Anjali Saqi, MD, MBA, and Geoffrey R. Oxnard, MD, prepared useful practice aids pertaining to lung cancer for this CME/MOC activity titled "Navigating the Complexities of Molecular Testing for EGFR Mutations to Guide Treatment Selection in Lung Cancer: Evidence, Practicalities, and Implications for Pathologists." For the full presentation, monograph, complete CME/MOC information, and to apply for credit, please visit us at http://bit.ly/2DkXD65. CME/MOC credit will be available until November 28, 2019.
This presentation summarizes data related to the CAR-T cell technology and its potential application for cancer therapy. This oral presentation was presented at the 39th PAMM winter meeting in Roma the 8th f February 2018 by Eric Raymond
Genes and Tissue Culture Technology - Next Generation Sequencing - Applicatio...Tiong Qi En
A short presentation on the applications of next generation sequencing in cancer treatment. All content displayed and shared remains the courtesy of Taylor's University. Published 17/10/18.
T cells genetically engineered to express chimeric antigen receptors (CAR) have proven an impressive therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. Key challenges relating to CAR T cells include the lack of tumor exclusive target, restricted CAR-T cell trafficking to tumor sites, antigen escape and heterogeneity as well as a highly immunosuppressive microenvironment. In this report, we review the current state of the CAR-T technologies as a clinical treatment in solid tumor and we highlight the preclinical innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with solid malignancies.
Anjali Saqi, MD, MBA, and Geoffrey R. Oxnard, MD, prepared useful practice aids pertaining to lung cancer for this CME/MOC activity titled "Navigating the Complexities of Molecular Testing for EGFR Mutations to Guide Treatment Selection in Lung Cancer: Evidence, Practicalities, and Implications for Pathologists." For the full presentation, monograph, complete CME/MOC information, and to apply for credit, please visit us at http://bit.ly/2DkXD65. CME/MOC credit will be available until November 28, 2019.
This presentation summarizes data related to the CAR-T cell technology and its potential application for cancer therapy. This oral presentation was presented at the 39th PAMM winter meeting in Roma the 8th f February 2018 by Eric Raymond
Genes and Tissue Culture Technology - Next Generation Sequencing - Applicatio...Tiong Qi En
A short presentation on the applications of next generation sequencing in cancer treatment. All content displayed and shared remains the courtesy of Taylor's University. Published 17/10/18.
T cells genetically engineered to express chimeric antigen receptors (CAR) have proven an impressive therapeutic activity in patients with certain subtypes of B cell leukaemia or lymphoma, with promising efficacy also demonstrated in patients with multiple myeloma. However, in patients with solid tumors, objective responses to CAR-T cell therapy remain sporadic and transient. Key challenges relating to CAR T cells include the lack of tumor exclusive target, restricted CAR-T cell trafficking to tumor sites, antigen escape and heterogeneity as well as a highly immunosuppressive microenvironment. In this report, we review the current state of the CAR-T technologies as a clinical treatment in solid tumor and we highlight the preclinical innovative designs of novel CAR T cell products that are being developed to increase and expand the clinical benefits of these treatments in patients with solid malignancies.
Chimeric Antigen Receptors (paper with corresponding power point)Kevin B Hugins
Gene therapy was first conceptualized to alter debilitating fates of genetic diseases. Gene therapy technology can help introduce new functional DNA to replace mutated genes. The idea first arose in 1972 when Friedmann and Roblin authored a paper, “Gene therapy for human genetic disease?”, demonstrating that exogenous DNA can be taken up by mammalian cells (1). They proposed that the same procedure could be done on humans to correct genetic defects by introducing therapeutic DNA. Currently, genetic modification of T lymphocytes has been the major area of research for treating malignant tumors. This technique seeks to create chimeric antigen receptor (CAR) in T cells by genetically modifying them in vitro and reintroduce them back into blood circulation. The T cells are unique to every patient and the chimeric antigen receptors are unique to the tumor that it is targeting.
Prostate cancer the androgenic fortified dogmaMohamed Abdulla
It describes the androgenic nature of prostate cancer and the androgenic axis should be tackled in all phases of prostate cancer. Also a special emphasis on recent data on management of metastatic hormone sensitive prostate cancer.
NSCLC: diagnóstico molecular, pronóstico y seguimiento; CTCMauricio Lema
Lo nuevo en diagnóstico molecular, pronóstico y seguimiento en NSCLC, y el impacto pronóstico de las Células Tumorales Circulantes. Para evento de cirugía de tórax, Hotel Intercontinental, Medellín, 22.05.2018 (se complementa con las la presentación de lo nuevo en terapia sistémica en NSCLC).
