Present and Future Impact of Cytogenetics on Acute Myeloid Leukemialarriva
Cytogenetics is an advancement in which clinicians can look for specific genetic mutations of chromosomal DNA and use that information to determine patient prognosis and individualize therapy. In this presentation I cover what cytogenetics are, how they impact patient risk, what therapies to use based on risk, and how genetically targeted agents may be used in the future.
Widespread human T cell receptor beta variable gene polymorphism: implication...Thermo Fisher Scientific
Polymorphism within the TCRB variable gene (TRBV) has been linked to chronic autoimmune diseases such as Type 1 Diabetes, Rheumatoid Arthritis, Psoriatic Arthritis, Multiple Sclerosis and Asthma (1-8), and may also be mechanistically linked to immune mediated adverse events (IMAEs) during immunotherapy (9-11). Here we use the Ion-AmpliSeq™ Immune Repertoire Plus TCRB assay to evaluate TRBV gene polymorphism in a group of 85 Caucasians with melanoma. The assay provides coverage of all three CDR domains to enable detection of TRBV polymorphism. We find evidence of extensive genetic diversity within the TRBV gene, including 15 nonsynonymous variants that are absent from the IMGT database (12). TRBV gene allele typing may provide rich biomarker information for the prediction of IMAEs and chronic autoimmune disease.
Insights into the tumor microenvironment and therapeutic T cell manufacture r...Thermo Fisher Scientific
TCRβ immune repertoire analysis by next-generation sequencing is emerging as a valuable tool for research studies of the tumor microenvironment and potential immune responses to cancer immunotherapy1-4. Here we describe a multiplex PCR-based TCRβ sequencing assay (Ion AmpliSeqTM Immune Repertoire Assay Plus – TCRβ) that leverages Ion AmpliSeq library construction chemistry and the long read capability of the Ion S5 530TM chip to provide coverage of all three CDR domains of the human TCRβ chain. We demonstrate use of the assay to evaluate tumor-infiltrating T cell repertoire features and monitor manufacture of therapeutic T cells.
Present and Future Impact of Cytogenetics on Acute Myeloid Leukemialarriva
Cytogenetics is an advancement in which clinicians can look for specific genetic mutations of chromosomal DNA and use that information to determine patient prognosis and individualize therapy. In this presentation I cover what cytogenetics are, how they impact patient risk, what therapies to use based on risk, and how genetically targeted agents may be used in the future.
Widespread human T cell receptor beta variable gene polymorphism: implication...Thermo Fisher Scientific
Polymorphism within the TCRB variable gene (TRBV) has been linked to chronic autoimmune diseases such as Type 1 Diabetes, Rheumatoid Arthritis, Psoriatic Arthritis, Multiple Sclerosis and Asthma (1-8), and may also be mechanistically linked to immune mediated adverse events (IMAEs) during immunotherapy (9-11). Here we use the Ion-AmpliSeq™ Immune Repertoire Plus TCRB assay to evaluate TRBV gene polymorphism in a group of 85 Caucasians with melanoma. The assay provides coverage of all three CDR domains to enable detection of TRBV polymorphism. We find evidence of extensive genetic diversity within the TRBV gene, including 15 nonsynonymous variants that are absent from the IMGT database (12). TRBV gene allele typing may provide rich biomarker information for the prediction of IMAEs and chronic autoimmune disease.
Insights into the tumor microenvironment and therapeutic T cell manufacture r...Thermo Fisher Scientific
TCRβ immune repertoire analysis by next-generation sequencing is emerging as a valuable tool for research studies of the tumor microenvironment and potential immune responses to cancer immunotherapy1-4. Here we describe a multiplex PCR-based TCRβ sequencing assay (Ion AmpliSeqTM Immune Repertoire Assay Plus – TCRβ) that leverages Ion AmpliSeq library construction chemistry and the long read capability of the Ion S5 530TM chip to provide coverage of all three CDR domains of the human TCRβ chain. We demonstrate use of the assay to evaluate tumor-infiltrating T cell repertoire features and monitor manufacture of therapeutic T cells.
Gene therapy is that the introduction of a traditional gene into an individual’s genome so as to repair a mutation that causes a genetic disorder.
When a traditional gene is inserted into a mutant nucleus, it presumably will integrate into a chromosomal site different from the defective allele; although this might repair the mutation, a replacement mutation may result if the traditional gene integrates into another functional gene.
Human gene therapy has been attempted only on somatic (body) cells for diseases like cancer and severe combined immunodeficiency syndrome (SCIDS).
