medicine Working Group – Interim Briefing about the Final Report
      1. Slide 1 National Library of Medicine Working Group – Interim Briefing about the Final Report
      2. Slide 2 The Context 1
      3. Slide 3 The Context 2
      4. Slide 4 The Context 3
      5. Slide 5 The Context 4
      6. Slide 6 Today's Focus
      7. Slide 7 Report
      8. Slide 8 Charge to the NLM Working Group
      9. Slide 9 Charge: Assess How NLM Should 1
      10. Slide 10 Charge: Assess How NLM Should 2
      11. Slide 11 Charge: Assess How NLM Should 3
      12. Slide 12 NLM Working Group Membership
      13. Slide 13 Deliberative (and Rapid) Process
      14. Slide 14 Listen and Learn from Community
      15. Slide 15 Observations 1
      16. Slide 16 Observations 2
      17. Slide 17 What We Heard... 1
      18. Slide 18 What We Heard... 2
      19. Slide 19 Resources
      20. Slide 20 Observations: NLM has Challenges 1
      21. Slide 21 Observations: NLM has Challenges 2
      22. Slide 22 Recommendations
      23. Slide 23 Recommendations #1: 'General Scope' 1
      24. Slide 24 Recommendations #1: 'General Scope' 2
      25. Slide 25 Recommendations #1: 'General Scope' 3
      26. Slide 26 Recommendations #1: 'General Scope' 4
      27. Slide 27 Recommendations #1: 'General Scope' 5
      28. Slide 28 Recommendations #2: 'Open Science' 1
      29. Slide 29 Recommendations #2: 'Open Science' 2
      30. Slide 30 Recommendations #2: 'Open Science' 3
      31. Slide 31 Recommendations #2: 'Open Science' 4
      32. Slide 32 Recommendations #2: 'Open Science' 5
      33. Slide 33 Recommendation #3: 'Data Science' 1
      34. Slide 34 Recommendation #3: 'Data Science' 2
      35. Slide 35 Recommendation #3: 'Data Science' 3
      36. Slide 36 Recommendation #3: 'Data Science' 4
      37. Slide 37 Recommendation #3: 'Data Science' 5
      38. Slide 38 Recommendation #4: 'Training' 1
      39. Slide 39 Recommendation #4: 'Training' 2
      40. Slide 40 Recommendation #4: 'Training' 3
      41. Slide 41 Recommendation #5: 'History' 1
      42. Slide 42 Recommendation #5: 'History' 2
      43. Slide 43 Recommendation #5: 'History' 3
      44. Slide 44 Recommendation #6: "Further Evaluation' 1
      45. Slide 45 Recommendation #6: "Further Evaluation' 2
      46. Slide 46 Concluding Remarks
      47. Slide 47 A Robust NLM is Vital 1
      48. Slide 48 A Robust NLM is Vital 2
      49. Slide 49 Questions?
    4. Using Semantic MEDLINE to Explore Glucan Research
      1. Slide 1 Using Semantic MEDLINE to Explore Glucan Research
      2. Slide 2 Web Application: Semantic Medline
      3. Slide 3 SemRep
      4. Slide 4 Semantic Predication
      5. Slide 5 ​Semantic Medline Overview
      6. Slide 6 SemMed: Semantic Predications
      7. Slide 7 Research on Glucans
      8. Slide 8 Predicational Overview
      9. Slide 9 AUGMENTS Immunologic Function
      10. Slide 10 PubMed Document 1
      11. Slide 11 Tumor cells, malignant LOCATION_OF
      12. Slide 12 PubMed Document 2
      13. Slide 13 TREATS Neoplasms
      14. Slide 14 PubMed Document 3
  3. Spotfire Dashboard
    1. ​NLM Semantic Medline Data Science Data Publication 1
    2. NIH Data Publication 1
  4. Research Notes
    1. 110th Meeting of the Advisory Committee to the Director (ACD)
      1. Thursday, June 11, 2015
      2. Friday, June 12, 2015
  5. Policy Makers: Future of NLM - Report
    1. Report
      1. Executive Summary
      2. Introduction
      3. Process for Deliberations
      4. Summary of Observations
      5. Recommendations
        1. RECOMMENDATION #1
        2. RECOMMENDATION #2
        3. RECOMMENDATION #3
        4. RECOMMENDATION #4
        5. RECOMMENDATION # 5
        6. RECOMMENDATION #6
      6. Concluding Remarks
      7. References
        1. 1
        2. 2
        3. 3
      8. Appendix A Roster
        1. Members
        2. Ex Officio Members
        3. Executive Secretary
      9. Appendix B NLM Consultations
      10. Appendix C Request for Information
        1. Purpose
        2. Background
        3. Information Requested
        4. How to Submit a Response
        5. Inquiries
  6. Public: NLM MedlinePlus
    1. NIH MedlinePlus-The Magazine
      1. Help Out For Health!
    2. Spring 2015 Issue: Volume 10 Number 1
      1. Feature: Celiac Disease
        1. How long did it take you to get your condition diagnosed?
        2. What were your thoughts when you were told you had celiac disease?
        3. How difficult has it been to eliminate your intake of gluten?
        4. Have you found inspiration from others who have celiac disease?
        5. What advice do you have for others who have been diagnosed with celiac disease?
      2. What is Celiac disease?
        1. Fast Facts
        2. How common is celiac disease?
        3. What other health problems do people with celiac disease have?
      3. Symptoms, Diagnosis & Treatment
        1. What are some of the symptoms of celiac disease?
        2. Why are celiac disease symptoms so varied?
        3. How is celiac disease diagnosed?
          1. Blood Tests
          2. Intestinal Biopsy
          3. Dermatitis Herpetiformis
          4. Screening
        4. How is celiac disease treated?
      4. Four Inches and Seven Pounds
        1. Hope through Research
      5. Learning to Live Well with Celiac Disease
        1. Find Out More
      6. Living Gluten Free
        1. Allowed Foods
        2. Foods to Avoid
  7. Researcher
    1. Press Release
      1. Youngevity (YGYI) Announces Acquisition of Restart Your Life
    2. Slides
      1. Slide 1 Glucan
      2. Slide 2 Leukemia & Lymphoma Journal Article
      3. Slide 3 This what you would see if you had really good eyes…or an electron microscope
      4. Slide 4 The phagocytosis of bacteria or phagocytosis of synthetic microspheres is often used for glucan evaluation
      5. Slide 5 The PAC MAN of the immune system in various states
      6. Slide 6 Demonstration of Oral Uptake of Yeast Beta 1,3-D Glucan 1
      7. Slide 7 Demonstration of Oral Uptake of Yeast Beta 1,3-D Glucan 2
      8. Slide 8 effects of two weeks of treatment with different glucans on size of tumors
      9. Slide 9 Long-term effect of orally-given glucans on secretion of IL-2 by spleen cells
      10. Slide 10 Glucan-induced recovery of bone marrow after irradiation of mice
      11. Slide 11 Effect of long-term feeding with individual glucans on blood cholesterol levels in experimentally-induced hypercholesterolemia
      12. Slide 12 Feeding with glucan can control the experimentally-induced hyperglycemia
      13. Slide 13 Effects of various glucans on ear swelling
      14. Slide 14 Glucan in diet reduces supression of immunity caused by mercury
      15. Slide 15 Effects of different glucans on immunosuppression caused by immunotoxic agents
      16. Slide 16 Glucan stimulates the wound healing of human skin cells
      17. Slide 17 Improvement in skin properties after application of glucan in creams
      18. Slide 18 Effect of 14 days of feeding on stress-induced levels of corticosterone
      19. Slide 19 Effects of glucan supplementation of antibody formation in children
      20. Slide 20 Effects of different immunomodulators on phagocytic activity
      21. Slide 21 Effects of various combinations on NK cell activity
      22. Slide 22 Differences in glucan content among different commercial glucans
      23. Slide 23 More glucan does not always mean higher activity as inferior glucans never reach the biological activities of superior glucans
      24. Slide 24 Effects of different combinations on production of IL-2
      25. Slide 25 Effects of resveratrol-vitamin C-glucan combination on antibody response
      26. Slide 26 Effects of resveratrol-vitamin C-glucan combination on phagocytosis in stressed mice
      27. Slide 27 Before and After
      28. Slide 28 Wound Healing
      29. Slide 29 How To Never Run Out of Leads
      30. Slide 30 Acknowledgement
  8. PubMed Search - Glucan
    1. See 1 citation found by title matching your search
    2. Author information
    3. Abstract
    4. Keywords
    5. PubMed Help
  9. Data Scientist: Publication - Leukemia & Lymphoma
    1. Original Article: Clinical
    2. Format Options
    3. Authors
    4. Abstract
    5. Keywords
    6. Agreement
    7. Result
      1. Abstract
      2. Introduction
      3. Methods
      4. Therapy
      5. Response evaluation
      6. Statistical analysis
    8. Results
      1. Table I Patient demographics
      2. Table II Treatment summary
      3. Toxicity
      4. Treatment response
        1. Figure 1. Time to progression
        2. Figure 2. Time to retreatment
    9. Discussion
    10. Acknowledgement
    11. Potential Conflict of Interest
    12. References
      1. 1
      2. 2
      3. 3
      4. 4
      5. 5
      6. 6
      7. 7
      8. 8
      9. 9
      10. 10
      11. 11
      12. 12
      13. 13
      14. 14
      15. 15
      16. 16
      17. 17
      18. 18
    13. Supplementary Material
  10. Semantic Medline
  11. Semantic Insights
  12. Tamr
  13. NEXT

  1. Story
  2. Slides
    1. NLM-Semantic Medline Data Science Data Publication Commons
      1. Slide 1 NLM-Semantic Medline Data Science Data Publication Commons
      2. Slide 2 Overview
      3. Slide 3 National Library of Medicine's Web Site
      4. Slide 4 Definitions for the National Library of Medicine's Permanence Levels
      5. Slide 5 Data Mining
      6. Slide 6 Databases, Resources & APIs
      7. Slide 7 NLM-SemMed Data Science Data Publication: Database Linked Data Spreadsheet
      8. Slide 8 Broad Subject Terms for Indexed Journals
      9. Slide 9 NLM-SemMed Data Science Data Publication: Broad Subject Terms Linked Data Spreadsheet
      10. Slide 10 NLM-SemMed Data Science Data Publication: SpotfireData Commons
      11. Slide 11 NLM-SemMed Data Science Data Publication: LOINC Big Data
      12. Slide 12 NLM-SemMed Data Science Data Publication: LOINC Big Data in Spotfire
      13. Slide 13 NLM-SemMed Data Science Data Publication: MindTouch Knowledge Base
      14. Slide 14 Conclusions and Recommendations
    2. NIh: Data Science & BD2K
      1. Slide 1 NIH: Data Science & BD2K
      2. Slide 2 NIH Big Data to Knowledge
      3. Slide 3 The Commons 1
      4. Slide 4 The Commons 2
      5. Slide 5 Data and Tool Resources at NIH
      6. Slide 6 BD2K & The Commons
    3. National Library of Medicine Working Group – Interim Briefing about the Final Report
      1. Slide 1 National Library of Medicine Working Group – Interim Briefing about the Final Report
      2. Slide 2 The Context 1
      3. Slide 3 The Context 2
      4. Slide 4 The Context 3
      5. Slide 5 The Context 4
      6. Slide 6 Today's Focus
      7. Slide 7 Report
      8. Slide 8 Charge to the NLM Working Group
      9. Slide 9 Charge: Assess How NLM Should 1
      10. Slide 10 Charge: Assess How NLM Should 2
      11. Slide 11 Charge: Assess How NLM Should 3
      12. Slide 12 NLM Working Group Membership
      13. Slide 13 Deliberative (and Rapid) Process
      14. Slide 14 Listen and Learn from Community
      15. Slide 15 Observations 1
      16. Slide 16 Observations 2
      17. Slide 17 What We Heard... 1
      18. Slide 18 What We Heard... 2
      19. Slide 19 Resources
      20. Slide 20 Observations: NLM has Challenges 1
      21. Slide 21 Observations: NLM has Challenges 2
      22. Slide 22 Recommendations
      23. Slide 23 Recommendations #1: 'General Scope' 1
      24. Slide 24 Recommendations #1: 'General Scope' 2
      25. Slide 25 Recommendations #1: 'General Scope' 3
      26. Slide 26 Recommendations #1: 'General Scope' 4
      27. Slide 27 Recommendations #1: 'General Scope' 5
      28. Slide 28 Recommendations #2: 'Open Science' 1
      29. Slide 29 Recommendations #2: 'Open Science' 2
      30. Slide 30 Recommendations #2: 'Open Science' 3
      31. Slide 31 Recommendations #2: 'Open Science' 4
      32. Slide 32 Recommendations #2: 'Open Science' 5
      33. Slide 33 Recommendation #3: 'Data Science' 1
      34. Slide 34 Recommendation #3: 'Data Science' 2
      35. Slide 35 Recommendation #3: 'Data Science' 3
      36. Slide 36 Recommendation #3: 'Data Science' 4
      37. Slide 37 Recommendation #3: 'Data Science' 5
      38. Slide 38 Recommendation #4: 'Training' 1
      39. Slide 39 Recommendation #4: 'Training' 2
      40. Slide 40 Recommendation #4: 'Training' 3
      41. Slide 41 Recommendation #5: 'History' 1
      42. Slide 42 Recommendation #5: 'History' 2
      43. Slide 43 Recommendation #5: 'History' 3
      44. Slide 44 Recommendation #6: "Further Evaluation' 1
      45. Slide 45 Recommendation #6: "Further Evaluation' 2
      46. Slide 46 Concluding Remarks
      47. Slide 47 A Robust NLM is Vital 1
      48. Slide 48 A Robust NLM is Vital 2
      49. Slide 49 Questions?
    4. Using Semantic MEDLINE to Explore Glucan Research
      1. Slide 1 Using Semantic MEDLINE to Explore Glucan Research
      2. Slide 2 Web Application: Semantic Medline
      3. Slide 3 SemRep
      4. Slide 4 Semantic Predication
      5. Slide 5 ​Semantic Medline Overview
      6. Slide 6 SemMed: Semantic Predications
      7. Slide 7 Research on Glucans
      8. Slide 8 Predicational Overview
      9. Slide 9 AUGMENTS Immunologic Function
      10. Slide 10 PubMed Document 1
      11. Slide 11 Tumor cells, malignant LOCATION_OF
      12. Slide 12 PubMed Document 2
      13. Slide 13 TREATS Neoplasms
      14. Slide 14 PubMed Document 3
  3. Spotfire Dashboard
    1. ​NLM Semantic Medline Data Science Data Publication 1
    2. NIH Data Publication 1
  4. Research Notes
    1. 110th Meeting of the Advisory Committee to the Director (ACD)
      1. Thursday, June 11, 2015
      2. Friday, June 12, 2015
  5. Policy Makers: Future of NLM - Report
    1. Report
      1. Executive Summary
      2. Introduction
      3. Process for Deliberations
      4. Summary of Observations
      5. Recommendations
        1. RECOMMENDATION #1
        2. RECOMMENDATION #2
        3. RECOMMENDATION #3
        4. RECOMMENDATION #4
        5. RECOMMENDATION # 5
        6. RECOMMENDATION #6
      6. Concluding Remarks
      7. References
        1. 1
        2. 2
        3. 3
      8. Appendix A Roster
        1. Members
        2. Ex Officio Members
        3. Executive Secretary
      9. Appendix B NLM Consultations
      10. Appendix C Request for Information
        1. Purpose
        2. Background
        3. Information Requested
        4. How to Submit a Response
        5. Inquiries
  6. Public: NLM MedlinePlus
    1. NIH MedlinePlus-The Magazine
      1. Help Out For Health!
    2. Spring 2015 Issue: Volume 10 Number 1
      1. Feature: Celiac Disease
        1. How long did it take you to get your condition diagnosed?
        2. What were your thoughts when you were told you had celiac disease?
        3. How difficult has it been to eliminate your intake of gluten?
        4. Have you found inspiration from others who have celiac disease?
        5. What advice do you have for others who have been diagnosed with celiac disease?
      2. What is Celiac disease?
        1. Fast Facts
        2. How common is celiac disease?
        3. What other health problems do people with celiac disease have?
      3. Symptoms, Diagnosis & Treatment
        1. What are some of the symptoms of celiac disease?
        2. Why are celiac disease symptoms so varied?
        3. How is celiac disease diagnosed?
          1. Blood Tests
          2. Intestinal Biopsy
          3. Dermatitis Herpetiformis
          4. Screening
        4. How is celiac disease treated?
      4. Four Inches and Seven Pounds
        1. Hope through Research
      5. Learning to Live Well with Celiac Disease
        1. Find Out More
      6. Living Gluten Free
        1. Allowed Foods
        2. Foods to Avoid
  7. Researcher
    1. Press Release
      1. Youngevity (YGYI) Announces Acquisition of Restart Your Life
    2. Slides
      1. Slide 1 Glucan
      2. Slide 2 Leukemia & Lymphoma Journal Article
      3. Slide 3 This what you would see if you had really good eyes…or an electron microscope
      4. Slide 4 The phagocytosis of bacteria or phagocytosis of synthetic microspheres is often used for glucan evaluation
      5. Slide 5 The PAC MAN of the immune system in various states
      6. Slide 6 Demonstration of Oral Uptake of Yeast Beta 1,3-D Glucan 1
      7. Slide 7 Demonstration of Oral Uptake of Yeast Beta 1,3-D Glucan 2
      8. Slide 8 effects of two weeks of treatment with different glucans on size of tumors
      9. Slide 9 Long-term effect of orally-given glucans on secretion of IL-2 by spleen cells
      10. Slide 10 Glucan-induced recovery of bone marrow after irradiation of mice
      11. Slide 11 Effect of long-term feeding with individual glucans on blood cholesterol levels in experimentally-induced hypercholesterolemia
      12. Slide 12 Feeding with glucan can control the experimentally-induced hyperglycemia
      13. Slide 13 Effects of various glucans on ear swelling
      14. Slide 14 Glucan in diet reduces supression of immunity caused by mercury
      15. Slide 15 Effects of different glucans on immunosuppression caused by immunotoxic agents
      16. Slide 16 Glucan stimulates the wound healing of human skin cells
      17. Slide 17 Improvement in skin properties after application of glucan in creams
      18. Slide 18 Effect of 14 days of feeding on stress-induced levels of corticosterone
      19. Slide 19 Effects of glucan supplementation of antibody formation in children
      20. Slide 20 Effects of different immunomodulators on phagocytic activity
      21. Slide 21 Effects of various combinations on NK cell activity
      22. Slide 22 Differences in glucan content among different commercial glucans
      23. Slide 23 More glucan does not always mean higher activity as inferior glucans never reach the biological activities of superior glucans
      24. Slide 24 Effects of different combinations on production of IL-2
      25. Slide 25 Effects of resveratrol-vitamin C-glucan combination on antibody response
      26. Slide 26 Effects of resveratrol-vitamin C-glucan combination on phagocytosis in stressed mice
      27. Slide 27 Before and After
      28. Slide 28 Wound Healing
      29. Slide 29 How To Never Run Out of Leads
      30. Slide 30 Acknowledgement
  8. PubMed Search - Glucan
    1. See 1 citation found by title matching your search
    2. Author information
    3. Abstract
    4. Keywords
    5. PubMed Help
  9. Data Scientist: Publication - Leukemia & Lymphoma
    1. Original Article: Clinical
    2. Format Options
    3. Authors
    4. Abstract
    5. Keywords
    6. Agreement
    7. Result
      1. Abstract
      2. Introduction
      3. Methods
      4. Therapy
      5. Response evaluation
      6. Statistical analysis
    8. Results
      1. Table I Patient demographics
      2. Table II Treatment summary
      3. Toxicity
      4. Treatment response
        1. Figure 1. Time to progression
        2. Figure 2. Time to retreatment
    9. Discussion
    10. Acknowledgement
    11. Potential Conflict of Interest
    12. References
      1. 1
      2. 2
      3. 3
      4. 4
      5. 5
      6. 6
      7. 7
      8. 8
      9. 9
      10. 10
      11. 11
      12. 12
      13. 13
      14. 14
      15. 15
      16. 16
      17. 17
      18. 18
    13. Supplementary Material
  10. Semantic Medline
  11. Semantic Insights
  12. Tamr
  13. NEXT