Chimeric Antigen Receptors (paper with corresponding power point)Kevin B Hugins
Gene therapy was first conceptualized to alter debilitating fates of genetic diseases. Gene therapy technology can help introduce new functional DNA to replace mutated genes. The idea first arose in 1972 when Friedmann and Roblin authored a paper, “Gene therapy for human genetic disease?”, demonstrating that exogenous DNA can be taken up by mammalian cells (1). They proposed that the same procedure could be done on humans to correct genetic defects by introducing therapeutic DNA. Currently, genetic modification of T lymphocytes has been the major area of research for treating malignant tumors. This technique seeks to create chimeric antigen receptor (CAR) in T cells by genetically modifying them in vitro and reintroduce them back into blood circulation. The T cells are unique to every patient and the chimeric antigen receptors are unique to the tumor that it is targeting.
Prostate cancer the androgenic fortified dogmaMohamed Abdulla
It describes the androgenic nature of prostate cancer and the androgenic axis should be tackled in all phases of prostate cancer. Also a special emphasis on recent data on management of metastatic hormone sensitive prostate cancer.
NSCLC: diagnóstico molecular, pronóstico y seguimiento; CTCMauricio Lema
Lo nuevo en diagnóstico molecular, pronóstico y seguimiento en NSCLC, y el impacto pronóstico de las Células Tumorales Circulantes. Para evento de cirugía de tórax, Hotel Intercontinental, Medellín, 22.05.2018 (se complementa con las la presentación de lo nuevo en terapia sistémica en NSCLC).
Translational Genomics and Prostate Cancer: Meet the NGS Experts Series Part 2QIAGEN
Advanced prostate cancer is highly heterogeneous but this inter-patient heterogeneity has until recently not been understood. We have through an international research effort dissected the molecular landscape of advanced castration resistant prostate, elucidating key molecular targets in this group of diseases. We have also shown that PARP inhibitors have antitumor activity against a significant proportion of these cancers, mainly in men whose cancers harbor DNA repair defects.
NSA Diagnostic Laboratory has been operating since 1958, founded by Prof. Nasseh Amin. NSA is considered as one of the most advanced labs in Egypt. Maintaining personalized services for its stakeholders, as well as the main role of the lab "Diagnosis"
NSA Diagnostic Laboratory operates through two different segments.
Firstly, a group of stand-alone labs located at prime locations all over Egypt, with the latest and up to date equipments.
Secondly, being the backbone of well reputed hospitals and some polyclinics where NSA is the lab that is responsible for all medical testing there, serving all our patients with class A quality.
Our main focus is delivering quality care and with Cost-value return. NSA plays a key role in improving the health of many Egyptians, by providing access to quality service for more than 200,000 patients annually.
Purpose: An inherited mutation in KRAS (LCS6-variant or rs61764370) results in altered control of the KRAS oncogene. We studied this biomarker’s correlation to anti-EGFR monoclonal antibody (mAb) therapy
response in patients with metastatic colorectal cancer.
Experimental Design: LCS6-variant and KRAS/BRAF mutational status was determined in 512 patients
with metastatic colorectal cancer treated with salvage anti-EGFR mAb therapy, and findings correlated with
outcome. Reporters were tested in colon cancer cell lines to evaluate the differential response of the LCS6-
variant allele to therapy exposure.
Results: In this study, 21.2% (109 of 512) of patients with metastatic colorectal cancer had the LCS6-
variant (TG/GG), which was found twice as frequently in the BRAF-mutated versus the wild-type (WT) group
(P = 0.03). LCS6-variant patients had significantly longer progression- free survival (PFS) with anti-EGFR
mAb monotherapy treatment in the whole cohort (16.85 vs. 7.85 weeks; P = 0.019) and in the double WT
(KRAS and BRAF) patient population (18 vs. 10.4 weeks; P = 0.039). Combination therapy (mAbs plus
chemotherapy) led to improved PFS and overall survival (OS) for nonvariant patients, and brought their
outcome to levels comparable with LCS6-variant patients receiving anti-EGFR mAb monotherapy. Combination
therapy did not lead to improved PFS or OS for LCS6-variant patients. Cell line studies confirmed a
unique response of the LCS6-variant allele to both anti-EGFR mAb monotherapy and chemotherapy.
Conclusions: LCS6-variant patients with metastatic colorectal cancer have an excellent response to anti-EGFR
mAb monotherapy, without any benefit from the addition of chemotherapy. These findings further confirm
the importance of thismutation as a biomarker of anti-EGFR mAb response in patients with metastatic colorectal cancer, and warrant further prospective confirmation.
Robert P. Edwards, MD, Chair of OB/GYN/RS, Co-Director of Women's Cancer Program at University of Pittsburgh, offers information about the current state of immunotherapy for recurrent ovarian cancer patients.