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
Diagnosing PM/DM is challenging due to rarity of the disease, their similar clinical presentation and the possibility of overlap syndromes. A comprehensive strategy for serological testing comprises of parallel determination of both MSA and MAA thereby reducing the time to diagnosis. Current immunoassays techniques (Immunoblot) targeting MAA & MSAs have –
The ability to include many parameters simultaneously which ensures higher detection rate; Become readily accessible & hence an opportunity for laboratories to contribute significantly in the disease diagnosis. MSA are highly specific for PM/DM, and many of them are also associated with a unique clinical subset of PM/DM, making them useful clinical diagnostic/prognostic biomarkers & continue to evolve.
detailed discussion on cytogenetics in CML - Pathophysiology, treatment, TKI Resistance, Mutation analysis timing, various mutations in CML, BCR-ABL1 Variants, Significance of mutations and management.
Gene therapy is that the introduction of a traditional gene into an individual’s genome so as to repair a mutation that causes a genetic disorder.
When a traditional gene is inserted into a mutant nucleus, it presumably will integrate into a chromosomal site different from the defective allele; although this might repair the mutation, a replacement mutation may result if the traditional gene integrates into another functional gene.
Human gene therapy has been attempted only on somatic (body) cells for diseases like cancer and severe combined immunodeficiency syndrome (SCIDS).
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
Diagnosing PM/DM is challenging due to rarity of the disease, their similar clinical presentation and the possibility of overlap syndromes. A comprehensive strategy for serological testing comprises of parallel determination of both MSA and MAA thereby reducing the time to diagnosis. Current immunoassays techniques (Immunoblot) targeting MAA & MSAs have –
The ability to include many parameters simultaneously which ensures higher detection rate; Become readily accessible & hence an opportunity for laboratories to contribute significantly in the disease diagnosis. MSA are highly specific for PM/DM, and many of them are also associated with a unique clinical subset of PM/DM, making them useful clinical diagnostic/prognostic biomarkers & continue to evolve.
detailed discussion on cytogenetics in CML - Pathophysiology, treatment, TKI Resistance, Mutation analysis timing, various mutations in CML, BCR-ABL1 Variants, Significance of mutations and management.
Never-smoker with Lung cancer in Southern California. Never-smokers with lung cancer have distinct genetic changes. Chao Family Comprehensive Cancer Center at UCI Irvine offers cutting edge clinical trials. Please call 1-714-456-8000
Newer biomarkers,techniques & their inclusion in 2016 WHO classification for leukaemia/lymphomas increases the responsibility of the pathologists, requiring to develop an integrated multidisciplinary approach for reporting.
Flu Vaccine Alert in Bangalore Karnatakaaddon Scans
As flu season approaches, health officials in Bangalore, Karnataka, are urging residents to get their flu vaccinations. The seasonal flu, while common, can lead to severe health complications, particularly for vulnerable populations such as young children, the elderly, and those with underlying health conditions.
Dr. Vidisha Kumari, a leading epidemiologist in Bangalore, emphasizes the importance of getting vaccinated. "The flu vaccine is our best defense against the influenza virus. It not only protects individuals but also helps prevent the spread of the virus in our communities," he says.
This year, the flu season is expected to coincide with a potential increase in other respiratory illnesses. The Karnataka Health Department has launched an awareness campaign highlighting the significance of flu vaccinations. They have set up multiple vaccination centers across Bangalore, making it convenient for residents to receive their shots.
To encourage widespread vaccination, the government is also collaborating with local schools, workplaces, and community centers to facilitate vaccination drives. Special attention is being given to ensuring that the vaccine is accessible to all, including marginalized communities who may have limited access to healthcare.
Residents are reminded that the flu vaccine is safe and effective. Common side effects are mild and may include soreness at the injection site, mild fever, or muscle aches. These side effects are generally short-lived and far less severe than the flu itself.
Healthcare providers are also stressing the importance of continuing COVID-19 precautions. Wearing masks, practicing good hand hygiene, and maintaining social distancing are still crucial, especially in crowded places.
Protect yourself and your loved ones by getting vaccinated. Together, we can help keep Bangalore healthy and safe this flu season. For more information on vaccination centers and schedules, residents can visit the Karnataka Health Department’s official website or follow their social media pages.
Stay informed, stay safe, and get your flu shot today!