Story

NLM - Semantic Medline Data Science Data Publication

The 2015 Health Datapalooza Session on The Precision Medicine Initiative - Changing the Future of Health and Medicine was:

The Precision Medicine Initiative, announced by the President in January, is a bold new research project to revolutionize how we improve health and treat disease. The initiative will pioneer a new model of participant-centered research that promises to accelerate biomedical discoveries and provide clinicians with new tools, knowledge, and therapies to select which treatments will work best for which patients. Translating initial successes to a larger scale will require a coordinated and sustained national effort. To get there, we need to incorporate many different types of data including genetic information, personal device and sensor data, and medical records collected by health care providers and by patients themselves. Success will require that health information can be easily shared between providers, researchers, and most importantly, patients and research participants.

Speakers: Mina Hsiang, U.S. Digital Service, The White House; Kathy Hudson, PhD, Deputy Director for Science, Outreach, and Policy, National Institutes of Health; Claudia Williams, Senior Advisor for Health Innovation and Technology, The White House.

During my attendance, I was prompted me to ask what the Federal Big Data Working Group Meetup, with over 800 data scientists, could do to help by (1) Analyzing existing data sets and/or (2) Helping create new data sets, in light of the fact that our Semantic Medline Data Science Team had previously found the following in early 2013: PubMed shows that cancer immunotherapy is becoming more successful than cancer chemotherapy and that certain enzymes are successful in schizophrenia treatment! Our Data Science Team came to this conclusion about a year before Science Magazine did as you can see below!

So doctors like, Dr. Joel D. Wallach, and others that say strengthen the bodies immunity against cancer are supported by the premier medical literature in the world (PubMed: about 30 Million documents in our 2013 pilot and more each day now on the Cray Graph Supercomputer at Oak Ridge National Laboratory). This is why our federal Big data Working Group has launched the Natural Medicine for Disease and Wellness Initative. Also see recent article (January 28, 2015) on Big data promises a health care remedy quoting me.

The response of the Speakers was very positive and included mention of a forthcoming report on the future of the NLM next week.

As a result, I met with the NLM Semantic Medline Team, led by Dr. Tom Rindflesch, and their newest addition, Dr. Sreenivas Rangan Sukumar, Oak Ridge National Laboratory, who presented at the 2015 Health Datapalooza, to hear an update on their work, and present my idea for an NLM - Semantic Medline Data Science Data Publication Pilot.

Their response was very encouraging and I outlined and quickly started an initial Data Science Data Publication below:

Data Science Data Publication: Natural Medicine for Disease and Wellness-Semantic Medline

  • Policy Makers: Future of NLM - Report
  • Public: NLM MedlinePlus - Gluten
  • Researcher: Press Release, Slides, & PubMed Search - Glucan
  • Data Scientist: Publication - Leukemia & Lymphoma My Note: I need to do the Reference Links (Done) and Copy the Tables to Spreadsheet and Try to Recreate the Graphics in Spotfire
  • Semantic Medline: Context - For Each & Add More Data (Genomic & Nutrition)
  • Researchers: Have Examples - Data Scientists Help Them

The Slides below document how The National Library of Medicine's Web Site was Data Mined for Databases, Resources & APIs into a Data Science Data Publication that supports the NIH ACD National Library of Medicine (NLM) Working Group Report.

Interestingly, as I listen to NIH ACD Meeting on June 11th, I added the Presentation Slides and Full Report (originally PDF) to this Knowledge Base. The mllennial generation would say that I "hacked" the NIH ACD Meeting! I also included the NIh: Data Science & BD2K Slides from the Health Datapalooza 2015 DataLab Session because Dr. Philip Bourne was present during the meeting to comment of the relationship between the NLM Working Group Report and his Data Science Program and the possibility that the Data Science Program might be eventually institutionalized within the NLM.

The NLM -Semantic Medline Data Science Data Publication consists of this Knowledge Base, a Spreadsheet, and ​NLM Semantic Medline Data Science Data Publication 1 in Spotfire. See NIH Data Publication 1, done for Dr. Philip Bourne earlier.

We will be adding Semantic Medline Queries and Interpretations and seeingif if Semantic Insights and Tamr are interested in this pilot and can produce results, in preparation for the July 20th Meetup on Data Science for ACA Data and Semantic Medline Precision Medicine.

The Conclusions and Recommendations are:

  • National Library of Medicine's Web Site was Data Mined for Sample Databases, Resources & APIs.
  • A NIH – Semantic Medline Data Science Data Publication Was Created For A NIH – Semantic Medline Data Science Data Publication Commons.
  • The NIH ACD National Library of Medicine (NLM) Working Group Report Was Repurposed (PDF-to-MindTouch and Inline Presentation Slides) for the Knowledge Base.
  • This Knowledge Base Was Prepared for July 20th Meetup of the Federal Big Data Working Group Meetup on Data Science for ACA Data and Semantic Medline Precision Medicine.
  • Additional NLM and NIH Institute Open Data Sets Will Be Mined, Integrated, and Federated in a Series of Data Science Data Publications for the Commons for Additional Data Science Tutorials and Meetups.

Some items for followup are:

The UMLS semantic network reduces the complexity of the Metathesaurus by grouping concepts according to the semantic types that have been assigned to them. For certain purposes, however, an even smaller and coarser-grained set of semantic type groupings may be desirable. The following principles were used to design the groupings: semantic validity, parsimony, completeness, exclusivity, naturalness, and utility. The 15 semantic groups provide a partition of the UMLS Metathesaurus for 99.5% of the concepts.

More information about the semantic groups is available in the following papers:

McCray AT, Burgun A, Bodenreider O. Aggregating UMLS semantic types for reducing conceptual complexity. Proceedings of Medinfo 2001;10(Pt 1):216-20. [download PDF]. My Note: This is missing and I notified Olivier Bodenreider.

Bodenreider O, McCray AT Exploring semantic groups through visual approaches. Journal of Biomedical Informatics 2003;36(6):414-432. [download PDF].

The UMLS semantic groups are made available through a file called SemGroups.txt. There is one line in this file for each semantic type. The identifier and the name of the semantic group are repeated for each semantic type included in the group, before the identifier (TUI) and the name (STY) of the semantic type. My Note: This is Spreadsheet Tab: SemGroups in the HDP2015 Spreadsheet.

Slides

NLM-Semantic Medline Data Science Data Publication Commons

Slides

Slide 2 Overview

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Slide 3 National Library of Medicine's Web Site

http://www.nlm.nih.gov/

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Slide 4 Definitions for the National Library of Medicine's Permanence Levels

http://www.nlm.nih.gov/permlevels.html

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Slide 5 Data Mining

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Slide 6 Databases, Resources & APIs

https://wwwcf2.nlm.nih.gov/nlm_ereso...h_database.cfm

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Slide 7 NLM-SemMed Data Science Data Publication: Database Linked Data Spreadsheet

HDP2015.xlsx

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Slide 8 Broad Subject Terms for Indexed Journals

https://wwwcf.nlm.nih.gov/serials/journals/index.cfm

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Slide 9 NLM-SemMed Data Science Data Publication: Broad Subject Terms Linked Data Spreadsheet

HDP2015.xlsx

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Slide 10 NLM-SemMed Data Science Data Publication: SpotfireData Commons

Web Player

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Slide 11 NLM-SemMed Data Science Data Publication: LOINC Big Data

http://loinc.org/downloads

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Slide 12 NLM-SemMed Data Science Data Publication: LOINC Big Data in Spotfire

Web Player

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Slide 13 NLM-SemMed Data Science Data Publication: MindTouch Knowledge Base

Semantic Community Data Science Data Science for Health Datapalooza 2015 NLM - Semantic Medline Data Science Data Publication

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Slide 14 Conclusions and Recommendations

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NIh: Data Science & BD2K

Slides

Slide 1 NIH: Data Science & BD2K

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Slide 2 NIH Big Data to Knowledge

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Slide 3 The Commons 1

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Slide 4 The Commons 2

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Slide 5 Data and Tool Resources at NIH

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Slide 6 BD2K & The Commons

https://datascience.nih.gov

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National Library of Medicine Working Group – Interim Briefing about the Final Report

Slides

Slide 1 National Library of Medicine Working Group – Interim Briefing about the Final Report

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Slide 2 The Context 1

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Slide 3 The Context 2

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Slide 4 The Context 3

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Slide 5 The Context 4

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Slide 6 Today's Focus

http://acd.od.nih.gov/meetings.htm

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Slide 7 Report

HarlanMKrumholz06112015Slide7.PNG

Slide 8 Charge to the NLM Working Group

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Slide 9 Charge: Assess How NLM Should 1

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Slide 10 Charge: Assess How NLM Should 2

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Slide 11 Charge: Assess How NLM Should 3

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Slide 12 NLM Working Group Membership

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Slide 13 Deliberative (and Rapid) Process

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Slide 14 Listen and Learn from Community

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Slide 15 Observations 1

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Slide 16 Observations 2

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Slide 17 What We Heard... 1

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Slide 18 What We Heard... 2

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Slide 19 Resources

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Slide 20 Observations: NLM has Challenges 1

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Slide 21 Observations: NLM has Challenges 2

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Slide 22 Recommendations

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Slide 23 Recommendations #1: 'General Scope' 1

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Slide 24 Recommendations #1: 'General Scope' 2

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Slide 25 Recommendations #1: 'General Scope' 3

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Slide 26 Recommendations #1: 'General Scope' 4

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Slide 27 Recommendations #1: 'General Scope' 5

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Slide 28 Recommendations #2: 'Open Science' 1

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Slide 29 Recommendations #2: 'Open Science' 2

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Slide 30 Recommendations #2: 'Open Science' 3

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Slide 31 Recommendations #2: 'Open Science' 4

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Slide 32 Recommendations #2: 'Open Science' 5

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Slide 33 Recommendation #3: 'Data Science' 1

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Slide 34 Recommendation #3: 'Data Science' 2

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Slide 35 Recommendation #3: 'Data Science' 3

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Slide 36 Recommendation #3: 'Data Science' 4

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Slide 37 Recommendation #3: 'Data Science' 5

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Slide 38 Recommendation #4: 'Training' 1

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Slide 39 Recommendation #4: 'Training' 2

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Slide 40 Recommendation #4: 'Training' 3

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Slide 41 Recommendation #5: 'History' 1

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Slide 42 Recommendation #5: 'History' 2

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Slide 43 Recommendation #5: 'History' 3

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Slide 44 Recommendation #6: "Further Evaluation' 1

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Slide 45 Recommendation #6: "Further Evaluation' 2

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Slide 46 Concluding Remarks

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Slide 47 A Robust NLM is Vital 1

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Slide 48 A Robust NLM is Vital 2

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Using Semantic MEDLINE to Explore Glucan Research

Dr. Tom Rindfleash, NIH/NLM, Slides

Slide 1 Using Semantic MEDLINE to Explore Glucan Research

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Slide 2 Web Application: Semantic Medline

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Slide 3 SemRep

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Slide 4 Semantic Predication

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Slide 5 ​Semantic Medline Overview

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Slide 6 SemMed: Semantic Predications

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Slide 7 Research on Glucans

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Slide 8 Predicational Overview

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Slide 9 AUGMENTS Immunologic Function

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Slide 11 Tumor cells, malignant LOCATION_OF

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Slide 13 TREATS Neoplasms

TomRindflesch07202015Slide13.PNG

Spotfire Dashboard

​NLM Semantic Medline Data Science Data Publication 1

For Internet Explorer Users and Those Wanting Full Screen Display Use: Web Player Get Spotfire for iPad App

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NIH Data Publication 1

See Story for Details

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Research Notes

https://nccih.nih.gov/

PDF-to-PPT: http://document.online-convert.com/convert-to-ppt

110th Meeting of the Advisory Committee to the Director (ACD)

http://acd.od.nih.gov/meetings.htm

National Institutes of Health (NIH)
Building 31, C Wing, 6th Floor, Conference Room 6, NIH Campus, Bethesda, Maryland
Draft Agenda

