This document summarizes research on the immunobiology of chronic lymphocytic leukemia (CLL). Key points include:
1. CLL results from the selection and transformation of B cells expressing B-cell receptors (BCRs) of restricted structure that can be polyreactive and autoreactive.
2. These BCRs bind to natural antigens as well as novel autoantigens generated during apoptosis.
3. CLL subgroups differ in retention of polyreactivity, with retention associated with worse clinical outcomes. Binding to autoantigens on apoptotic cells correlates with poor survival.
HCT and Gene Therapy for Thalassemia Major
Mark Walters, M.D.
January 18, 2014
Thalassemia Patient and Family Conference
Northern California Comprehensive Thalassemia Center
Children's Hospital Oakland
HCT and Gene Therapy for Thalassemia Major
Mark Walters, M.D.
January 18, 2014
Thalassemia Patient and Family Conference
Northern California Comprehensive Thalassemia Center
Children's Hospital Oakland
A case report of a patient with AML who had undergone allogeneic stem call transplantation. She relapsed within 6 months post transplant with lineage switch to ALL. this is follwed by a sfort review of Lineage switch in acute leukemia
diffuse large B cell lymphoma recent molecular classification
molecular classification and their time frame with references
Recent advantages of DLBCL and thier implication in therapy
Generation of Antibody Diversity- Quick revision from Kuby through presentationSharmistaChaitali
Immunology, Kuby's fifth edition notes for strong background in the topic, General introduction, Types of Antibody and Structure, Experiments, Mechanisms
micro teaching on communication m.sc nursing.pdfAnurag Sharma
Microteaching is a unique model of practice teaching. It is a viable instrument for the. desired change in the teaching behavior or the behavior potential which, in specified types of real. classroom situations, tends to facilitate the achievement of specified types of objectives.
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TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Verified Chapters 1 - 19, Complete Newest Version.pdf
ARTIFICIAL INTELLIGENCE IN HEALTHCARE.pdfAnujkumaranit
Artificial intelligence (AI) refers to the simulation of human intelligence processes by machines, especially computer systems. It encompasses tasks such as learning, reasoning, problem-solving, perception, and language understanding. AI technologies are revolutionizing various fields, from healthcare to finance, by enabling machines to perform tasks that typically require human intelligence.
Lung Cancer: Artificial Intelligence, Synergetics, Complex System Analysis, S...Oleg Kshivets
RESULTS: Overall life span (LS) was 2252.1±1742.5 days and cumulative 5-year survival (5YS) reached 73.2%, 10 years – 64.8%, 20 years – 42.5%. 513 LCP lived more than 5 years (LS=3124.6±1525.6 days), 148 LCP – more than 10 years (LS=5054.4±1504.1 days).199 LCP died because of LC (LS=562.7±374.5 days). 5YS of LCP after bi/lobectomies was significantly superior in comparison with LCP after pneumonectomies (78.1% vs.63.7%, P=0.00001 by log-rank test). AT significantly improved 5YS (66.3% vs. 34.8%) (P=0.00000 by log-rank test) only for LCP with N1-2. Cox modeling displayed that 5YS of LCP significantly depended on: phase transition (PT) early-invasive LC in terms of synergetics, PT N0—N12, cell ratio factors (ratio between cancer cells- CC and blood cells subpopulations), G1-3, histology, glucose, AT, blood cell circuit, prothrombin index, heparin tolerance, recalcification time (P=0.000-0.038). Neural networks, genetic algorithm selection and bootstrap simulation revealed relationships between 5YS and PT early-invasive LC (rank=1), PT N0—N12 (rank=2), thrombocytes/CC (3), erythrocytes/CC (4), eosinophils/CC (5), healthy cells/CC (6), lymphocytes/CC (7), segmented neutrophils/CC (8), stick neutrophils/CC (9), monocytes/CC (10); leucocytes/CC (11). Correct prediction of 5YS was 100% by neural networks computing (area under ROC curve=1.0; error=0.0).