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
Ethanol (CH3CH2OH), or beverage alcohol, is a two-carbon alcohol
that is rapidly distributed in the body and brain. Ethanol alters many
neurochemical systems and has rewarding and addictive properties. It
is the oldest recreational drug and likely contributes to more morbidity,
mortality, and public health costs than all illicit drugs combined. The
5th edition of the Diagnostic and Statistical Manual of Mental Disorders
(DSM-5) integrates alcohol abuse and alcohol dependence into a single
disorder called alcohol use disorder (AUD), with mild, moderate,
and severe subclassifications (American Psychiatric Association, 2013).
In the DSM-5, all types of substance abuse and dependence have been
combined into a single substance use disorder (SUD) on a continuum
from mild to severe. A diagnosis of AUD requires that at least two of
the 11 DSM-5 behaviors be present within a 12-month period (mild
AUD: 2–3 criteria; moderate AUD: 4–5 criteria; severe AUD: 6–11 criteria).
The four main behavioral effects of AUD are impaired control over
drinking, negative social consequences, risky use, and altered physiological
effects (tolerance, withdrawal). This chapter presents an overview
of the prevalence and harmful consequences of AUD in the U.S.,
the systemic nature of the disease, neurocircuitry and stages of AUD,
comorbidities, fetal alcohol spectrum disorders, genetic risk factors, and
pharmacotherapies for AUD.
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.
Anti ulcer drugs and their Advance pharmacology ||
Anti-ulcer drugs are medications used to prevent and treat ulcers in the stomach and upper part of the small intestine (duodenal ulcers). These ulcers are often caused by an imbalance between stomach acid and the mucosal lining, which protects the stomach lining.
||Scope: Overview of various classes of anti-ulcer drugs, their mechanisms of action, indications, side effects, and clinical considerations.
MANAGEMENT OF ATRIOVENTRICULAR CONDUCTION BLOCK.pdfJim Jacob Roy
Cardiac conduction defects can occur due to various causes.
Atrioventricular conduction blocks ( AV blocks ) are classified into 3 types.
This document describes the acute management of AV block.
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
- Video recording of this lecture in English language: https://youtu.be/lK81BzxMqdo
- Video recording of this lecture in Arabic language: https://youtu.be/Ve4P0COk9OI
- Link to download the book free: https://nephrotube.blogspot.com/p/nephrotube-nephrology-books.html
- Link to NephroTube website: www.NephroTube.com
- Link to NephroTube social media accounts: https://nephrotube.blogspot.com/p/join-nephrotube-on-social-media.html
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.
These simplified slides by Dr. Sidra Arshad present an overview of the non-respiratory functions of the respiratory tract.
Learning objectives:
1. Enlist the non-respiratory functions of the respiratory tract
2. Briefly explain how these functions are carried out
3. Discuss the significance of dead space
4. Differentiate between minute ventilation and alveolar ventilation
5. Describe the cough and sneeze reflexes
Study Resources:
1. Chapter 39, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 34, Ganong’s Review of Medical Physiology, 26th edition
3. Chapter 17, Human Physiology by Lauralee Sherwood, 9th edition
4. Non-respiratory functions of the lungs https://academic.oup.com/bjaed/article/13/3/98/278874
These lecture slides, by Dr Sidra Arshad, offer a quick overview of physiological basis of a normal electrocardiogram.
Learning objectives:
1. Define an electrocardiogram (ECG) and electrocardiography
2. Describe how dipoles generated by the heart produce the waveforms of the ECG
3. Describe the components of a normal electrocardiogram of a typical bipolar leads (limb II)
4. Differentiate between intervals and segments
5. Enlist some common indications for obtaining an ECG
Study Resources:
1. Chapter 11, Guyton and Hall Textbook of Medical Physiology, 14th edition
2. Chapter 9, Human Physiology - From Cells to Systems, Lauralee Sherwood, 9th edition
3. Chapter 29, Ganong’s Review of Medical Physiology, 26th edition
4. Electrocardiogram, StatPearls - https://www.ncbi.nlm.nih.gov/books/NBK549803/
5. ECG in Medical Practice by ABM Abdullah, 4th edition
6. ECG Basics, http://www.nataliescasebook.com/tag/e-c-g-basics
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.
High-Risk Multiple Myeloma: Distinguishing Early Failures from Sustained Control
1. HIGH-RISK MULTIPLE MYELOMA (MM): DISTINGUISHING EARLY FAILURES (EF) FROM SUSTAINED CONTROL (SC) B. Barlogie, J. D. Shaughnessy Jr, J. Haessler, A. Hoering, F. Van Rhee, E. J. Anaissie, J. Crowley University of Arkansas for Medical Sciences Little Rock, AR Cancer Research And Biostatistics Seattle, WA
2.