Thursday, June 11, 2015

Source: http://acd.od.nih.gov/agendas/062015_Day1_Agenda.pdf

9:00 am OPEN SESSION: Welcome and NIH Director’s Report

  • Francis S. Collins, M.D., Ph.D., Director, NIH

10:30 am Discussion
11:00 am BREAK
11:15 am ACD National Library of Medicine (NLM) Working Group Report Slides and Report

  • Harlan Krumholz, M.D. (co-chair), Yale University
  • Eric Green, M.D., Ph.D. (co-chair), National Human Genome Research Institute

12:45 pm Discussion
1:15 pm GROUP PHOTO and LUNCH
2:15 pm Planning for the NIH-Wide Strategic Plan

  • Lawrence A. Tabak, D.D.S., Ph.D., Principal Deputy Director, NIH

3:00 pm Discussion
3:15 pm ACD HeLa Working Group Update

  • Clyde Yancy, M.D. (co-chair), Northwestern University
  • Kathy L. Hudson, Ph.D. (co-chair), Deputy Director for Science, Outreach, and Policy, NIH

3:30 pm Discussion
3:45 pm BREAK
4:00 pm ACD Physician-Scientist Workforce Working Group Report

  • Presented by Sherry Mills, M.D., M.P.H., Director, Office of Extramural Programs, NIH

4:30 pm Discussion
5:00 pm Adjourn

Friday, June 12, 2015

Source: http://acd.od.nih.gov/agendas/062015_Day2_Agenda.pdf

9:00 am OPEN SESSION: Opening Remarks

  • Francis S. Collins, MD, PhD, Director, NIH

Review of Outside Awards for ACD Approval

  • Lawrence A. Tabak, DDS, PhD, Principal Deputy Director, NIH

9:15 am ACD Precision Medicine Initiative (PMI) Working Group (WG) Update

  • Kathy L. Hudson, PhD, Deputy Director for Science, Outreach, and Policy, NIH, and PMI WG co-Chair
  • Richard Lifton, MD, PhD, Yale University, and PMI WG co-Chair
  • Bray Patrick-Lake, MFS, Duke University, and PMI WG co-Chair

10:00 am Discussion
10:30 am NIH Response to the ACD Long-Term Intramural Research Program (LT-IRP) Planning Working Group

  • Michael Gottesman, MD, Deputy Director for Intramural Research, NIH

11:00 am Discussion
11:30 am Closing Statement and Adjourn

Policy Makers: Future of NLM - Report

Source: http://acd.od.nih.gov/reports/Report...112015-ACD.pdf (PDF)

  • Report of the NLM Working Group of the Advisory Committee to the NIH Director, June 11 at 11:15 am ET
  • From NLM Acting Director Betsy L. Humphreys:
    • The NLM Working Group of the Advisory Committee to the Director of NIH (ACD) will present its vision and recommendations for an expansive and exciting future for NLM to the full ACD on June 11, 2015.
    • The presentation is scheduled to begin at 11:15 am.  You will find the full agenda for the ACD meeting at http://acd.od.nih.gov/meetings.htm
    • The meeting will be broadcast live and also archived so you will be able to watch it at http://videocast.nih.gov/
    • The text of the report will be posted on the ACD website soon after the meeting.  Recruitment for a new permanent NLM Director will begin shortly thereafter, too.

Source: Blog

Report

Source: http://acd.od.nih.gov/reports/Report...112015-ACD.pdf (PDF)

National Institutes of Health

Advisory Committee to the Director

National Library of Medicine (NLM) Working Group

FINAL REPORT – JUNE 11, 2015

MEMBERS: Eric Green (co-­‐chair), Harlan Krumholz (co-­‐chair), Russ Altman, Howard Bauchner, Deborah Brooks, Doug Fridsma, Steven Goodman, Eric Horvitz, Trudy MacKay, Alexa McCray, Chris Shaffer, David Van Essen, Joanne Waldstreicher, James Williams, II, Kathy Hudson (ex officio), Lyric Jorgenson (executive secretary) (titles and affiliations listed in Appendix A)

Executive Summary

The NIH Director charged the National Library of Medicine (NLM) Working Group, hereafter referred to as the Working Group, with articulating a strategic vision for NLM to ensure that NLM remains an international leader in biomedical and health information. Over the course of five months of deliberations, the Working Group reviewed numerous documents and reports pertaining to NLM’s mission and activities, consulted with NLM leadership and staff, and solicited public comments and suggestions. The Working Group recognizes that NLM has an important opportunity to play a key leadership role in one of the most exciting periods of biomedical history: data science is increasing rapidly, computational power is expanding at a breathtaking pace, the breadth and depth of digital health data are undergoing unprecedented and accelerating growth, a movement towards more interdisciplinary work and team science continues to gain momentum, a broad commitment to open science is becoming increasingly adopted, and the demand for services to support an ever more engaged and informed public is expanding. To leverage these historic changes, the Working Group, with respect for the outstanding history of NLM and its potential for the future, formulated a series of recommendations to guide the future of NLM:

RECOMMENDATION #1. NLM must continually evolve to remain a leader in assimilating and disseminating accessible and authoritative biomedical research findings and trusted health information to the public, healthcare professionals, and researchers worldwide.

RECOMMENDATION #2. NLM should lead efforts to support and catalyze open science, data sharing, and research reproducibility, striving to promote the concept that biomedical information and its transparent analysis are public goods.

RECOMMENDATION #3. NLM should be the intellectual and programmatic epicenter for data science at NIH and stimulate its advancement throughout biomedical research and application.

RECOMMENDATION #4. NLM should strengthen its role in fostering the future generation of professionals in biomedical informatics, data science, library sciences, and related disciplines through sustained and focused training efforts.

RECOMMENDATION #5. NLM should maintain, preserve, and make accessible the nation’s historical efforts in advancing biomedical research and medicine, thereby ensuring that this legacy is both safe and accessible for long-­‐term use.

RECOMMENDATION #6. New NLM leadership should evaluate what talent, resources, and organizational structures are required to ensure NLM can fully achieve its mission and best allocate its resources.

The collective vision represented by these recommendations aims to position NLM to capitalize fully on current and future opportunities and to emerge as a unifying force in biomedicine that promotes and accelerates knowledge generation, dissemination, and understanding in the United States and internationally.

Introduction

NLM has an outstanding record of being at the forefront of how biomedical data and health information are collected, shared, and analyzed. It has, particularly over the past two decades, responded to changing opportunities and emerging technological capabilities. For many people around the world, NLM is a trustworthy and comprehensive source of health and biomedical information, with PubMed as its most visible asset (but with many other essential and valued programs representing critical NLM contributions). In addition, NLM is a source of support for training the next generation of data scientists and librarians, the place to learn about the past and explore the history of medicine and biomedical research, a source of new knowledge and standards as a result of its intramural research programs, and a repository of data for use in myriad research studies. The remarkable work of NLM has generated international goodwill and reflected positively on NIH and the United States. In fact, for many, NLM is the most visible face of NIH.

Though NLM’s accomplishments are numerous, there is a need to assess how NLM can leverage new opportunities and address the many challenges that lie ahead. Biomedical and healthcare science is at a critical juncture, with the growth of data science, leaps in computational power to store and analyze the data, and the ubiquitous reach of large-­‐scale networked systems in science and society. At the same time, biomedical research has evolved to become more interdisciplinary and team-­‐oriented, with an increasing commitment to the use of ‘big data’ and open science. Finally, with the growth and ubiquity of the Internet, the general public needs easy access to online, high-­‐quality services and information, especially related to their health. Framed by this context, the recommendations in this report aim to provide guidance on efforts and investments that will position NLM to become a trusted and valuable 21st-­‐century nexus for health and biomedical information – a visionary library of the future.

Recognizing the opportunities and challenges on the horizon, the NIH Director convened this Working Group of the Advisory Committee to the NIH Director (ACD) to articulate a strategic vision for NLM to ensure that it remains an international leader in biomedical and health information. In addressing its charge, the Working Group was asked to specifically assess how NLM should:

  • Continue to meet the biomedical community’s rapidly evolving scientific and technological needs;
  • Lead the development and adoption of information technologies;
  • Facilitate the collection, storage, and use of biomedical data by the biomedical and health research communities;
  • Continue to lead in promoting open access models for biomedical data and scientific literature;
  • Balance computational methods and human-­‐based approaches for indexing;
  • Maximize the utilization and cost-­‐efficiency of NLM’s National Network of Libraries ofMedicine;
  • Maximize the usefulness of NLM’s other outreach and exhibits programs in the contextof future opportunities;
  • Interface effectively with the broader and expanding NIH efforts in data science; and
  • Directly contribute to addressing the major data science challenges facing thebiomedical research enterprise.

This report summarizes the deliberations, observations, and recommendations of the Working Group.

Process for Deliberations

To address its charge, the Working Group met on four conference calls and at two in-­‐person meetings over five months to review the current mission, organization, and programmatic priorities of NLM; consult with NIH and NLM leadership (see Appendix B); evaluate NLM’s strengths and weaknesses; identify emerging opportunities and challenges; and craft final recommendations. Frequent and considerable communications between and among Working Group members took place between meetings. The Working Group studied numerous materials, including NLM’s Long Range Plan issued for 2006-­‐2016 1, allocation and utilization of resources, programmatic activities, priority setting processes, oversight structures, and relationships with other entities.

Given the diversity and scope of NLM’s mission and its stakeholders, the Working Group felt that it was critical to solicit broad public input. Thus, NIH issued a Request For Information (RFI) on the Working Group’s behalf to gain further insights into what is needed from a future NLM (see Appendix C). In addition, the Working Group collected public comments throughout the process and considered them throughout its deliberations. It should be noted that the Working Group recognized that its task was to define the strategic vision and direction for NLM, but not define the operational path needed for achieving that vision. The Working Group recognizes that, ultimately, it will be the new NLM director who must create a strategic plan to build upon and implement the vision described by the Working Group. Therefore, the report does not specify changes, and the assumption is that an operational plan will follow based on subsequent analyses and deliberations.

Summary of Observations

NLM has been a center of information innovation since its founding in 1836. Its stated purpose is “to assist the advancement of medical and related sciences and to aid the dissemination and exchange of scientific and other information important to the progress of medicine and to the public health” 2. This mission is achieved through the conduct of many crucial functions, among them, NLM:

  • Serves as a national information resource for medical education, research, and service activities of Federal and private agencies, organizations, and institutions;
  • Serves as a national information resource for the public, patients, and families by providing electronic access to reliable health information issued by NIH and other trusted sources;
  • Publishes in print and electronically guides to health sciences information in the form of catalogs, bibliographies, indexes, and online databases;
  • Provides support for medical library development and for training of biomedical librarians and other health information specialists;
  • Conducts and supports research in methods for recording, storing, retrieving, preserving, and communicating health information;
  • Creates information resources and access tools for molecular biology, biotechnology, toxicology, environmental health, and health services research; and
  • Provides technical consultation services and research assistance.

Given the breadth of its functions and activities, it is not surprising that NLM has many stakeholders – many of whom express resounding support for its mission. This enthusiasm was evident in Working Group’s analysis of the responses to the RFI issued by NIH; in total, 650 responses were received from both domestic and international individuals and organizations. Working Group members undertook an in-­‐depth review of these submissions, finding broad support for many of NLM’s programs and tools (e.g., PubMed, MedlinePlus, ClinicalTrials.gov), along with its functions in organizing, indexing, and providing access to data. NLM’s training programs were also prominently commended for their essential role in cultivating the next generation of biomedical informaticians, health science librarians, health services researchers, and related professionals. The responses highlighted the diversity of users and breadth of programs that NLM has managed over its illustrious history. NLM is a trusted authority for the sharing of quality health information to the public and is relied upon for many programs and resources, including health information, data services, and training programs.

Over its history, NLM has become a leader in making high-­‐quality health and science information easily, publicly, and freely available to everyone. The provision of access to scientific literature through PubMed and PubMed Central is invaluable to researchers, clinicians, and the public all over the world. The creation and maintenance of public health information portals like MedlinePlus and ToxNet, and improved transparency of the research process for patients and the public through ClinicalTrials.gov are further examples of NLM seeking to improve the availability of health knowledge. Additionally, NLM’s unparalleled collection of primary historical sources and growing digital collections of medical artifacts are depended upon by historical researchers and educators.

NLM has been a critical partner in the advancement of library science innovation and established its reputation as an institution of expertise and leadership in the collection, organization, curation, and dissemination of biomedical data. NLM recognized the burgeoning need for genomic data infrastructure and informatics research, leading to the creation of the National Center for Biotechnology Information (NCBI) and a public reputation for assimilating biomedical and genomic data, maintained and made accessible in numerous high-­‐quality databases and data resources.

NLM’s information and data services are relied upon every day by millions of scientists, health professionals, and the public everywhere, in the United States and around the world. The incredibly positive relationship that NLM has built with its broad range of users is a tribute to its long and illustrious legacy. It also enables NLM to serve as the most well-­‐known ambassador of the NIH to the world, and this role will continue to be a tremendous opportunity for NLM and NIH going forward.

However, NLM is not without its challenges. Reflecting its broad mission, NLM has been adept at absorbing additional functions and responsibilities related to information collection and dissemination when called upon by public need. However, in being responsive to varied mandates over its ~180 year history, the organization has faced challenges in the integration of its programs into a prospective framework. NLM’s broad range of users creates diverse needs for NLM programs and tools. A major challenge for NLM is maintaining interaction with users across programs in a consistent fashion; this interaction is critical for optimizing the development and use of NLM products. Moving into the future of biomedical research, in which data science will continue to play an increasing role, NLM will encounter greater demands on its expertise and resources. The rapid expansion of data science and biomedical informatics, in the face of ongoing budget constraints, will force NLM to maximize efficiency of its existing functions and future priorities into a cohesive structure. NLM’s involvement in data science applications in biomedical research has been essential, but careful consideration and strategic planning will be essential for NLM to maintain (and likely expand) that role.

In summary, NLM’s path going forward must build upon its prior successes, leverage existing strengths, and capitalize on emerging opportunities. Choices will need to be made with respect to what new programs should be developed, as well as what current programs should be expanded or stopped. The recommendations set forth in this report aim to encompass these principles to craft a bold yet attainable vision for NLM.

Recommendations

RECOMMENDATION #1

NLM must continually evolve to remain a leader in assimilating and disseminating accessible and authoritative biomedical research findings and trusted health information to the public, healthcare professionals, and researchers worldwide.

While NLM has been a leader in identifying, storing, promoting, and disseminating a wealth of biomedical information to individuals and organizations around the world, it needs to adapt to a rapidly changing science and technology landscape. To succeed in these efforts, NLM must leverage emerging technologies, promote data standards, and engage directly with biomedical researchers, healthcare professionals, industry, government organizations, and the public in carrying out its mandate. In short, NLM must remain committed to consistent and sustained interactions with its broad base of stakeholders in carrying out its activities. From identification of user requirements to development of services to evaluation of impact, the success of NLM’s programs will be enhanced by user engagement.

Recommendation #1a. NLM should coordinate with other U.S. and international agencies on the collection, interpretation, and access of biomedical and healthcare-­‐related information.

Recommendation #1b. NLM should directly engage its constituents in an iterative process of resource creation, maintenance, and evaluation. This process should be uniformly applied across NLM programs to achieve meaningful interactions with users.

Recommendation #1c. NLM should promote the connection of disparate data sources and streams to enable improved knowledge integration and generation. Techniques or integration resources should be identified and developed that can assure better links between and among NLM informational resources, including PubMed, MedlinePlus, biobanks, model organism databases, and registries. NLM should also play a leadership role in harmonizing and connecting with international databases. For example, one could envision a future in which ClinicalTrials.gov drives global harmonization of requirements and standards, while also expanding in scope to accommodate the hosting of metadata and even participant level data.