CONCLUSIONS: 5YS of LCP after radical procedures significantly depended on: 1) PT early-invasive cancer; 2) PT N0--N12; 3) cell ratio factors; 4) blood cell circuit; 5) biochemical factors; 6) hemostasis system; 7) AT; 8) LC characteristics; 9) LC cell dynamics; 10) surgery type: lobectomy/pneumonectomy; 11) anthropometric data. Optimal diagnosis and treatment strategies for LC are: 1) screening and early detection of LC; 2) availability of experienced thoracic surgeons because of complexity of radical procedures; 3) aggressive en block surgery and adequate lymph node dissection for completeness; 4) precise prediction; 5) adjuvant chemoimmunoradiotherapy for LCP with unfavorable prognosis.
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Prix Galien International 2024 Forum ProgramLevi Shapiro
June 20, 2024, Prix Galien International and Jerusalem Ethics Forum in ROME. Detailed agenda including panels:
- ADVANCES IN CARDIOLOGY: A NEW PARADIGM IS COMING
- WOMEN’S HEALTH: FERTILITY PRESERVATION
- WHAT’S NEW IN THE TREATMENT OF INFECTIOUS,
ONCOLOGICAL AND INFLAMMATORY SKIN DISEASES?
- ARTIFICIAL INTELLIGENCE AND ETHICS
- GENE THERAPY
- BEYOND BORDERS: GLOBAL INITIATIVES FOR DEMOCRATIZING LIFE SCIENCE TECHNOLOGIES AND PROMOTING ACCESS TO HEALTHCARE
- ETHICAL CHALLENGES IN LIFE SCIENCES
- Prix Galien International Awards Ceremony
Title: Sense of Smell
Presenter: Dr. Faiza, Assistant Professor of Physiology
Qualifications:
MBBS (Best Graduate, AIMC Lahore)
FCPS Physiology
ICMT, CHPE, DHPE (STMU)
MPH (GC University, Faisalabad)
MBA (Virtual University of Pakistan)
Learning Objectives:
Describe the primary categories of smells and the concept of odor blindness.
Explain the structure and location of the olfactory membrane and mucosa, including the types and roles of cells involved in olfaction.
Describe the pathway and mechanisms of olfactory signal transmission from the olfactory receptors to the brain.
Illustrate the biochemical cascade triggered by odorant binding to olfactory receptors, including the role of G-proteins and second messengers in generating an action potential.
Identify different types of olfactory disorders such as anosmia, hyposmia, hyperosmia, and dysosmia, including their potential causes.
Key Topics:
Olfactory Genes:
3% of the human genome accounts for olfactory genes.
400 genes for odorant receptors.
Olfactory Membrane:
Located in the superior part of the nasal cavity.
Medially: Folds downward along the superior septum.
Laterally: Folds over the superior turbinate and upper surface of the middle turbinate.
Total surface area: 5-10 square centimeters.
Olfactory Mucosa:
Olfactory Cells: Bipolar nerve cells derived from the CNS (100 million), with 4-25 olfactory cilia per cell.
Sustentacular Cells: Produce mucus and maintain ionic and molecular environment.
Basal Cells: Replace worn-out olfactory cells with an average lifespan of 1-2 months.
Bowman’s Gland: Secretes mucus.
Stimulation of Olfactory Cells:
Odorant dissolves in mucus and attaches to receptors on olfactory cilia.
Involves a cascade effect through G-proteins and second messengers, leading to depolarization and action potential generation in the olfactory nerve.
Quality of a Good Odorant:
Small (3-20 Carbon atoms), volatile, water-soluble, and lipid-soluble.
Facilitated by odorant-binding proteins in mucus.
Membrane Potential and Action Potential:
Resting membrane potential: -55mV.
Action potential frequency in the olfactory nerve increases with odorant strength.