3. TT2 (BOTH ARMS): CLINICAL OUTCOMES ACCORDING TO GEP-DEFINED RISK OVERALL SURVIVAL 0% 20% 40% 60% 80% 100% 0 2 4 6 8 10 Years from Start of Protocol Therapy Low Risk: 109/305 High Risk: 35/46 P < 0.0001 EVENT-FREE SURVIVAL 0% 20% 40% 60% 80% 100% 0 2 4 6 8 10 Years from Start of Protocol Therapy Low Risk: 186/305 High Risk: 39/46 P < 0.0001 2 distinct components in high-risk disease: early failure (EF) and sustained control (SC): breakpoint at 3 years EF SC EF SC
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6. HIGHER FREQUENCY OF UNFAVORABLE GEP FEATURES IN EF vs SC MYELOMA Logistic Regression – OLD DEF 3 ( Not yet died or survived >= 3yrs post enrollment vs. rest ): SURVIVAL MODEL CR DUR MODEL VARIABLE EF (N=65) SC (N=58) P EF (N=38) SC (N=28) P B2M >=5.5mg/L 45% 50% 0.55 45% 32% 0.30 Albumin <3.5g/dL 49% 45% 0.63 50% 29% 0.08 LDH >= 190 U/L 60% 43% 0.06 66% 50% 0.20 CA 78% 67% 0.18 78% 79% 0.99 GEP >median score 60% 38% <0.02 68% 39% 0.02 GEP delTP53 22% 5% <0.01 18% 7% 0.28
7. MV LOGISTIC REGRESSION ANALYSIS OF VARIABLES LINKED TO EF vs SC Logistic Regression – OLD DEF 3 ( Not yet died or survived >= 3yrs post enrollment vs. rest ): * > MEDIAN IN HIGH-RISK MM % EF WITH FACTOR MODEL Variable N YES NO OR P SURVIVAL GEP delTP53 120 81% 48% 4.60 0.025 GEP very high risk* 120 64% 42% 2.41 0.022 CR DURATION GEP very high risk* 64 69% 41% 3.09 0.031
8. SHIFT TO HIGHER GEP RISK SCORE IN EF vs SC HIGH-RISK MYELOMA p-value=0.007 p-value=0.003 SURVIVAL MODEL CR DURATION MODEL SC EF
9. SURVIVAL MODEL-BASED GEP DIFFERENCES BETWEEN EF AND SC p-value=0.015 Most CD-1 is EF Shift to higher PI in EF vs SC p-value=0.348 60 40 30 10 20 50 Frequency 0.10 0.8 0.4 0.2 0 0.6 0.12 PR MY MS MF LB HY CD-2 CD-1
10. 14 GENES DISTINGUISH EF AND SC SUBGROUPS OF HIGH-RISK MYELOMA EF SC C20orf142 TP53INP ST6GAL1 235659_at YIPF6 MAN2A1 MEIS1 SPIB RNF43 SHISA SLC43A3 PLK1 RUNX2 PMAIP1 P < 0.0001 (FDR: 15.8%)
11. EXAMPLES OF EF-ASSOCIATED GENES Gene Description Chr SHISA WNT repressor and head inducer ; endoplasmic reticulum ; Wnt ligand signals through co-receptor on PM; single pass LRP5 and seven pass Frizzled (Fz); SHISA removes Frizzled receptor from PM via ER retention; NOTE: DKK1, head inducer; secreted; WNT repressor; removes LRP5/6 from PM thru endocytosis ; Supports role for Wnt suppression in MM pathogenesis 4p13 PLK1 S/K kinase ; nuclear; regulates centrosome maturation, spindle assembly, chromosome arm cohesions, APC/C inhibition, mitotic exit and cytokinesis; Interacts with EVI5, EVI5 is one of 19 in GEP70; may suppress EVI5? 16p12 SPIB Ets family transcription factor ; nuclear ; controls pDC and B-cell development; expressed in liver stem cells; linked to recent surge in liver mets?; Is EF disease a plasmacytoid dendritic cell neoplasm? 19q13 TP53INP1 TP53 inducible; nuclear ; concentrated in PML/POD/ND10 nuclear bodies; induces TP53-phosphorylation and TP53-mediated apoptosis 8q22 MAN2A1 Complex N-glycan biosynthesis; Golgi; Mutations causes SLE-like Dx in mice; inversely correlated with SHISA; Does Wnt suppression eliminate N-glycan modifications in MM cells? 5q21.2
12.