Recommendation #1d. NLM should seek to understand, integrate, and leverage the complementarity of its resources and services with the access and availability of biomedical and health information via search engines and browsing of other sources of health information on the web, whether commercial, non-­‐profit, or open-­‐source. It should augment these other resources to provide high-­‐quality resources and services unique to the mission of NLM.

RECOMMENDATION #2

NLM should lead efforts to support and catalyze open science, data sharing, and research reproducibility, striving to promote the concept that biomedical information and its transparent analysis are public goods.

NLM should be a leader and innovator in open science efforts worldwide, leveraging the power of data and devising new strategies for integrating and sharing diverse data types, along with building upon its prior successes. NLM should make data accessible (i.e., curating and exposing data, promoting the development and availability of application program interfaces (APIs), and identifying standards when necessary). Its efforts should support the creation of markets for data and encourage the development of reusable tools and resources that provide health information and knowledge at the point of need. Tools and resources must be designed for efficient and effective integration into workflows in support of users with different roles and with varying levels of expertise. Methods and services should be made transparent, and efforts should be directed towards a future where valuable health-­‐related data can be logged, accessed, searched, and shared to enhance the reproducibility of results and to maximize the value of investments in biomedical research. The overarching goal is to empower people, including scientists, with data to improve knowledge generation and promote an understanding of biomedical information. Overall, this represents a strong commitment to transparency.

Recommendation #2a. NLM should serve as a locus of expertise for the management and evaluation of NIH databases and knowledge bases, maintaining a broad perspective of trans-­‐NIH database management efforts, playing a role in establishing common policies and coordination strategies, and promoting sharing in the most responsible ways.

Recommendation #2b. NLM should lead NIH efforts to engage the research community and public in examining the ethical, legal, and social implications of sharing biomedical data, and should participate in the broader efforts to develop policies in these areas.

Recommendation #2c. NLM should lead efforts to promulgate and implement best practices in open source, open science, standards, and data harmonization, forming partnerships across communities, stakeholder organizations, agencies, and countries. NLM should be an active participant in the design and oversight of programs that incentivize and celebrate the open sharing of data and resources.

Recommendation #2d. NLM should actively collaborate with developer communities. Tools and resources should be disseminated using industry standards for data sharing and programmatic access (e.g. well documented APIs or SPARQL endpoints) to enable reuse by researchers and other stakeholders.

RECOMMENDATION #3

NLM should be the intellectual and programmatic epicenter for data science at NIH and stimulate its advancement throughout biomedical research and application.

The last decade has brought breathtaking advances in both our ability to collect biomedical data and our ability to analyze large datasets. As a result, NIH (and indeed, the entire biomedical research enterprise) faces extraordinary ‘big data’ opportunities as well as challenges. In 2012, the NIH ACD Data and Informatics Working Group 3 made recommendations about these circumstances, focusing on the need for systematic efforts in data sharing, methods, and workforce development, and refining NIH’s internal structure and operations in this area. The acceptance and implementation of these recommendations was ultimately framed around the recently coined term “data science”, construed broadly to reflect multiple contributing technical disciplines (e.g., computer science, statistics, bioinformatics, biostatistics, computational biology, medical informatics, information science, quantitative biology).

Among the initial steps to nurture and accelerate data science programs at NIH were the establishment of a new NIH leadership position (the NIH Associate Director for Data Science) and the launching of a major new trans-­‐NIH program—the Big Data to Knowledge (BD2K) Initiative, which includes training, creation of research hubs, support for investigator research, and other key activities. However, these steps represent just the beginning of a series of needed long-­‐term institutional efforts to adequately position the NIH for a future in which data science is central to virtually all aspects of biomedical research. The Data and Informatics Working Group left unresolved the issue of where the center of intellectual and programmatic activities in biomedical data science should reside at NIH.

NLM is now poised to build on its activities in computational-based research, data dissemination, and training to assume the NIH leadership role in data science. Indeed, while essentially all the other NIH Institutes/Centers are involved with and depend upon data science, none is best situated to serve as its epicenter within NIH. Partly for this reason, the new BD2K Initiative was launched as a trans-NIH effort. It is clear, however, that BD2K must have a stable, long-term home to provide support sustainable oversight and an appropriate programmatic infrastructure. NLM’s history of innovation together with its strengthened focus on supporting and catalyzing open science make it the obvious choice to oversee these activities under the leadership of its incoming director.

Recommendation 3a. NLM should become the programmatic and administrative home for the BD2K Initiative, taking the lead in advancing BD2K and defining subsequent data science efforts. In addition, NLM should lead the coordination of data science programs (and programs with large data science components) conducted at other NIH Institutes/Centers, in order to maximize synergies and minimize redundancies.

Recommendation 3b. NLM should promulgate intramural and/or extramural expertise, knowledge generation and dissemination, and leadership in areas of data science that are critical to the NIH mission. For example, NLM should help nurture a national talent pool in the science and engineering of Electronic Health Records (EHRs), the analysis of biomedical text, the integration of diverse and multimodal datasets, the application of novel computational and statistical methods to extract knowledge, and future domains that involve extracting data and producing knowledge from digital health sources. These areas are just a sample of those required to advance important health initiatives, such as the recently announced Precision Medicine Initiative. Other data science areas that need robust research and/or training programs at NIH should be identified as part of NLM’s strategic planning efforts.

RECOMMENDATION #4

NLM should strengthen its role in fostering the future generation of professionals in biomedical informatics, data science, library sciences, and related disciplines through sustained and focused training efforts.

NLM should expand its role in training the next generation workforce in its mission-­‐critical areas, either as a primary sponsor or a facilitator working with other NIH Institutes/Centers, agencies, and organizations. The efforts should range from high school programs and/or curricula through post-­‐doctoral programs. NLM should also be a leader in developing programs or materials for practitioners who could use NLM resources in the provision of medical care and public health services. This workforce includes medical students and physicians, public health professionals, nurses, first responders in many domains, and information specialists who support such activities. The dearth of human capital in this area must be addressed by a national strategy that is led by NLM.

Given the above recommendation about data science (Recommendation #3), it is imperative that NLM develop a national strategy for training data scientists in a manner that recognizes the breadth of fields that need this expertise (beyond bioinformatics) and the intrinsic interdisciplinary nature of successful science. In addition to directly supporting training, NLM needs a comprehensive understanding of the nature, number, and coordination of training programs in the various disciplines of data science across NIH, government partners, and the general biomedical research community.

Recommendation #4a. NLM should develop and support new, comprehensive, and coordinated strategic training initiatives related to professional development across multiple spheres – from training for librarians on NLM’s various databases to designated point-­‐of-­‐need training for clinicians, data managers, first responders, historians, and nurses. Health sciences curricula on the use of NLM resources for patient care and research should also be developed.

Recommendation #4b. NLM should be the center for nurturing the core science and methodologies of biomedical informatics, data science, and library science through research and training programs; it should also nurture partnerships with other NIH programs, other Federal agencies, and outside organizations in which informatics and biostatistics are a core component.

RECOMMENDATION # 5

NLM should maintain, preserve, and make accessible the nation’s historical efforts in advancing biomedical research and medicine, thereby ensuring that this legacy is both safe and accessible for long-­‐term use.

NLM should continue to be the national custodian of historically important biomedical data and health information in print and digital formats (e.g., film, audio, video, paper, data, and databases). NLM should enable access to these materials and those housed by other institutions, so that they can be used to conduct basic and applied research, practice evidence-­‐based medicine, and make informed healthcare decisions. Preservation and access are basic tenets for libraries, and NLM is no different. NLM should thus be a leader in the preservation and access domain. Digital preservation in this case assumes continuous processes for bit validation and bit-­‐checking. It assumes robust dark and light storage, redundancy in digital preservation sites, and preservation of all formats of information. It also assumes persistent and intuitive search and retrieval protocols that provide recall over time, regardless of the audience or inquiry.

Recommendation #5a. NLM should lead and form partnerships to advance the core professional domains of data and knowledge capture, such as archiving, search, and analysis.

Recommendation #5b. NLM should develop and implement a strategic preservation and access plan for medical knowledge in all formats, including the ephemeral forms that are increasingly dominating medical communication (e.g., online journals, blogs, and databases).

RECOMMENDATION #6

New NLM leadership should evaluate what talent, resources, and organizational structures are required to ensure NLM can fully achieve its mission and best allocate its resources.

In making this recommendation, the Working Group focused on the vision for NLM’s future, not on evaluating how it might have to modify its existing priorities, functions, and organizational structure to achieve that vision. There is a recognition that resources for NLM are unlikely to increase markedly, and there will thus be a need to seek efficiencies, eliminate redundancies, leverage technologies, and make difficult choices in order to implement these recommendations. The new NLM Director will need to conduct a rigorous and thorough review of all components of the organization to determine which ones are optimally positioned to accomplish these recommendations. A particular challenge will be to determine clear programmatic and oversight distinctions between activities, scientific services, and resources that are administered through NLM’s intramural program versus those served through NLM’s extramural program – and how critical knowledge generation that resonates with NLM’s mission can be best accomplished. This will require a careful assessment of how to best position the overall research program to be most highly impactful.

The Working Group concluded that such a ‘functional audit’ of all NLM programs and subcomponents is needed, but recognized that it could not adequately complete such a task on the short timeline assigned.

Recommendation #6a. NLM leadership should critically evaluate the current NLM portfolio of databases, resources, and services. The objective should be to ensure the continued success and enhancement of services that are vital to the community, and to identify and address efforts that are not serving the community optimally. This evaluation should also be undertaken in the context of the broader NIH, aiming to make strategic recommendations on consolidating and/or better coordinating overlapping programs across the agency.

Recommendation #6b. NLM leadership should review and potentially reorganize the structure and functions of NLM to ensure that they align with the contemporary vision and mission. The existing advisory and oversight structures should be reviewed, with consideration of how they can best assist the NLM Director.

Concluding Remarks

NLM has an exemplary history of excellence, both in terms of accomplishments and world-­‐wide reputation in the research and health sciences communities. This report provides an overarching vision for NLM to continue that legacy into the future as part of NIH’s mission “to seek fundamental knowledge about the nature and behavior of living systems and the application of that knowledge to enhance health, lengthen life, and reduce illness and disability.” In doing so, NLM has the opportunity to modernize the conceptualization of a ‘library’—leading the way in demonstrating how information and knowledge can best be developed, assimilated, organized, applied, and disseminated in the 21st century.

To realize the vision embodied by the above recommendations, the Working Group believes that NLM must evolve to seize this critical moment in biomedical history and be a trustworthy source of biomedical data and information, an advocate for open science, a promoter of the next generation of data scientists, a protector of the legacy of the past, and a vital partner for those who are generating biomedical knowledge for the future. NLM is a precious national resource with international reach. It succeeds best when its work produces better health, better science, and better information for all. Achieving these recommendations will ensure the continued success of this critical resource in a period of immense opportunity in biomedical research, healthcare delivery, and public health.

Appendix A Roster

Members

Eric Green, MD, PhD (co-­‐chair) National Institutes of Health

Harlan Krumholz, MD (co-­‐chair) Yale University

Russ Altman, MD, PhD Stanford University

Howard Bauchner, MD Journal of the American Medical Association

Deborah Brooks Michael J Fox Foundation

Doug Fridsma, MD, PhD American Medical Informatics Association

Steven Goodman, MD, MHS, PhD Stanford University

Eric Horvitz, MD, PhD Microsoft Research

Trudy MacKay, PhD, FRS North Carolina State University

Alexa McCray, PhD Harvard University

Chris Shaffer, MS Oregon Health and Science University

David Van Essen, PhD Washington University

Joanne Waldstreicher, MD Johnson & Johnson

James Williams, II, MS University of Colorado, Boulder

Ex Officio Members

Kathy Hudson, PhD National Institutes of Health

Executive Secretary

Lyric Jorgenson, PhD National Institutes of Health

Appendix B NLM Consultations

Donald Lindberg, MD – Director, National Library of Medicine, National Institutes of Health

Betsy Humphreys, MLS – Deputy Director, National Library of Medicine, National Institutes of Health

Philip Bourne, PhD -­‐ Associate Director for Data Science, National Institutes of Health

Joyce Backus, MSLS – Associate Director for Library Operations, National Library of Medicine, National Institutes of Health

Ivor D’Souza – Director of Information Systems, National Library of Medicine, National Institutes of Health

Valerie Florance, PhD – Associate Director for Extramural Programs, National Library of Medicine, National Institutes of Health

David Lipman, MD – Director, National Center for Biotechnology Information, National Library of Medicine, National Institutes of Health

Clement McDonald, MD – Director, Lister Hill National Center for Biomedical Communications, National Library of Medicine, National Institutes of Health

Steven Phillips, MD – Associate Director for Specialized Information Services, National Library of Medicine, National Institutes of Health

Appendix C Request for Information

Request for Information (RFI) Soliciting Input into the Deliberations of the Advisory Committee to the NIH Director (ACD) Working Group on the National Library of Medicine (NLM)

Notice Number: NOT-OD-15-067

Key Dates Release Date: February 13, 2015

Related Announcements None

Issued by National Institutes of Health (NIH)

Purpose

This Notice is a time-sensitive Request for Information (RFI) soliciting input into the deliberations of the Advisory Committee to the NIH Director (ACD) Working Group on the National Library of Medicine (NLM).

Background

As defined in statute, the NLM was established to “assist the advancement of medical and related sciences and to aid the dissemination and exchange of scientific and other information important to the progress of medicine and to the public health.” The world’s largest biomedical library, the NLM maintains and makes available a vast multimedia collection of published literature, organizational archives and manuscripts, and still and moving images; builds and provides electronic information resources used billions of times each year by millions of scientists, health professionals, and members of the public; supports and conducts research, development, and training in biomedical informatics, data and information science, and health information technology; and coordinates a ~6,100-member National Network of Libraries of Medicine that promotes and provides access to health information in communities across the United States. In pursuit of its mission, the NLM has achieved many successes, such as pioneering free Internet access to PubMed, access to genetic and genomic data through GenBank, clinical trial registration and results through clinicaltrials.gov, NIH-funded biomedical research as part of the NIH Public Access Policy, and supporting the research and training programs of institutions throughout the country. The full scope of activities of the NLM can be found at http://www.nlm.nih.gov/. Ultimately, the creation and maintenance of these resources help to support and enable access to the results of research funded by NIH and many other organizations.

NIH is committed to ensuring that the NLM continues to leverage technological advances in information and data science to facilitate scientific breakthroughs and understanding of health and disease by scientists, health professionals, and the public. In order to help chart the course for the future of the NLM, the NIH Director established a working group charged with (1) reviewing the current mission, organization, and programmatic priorities of the NLM; and (2) articulating a strategic vision for the NLM to ensure that it remains an international leader in biomedical and health information. In addressing its charge, the working group is to assess specifically how the NLM should:

  • Continue to meet the biomedical community’s rapidly evolving scientific and technological needs;
  • Lead the development and adoption of information technologies;
  • Facilitate the collection, storage, and use of biomedical data by the biomedical and health research communities;
  • Continue to lead in promoting open access models for biomedical data and scientific literature;
  • Balance computational methods and human-based approaches for indexing;
  • Maximize the utilization and cost-efficiency of the NLM’s National Network of Libraries of Medicine;
  • Maximize the usefulness of the NLM’s other outreach and exhibits programs in the context of future opportunities;
  • Interface effectively with the broader and expanding NIH efforts in data science; and
  • Directly contribute to addressing the major data science challenges facing the biomedical research enterprise.

As part of the working group’s deliberations, NIH is seeking input from stakeholders and the general public through this RFI.