Adaptation Towards the Sense of Smell:
Rapid adaptation within the first second, with further slow adaptation.
Psychological adaptation greater than receptor adaptation, involving feedback inhibition from the central nervous system.
Primary Sensations of Smell:
Camphoraceous, Musky, Floral, Pepperminty, Ethereal, Pungent, Putrid.
Odor Detection Threshold:
Examples: Hydrogen sulfide (0.0005 ppm), Methyl-mercaptan (0.002 ppm).
Some toxic substances are odorless at lethal concentrations.
Characteristics of Smell:
Odor blindness for single substances due to lack of appropriate receptor protein.
Behavioral and emotional influences of smell.
Transmission of Olfactory Signals:
From olfactory cells to glomeruli in the olfactory bulb, involving lateral inhibition.
Primitive, less old, and new olfactory systems with different path
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Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journeygreendigital
Tom Selleck, an enduring figure in Hollywood. has captivated audiences for decades with his rugged charm, iconic moustache. and memorable roles in television and film. From his breakout role as Thomas Magnum in Magnum P.I. to his current portrayal of Frank Reagan in Blue Bloods. Selleck's career has spanned over 50 years. But beyond his professional achievements. fans have often been curious about Tom Selleck Health. especially as he has aged in the public eye.
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Introduction
Many have been interested in Tom Selleck health. not only because of his enduring presence on screen but also because of the challenges. and lifestyle choices he has faced and made over the years. This article delves into the various aspects of Tom Selleck health. exploring his fitness regimen, diet, mental health. and the challenges he has encountered as he ages. We'll look at how he maintains his well-being. the health issues he has faced, and his approach to ageing .
Early Life and Career
Childhood and Athletic Beginnings
Tom Selleck was born on January 29, 1945, in Detroit, Michigan, and grew up in Sherman Oaks, California. From an early age, he was involved in sports, particularly basketball. which played a significant role in his physical development. His athletic pursuits continued into college. where he attended the University of Southern California (USC) on a basketball scholarship. This early involvement in sports laid a strong foundation for his physical health and disciplined lifestyle.
Transition to Acting
Selleck's transition from an athlete to an actor came with its physical demands. His first significant role in "Magnum P.I." required him to perform various stunts and maintain a fit appearance. This role, which he played from 1980 to 1988. necessitated a rigorous fitness routine to meet the show's demands. setting the stage for his long-term commitment to health and wellness.
Fitness Regimen
Workout Routine
Tom Selleck health and fitness regimen has evolved. adapting to his changing roles and age. During his "Magnum, P.I." days. Selleck's workouts were intense and focused on building and maintaining muscle mass. His routine included weightlifting, cardiovascular exercises. and specific training for the stunts he performed on the show.
Selleck adjusted his fitness routine as he aged to suit his body's needs. Today, his workouts focus on maintaining flexibility, strength, and cardiovascular health. He incorporates low-impact exercises such as swimming, walking, and light weightlifting. This balanced approach helps him stay fit without putting undue strain on his joints and muscles.
Importance of Flexibility and Mobility
In recent years, Selleck has emphasized the importance of flexibility and mobility in his fitness regimen. Understanding the natural decline in muscle mass and joint flexibility with age. he includes stretching and yoga in his routine. These practices help prevent injuries, improve posture, and maintain mobilit
Couples presenting to the infertility clinic- Do they really have infertility...Sujoy Dasgupta
Dr Sujoy Dasgupta presented the study on "Couples presenting to the infertility clinic- Do they really have infertility? – The unexplored stories of non-consummation" in the 13th Congress of the Asia Pacific Initiative on Reproduction (ASPIRE 2024) at Manila on 24 May, 2024.
New Directions in Targeted Therapeutic Approaches for Older Adults With Mantl...i3 Health
i3 Health is pleased to make the speaker slides from this activity available for use as a non-accredited self-study or teaching resource.