13. Vel and VTDPACE PGx: Differential Sensitivity of TP53INP1 to Induction Chemo UP-REGULATION WITHIN 48HR OF TP53INP1 BY BORTEZOMIB AND AUGMENTED BY ADDED TDPACE RANKING TP53INP1 BASELINE VALUES FROM LOW TO HIGH, 48HR F/U POST-VEL & VTDPACE AS PART OF TOTAL THERAPY 3
14. TP53INP1 PGx Melphalan (10mg/m 2 x 48h) in Newly Diagnosed Disease TP53INP1 CAN BE UP-REGULATED BY TEST DOSE OF MELPHALAN 10MG/M 2 IN 48HR
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Editor's Notes
NOTES: No genes overlapping with GEP70. Note high correlation of genes within each group PMAIP1/NOXA may define unique disease subset; NOXA targets MCL1, a 1q21 candidate gene, for proteasomal degradation; is VEL contraindicated; Note: MYB also removed/neutralized by proteasomal degradation PLK interacts with EVI5 a low 19 in GEP70 mapping to 1p22; high PLK might cooperate with del1p TP53INP1 regulated by TP53; high denovo TP53INP1 points to active TP53 in SC or cure fraction MAN2A1 and ST6GAL in EF point to loss of N-glycan biosynthesis; This is supported by MS proteomics SHISA, a Wnt suppressor that sequesters Frizzled in ER, acts similar to DKK1, which sequesters LRP5 by removal from PM SPIB induces plasmacytoid-dendritic cell differentiation; does this mean EF disease is pDC?; Wnt regulates keratinocyte differentiation/pDC like; are these are these pDC? MM can make dendritic processes, especially in MMCL; Lenalidomide induces RUNX2 is an osteoblast marker and FITM2 is an adipocyte marker; Ultra high risk is RUNX-positive OB-like
If high expression is good then it stands to reason that upregulation following short term PGx should be good too! Is a a) baseline, b) post drug, or c) change in TP53INP1 expression related to outcome? If not, such a link might be masked, e,g, they are GEP70 dependent? Subtype specific? delTp53 dependent? MDM2 and TP53 status? TP53INP1 is ROS activated (Ref). This may explain important role of ROS inducers, i.e. IMiDs in Mel-based ASCT? Does upregulation or lack thereof reflect degree of endogenous ROS? Can another type of drug, i.e. lenalidomide, which is a potent inducer of ROS, activate TP53INP1 to a greater degree and especially lift those disease entities exhibiting negligible change in response to Vel-Mel PGx challenge? Differentiate GEP signatures of those that do VERSUS those that don’t activate TP53INP1 following Vel-Mel ? And then compare such results to Len-Mel If hypotheses hold up, we will consider such to be strong rationale for ”HIGH DOSE LENALIDOMIDE IN COMBO WITH HIGH DOSE MEL” Does prior Velcade alter/influence Mel-induced changes seen here? IF true, does this shed light on Vel-Mel synergy, which is purported to be related to DNA repair pathway? IF true is this related to the improved outcome in TT3 v TT2? Reduction in expression tends to occur in the 20% with. One could hypothesize that the reduction is due to treatment induced apoptosis in a TP53INP1 HIGH population. This could be true for all cases where there is a reduction after treatment. Do we see similar changes in BX?
If high expression is good then it stands to reason that upregulation following short term PGx should be good too! Is a a) baseline, b) post drug, or c) change in TP53INP1 expression related to outcome? If not, such a link might be masked, e,g, they are GEP70 dependent? Subtype specific? delTp53 dependent? MDM2 and TP53 status? TP53INP1 is ROS activated (Ref). This may explain important role of ROS inducers, i.e. IMiDs in Mel-based ASCT? Does upregulation or lack thereof reflect degree of endogenous ROS? Can another type of drug, i.e. lenalidomide, which is a potent inducer of ROS, activate TP53INP1 to a greater degree and especially lift those disease entities exhibiting negligible change in response to Vel-Mel PGx challenge? Differentiate GEP signatures of those that do VERSUS those that don’t activate TP53INP1 following Vel-Mel ? And then compare such results to Len-Mel If hypotheses hold up, we will consider such to be strong rationale for ”HIGH DOSE LENALIDOMIDE IN COMBO WITH HIGH DOSE MEL” Does prior Velcade alter/influence Mel-induced changes seen here? IF true, does this shed light on Vel-Mel synergy, which is purported to be related to DNA repair pathway? IF true is this related to the improved outcome in TT3 v TT2? Reduction in expression tends to occur in the 20% with. One could hypothesize that the reduction is due to treatment induced apoptosis in a TP53INP1 HIGH population. This could be true for all cases where there is a reduction after treatment. Do we see similar changes in BX?
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