Information Requested

This Request for Information (RFI) seeks input regarding the strategic vision for the NLM to ensure that it remains an international leader in biomedical data and health information. In particular, comments are being sought regarding the current value of and future need for NLM programs, resources, research and training efforts, and services (e.g., databases, software, collections) – collectively referred to in this RFI hereafter as “NLM elements”. Your comments can include but are not limited to the following topics:

  • Current NLM elements that are of the most, or least, value to the research community (including biomedical, clinical, behavioral, health services, public health, and historical researchers) and future capabilities that will be needed to support evolving scientific and technological activities and needs.
  • Current NLM elements that are of the most, or least, value to health professionals (e.g., those working in health care, emergency response, toxicology, environmental health, and public health) and future capabilities that will be needed to enable health professionals to integrate data and knowledge from biomedical research into effective practice.
  • Current NLM elements that are of most, or least, value to patients and the public (including students, teachers, and the media) and future capabilities that will be needed to ensure a trusted source for rapid dissemination of health knowledge into the public domain.
  • Current NLM elements that are of most, or least, value to other libraries, publishers, organizations, companies, and individuals who use NLM data, software tools, and systems in developing and providing value-added or complementary services and products and future capabilities that would facilitate the development of products and services that make use of NLM resources.
  • How NLM could be better positioned to help address the broader and growing challenges associated with:
  • Biomedical informatics, “big data”, and data science;
  • Electronic health records;
  • Digital publications; or
  • Other emerging challenges/elements warranting special consideration.
How to Submit a Response

Responses to this RFI must be submitted electronically via: http://grants.nih.gov/grants/rfi/rfi.cfm?ID=41. Responses will be accepted through March 13, 2015. Responses to this RFI are voluntary. Please do not include any proprietary, classified, confidential, or sensitive information in your response. The NIH will use the information submitted in response to this RFI at its discretion and will not provide comments to any responder's submission. The collected information will be reviewed by NIH staff, may appear in reports, and may be shared publicly on an NIH website. The Government reserves the right to use any non-proprietary technical information in summaries of the state of the science, and any resultant solicitation(s). The NIH may use the information gathered by this RFI to inform the development of future funding opportunity announcements. This RFI is for information and planning purposes only and should not be construed as a solicitation or as an obligation on the part of the Federal Government, the National Institutes of Health (NIH), or individual NIH Institutes and Centers. No basis for claims against the U.S. Government shall arise as a result of a response to this request for information or from the Government’s use of such information.

Inquiries

Please direct all inquiries to

Lyric Jorgenson, Ph.D.

Office of the Deputy Director for Science, Outreach, and Policy

Telephone: 301-496-1455

Email: jorgensonla@od.nih.gov

Public: NLM MedlinePlus

http://www.nlm.nih.gov/

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Spring 2015 Issue: Volume 10 Number 1

Feature: Celiac Disease

Jennifer Esposito and Louis Dowler

Jennifer Esposito and husband Louis Dowler now run a New York City gluten-free bakery, Jennifer's Way, sparked by Esposito's struggles with celiac disease.
Photo courtesy of Jennifer Esposito

Celiac disease is an immune disease in which people can't eat the protein gluten because it will damage their small intestine.

For actress Jennifer Esposito, going from one doctor to the next, seeking relief, and even getting a correct diagnosis of her condition, proved to be a nightmare. As her symptoms worsened, Esposito continued her busy life, while also looking for answers. She was a hard-working, award-winning actress for almost 15 years. She managed to own her own home by the age of 25. But almost everything she ate was toxic to her system. Then, finally, a doctor mentioned a term she had not heard before: celiac disease.

Celiac disease, she learned, affects each person differently. Symptoms may occur in the digestive system, or in other parts of the body. One person might have diarrhea and abdominal pain, while another person may be irritable or depressed. Today, Esposito has totally changed her diet. And while still an actress, she has also made time to start a gluten-free bakery called Jennifer's Way and written a book by the same name that details her journey with the disease and shares resources for others with the condition.

NIH MedlinePlus magazine recently asked Jennifer Esposito about her celiac disease experiences:

How long did it take you to get your condition diagnosed?

Even though my very first symptoms started at birth, with severe rashes all over my body, it wasn't until I was 15 that my journey to be diagnosed began. Although I never knew what I was looking for during the next 20 years, I did know the way I was feeling. As time went on, and I became more and more unwell, I knew there was something going on.

What were your thoughts when you were told you had celiac disease?

I was actually thrilled when I was finally diagnosed. To know that what my body was telling me and what I knew in my gut for years, that something was very wrong and it wasn't all in my head, was an absolute gift, even if that meant having a disease. The not knowing and the implications of being a hypochondriac, dramatic, crazy, hormonal, or whatever else I was told, was almost harder than the disease itself.

How difficult has it been to eliminate your intake of gluten?

Once you understand how much damage gluten is doing to you, there really isn't much of a choice. I don't choose to feel like I'm dying just to eat a piece of bread. You must realize that this isn't a change of diet, this is a change of life!

Have you found inspiration from others who have celiac disease?

The celiac community was the only place I found answers, understanding, and true compassion that only others with celiac could give, because they have experienced what I was going through. I suggest for anyone dealing with this disease—or any disease for that matter—to find others who are going through the same thing. The support from others who have been there is what will pull you through the hard times.

What advice do you have for others who have been diagnosed with celiac disease?

My suggestion for any new celiac patient is to get my book. This is not a sales pitch—you can check the book out of your local library or borrow it from a friend. But this is the book I wish I'd had when I was diagnosed. It tells you everything you need to know: what to expect, what other factors of your diet to look at, lifestyle changes, emotional aspects of the disease, and it even gives some recipes.

But, mostly what it does is make you realize, through my journey, that you are not only on the crazy ride that this autoimmune disease takes you on; it is also a gift, at such a hard time. The letters I receive from people all around the world who have been helped by my book have been overwhelming and heartwarming, to say the very least. It made me realize this disease wasn't a bad thing in my life, but a true gift.

What is Celiac disease?

Celiac disease is an immune disorder in which people can't eat gluten because it will damage their small intestine. Gluten is a protein found in wheat, rye, and barley. Gluten may also be used in products such as vitamin and nutrient supplements, lip balms, and some medicines.

Your body's natural defense system—called the immune system—keeps you healthy by fighting against things that can make you sick, such as bacteria and viruses. When people with celiac disease eat gluten, their body's immune system reacts to the gluten by attacking the lining of the small intestine. The immune system's reaction to gluten damages small, fingerlike growths called villi. When the villi are damaged, the body cannot get the nutrients it needs.

Celiac disease is hereditary, meaning it runs in families. Adults and children can have celiac disease. As many as 2 million Americans may have celiac disease, but most don't know it.

Celiac disease can be very serious. It often causes long-lasting digestive problems and keeps your body from getting all the nutrition it needs. Over time, celiac disease can cause anemia, infertility, weak and brittle bones, an itchy skin rash, and other health problems.

Fast Facts
  • Celiac disease is an immune disorder in which people can't eat gluten or use items with gluten in them.
  • Celiac disease harms the small intestine.
  • People with untreated celiac disease can't get needed nutrients.
  • Without treatment, people with celiac disease can develop other health problems.
  • Celiac disease is diagnosed by blood tests and a biopsy of the small intestine.
  • The only treatment for celiac disease is to avoid gluten.
  • A dietitian can help people choose the right foods.
How common is celiac disease?

Celiac disease affects people in all parts of the world. Originally thought to be a rare childhood syndrome, celiac disease is now known to be a common genetic disorder. More than 2 million people in the United States have the disease, or about 1 in 133 people. Among people who have a first-degree relative—a parent, sibling, or child—diagnosed with celiac disease, as many as 1 in 22 people may have the disease.

Celiac disease is also more common among people with other genetic disorders including Down syndrome and Turner syndrome, a condition that affects girls' development.

What other health problems do people with celiac disease have?

People with celiac disease tend to have other diseases in which the immune system attacks the body's healthy cells and tissues. The connection between celiac disease and these diseases may be genetic. They include:

  • type 1 diabetes
  • autoimmune thyroid disease
  • autoimmune liver disease
  • rheumatoid arthritis
  • Addison's disease, a condition in which the glands that produce critical hormones are damaged
  • Sjögren's syndrome, a condition in which the glands that produce tears and saliva are destroyed

Symptoms, Diagnosis & Treatment

What are some of the symptoms of celiac disease?

Some people with celiac disease may not feel sick or have symptoms. Or, if they feel sick, they don't know celiac disease is the cause. Most people with celiac disease have one or more symptoms. Not all people with celiac disease have digestive problems. Having one or more of these symptoms does not always mean a person has celiac disease because other disorders can cause these symptoms.

  • stomach pain
  • gas
  • diarrhea
  • extreme tiredness
  • change in mood
  • weight loss
  • a very itchy skin rash with blisters
  • slowed growth
Why are celiac disease symptoms so varied?

Researchers are studying the reasons celiac disease affects people differently. The length of time a person was breastfed, the age a person started eating gluten-containing foods, and the amount of gluten-containing foods one eats are three factors thought to play a role in when and how celiac disease appears. Some studies have shown, for example, that the longer a person was breastfed, the later the symptoms of celiac disease appear.

Symptoms also vary depending on a person's age and the degree of damage to the small intestine. Many adults have the disease for a decade or more before they are diagnosed. The longer a person goes undiagnosed and untreated, the greater the chance of developing long-term complications.

How is celiac disease diagnosed?

"Celiac disease can be hard to diagnose because some of its symptoms are like the symptoms of other diseases," says Dr. Griffin Rodgers, director of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK). "If your doctor thinks you might have celiac disease, you may need a blood test and biopsy.

"Before the blood test, it is important to be on your regular diet," he says. "If not, the results could be wrong. A biopsy involves taking a tiny piece of tissue from your small intestine. The tissue will be viewed with a microscope to look for signs of celiac damage."

Blood Tests

People with celiac disease have higher-than-normal levels of certain autoantibodies—proteins that react against the body's own cells or tissues—in their blood. To diagnose celiac disease, doctors will test blood for high levels of anti-tissue transglutaminase antibodies (tTGA) or anti-endomysium antibodies (EMA). If test results are negative but celiac disease is still suspected, additional blood tests may be needed.

Before being tested, one should continue to eat a diet that includes foods with gluten, such as breads and pastas. If a person stops eating foods with gluten before being tested, the results may be negative for celiac disease, even if the disease is present.

Intestinal Biopsy

If blood tests and symptoms suggest celiac disease, a biopsy of the small intestine is performed to confirm the diagnosis. During the biopsy, the doctor removes tiny pieces of tissue from the small intestine to check for damage to the villi. To obtain the tissue sample, the doctor eases a long, thin tube called an endoscope through the patient's mouth and stomach into the small intestine. The doctor then takes the samples using instruments passed through the endoscope.

Dermatitis Herpetiformis

Dermatitis herpetiformis (DH) is an intensely itchy, blistering skin rash that affects 15 to 25 percent of people with celiac disease. The rash usually occurs on the elbows, knees, and buttocks. Most people with DH have no digestive symptoms of celiac disease.

DH is diagnosed through blood tests and a skin biopsy. If the antibody tests are positive and the skin biopsy has the typical findings of DH, patients do not need to have an intestinal biopsy. Both the skin disease and the intestinal disease respond to a gluten-free diet and recur if gluten is added back into the diet. The rash symptoms can be controlled with antibiotics such as dapsone. Because dapsone does not treat the intestinal condition, people with DH must maintain a gluten-free diet.

Screening

Screening for celiac disease means testing for the presence of autoantibodies in the blood in people without symptoms. Americans are not routinely screened for celiac disease. However, because celiac disease is hereditary, family members of a person with the disease may wish to be tested. Four to 12 percent of an affected person's first-degree relatives will also have the disease.

How is celiac disease treated?

The only treatment for celiac disease is a gluten-free diet. Doctors may ask a newly diagnosed person to work with a dietitian on a gluten-free diet plan. A dietitian is a healthcare professional who specializes in food and nutrition. Someone with celiac disease can learn from a dietitian how to read ingredient lists and identify foods that contain gluten in order to make informed decisions at the grocery store and when eating out.

For most people, following this diet will stop symptoms, heal existing intestinal damage, and prevent further damage. Improvement begins within days of starting the diet. The small intestine usually heals in 3 to 6 months in children but may take several years in adults. A healed intestine means a person now has villi that can absorb nutrients from food into the bloodstream.

To stay well, people with celiac disease must avoid gluten for the rest of their lives. Eating even a small amount of gluten can damage the small intestine. The damage will occur in anyone with the disease, including people without noticeable symptoms. Depending on a person's age at diagnosis, some problems will not improve, such as short stature and dental enamel defects.

Some people with celiac disease show no improvement on the gluten-free diet. The most common reason for poor response to the diet is that small amounts of gluten are still being consumed. Hidden sources of gluten include additives such as modified food starch, preservatives, and stabilizers made with wheat. And because many corn and rice products are produced in factories that also manufacture wheat products, they can be contaminated with wheat gluten.

Rarely, the intestinal injury will continue despite a strictly gluten-free diet. People with this condition, known as refractory celiac disease, have severely damaged intestines that cannot heal. Because their intestines are not absorbing enough nutrients, they may need to receive nutrients directly into their bloodstream through a vein, or intravenously. Researchers are evaluating drug treatments for refractory celiac disease.

Four Inches and Seven Pounds

Maghann and her daughter Stella

Maghann and Stella—managing celiac disease.
Photo courtesy of Maghann Ruiz

Much to her family's relief, Stella Ruiz, who will be five years old in October, grew four inches and gained seven pounds between last September and February—despite her celiac disease.

Her favorite foods are fresh fruit and pancakes—as long as they are gluten-free.

"Stella has celiac disease," explains her mother, Maghann. "She's a normal little girl, who goes to school, has friends, and does gymnastics."

"She's a normal little girl, who goes to school, has friends, and does gymnastics."

But it took months of stomach aches, chronic diarrhea, minimal growth, many visits to her pediatrician, and much testing before a gastrointestinal specialist finally diagnosed Stella. She's been on a strict gluten-free diet ever since, like so many thousands and thousands of other people young and old with celiac.

The biggest hurdle the family faces in managing the disease is guarding Stella's food from contamination. "Even a crumb of wheat is critical to her health," says Maghann. "So we bought a new toaster, for example. But it's very difficult at school or restaurants, and when we travel, which we do a lot."

Maghann's solution is to make most of the family's food, being especially vigilant about sourcing ingredients from "gluten-free certified" producers. "You really have to read the labels closely to see if the product is from a gluten-free facility," she says.

"Because we have had other serious medical issues, we are used to celiac."

Maghann's advice for those newly coming to the condition are to:

  • Learn about celiac disease on www.medlineplus.gov and keep up with the latest developments
  • Share what you know about celiac with your children, family, friends, caregivers, teachers—everyone
  • Tell your kids never to share their friends' foods
  • Create gluten-free, safe menus
  • Join celiac family forums, great for mutual understanding and support, not to mention favorite gluten-free recipes.

"It is so important to learn and share with other families," Maghann emphasizes, "because we're all in this together."

Hope through Research

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) conducts and supports research on celiac disease. Researchers are studying new options for diagnosing celiac disease, including capsule endoscopy, which involves patients swallowing a capsule containing a tiny video camera that records images of the small intestine.

Several drug treatments for celiac disease are being studied. Researchers are also studying a combination of enzymes—proteins that aid chemical reactions in the body—that might change gluten in ways that prevent it from causing an immune reaction before it enters the small intestine.

Scientists are also developing educational materials for standardized medical training to raise awareness among healthcare providers. The hope is that increased understanding and awareness will lead to earlier diagnosis and treatment of celiac disease.

Participants in clinical trials can play a more active role in their own health care, gain access to new research treatments before they are widely available, and help others by contributing to medical research.

For information about current studies, visit http://www.clinicaltrials.gov

Learning to Live Well with Celiac Disease

Tibbie Klose raises sheep in the Hudson River Valley of New York.
Photo courtesy of Chris Klose

"So far, so good," says Tibbie Klose of her celiac disease. It's been nine years since she was diagnosed with the now-common illness. Nine years of watching everything she eats—at home, with family or friends, at public gatherings where food is served, and especially when traveling.

Otherwise healthy, the 75-year old sheep farmer began suffering from constant intestinal upset and debilitating weakness. Most alarming, she began to lose weight, fast: 15 pounds in two weeks.

"I went straight to my doctor," Klose recalls. "And she sent me to a gastroenterologist for a complete exam, including a colonoscopy. The diagnosis: celiac disease. It was very startling. I'd never heard of it."