This slide deck presented by Dr. Kami Maddocks, Professor-Clinical in the Division of Hematology and
Associate Division Director for Ambulatory Operations
The Ohio State University Comprehensive Cancer Center, will provide insight into new directions in targeted therapeutic approaches for older adults with mantle cell lymphoma.
STATEMENT OF NEED
Mantle cell lymphoma (MCL) is a rare, aggressive B-cell non-Hodgkin lymphoma (NHL) accounting for 5% to 7% of all lymphomas. Its prognosis ranges from indolent disease that does not require treatment for years to very aggressive disease, which is associated with poor survival (Silkenstedt et al, 2021). Typically, MCL is diagnosed at advanced stage and in older patients who cannot tolerate intensive therapy (NCCN, 2022). Although recent advances have slightly increased remission rates, recurrence and relapse remain very common, leading to a median overall survival between 3 and 6 years (LLS, 2021). Though there are several effective options, progress is still needed towards establishing an accepted frontline approach for MCL (Castellino et al, 2022). Treatment selection and management of MCL are complicated by the heterogeneity of prognosis, advanced age and comorbidities of patients, and lack of an established standard approach for treatment, making it vital that clinicians be familiar with the latest research and advances in this area. In this activity chaired by Michael Wang, MD, Professor in the Department of Lymphoma & Myeloma at MD Anderson Cancer Center, expert faculty will discuss prognostic factors informing treatment, the promising results of recent trials in new therapeutic approaches, and the implications of treatment resistance in therapeutic selection for MCL.
Target Audience
Hematology/oncology fellows, attending faculty, and other health care professionals involved in the treatment of patients with mantle cell lymphoma (MCL).
Learning Objectives
1.) Identify clinical and biological prognostic factors that can guide treatment decision making for older adults with MCL
2.) Evaluate emerging data on targeted therapeutic approaches for treatment-naive and relapsed/refractory MCL and their applicability to older adults
3.) Assess mechanisms of resistance to targeted therapies for MCL and their implications for treatment selection
Pulmonary Thromboembolism - etilogy, types, medical- Surgical and nursing man...VarunMahajani
Disruption of blood supply to lung alveoli due to blockage of one or more pulmonary blood vessels is called as Pulmonary thromboembolism. In this presentation we will discuss its causes, types and its management in depth.
1. Immunobiology of chronic lymphocytic leukemia Nicholas Chiorazzi Departments of Cell Biology and of Medicine Albert Einstein College of Medicine and The Feinstein Institute for Medical Research North Shore – LIJ Health System
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5. Chronic Lymphocytic Leukemia Lymphocytosis seen in blood, but most leukemic cells are in non-vascular areas including bone marrow, lymph nodes, and spleen Usually detected upon routine blood workup as an elevated white cell or lymphocyte count (~3x10 10 total in blood) Clonal expansion of a CD5 + B lymphocyte with low surface immunoglobulin (Ig) Most clones express predominantly IgM isotype surface Ig, but ~7% are predominantly IgG or IgA, though in those cases IgM clonal relatives can be found
7. Take home messages 1. CLL results from the non-random selection and transformation of B lymphocytes expressing B-cell antigen receptors (BCRs) of restricted amino acid structure 2. These BCRs can be poly- and auto-reactive, binding natural as well as novel autoantigens generated by apoptosis and other catabolic processes 3. The clinically-distinct subgroups differ in the retention or loss of poly- and auto-reactivity, with the retention of polyreactivity being associated with worse clinical disease