Similar to Personalized Oncology Through Integrative High-Throughput Sequencing: (20)
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.
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.
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.
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
Explore natural remedies for syphilis treatment in Singapore. Discover alternative therapies, herbal remedies, and lifestyle changes that may complement conventional treatments. Learn about holistic approaches to managing syphilis symptoms and supporting overall health.
TEST BANK for Operations Management, 14th Edition by William J. Stevenson, Ve...kevinkariuki227
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
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.
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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
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.
3. TRAININGTEST
• Tumor mouse-xenografts
from two living patients
• No mention of how
xenografts were
established
• Assumes that genomic
landscape/events in
xenograft and patient are
similar
• Findings in training set
were only evaluated in the
xenograft specimen and
not intended to deliver
therapy
3
(mouse-xenografts)
4. Patient
Tumor
Content
Sequencing
Type
Estimated
Coverage
Sequencing
Platform
Exome Capture Kit
Patient 1 > 90 %
Whole Genome 3.76 X
Illumina HiSeq 2000
-
Tumor Exome 86 X
Agilent v38
Normal Exome 101 X
Transcriptome NA -
Patient 2 > 90 %
Whole Genome 4.27 X
Illumina HiSeq 2000
-
Tumor Exome 82 X
Agilent v38
Normal Exome 87 X
Transcriptome NA -
Patient 3 60 - 70 %
Whole Genome 4.8 X
Illumina HiSeq 2000
-
Tumor Exome 126 X
Roche V2.0
Normal Exome 128 X
Transcriptome NA -
Patient 4 75 - 80 %
Whole Genome 4.8 X
Illumina HiSeq 2000
-
Tumor Exome 124 X
Roche V2.0
Normal Exome 121 X
Transcriptome NA -
4
5. • low PTEN expression in this patient relative
to an existing prostate RNA-Seq cohort
• These findings were only evaluated in the
xenograft specimen
5
6. • CPNE4-NEK11 gene fusion has unknown
clinical significance but warrants further
biological validation
• Polo-like kinases regulate the transition
from G2 to M phase and are being
targeted as a class due to their ubiquitous
expression in cancer
6
7. • homozygous inactivation of TP53 (via point
mutation and copy number loss)
• dual copy number gain and point mutation
in Aurora kinase A (AURKA)
• point mutations in smooth muscle myosin
heavy chain (MYH11) and FAS death
receptor
• copy number gains of EGFR
• a large region of chromosome 13 containing
CDK8 was prominently amplified
• CDK8 was also overexpressed in the RNA-
Seq outlier analysis
7
8. • Most of the findings were biologically interesting but not clinically
significant
– tumor had a point mutation in MYH11, which is rearranged in AML
and reported in intestinal cancer
– functional role of mutation in FAS death receptor not known (though it
is known that FAS intracellular mutation can protect against apoptosis)
– Role of ASMTL-AS1/PPP2R3B gene fusion unknown though it has been
reported in colon and lung tumors
• Patient potentially matched to clinical trials with MEK, PI3K or CDK
inhibitors
• Current clinical testing often disregards NRAS because of its low
frequency (2%) in CRC
• but activating mutations in NRAS are biologically similar to KRAS (35
to 40% of CRC), which predict resistance to antibody therapies
against EGFR
• trials may include CRC patients with KRAS or BRAF mutations for
Raf inhibitors, but fail to include patients with NRAS mutations
• amplification of CDK8 has been implicated in 15 to 20% of CRC as a
positive regulator of catenin signaling and is a viable target for CDK
inhibitors in clinical trials
8
9. • point mutation in the ETS transcription factor
family member ELK1 (R74C)
• could potentially qualify for an upcoming trial
of combined treatment with PI3K and MEK
inhibitors for specified solid tumor
malignancies with KRAS, NRAS, and BRAF
mutations (NCT01363232)
9
10. Clinical Validation
• The pilot study was implemented in a research setting
• Any results that affect clinical decision-making must be
validated using a Clinical Laboratory Improvement
Amendments (CLIA)-certified test
• CLIA validation of results through Sanger sequencing, qPCR, or
FISH will be performed
• The author’s lab was in a process of getting CLIA-certified so
clinical validations were not performed till the publication
date
10
11. Conclusions
• Integrative sequencing/analysis helpful to find
potential informative aberrations
– Can provide orthogonal support for some key
findings
• Effect of low tumor content can be
compensated by high depth of sequencing
11
12. Conclusions
• Both patients 3 and 4 had potentially informative
aberrations, but these patients did not fit into
available trials.
• Highlighted the need to restructure the eligibility
criteria for trials of molecularly targeted therapies
• Highlighted the issue that most clinical trials or
pharmaceutical research interested in high
frequency mutation
– Low frequency mutation can be critical from the
perspective of personalized oncology
12