The remedy? A completely new—and gluten-free—diet. No more sandwiches with wheat bread for lunch, regular pasta for dinner, or baked goods with gluten, period. Does she miss them?

"Yes and no. Celiac upset me at first, and it can be really hard on others, including people who have to serve me differently. It is very important to tell people you have celiac, for your safety and their convenience."

Now a stable 110 pounds, Klose's top tips for celiac success include:

  1. Learn as much as possible about the disease, starting at http://www.medlineplus.gov.
  2. Tell people you need gluten-free foods.
  3. Look for "gluten-free" on food packages and labels.
  4. Eat locally grown fresh fruits and vegetables.

Living Gluten Free

Allowed Foods

Allowed Foods

  • amaranth
  • arrowroot
  • buckwheat
  • cassava
  • corn
  • flax
  • Indian rice grass
  • Job's tears
  • legumes
  • millet
  • nuts
  • potatoes
  • quinoa
  • rice
  • sago
  • seeds
  • sorghum
  • soy
  • tapioca
  • teff
  • wild rice
  • yucca
Foods to Avoid

Foods to Avoid- Processed Foods that May Contain Wheat, Barley or Rye. Wheat and Wheat Products

 

  • wheat
    • including einkorn, emmer, spelt, kamut
    • wheat starch, wheat bran, wheat germ, cracked wheat, hydrolyzed wheat protein barley
  • rye
  • triticale (a cross between wheat and rye) bromated flour
  • durum flour
  • enriched flour
  • farina
  • graham flour
  • phosphated flour
  • plain flour
  • self-rising flour
  • semolina
  • white flour
  • bouillon cubes
  • brown rice syrup
  • candy
  • chips/potato chips
  • cold cuts, hot dogs, salami, sausage
  • communion wafers
  • French fries
  • gravy
  • imitation fish
  • matzo
  • rice mixes
  • sauces
  • seasoned tortilla chips
  • self-basting turkey
  • soups
  • soy sauce
  • vegetables in sauce

Researcher

Press Release

Youngevity (YGYI) Announces Acquisition of Restart Your Life

Source: http://ygyi.com/wordpress/press-rele...-restart-life/

Youngevity Enters Into Agreement to Expand Its Product and Service Offerings

San Diego, CA – October 2, 2014 – Growing direct-selling conglomerate, Youngevity Essential Life Sciences, a wholly owned subsidiary of Youngevity International, Inc. (OTCQX: YGYI) (http://www.YGYI.com), announced today that it consummated the acquisition of the business of Restart Your Life, (http://www.Restartyl.com), a dietary supplement company and provider of immune system support products and therapeutic skin lotions.

As a result of the business combination, Youngevity distributors and customers will have access to the unique line of high-quality products from Restart Your Life.  In turn, Restart Your Life distributors and customers will gain access to more than 1,000 high-quality products offered by Youngevity, including nutritional supplements, sports and energy drinks, health and wellness-related services, weight management, lifestyle products (pets, spa and bath, garden), gourmet coffee, packaged foods, skincare, cosmetics, apparel and accessories.

Joyce Cordell, CEO of Restart Your Life said, “The Restart Your Life story is one of scientific innovation and excellence in the field of immunology.  By joining the Youngevity family we have become an international company with a solid foundation backed by the stability of an established leader in the direct selling industry.  This expands the Restart brand globally and we could not be more excited for our entire distributor base.  This is a huge win for the Restart Your Life family.”

A.J. Lanigan, Co-Founder of Restart Your Life said, “Since 1996, I have been working to develop Beta 1, 3-D Glucan as the most relevant immune support compound in the world.  Countless peer reviewed medical articles have attested to its safety and benefits.  I am a big believer that network marketing is a proper channel to help rapidly advance this type of product.  I look forward to working with the corporate staff, the tremendously talented field force and the most important asset, the great customers that I expect will enjoy good health and have an opportunity for great financial success.  I would encourage all to avail themselves of the vast reservoir of knowledge available to make sure they reach their goals.  I want to give special recognition to Dr. Joel Wallach.  He has blazed a trail as a pioneer in this field and it is my honor to assist him to accomplish his dreams for a better world.”

“We proudly welcome Restart Your Life to our growing Youngevity family as we provide our distributors and customers with more high quality product and service offerings,” said Steve Wallach, CEO of Youngevity.  “We are excited about the Restart Your Life acquisition as we expect it will expand our presence in the dietary supplements market.  This represents Youngevity’s third strategic acquisition over the past three quarters of 2014 and we are well positioned to continue this growth going into 2015.”

About Youngevity International, Inc.

Youngevity International Inc., (OTCQX: YGYI) (www.YGYI.com) is a fast-growing, innovative, multi-dimensional company that offers a wide range of consumer products and services, primarily through person-to-person selling relationships that comprise a “network of networks.”  The Company also is a vertically integrated producer of the finest coffees for the commercial, retail and direct sales channels, and has launched a new Green Coffee sales division to leverage its recently acquired coffee plantation and Green Coffee processing plant in Nicaragua.  The Company was formed after the merger of Youngevity Essential Life Sciences (http://www.youngevity.com) and Javalution Coffee Company in the summer of 2011, and changed its name to Youngevity International Inc. from AL International, Inc. in July 2013.

Safe Harbor Statement

This release includes forward-looking statements on our current expectations and projections about future events. In some cases forward-looking statements can be identified by terminology such as “may,” “should,” “potential,” “continue,” “expects,” “anticipates,” “intends,” “plans,” “believes,” “estimates,” and similar expressions. These statements include statements about our intended expansion and growth and the expected benefits of the Restart Your Life acquisition and its products, including Beta 1, 3-D Glucan.  These statements are based upon current beliefs, expectations and assumptions and are subject to a number of risks and uncertainties, many of which are difficult to predict, including our ability to successfully integrate Restart Your Life into our company and our ability to continue our growth.  The information in this release is provided only as of the date of this release, and we undertake no obligation to update any forward-looking statements contained in this release based on new information, future events, or otherwise, except as required by law.

Youngevity International, Inc.
Investor Relations
John Zervas
800-982-3189 X 6509

Slides

Slides

Slide 1 Glucan

The most extensively studied glucan is derived from Bakers Yeast (Saccharomyces cerevisiae) , perhaps because it has been proven to produce the highest biological effects.  For readers interested in an introduction to a number of biologically active glucans, we recommend an excellent review by Harada and Ohno (2008). The general structure of b-glucan is summarized in Figure 1 a, and below it is a three-dimensional picture of the same molecule. Among all glucans, those with a 1,3 configurations are best characterized in the literature. An excellent review of glucans as biological response modifiers, and the relationship between structure and functional activity is given in (Bohn and BeMiller, 1995). 

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Slide 2 Leukemia & Lymphoma Journal Article

See below: Data Scientist: Publication - Leukemia & Lymphoma

Early treatment of high risk chronic lymphocytic leukemia with alemtuzumab, rituximab and poly-(1-6)-beta-glucotriosyl-(1-3)- beta-glucopyranose beta-glucan is well tolerated and achieves high complete remission rates

Poly-[1–6]-β-glucopyranosyl-[1–3]-β-glucopyranose (PGG) beta glucan is a Saccharomyces cerevisiae derived 1,3/1,6 glucose polymer with innate immune system activation potential. This phase I/II clinical trial enrolled 20 eligible patients with chronic lymphocytic leukemia with high-risk biological markers for early initial treatment with alemtuzumab, rituximab and PGG beta glucan (1–2–4 mg/kg/dose) over 31 days. PGG beta glucan at 4 mg/kg was well tolerated and used for the phase II study. There were three grade 3–4 toxicities at least possibly attributed to treatment. Nineteen (95%) patients responded to treatment with 13 (65%) complete responses. All patients were alive at a median follow-up of 24.4 months (range: 9.5–37). Eleven patients had progressive disease (median 17.6 months, 95% confidence interval [CI]: 9.7, 32.1) and eight patients were retreated (median 35.3 months, 95% CI: 17.9, not reached). We conclude that PGG beta glucan, alemtuzumab and rituximab treatment is tolerable and results in a high complete response rate.

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Slide 3 This what you would see if you had really good eyes…or an electron microscope

This what you would see if you had really good eyes…or an electron microscope.

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Slide 4 The phagocytosis of bacteria or phagocytosis of synthetic microspheres is often used for glucan evaluation

The phagocytosis of bacteria or phagocytosis of synthetic microspheres is often used for glucan evaluation.

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Slide 5 The PAC MAN of the immune system in various states

Here we see a wide variety of phagocytes in the brain, tissue, organs ,etc.  Red blood cells, asbestos, bacteria and other targets are involved in immune processes that there immune cells conduct.

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Slide 6 Demonstration of Oral Uptake of Yeast Beta 1,3-D Glucan 1

We are the only company to actually prove that our product is taken up in the gut, transported throughout the body and ultimately activated the glucan receptor (CR3).

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Slide 7 Demonstration of Oral Uptake of Yeast Beta 1,3-D Glucan 2

It is the immune cells themselves (macrophages and neutrophils) that digest and then transport the glucan throughout the body’s organs and tissues.  This is all part of the mechanism of action that has been proven, published in numerous medical journals and has passed FDA scrutiny in safety trials.

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Slide 8 effects of two weeks of treatment with different glucans on size of tumors

Shows the results of experiments comparing the effects of three types of commercially available glucans (yeast-, seaweed- and mushroom-derived glucans) on the growth of both lung and breast cancers. From these data, one can clearly see that both yeast-derived and seaweed-derived glucans were significantly more active in tumor growth reduction than glucan isolated from mushrooms.

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Slide 9 Long-term effect of orally-given glucans on secretion of IL-2 by spleen cells

From these data, one can clearly see that both yeast-derived and seaweed-derived glucans were significantly more active in tumor growth reduction than glucan isolated from mushrooms. These data correspond with long-term effects of orally-administered glucans on secretion of IL-2 by mouse spleen cells.

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Slide 10 Glucan-induced recovery of bone marrow after irradiation of mice

This figure shows glucan-induced recovery of bone marrow cells after sub-lethal irradiation of mice. The data demonstrate that regardless of whether the glucan was used simultaneously with irradiation or one or two weeks earlier, the bone marrow recovery was significantly improved. Fifteen days after irradiation, the control group (without glucan) still showed lower cell numbers than before irradiation. On the other hand, in all glucan-treated cases, the number of immunocytes in damaged bone marrow returned to normal levels much faster. These research data might be more important than ever – as the recent situation in Japan raised the possibility of a radioactive cloud. With b glucan we can prepare ourselves for possible negative effects of radiation, both from the air or from contaminated products.

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Slide 11 Effect of long-term feeding with individual glucans on blood cholesterol levels in experimentally-induced hypercholesterolemia

The mice were then given a diet with added cholesterol. The blood cholesterol levels obtained after two weeks of cholesterol feeding were used as a positive control. The cholesterol-rich diet was followed by 40 days of feeding with a glucan-rich diet. Individual groups of mice were examined in 10-day-intervals and their cholesterol levels were evaluated. The results show that during short time intervals, all glucans lowered the cholesterol levels in hypercholesterolemic animals, but in the long term only Glucan #300retained this activity. The usefulness of glucan in lipid lowering was further confirmed by a recent meta-analysis of randomized, controlled trials (AbuMweis et al., 2010).

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Slide 12 Feeding with glucan can control the experimentally-induced hyperglycemia

Later, attention was focused on the effects of glucan administration on the levels of blood sugar. Feeding with glucan did not significantly affect the sugar levels. However, a different situation was found when using mice with experimentally-induced hyperglycemia. After two weeks of feeding, Glucan #300 significantly lowered the sugar levels to almost normal. A longer application of glucan resulted in additional significant activity of ImmunoFibreglucan. Experiments describing the effects of glucans on cholesterol and blood sugar are described in full detail in Vetvicka and Vetvickova (2007 b). Readers seeking more information on glucan and cholesterol should seek the recent review (Ulbricht and Windsor, 2014).

Streptozotocin is a naturally occurring chemical that is particularly toxic to the insulin-producing beta cells of the pancreas in mammals. It is used in medicine for treating certain cancers of the Islets of Langerhans and used in medical research to produce an animal model for Type 1 diabetes in large dose as well asType 2 diabetes with multiple low doses.

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Slide 13 Effects of various glucans on ear swelling

In Vetvickas study, they focused on the potential effects of glucan on skin inflammation. They used an anthralin-induced skin inflammation. When they used Glucan #300 (Glucan 1) 30 minutes before irritation, they found significant inhibition of skin irritation for up to 24 hrs. The same results were found when they fed the animals with glucan for 2 weeks. When they compared four different glucans, they found that only Glucan #300 offered consistent and long inhibition of ear swelling, the other three glucans were much less active. These results not only show that glucan can be used for inhibition of inflammation, but also the fact that not all glucans are created equal.

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Slide 14 Glucan in diet reduces supression of immunity caused by mercury

Glucan was also tested in the case of mercury poisoning. Global mercury recycling has resulted in a significant presence of mercury salts in the environment, with the fish industry being hit particularly hard. In addition, thimerosal (containing an organic ethylmercury), still represents a substance with dangerous immunosuppressive effects. Other mercury salts also possess immunosuppressive and toxic properties. A more detailed study showed that two week exposure of mice to either thimerosal or mercury acetate in drinking water caused significant suppression of humoral and cellular immune reactions such as antibody response, cytokine secretion, phagocytosis, cell proliferation and natural killer activity. However, a two-week feeding with yeast-derived insoluble glucan resulted in significantly lower immunosuppressive effects of mercury (Vetvicka and Vetvickova 2012 c). The effects of glucan on mercury-caused immunosuppression are shown.

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Slide 15 Effects of different glucans on immunosuppression caused by immunotoxic agents

Vetvickas laboratory sought information to determine if glucan can help to reduce the immunotoxic effects of these compounds. His studies showed that oral exposure to perfluooctanesulphonic acid or perluorooctanic acid resulted in severe immunosuppression. This was tested by natural killer cell activity, phagocytosis, cell proliferation and antibody response. Most of this suppression was, however, reduced by an oral administration of the glucan. The effects on phagocytosis of peripheral blood neutrophils are shown.

These data represent the first study demonstrating that significant immunosuppression caused by environmental pollution can be reduced or partly restored by oral administration of a combination of glucan with other bioactive molecules.  This might open a new, clinically important pathway for blocking the immunosuppressive or immunotoxic effects of various compounds. In addition, these data can also be interpreted as the possible use of glucan combination in the prophylactic treatment of toxicity caused by perfluorinated compounds and possible additional toxins. However, additional studies must be performed to fully explain these effects.

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Slide 16 Glucan stimulates the wound healing of human skin cells

Vetvickas recent data compared the wound healing ability of four different types of glucanGlucan #300, Glucagel, NOW Glucan and Epicor. He used the well-established model of scratch wound of a monolayer of human cell line HaCaT.  The results are summarized above and show that all glucans supported the wound healing processes. However, those results again confirmed that not all glucans are created equal, with Glucan #300 showing the strongest activity.

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Slide 17 Improvement in skin properties after application of glucan in creams

Additional clinical study of 150 women with topical application of glucan resulted in 27% improvement in skin hydration, 29% improvement in dryness of the skin, and 56% improvement in facial wrinkles.

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Slide 18 Effect of 14 days of feeding on stress-induced levels of corticosterone

Measurement of the effects of various types of glucan on the levels of stress-induced corticosterone were performed. To experimentally induce stress, either restraint or cold was used. The results showed that the glucans- Glucan #300 and NOW, successfully helped to keep the stress hormone corticosterone at almost normal levels.  Again, the #300 sample performed best.

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Slide 19 Effects of glucan supplementation of antibody formation in children

In addition to acute inflammatory response, the effects on formation of salivary antibodies were studied. Data above demonstrates that at the beginning of the study the levels of antibodies were comparable in both groups. However, at the end of the study it was found that there was an increase of all three types of antibodies only in the glucan-treated group, whereas the placebo group expressed no changes or even a decrease in antibody production. In addition, glucan-supplemented children showed an increase in physical endurance and in overall health (Vetvicka et al., 2013 a,b,c). These findings represent just another stone in the mosaic of glucan-mediated response in disease prone-children.