8. Take home messages 1. CLL results from the non-random selection and transformation of B lymphocytes expressing B-cell antigen receptors (BCRs) of restricted amino acid structure
9. Ig molecules and their genes V H D J H C H Chromosome 14 Chromosome 2 V K J H C K Ig Genes Ig Molecule V Region Hinge Region C K COOH NH 2 -S - S- Fab Fc V K C H 1 V H C H 2 C H 3 V K J K V H D J H CDR3 CDR1 CDR2 FR4 FR3 FR2 FR1
10. CLL cells differ from normal CD5 + B cells by the overuse of certain autoreactive genes Fais et al. J Clin Invest 98: 1659, 1998
11. CLL clones differ in the degree of somatic mutations, especially in particular IgV genes V H Specific % Cases with Family V H Gene Mutations All cases - 50.7 1 - 33.3 1-69 10.0 3 - 66.7 3-07 90.0 4 - 41.2 4-34 55.0 Fais et al. J Clin Invest 98: 1659, 1998
12. Ig V H gene mutation status of CLL cells is an important prognostic indicator of outcome Damle et al. Hamblin et al. Blood 94: 1840, 1999 Blood 94: 1848, 1999 ≥ 2% mutation < 2% mutation ≥ 2% mutation < 2% mutation
13. Ig molecules and their genes V H D J H C H Chromosome 14 Chromosome 2 V K J H C K Ig Genes Ig Molecule V Region Hinge Region C K COOH NH 2 -S - S- Fab Fc V K C H 1 V H C H 2 C H 3 V K J K V H D J H CDR3 CDR1 CDR2 FR4 FR3 FR2 FR1
14. CLL clones are culled from the normal B-cell repertoire based on structural constraints of the B-cell antigen receptor
15. IgV gene segment recombination Heavy Chain Light Chain ( / λ ) V H (44) HC = V H x D x J H = 44 x 27 x 6 = 7,128 D (27) J H (6) J L (5/7) V L (46/36) V H DJ H rearrangement: ~1 : 7,000 = RAG mediated recombination
16.
17. Ig V region gene segment recombination Heavy Chain Light Chain ( / λ ) V H (44) HC = V H x D x J H = 44 x 27 x 6 = 7,128 = V x J = 46 x 5 = 230 = V x J = 36 x 7 = 252 D (27) J H (6) J L (5/7) V L (46/36) V H DJ H / V L J L rearrangement: ~1 : 3 x 10 6 = RAG mediated recombination
18. CLL cases with remarkably similar B-cell receptors Ghiotto et al . J Clin Invest 113: 1008 , 2004
19. IgV gene segment recombination Heavy Chain Light Chain ( / λ ) V H (44) D (27) J H (6) J L (5/7) V L (46/36) = RAG mediated recombination
20. Because of the differences that occur at the junctions when gene segments combine, the likelihood that the same V H DJ H - V L J L rearrangement with the same junctional characteristic would occur in two different B cells is even much more remote ≈ 1 / 1x10 8 – 1 : 1x10 12 Therefore, if the gene structure of the Ig variable region found in B-CLL cells from different patients is very similar or identical, then this must indicate a selective process of leukemogenesis that targets B cells with a given type of Ig V region.
21. CLL068 : CAR GG D YDYVWGSYR S N DAFDIWG CLLSMI : CAR GG N YDY I WGSYR S N DAFDIWG CLL258 : CAR GG I YDYVWGSYR P N DAFDIWG aCLA*: CAR GG N YDY I WGSYR S N DAFDIWG CAR YYDYVWGSYRY DAFDIWG D3-16 J H 3 V H 1-69 Heavy chain sequence alignment CLL022 : CAR GG D YDYVWGSYR P N DAFDIWG Natural autoantibody * aCLA = anti-cardiolipin ab Messmer et al . J Exp Med 2004; 200: 519-525
22. Almost 30% of patients with chronic lymphocytic leukemia carry stereotyped receptors Stamatopoulos et al . Blood 109:259-270, 2007 Murray et al . Blood 111:1524- 15 33 , 2008 >35% chance of fitting into a stereotypic set if U-CLL or if express a specific V H gene (1-69, 3-21, 4-39) associated with poor outcome
23. Take home messages 2. These BCRs can be poly- and auto-reactive, binding natural as well as novel autoantigens generated by apoptosis and other catabolic processes
24. Expression of recombinant CLL mAbs 293T HEK cell line Antibody purification using Protein G beads Wardemann et al . Science 301:1374, 2003 Immuno assay for quantification of CLL mAb 4-5 days of culture 1. Plasmid DNA carrying heavy and light chain Ig gene 2. Lipofectamine 2000 Reagent 3. Lipofectamine 2000 Reagent and DNA are mixed and incubated 4. Liposomes are added in 293T HEK cell culture Transfection of 293T HEK cells using Lipofectamine 2000
25. Herve et al . J Clin Invest 115:1636-1643, 2005
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27.
28. Herve et al . J Clin Invest 115:1636-1643, 2005
29. CLL068 : CAR GG D YDYVWGSYR S N DAFDIWG CLLSMI : CAR GG N YDY I WGSYR S N DAFDIWG CLL258 : CAR GG I YDYVWGSYR P N DAFDIWG aCLA*: CAR GG N YDY I WGSYR S N DAFDIWG CAR YYDYVWGSYRY DAFDIWG D3-16 J H 3 V H 1-69 Heavy chain sequence alignment CLL022 : CAR GG D YDYVWGSYR P N DAFDIWG Natural autoantibody * aCLA = anti-cardiolipin ab Messmer et al . J Exp Med 2004; 200: 519-525
30. mAb 068 binds 225KDa molecule C. Chu et al . Blood 112: 5122-5129, 2008
31. LC MS/MS identifies 225KDa band as non-muscle myosin heavy chain IIA (MYHIIA) C. Chu et al . Blood 112: 5122-5129, 2008
32. CLL mAb 068 co-localizes with pAbs to MYHIIA C. Chu et al . Blood 112: 5122-5129, 2008
33.
34. CLL mAbs react with apoptotic (not healthy) cells R. Catera et al . Mol Med 14: 665-674, 2008 Jurkat RAMOS Annexin V CLL014 DO13 C D Annexin V CLL014 DO13 A B 28.17 0.92 3.70 67.27 13.86 0.23 69.14 16.77 52.86 18.12 0.55 28.47 55.35 16.96 0.32 27.37
35.
36. Antigens bound at the surface of apoptotic cells have translocated from intracellular compartments Cytox Orange Annexin V CLL 114 Merge Membrane blebs Apoptotic body without DNA Apoptotic body with DNA R. Catera et al . Mol Med 14: 665-674, 2008
37. MYHIIA is one of the intracellular antigens that translocates to the surface and is bound by CLL mAbs
38. Live Late apoptotic Early apoptotic Chu et al . Blood 2010 in press MEAC : M YHIIA e xposed a poptotic c ell
39. CLL 068 mAb binds to MEACs Chu et al . Blood 2010 in press Negative Apoptotic MEACs
40. Many CLL mAbs bind MEACs MEAC binding Subset Mutation Chu et al . Blood 2010 in press
41. Take home messages 3. The clinically-distinct subgroups differ in the retention or loss of poly- and auto-reactivity, with the retention of polyreactivity being associated with worse clinical disease
42. Herve et al . J Clin Invest 115:1636-1643, 2005 Polyreactivity is a feature primarily of unmutated CLL cells
43. Ig V H gene mutation status of CLL cells is an important prognostic indicator of outcome Damle et al. Hamblin et al. Blood 1999; 94: 1840 Blood 1999; 94: 1848 ≥ 2% mutation < 2% mutation ≥ 2% mutation < 2% mutation
44. Binding well to MEACs correlates with poor patient survival Hi binding 99 months (n = 15) Lo binding ?? Months (n = 9) Chu et al . Blood 2010 in press
45. Unmutated 118 months (n = 18) Mutated ?? Months (n = 6) In this limited series, MEAC binding correlates better with patient survival than IGHV mutation status Chu et al . Blood 2010 in press
46. Many CLL mAbs bind MEACs MEAC binding Subset Mutation Chu et al . Blood 2010 in press
47.