AJLanigan03072015Slide19.PNG

Slide 20 Effects of different immunomodulators on phagocytic activity

Stimulation of phagocytosis is usually the first effect of any natural immunomodulator. Data showed that only glucan and Astragalus significantly increased phagocytic activity of blood neutrophils and peritoneal macrophages. Internalization of foreign material represents the first step in the complex mechanisms of phagocytosis and elimination of prey. An additional step is connected with a burst of metabolic activity and involves production and secretion of active oxygen species. Therefore, the next part of the study focused on production of superoxide anion. We found that curcumin, Astragalus, glucan and vitamin C were significantly potentiating the production of this anion.

AJLanigan03072015Slide20.PNG

Slide 21 Effects of various combinations on NK cell activity

Started with phagocytosis again, three mixtures had no activity at all, the other three only in the highest doses of 400 or even 800 micrograms. For comparison, high quality glucan is active already at 50 micrograms. Effects on superoxide anion and nitrite oxide formation were slightly better, but the effects were still much lower than the effects of glucan. Similar effects were found when testing the effects on antibody formation, IL-2 secretion or NK cell activity. Readers seeking more details can read the original study by Vetvicka and Vetvickova (2012 a). Overall, data presented in this study clearly demonstrated significant differences among individual types of immunostimulating combinations. In all tested activities, glucan was much more active than any of these combinations, despite the fact that some contain otherwise well-documented glucans such as Shiitake or Maitakeglucans. There are two possible explanations – one is that the doses of glucans used in these preparations was not high enough, or that some of the additional parts of these mixtures do not work in synergy but in fact negate each other. The first possibility is hard to answer, as all these mixtures state only the total amount of bioactive substances and not their individual components. The second possibility is difficult to answer as well due to the lack of research evaluating the individual components in most of these combinations.

AJLanigan03072015Slide21.PNG

Slide 22 Differences in glucan content among different commercial glucans

The question of purification can be confusing. In an ideal world, every glucan on the market would be 100% pure. In reality, it is commercially almost impossible to achieve this purity and still keep the price in the reasonable range. The level of purity is still important, but, as always, the devil is in the details. The definition of glucan content varies according to the manufacturers methods. Some companies calculate glucan content by the percentage of carbohydrates, hexose, or glucose. That would work fine in the case of 100% glucan, but not if the sample contains glucan plus other carbohydrates such as mannoproteins or even glucose. Therefore, it is important to look for a product that guarantees the beta glucan content. This is a comparison of glucan content among numerous different commercial glucans, and the results are quite surprising.

AJLanigan03072015Slide22.PNG

Slide 23 More glucan does not always mean higher activity as inferior glucans never reach the biological activities of superior glucans

Direct comparison of various immune supplements is shown.

AJLanigan03072015Slide23.PNG

Slide 24 Effects of different combinations on production of IL-2

A comparison of several different supposedly bioactive combinations vs. a resveratrol-glucan-vitamin C combination was done and very little, if any, effects were found (Vetvicka and Vetvickova, 2012). An example of effects of six different combinations in stimulation of IL-2 secretion is shown above.

AJLanigan03072015Slide24.PNG

Slide 25 Effects of resveratrol-vitamin C-glucan combination on antibody response

Based on these promising results, a unique combination consisting of resveratrol, glucan and vitamin C was prepared. After multiple series of tests, one can conclude that this combination has better biological and, most of all, immunological effects. It is not only superior to individual components, but it is also superior when compared to other combinations of natural immunomodulators. This combination is better in stimulation of various aspects of immune reaction from phagocytosis to antibody response, cytokine stimulation, NK cell activities and cancer inhibition (Vetvicka and Vetvickova, 2012 a). This combination also offered higher protections against immunotoxic agents such as mercury or perfluorinated hydrocarbons (Vetvicka and Vetvickova, 2012 b). In addition, it is the strongest reducer of stress-related symptoms, including corticosterone levels and IL-6, IL-2 and IFN-g production (Vetvicka and Vetvickova, 2014 a). The figure above summarizes the effects on antibody response.

AJLanigan03072015Slide25.PNG

Slide 26 Effects of resveratrol-vitamin C-glucan combination on phagocytosis in stressed mice

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Slide 27 Before and After

Patient #1 - I was preparing to fry chicken in very hot oil.  When I dropped the first piece into the oil, it erupted and sprayed the oil onto my face, neck and hands.  It was extremely painful and, within minutes, everywhere that I had been burned, started to swell with glaring red welts.  I was horrified, because my wedding day was only two weeks away! My face and neck were covered with large reddish marks that I feared would not heal very quickly and may leave scars. I called my parents and they brought me some beta glucan products, that they had been using.  I took the beta glucan capsules, plus I applied the beta glucan lotion twice daily.  The first thing I noticed was that the severe burning sensation was dramatically eased.  Within the first day, I could see and feel an improvement.  I kept the areas dry and out of the sun for about a week.  To my surprise (and joy), I was almost completely healed.

My wedding pictures, including close-ups, showed absolutely no skin damage. I typically would have taken much longer to heal, and scarring from burns like this would have been very likely.  Thanks to the beta glucan pills and lotion, my healing was complete. I give all the credit for my rapid healing to beta glucan.  My wedding was magical!

Thanks Beta Glucan!

Lindsay, Greenville SC

Glucans, either alone or in cream, have strong healing effects, most of all due to their stimulation of keratinocytes and fibroblast. Published reports on wound healing supports the effects described in this testimony. The effects of glucan described in this testimony are shown above, both before application and after using glucan

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Slide 28 Wound Healing

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Slide 29 How To Never Run Out of Leads

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Slide 30 Acknowledgement

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PubMed Search - Glucan

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Leuk Lymphoma. 2015 Mar 17:1-6. [Epub ahead of print]

Early treatment of high risk chronic lymphocytic leukemia with alemtuzumabrituximab and poly-(1-6)-beta-glucotriosyl-(1-3)- beta-glucopyranose beta-glucan is well tolerated and achieves high complete remission rates.

Abstract

Poly-[1–6]-β-glucopyranosyl-[1–3]-β-glucopyranose (PGG) beta glucan is a Saccharomyces cerevisiae derived 1,3/1,6 glucose polymer with innate immune system activation potential. This phase I/II clinical trial enrolled 20 eligible patients with chronic lymphocytic leukemia with high-risk biological markers for early initial treatment with alemtuzumab, rituximab and PGG beta glucan (1–2–4 mg/kg/dose) over 31 days. PGG beta glucan at 4 mg/kg was well tolerated and used for the phase II study. There were three grade 3–4 toxicities at least possibly attributed to treatment. Nineteen (95%) patients responded to treatment with 13 (65%) complete responses. All patients were alive at a median follow-up of 24.4 months (range: 9.5–37). Eleven patients had progressive disease (median 17.6 months, 95% confidence interval [CI]: 9.7, 32.1) and eight patients were retreated (median 35.3 months, 95% CI: 17.9, not reached). We conclude that PGG beta glucan, alemtuzumab and rituximab treatment is tolerable and results in a high complete response rate.

Keywords

CLL; Chronic lymphocytic leukemia/small lymphocytic lymphoma; PGG beta glucanalemtuzumabhigh riskrituximab

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Data Scientist: Publication - Leukemia & Lymphoma

http://informahealthcare.com/doi/abs/10.3109/10428194.2015.1016932

Original Article: Clinical

Early treatment of high risk chronic lymphocytic leukemia with alemtuzumab, rituximab and poly-(1-6)-beta-glucotriosyl-(1-3)- beta-glucopyranose beta-glucan is well tolerated and achieves high complete remission rates
 
Posted online on March 17, 2015. (doi:10.3109/10428194.2015.1016932)

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Authors

, and 

1Division of Hematology
2Department of Health Sciences Research, Mayo Clinic
Rochester, MN
USA
3Holden Comprehensive Cancer Center and Department of Internal Medicine, University of Iowa
Iowa City, IA
USA
Correspondence: Clive S. Zent, MD, Wilmot Cancer Institute, University of Rochester Medical Center
601 Elmwood Avenue Box 704, Rochester 14642, NY
USA. Tel: 585-273-3258. Fax: 585-276-3050. E-mail: 

Abstract

Poly-[1–6]-β-glucopyranosyl-[1–3]-β-glucopyranose (PGG) beta glucan is a Saccharomyces cerevisiae derived 1,3/1,6 glucose polymer with innate immune system activation potential. This phase I/II clinical trial enrolled 20 eligible patients with chronic lymphocytic leukemia with high-risk biological markers for early initial treatment with alemtuzumab, rituximab and PGG beta glucan (1–2–4 mg/kg/dose) over 31 days. PGG beta glucan at 4 mg/kg was well tolerated and used for the phase II study. There were three grade 3–4 toxicities at least possibly attributed to treatment. Nineteen (95%) patients responded to treatment with 13 (65%) complete responses. All patients were alive at a median follow-up of 24.4 months (range: 9.5–37). Eleven patients had progressive disease (median 17.6 months, 95% confidence interval [CI]: 9.7, 32.1) and eight patients were retreated (median 35.3 months, 95% CI: 17.9, not reached). We conclude that PGG beta glucan, alemtuzumab and rituximab treatment is tolerable and results in a high complete response rate.

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Abstract

Poly-[1–6]-β-glucopyranosyl-[1–3]-β-glucopyranose (PGG) beta glucan is a Saccharomyces cerevisiae derived 1,3/1,6 glucose polymer with innate immune system activation potential. This phase I/II clinical trial enrolled 20 eligible patients with chronic lymphocytic leukemia with high-risk biological markers for early initial treatment with alemtuzumab, rituximab and PGG beta glucan (1–2–4 mg/kg/dose) over 31 days. PGG beta glucan at 4 mg/kg was well tolerated and used for the phase II study. There were three grade 3–4 toxicities at least possibly attributed to treatment. Nineteen (95%) patients responded to treatment with 13 (65%) complete responses. All patients were alive at a median follow-up of 24.4 months (range: 9.5–37). Eleven patients had progressive disease (median 17.6 months, 95% confidence interval [CI]: 9.7, 32.1) and eight patients were retreated (median 35.3 months, 95% CI: 17.9, not reached). We conclude that PGG beta glucan, alemtuzumab and rituximab treatment is tolerable and results in a high complete response rate.

 

Introduction

Unconjugated monoclonal antibodies (mAbs) have a well-established role in the management of chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL). However, monotherapy with either rituximab or alemtuzumab rarely achieves a complete response (CR) or sustained response and is not curative. Combination therapy with alemtuzumab and rituximab is effective and tolerable, resulting in high CR rates in phase II studies [1–5]. Although these response rates appear to be better than those reported previously for monotherapy with either mAb [1–5], there are no reported randomized studies comparing therapy with alemtuzumab alone with the combination of alemtuzumab and rituximab. In addition, the outcomes for both of these regimens are suboptimal, and even patients who achieve a CR to therapy have a relatively short duration of response. Novel drug combinations that improve mAb efficacy without increasing toxicity could be highly beneficial in the treatment of patients with CLL.

The cytotoxic effects of alemtuzumab and rituximab are primarily mediated by the innate immune system [67]. Treatment efficacy could thus be improved by interventions that increase the cytotoxic capacity of the innate immune system. We have previously reported that adding granulocyte-macrophage colony stimulating factor (GM-CSF) to alemtuzumab and rituximab for early therapy of patients with high risk CLL in a phase II trial was not sufficiently promising to support further testing of this combination [4]. We now report the results of a phase I/II clinical trial testing the efficacy and safety of combining poly-[1–6]-β-glucopyranosyl-[1–3]-β-glucopyranose (PGG) beta glucan with alemtuzumab and rituximab in the early treatment of patients with high risk CLL.

The human innate immune system has evolved to recognize and respond to fungal antigens [8]. Yeast cell wall carbohydrate beta glucan can activate the innate immune system, as reviewed by Chan et al. [8]. Larger and insoluble beta glucan molecules activate mediators of the innate immune system by ligating Toll like receptor 2 (TLR2), TLR6 and Dectin-1. In contrast, the smaller soluble beta glucan molecules produced by macrophage digestion of larger beta glucan molecules bind complement receptor 3 (CR3), increasing its affinity for the complement component 3 (C3) metabolite iC3b [8–10]. Binding of soluble low molecular weight beta glucan with CR3 has been shown to increase mAb mediated complement dependent cellular cytotoxicity of tumor cells in animal models of malignancy [11]. Use of soluble low molecular weigh beta glucan could thus potentially increase the efficacy of mAb therapy in patients with CLL.

PGG beta glucan (Imprime PPG; Biothera, Eagan, MN) is an intravenous (IV) formulation of a 1,3/1,6 glucose polymer prepared from a strain of Saccharomyces cerevisiae. This low molecular weight soluble beta glucan has been developed as an adjunct to complement activating mAb (Biothera Investigator's Brochure; Biothera, Eagan, MN; January 2010). Two phase I studies in healthy subjects and one phase I/II study with PGG beta glucan in combination with granulocyte colony stimulating factor (G-CSF) showed no serious adverse events (Imprime PPG Investigator's Brochure; Biothera, Eagan, MN). PGG beta glucan at doses up to 6 mg/kg was tolerated in clinical trials in combination regimens including cetuximab or bevacizumab in the treatment of colon and non-small cell lung cancer (Imprime PPG Investigator's Brochure). At the time that this study was planned, there was no published evidence to suggest that beta glucan could stimulate the growth of CLL cells. However, a recently published study showed that CLL cells from a small subset of patients (∼0.3%) expressing a somatically hypermutated immunoglobulin heavy chain variable gene (IGHV) utilizing VH3-7 have a B cell receptor that ligates yeast derived beta glucans, resulting in increased proliferation in culture [12]. The ability of PGG beta glucan to interact with these cells has not been tested.

We now report that the addition of PGG beta glucan to therapy with alemtuzumab and rituximab was well tolerated and resulted in high CR rates.

Methods

This phase I/II study (LS1084) was conducted at Mayo Clinic Rochester and the University of Iowa with the approval of both institutional review boards according to the principles of the Declaration of Helsinki, and was registered with ClinicalTrials.gov (NCT01269385). Rituximab and alemtuzumab were used for early treatment of patients with high risk CLL as previously described [34]. The primary aims of this study were to determine the maximum tolerated dose (MTD) of PGG beta glucan in combination with alemtuzumab and rituximab (phase I) and to assess the CR rate of patients with high risk early-intermediate stage CLL treated with alemtuzumab, rituximab and PGG beta glucan before meeting standard National Cancer Institute-International Workshop on Chronic Lymphocytic Leukemia (NCI-IWCLL) criteria for treatment [13] (phase II). The secondary aims were to evaluate treatment toxicity, measure the overall response rate (ORR) and duration of response using time to disease progression, time to next treatment (TTT) and overall survival (OS).

All qualifying sequential consenting patients were enrolled into this clinical trial at the Mayo Clinic Rochester. Inclusion criteria included no prior treatment for CLL, age ≥ 18 years, a diagnosis of CLL based on standard immunophenotypic criteria [13] with an absolute blood lymphocyte count (ALC) of > 5 × 109/L, and an interphase fluorescence in situ hybridization (FISH) analysis negative for IGH/CCND1 and/or immunostaining negative for cyclin D1 expression. High-risk status was defined as at least one of the following poor prognostic factors determined in a hierarchical manner: 17p13 deletion; 11q22.3 deletion; unmutated IGHV (< 2%) or VH3-21 gene segment usage (irrespective of IGHV mutation status) together with either CD38 expression (≥ 30%) and/or ZAP70 expression (≥ 20%). Early treatment was defined as therapy of patients with Rai [14] stage 0–II CLL that did not meet standard NCI-IWCLL criteria for therapy of their disease [13] and had limited clinical disease burden (no lymph nodes > 5 cm in any diameter, splenomegaly < 6 cm below the left costal margin in the midclavicular line at rest on clinical examination). Patients required adequate organ function (creatinine < 1.5 × upper limit of normal [UNL], bilirubin < 3.0 × UNL) and Eastern Cooperative Oncology Group (ECOG) performance status of 0–2. Exclusion criteria included New York Heart Association class III or IV heart disease, recent myocardial infarction (< 1 month), pregnancy, uncontrolled infection, and infection with the human immunodeficiency virus (HIV/AIDS), serological evidence of active hepatitis B or C infection, active autoimmune complications, or other active primary malignancy requiring treatment or limiting survival to < 2 years.

Therapy

PGG beta glucan was given IV on days 1, 5, 10, 17, 24 and 31. The starting dose (dose level 0) in the phase I study was 1 mg/kg, dose level 1 was 2 mg/kg/dose and dose level 2 was 4 mg/kg/dose. For the first dose of PGG beta glucan patients were premedicated with 1000 mg acetaminophen by mouth (po), 50 mg diphenhydramine po and 100 mg hydrocortisone IV. Based on the standard phase I trial design, the study was designed to treat a minimum of three and maximum of six patients at each dose level. There was no planned dose escalation in each patient. The same previously described short duration alemtuzumab and rituximab regimen was used for all patients [4]. In brief, patients initiated therapy with subcutaneous (SQ) alemtuzumab therapy daily for a dose escalation from 3–10–30 mg/day on days 3–5 of treatment if tolerated. Subsequent therapy was alemtuzumab 30 mg SQ starting on day 8 and given three times a week (Monday– Wednesday–Friday) for 4 weeks. During alemtuzumab dose escalation patients were premedicated with acetaminophen (1000 mg po) and diphenhydramine (50 mg po) and subsequent premedication was used only as required. Competent patients who were tolerating alemtuzumab therapy could be trained to self-administer the drug from the second week of therapy. Rituximab therapy was given at 375 mg/m2/week IV for four doses starting on day 10 of treatment with standard premedication. All patients received herpes virus and Pneumocystis jiroveci prophylaxis during treatment and then for an additional 6 months. All patients had blood testing for cytomegalovirus (CMV) DNA by polymerase chain reaction (PCR) weekly during therapy and then monthly for 3 months. Patients with detectable circulating CMV DNA were evaluated for clinical evidence of CMV infection. Asymptomatic or mildly symptomatic patients were treated with oral valganciclovir for a minimum of 2 weeks and therapy was continued until weekly CMV DNA testing by PCR was negative on two consecutive occasions. Patients with more severe CMV infections were managed with appropriate anti-CMV therapy and CLL therapy was suspended until the CMV infection had resolved.

Response evaluation

Patients were evaluated by physical examination and blood testing weekly during treatment, then monthly for 3 months, and then at 6, 9 and 12 months after completing therapy followed by event monitoring every 6 months for up to 4 more years. Treatment toxicity was evaluated using NCI Common Terminology Criteria for Adverse Events v4.0 except for anemia, thrombocytopenia and neutropenia, which were graded according to the grading scale for hematologic toxicity in CLL studies [13]. Increased white blood cell counts due to CLL related lymphocytosis and treatment induced lymphocytopenia were not reported as treatment toxicity.

Dose-limiting toxicity (DLT) was defined as an adverse event not clearly related to disease progression or intercurrent illness and meeting at least one of the following criteria: (1) absolute neutrophil count (ANC) ≤ 0.5 × 109/L for more than 5 days; (2) febrile neutropenia of any duration (ANC < 1.0 × 109/L and fever ≥ 38.5°C); (3) grade 4 thrombocytopenia or grade 3 thrombocytopenia with bleeding or any requirement for platelet transfusion; (4) grade 4 anemia; (5) any non-hematologic grade 3 as per NCI Common Terminology Criteria for Adverse Events v4.0.

Response evaluation used the NCI-IWCLL criteria of 2008 [13] with no imaging for initial CLL staging or evaluation of response to treatment. CR required all of the following for a period of at least 2 months: (1) resolution of palpable lymphadenopathy (lymph nodes > 1.5 cm) and hepatosplenomegaly on physical examination; (2) no constitutional symptoms; (3) complete blood count (CBC) with neutrophils > 1.5 × 109/L, platelets > 100 × 109/L, hemoglobin > 11.0 g/dL and ALC < 4 × 109/L. In addition, a bone marrow biopsy study 3 months after completion of treatment was required to be at least normocellular with < 30% lymphocytes and no nodules comprising CLL cells. Patients who fulfilled all criteria for a CR but who had persistent cytopenia not attributable to residual CLL were classified as having CR with incomplete marrow recovery (CRi) [13]. A stringent CR (sCR) was defined as a CR with no evidence of residual CLL on a bone marrow study that included immunohistochemical staining for minimal residual disease sensitive to ∼1% CLL cells, as previously described [4]. Patients who met all the criteria for a CR except for having nodules of CLL cells in the bone marrow were defined as having a nodular partial remission (nPR). Partial response (PR) was defined as a ≥ 50% decrease in ALC and ≥ 50% reduction in the sum of the products of the maximal perpendicular diameters of palpable lymph nodes and size of liver and/or spleen as measured by physical examination as well as a 50% improvement in ANC, platelet counts and hemoglobin above baseline or ANC > 1.5 × 109/L, platelet count > 100 × 109/L and hemoglobin > 11 g/dL. Progressive disease (PD) was defined as a ≥ 50% increase in the sum of the products of at least two lymph nodes on two consecutive determinations 2 weeks apart or the appearance of new palpable lymph nodes > 1.5 cm or a ≥ 50% increase in the size of the liver and/or spleen as determined by measurement below the respective costal margin on two consecutive determinations 2 weeks apart; or appearance of hepatomegaly or splenomegaly that was not previously present at baseline or a ≥ 50% increase in the ALC above the lowest ALC recorded since the start of treatment and with an ALC of at least 5 × 109/L. For patients who achieved a CR or nPR, progression was defined as recurrence of a circulating leukemia cell clone with an ALC > 5 × 109/L or recurrence of adenopathy > 1.5 cm not due to a tumor flare. Stable disease (SD) was defined as not meeting any of the criteria for response or PD.

Statistical analysis

The MTD of PGG beta glucan was defined as the dose level below the lowest dose that induced DLT in at least one-third of patients (at least two of a maximum of six new patients). A total of six patients treated at the MTD was considered sufficient to identify common toxicities at the MTD. A standard 3 + 3 phase I study design was used.

The phase II study was designed to evaluate the safety and efficacy of the treatment regimen. Based on the results of a previous study of this antibody regimen in a comparable patient population in which 37% of patients achieved a CR [3], we proposed that in the phase II component of the study, a CR rate of 30% would not be of interest and a CR rate of 50% would be considered promising. Using a one-stage three- outcome design with an interim analysis [15], we calculated that a minimum of 17 and a maximum of 39 evaluable patients would be required to test the null hypothesis that the true success proportion would be at most 30%.

Time to disease progression was defined as the time from registration to the earliest date of documentation of disease progression. Time to subsequent treatment was defined as the time from registration to the time that subsequent therapy was initiated. The distribution of all time-to-event endpoints was estimated using the method of Kaplan–Meier [16].

Results

Twenty-two patients (four at dose level 0, four at dose level 1 and 14 at dose level 2) were enrolled between February 2011 and May 2013 and data were frozen on 23 September 2014. Two patients enrolled in the phase I component of the trial were replaced. One patient on dose level 0 developed neutropenia mandating holding of therapy which did not occur as required per protocol, and one patient on dose level 1 had an extensive cutaneous hypersensitivity reaction attributed to alemtuzumab, and all therapy was stopped. The 20 evaluable patients were included in this analysis and their characteristics and treatment are summarized in Tables I and II. Patients were considered to have high risk CLL because of 17p13 deletion in five (one of these patients also had 11q22 deletion), 11q22 deletion in seven, unmutated IGHV + ZAP70 positive in seven (all negative for expression of CD38) and VH3-21 (mutated) + ZAP70 positive (CD38 negative) in one.

Table I Patient demographics

Factor n (%)
Age, median (min, max) 61 (47, 77)
Male 14 (70%)
Rai stage  
 0 7 (35%)
 1 10 (50%)
 2 3 (15%)
CD38  
 Positive 3 (15%)
 Negative 17 (85%)
ZAP70  
 Positive 17 (85%)
 Negative 3 (15%)
IGHV  
 Unmutated 14 (70%)
 Mutated 5 (25%)
 Indeterminate 1 (5%)
FISH*  
 17p− 5 (25%)
 11q− 7 (35%)
 Trisomy 12 3 (15%)
 13q− 3 (15%)
 Negative 2 (10%)

IGHV, immunoglobulin heavy chain variable; FISH, fluorescence in situ hybridization.

*Hierarchical classification [18].

Table II Treatment summary

Phase Dose level No. of patients Beta glucan dose DLTs Responses
I 0 3 1 mg/kg 0/3 2 CR, 1 PR
I 1 3 2 mg/kg 0/3 2 CR, 1 nPR
I 2 6 4 mg/kg 1/6 3 CR, 1 CRi, 2 PR
II 2 8 4 mg/kg NA 1 sCR, 3 CR, 1 CRi, 1 nPR, 1 PR, 1 SD

DLT, dose limiting toxicity; NA not applicable; CR, complete response; PR, partial response; nPR, nodular partial response; CRi, complete response with incomplete marrow recovery; sCR stringent complete response; SD stable disease.

Toxicity

Of the 12 evaluable patients for determining the MTD on the phase I component of the study, one DLT was seen at dose level 2 (Table II). This patient had grade 3 diarrhea possibly related to treatment. Dose level 2 (PGG beta glucan 4 mg/kg/dose) was thus used for the phase II component of the study, and eight additional evaluable patients were accrued at this dose level. Three grade 3–4 toxicities at least possibly related to treatment occurred in the 20 evaluable patients (grade 3 diarrhea, grade 4 neutropenia, grade 4 febrile neutropenia). CMV reactivation was detected in four (20%) patients at low viral load (< 10 000 copies/mL) and responded well to oral valganciclovir therapy.

Seven patients had therapy interruptions: four had rituximab first dose reactions, two had PGG beta glucan first dose reactions (infusion reaction n = 1, grade 1 chest pressure n = 1), and one had an interruption in administration of all three drugs because of grade 3 diarrhea possibly related to treatment. This last patient missed one dose of alemtuzumab. No other doses were missed in any patients. There were no dose reductions for any drugs.

Treatment response

Nineteen patients responded to therapy, resulting in an ORR of 95% (95% confidence interval [CI]: 75, 100) with 13 (65%) CRs (CR n = 11/CRi n = 2) (95% CI: 41, 85) and two (10%) nPRs (Table II). Only one of the 13 patients with a CR was negative for minimal residual disease by immunohistochemical staining of the bone marrow (sCR). All patients were alive at the time of this report with a median follow-up of 24.4 months (range: 9.5–37 months). Eleven patients have had PD with a median time to progression (TTP) of 17.6 months (95% CI: 9.7, 32.1) (Figure 1). Eight patients have been retreated (one before meeting the criteria for progressive disease) with a median time to retreatment of 35.3 months (95% CI: 17.9, not reached) (Figure 2). The retreatment regimens were fludarabine, cyclophosphamide and rituximab (FCR, n = 4), pentostatin, cyclophosphamide and rituximab (PCR, n = 2), cyclophosphamide (n = 1) and high dose methylprednisolone and rituximab (n = 1).

Figure 1. Time to progression

Nineteen patients responded to treatment, and at a median follow-up duration of 24.4 months (range: 9.5–37) 11 have progressive disease as shown by this Kaplan–Meier survival curve.

glal_1016932_f001.jpeg

 

 
Figure 2. Time to retreatment

Kaplan–Meier survival curves for time to treatment from three sequential phase II clinical trials using the same 5-week regimen of alemtuzumab and rituximab for early treatment of high risk CLL are plotted for comparison. MCO38G [3] used only alemtuzumab and rituximab (A + R) and enrolled 30 patients with a median time of follow-up of 5.2 years (range: 2.7–8.2). Twenty-four (80%) patients required retreatment for progressive CLL at a median time of 3.5 years (95% CI 2.1, 4.4). The subsequent trial MC0785 [4] added GM-CSF to the regimen (A + R + GM-CSF) and enrolled 33 patients with a median follow-up of 5.0 years (range: 3.9–5.6). Twenty-six (79%) of these patients have required retreatment at a median time of 2.9 years (95% CI 2.2, 3.8). The LS1084 study reported in this article (A + R + beta glucan) enrolled 20 eligible patients with a median follow-up of 2.0 years (range: 0.8–3.1). Eight (40%) of these patients have required retreatment with a median time to retreatment of 2.9 years (range: 1.5–not reached).

 

glal_1016932_f002.jpeg

Discussion

This phase I study shows that PGG beta glucan can be safely combined with alemtuzumab and rituximab for the early therapy of patients with high risk CLL. The limited data set suggests that this combination is effective at achieving a high rate of complete responses. However, because of the limited accrual to the phase II component of the study, these data remain preliminary.

PGG beta glucan was generally well tolerated and the 3 grade 3–4 toxicities at least possibly attributable to the study drug were manageable with no long-term adverse consequences. There were two PGG beta glucan first dose reactions requiring interruptions in drug administration, but both these patients subsequently received the full planned dose of therapy. There was no observed increase in the rate of first dose reactions to IV rituximab or SQ alemtuzumab. These data suggest that PGG beta glucan can be safely administered in combination with rituximab and alemtuzumab.

This study was designed to test the null hypothesis that the CR rate is ≤ 30% in 37 patients accrued to the phase II component of the study. The lower limit of the 95% CI for the CR rate in all 20 eligible patients was 41%. However, because only 14 patients were treated at the phase II dose level of 4 mg/kg of PGG beta glucan, no conclusions can be made about the efficacy of this regimen.

The major limitation of this study was the low accrual to the phase II component of the trial. Accrual was affected by several factors not directly related to the design or conduct of the study. The interest in alemtuzumab containing clinic trials among treating physicians and patients with CLL was substantially decreased following the removal of alemtuzumab from the market in the USA by the manufacturers in 2012 for commercial reasons unrelated to the treatment of CLL. Interest in this trial was further decreased by the introduction of highly effective novel targeted B cell receptor pathway targeting drugs, which are considerably less immunosuppressive than alemtuzumab. However, rituximab and later generation anti-CD20 mAbs remain of considerable interest in the management of CLL and other B cell malignancies. The data generated by this trial are important for developing combination therapy regimens designed to test whether PGG beta glucan can improve the efficacy of anti-CD20 mAb in the treatment of CLL and other B cell malignancies.

The short treatment regimen used in this study achieved a high CR rate according to standard criteria. However, bone marrow biopsy examination using immunohistochemistry (sensitive to ∼1% residual CLL) showed that 12 of the 13 (92%) patients with CR had residual bone marrow disease. Despite the early treatment of patients with a lower CLL disease burden, the treatment regimen rarely achieved a minimal residual disease negative status. Minimal residual disease negative status evaluation using a more sensitive flow cytometry assay (sensitive to ∼0.01% residual CLL) has previously been shown to predict a durable response to treatment with alemtuzumab based therapy [17]. In our study, the high rate of detection of minimal residual disease in patients with CR, together with the adverse disease biology of the patients enrolled in this study, is likely to contribute to the short duration of response to treatment for most patients. This study was too small to provide any preliminary data on whether the addition of PGG beta glucan improved the duration of response to therapy with alemtuzumab and rituximab. However, the similar time to next treatment for the patients treated in the present study compared to historical data (Figure 2) suggests that a major improvement is unlikely.

In conclusion, the phase I study determined that PGG beta glucan (4 mg/kg) can be safely used in combination with mAb in the treatment of patients with CLL, and the limited phase II study data could be useful for designing future studies of novel combinations including PGG beta glucan for the treatment of B cell malignancies.

Acknowledgement

This study was funded by the University of Iowa/Mayo Clinic Lymphoma SPORE (CA097274), The Gateway for Cancer Research and Biothera.

Potential Conflict of Interest

Disclosure forms provided by the authors are available with the full text of this article at http://www.informahealthcare.com/lal.

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, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia: a report from the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) updating the National Cancer Institute-Working Group (NCI-WG) 1996 guidelinesBlood 2008;111:54465456.

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Supplementary Material

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