48. B-CLL evolution hypothesis MEACs MYHIIA+ Vimentin Filamin B Oxidation Chemical Modification M-CLL U-CLL Initiation Progression
Editor's Notes
I would like to thank the organizers for giving me the opportunity to discuss our research results with you. This represents the work of not only myself but of many others including… Lu, Katerina, Rosa Steve and Kanti for clinical collaboration Nick for support, guidance and inspiration and others that I will acknowledge throughout the talk
This is a typical example of flow cytometry data showing that CLL 068 mAb reacts to MEACs. This is a negative control. This shows that CLL 068 binds to a subset of dead cells (AV-PE positive) and not live cells. This shows that CLL 068 binds only to MEACs (MYHIIA positive). And not other cells.
This is a graph that shows the binding of 26 CLL mAbs listed on the x-axis to MEACs… … with the cutoff of 1.5 for MEAC binding. 16 mAbs bind well/. This is a grouping of the CLL mAbs based on having a shared common “stereotyped” sequence, which I do not have time to describe, … but would just like to point out that the stereotyped groups bind in the same manner. This shows which CLL mAbs are mutated or unmutated, … U = is less than 2% mutation in the IGHV, which correlates with bad patient survival … M = is greater than 2% mutation in the IGHV, which correlates with good patient outcome. All the MEAC binding mAbs are UM, except for 1 (15/16), which binds like the same stereotype subgroup “1” and is a borderline “Mut”. Those mAbs that do not bind MEACs well are a mixture of Mut (6) and four UM (4) mAbs. Because survival correlates with IGHV mutation, perhaps MEAC binding correlates with survival and help distinguish the UM that may survive better.. .
Indeed binding well to MEACs correlates to poor patient survival (24 patients have survival data)… Hi binding has a median survival of 99 months (n=15), Whereas Lo binding has not reached median survival (n=9). This is statistically significant P<0.0087. This significance is better than that for UM versus Mut (P<0.06) in this patient cohort. … this is because one mutated (CLL 154) and two unmutated (CLL 376 and 412) IGHV CLL patients having survival outcomes contrary to that expected for their IGHV mutation status.
IGHV mutation status versus patient survival (24 patients have survival data)… UM IGHV has a median survival of 118 months (n=18), Whereas Mut IGHV has not reached median survival (n=6). This is not quite statistically significant P<0.06. This significance is not as good as MEAC binding. … this is because one mutated (CLL 154) and two unmutated (CLL 376 and 412) IGHV CLL patients having survival outcomes contrary to that expected for their IGHV mutation status.
This is a graph that shows the binding of 26 CLL mAbs listed on the x-axis to MEACs… … with the cutoff of 1.5 for MEAC binding. 16 mAbs bind well/. This is a grouping of the CLL mAbs based on having a shared common “stereotyped” sequence, which I do not have time to describe, … but would just like to point out that the stereotyped groups bind in the same manner. This shows which CLL mAbs are mutated or unmutated, … U = is less than 2% mutation in the IGHV, which correlates with bad patient survival … M = is greater than 2% mutation in the IGHV, which correlates with good patient outcome. All the MEAC binding mAbs are UM, except for 1 (15/16), which binds like the same stereotype subgroup “1” and is a borderline “Mut”. Those mAbs that do not bind MEACs well are a mixture of Mut (6) and four UM (4) mAbs. Because survival correlates with IGHV mutation, perhaps MEAC binding correlates with survival and help distinguish the UM that may survive better.. .
These results lead to the following inferences…
Just to end with a MODEL cell death (CLL or other) leading to MEAC formation and exposure of MYHIIA and other epitopes observed by Rosa This could be important for the initiation of CLL or the ongoing stimulation that may be required for CLL growth and development.