1. Certain single nucleotide polymorphisms (SNPs) are associated with increased risk of type 2 diabetes mellitus by affecting glucose handling and insulin secretion or action.
2. Some SNPs have been shown to alter patient response to common antidiabetic drugs like sulfonylureas through effects on glucose handling pathways.
3. Understanding the pharmacogenomic implications of diabetes risk SNPs may help optimize treatment and achieve better glycemic control for individual patients.
DRUG INFORMATIONOF GILTERITINIB AND ITS EFFICACY IN REFRACTORY FLT3- MUTATED AMLPARUL UNIVERSITY
Acute myeloid leukemia is a malignancy of proliferative, abnormally, or poorly differentiated cells of the hematopoietic system,
characterized by genetic heterogeneity. FMS-like tyrosine kinase 3- internal tandem duplication remains one of the most frequently mutated
genes in acute myeloid leukemia, especially in those with normal cytogenetics. The FMS-like tyrosine kinase 3- internal tandem duplication
and FLT3 tyrosine kinase domain mutations are biomarkers for high-risk acute myeloid leukemia and are associated with drug resistance
and high risk of relapse. Various FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin,
gilteritinib, and crenolanib. Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases that also act as FMS-like tyrosine
kinase 3. Gilteritinib, a next-generation tyrosine kinase inhibitor, is approved in several countries worldwide for the treatment of relapsed or
refractory acute myeloid leukemia in adults with FMS-like tyrosine kinase 3 mutations. Gilteritinib demonstrated the ability to inhibit FLT3
receptor signaling and production in cells exogenously expressing FLT3 including FLT3 internal tandem duplication and tyrosine kinase
domain mutations FLT3-D835Y and FLT3-ITD-D835Y, and it induced apoptosis in leukemic cells possessing FLT3 internal tandem
duplication. In conclusion, gilteritinib therapy led to higher percentages of patients with the response and longer survival than salvage
chemotherapy among patients with relapsed or refractory FLT3-mutated acute myeloid leukemia
DRUG INFORMATIONOF GILTERITINIB AND ITS EFFICACY IN REFRACTORY FLT3- MUTATED AMLPARUL UNIVERSITY
Acute myeloid leukemia is a malignancy of proliferative, abnormally, or poorly differentiated cells of the hematopoietic system,
characterized by genetic heterogeneity. FMS-like tyrosine kinase 3- internal tandem duplication remains one of the most frequently mutated
genes in acute myeloid leukemia, especially in those with normal cytogenetics. The FMS-like tyrosine kinase 3- internal tandem duplication
and FLT3 tyrosine kinase domain mutations are biomarkers for high-risk acute myeloid leukemia and are associated with drug resistance
and high risk of relapse. Various FLT3 inhibitors are in clinical development, including lestaurtinib, tandutinib, quizartinib, midostaurin,
gilteritinib, and crenolanib. Gilteritinib is a small molecule that inhibits multiple receptor tyrosine kinases that also act as FMS-like tyrosine
kinase 3. Gilteritinib, a next-generation tyrosine kinase inhibitor, is approved in several countries worldwide for the treatment of relapsed or
refractory acute myeloid leukemia in adults with FMS-like tyrosine kinase 3 mutations. Gilteritinib demonstrated the ability to inhibit FLT3
receptor signaling and production in cells exogenously expressing FLT3 including FLT3 internal tandem duplication and tyrosine kinase
domain mutations FLT3-D835Y and FLT3-ITD-D835Y, and it induced apoptosis in leukemic cells possessing FLT3 internal tandem
duplication. In conclusion, gilteritinib therapy led to higher percentages of patients with the response and longer survival than salvage
chemotherapy among patients with relapsed or refractory FLT3-mutated acute myeloid leukemia
I received a PhD in April of 2007 from the Schultz Lab at the Scripps Research Institute in La Jolla, CA. Here is a PowerPoint presentation of my primary work - a use of functional genomics tools to probe cellular disease problems, notably in cancer models.
I received a PhD in April of 2007 from the Schultz Lab at the Scripps Research Institute in La Jolla, CA. Here is a PowerPoint presentation of my primary work - a use of functional genomics tools to probe cellular disease problems, notably in cancer models.
Journal Club about the Phase 2 study of Selonsertib in Diabetic Kidney Disease to Our Division on 12/9/19.
Also an intro about the Phase 3 study (MOSAIC) we will be launching before the end of the year
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.
Glucagon like peptide-1 (GLP-1) is an incretin secretory molecule. GLP-1 receptor agonists (GLP-1RAs) are widely used in the treatment of type 2 diabetes (T2DM) due to their attributes such as body weight loss, protection of islet β cells, promotion of islet β cell proliferation and minimal side effects. Studies have found that GLP-1R is widely distributed on pancreatic and other tissues and has multiple biological effects, such as reducing neuroinflammation, promoting nerve growth, improving heart function, suppressing appetite, delaying gastric emptying, regulating blood lipid metabolism and reducing fat deposition. Moreover, GLP-1RAs have neuroprotective, anti-infectious, cardiovascular protective, and metabolic regulatory effects, exhibiting good application prospects. Growing attention has been paid to the relationship between GLP-1RAs and tumorigenesis, development and prognosis in patient with T2DM. Here, we reviewed the therapeutic effects and possible mechanisms of action of GLP-1RAs in the nervous, cardiovascular, and endocrine systems and their correlation with metabolism, tumours and other diseases.
Association between polymorphisms of the DNA repair gene (OGG1) in Iraqi pati...iosrjce
IOSR Journal of Pharmacy and Biological Sciences(IOSR-JPBS) is a double blind peer reviewed International Journal that provides rapid publication (within a month) of articles in all areas of Pharmacy and Biological Science. The journal welcomes publications of high quality papers on theoretical developments and practical applications in Pharmacy and Biological Science. Original research papers, state-of-the-art reviews, and high quality technical notes are invited for publications.
How to link glucose control to cv outcomesYichi Chen
Outline
1.CV risk of DM patient
2.Glucose to CV outcome - Intensive control vs Conventional control
3.Hypoglycemia
4.Different drugs, different outcomes
5.Expect to Future
Similar to Pharmacogenomics implication of risk SNPs in diabetes (20)
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
Basavarajeeyam is an important text for ayurvedic physician belonging to andhra pradehs. It is a popular compendium in various parts of our country as well as in andhra pradesh. The content of the text was presented in sanskrit and telugu language (Bilingual). One of the most famous book in ayurvedic pharmaceutics and therapeutics. This book contains 25 chapters called as prakaranas. Many rasaoushadis were explained, pioneer of dhatu druti, nadi pareeksha, mutra pareeksha etc. Belongs to the period of 15-16 century. New diseases like upadamsha, phiranga rogas are explained.
Report Back from SGO 2024: What’s the Latest in Cervical Cancer?bkling
Are you curious about what’s new in cervical cancer research or unsure what the findings mean? Join Dr. Emily Ko, a gynecologic oncologist at Penn Medicine, to learn about the latest updates from the Society of Gynecologic Oncology (SGO) 2024 Annual Meeting on Women’s Cancer. Dr. Ko will discuss what the research presented at the conference means for you and answer your questions about the new developments.
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
New Drug Discovery and Development .....NEHA GUPTA
The "New Drug Discovery and Development" process involves the identification, design, testing, and manufacturing of novel pharmaceutical compounds with the aim of introducing new and improved treatments for various medical conditions. This comprehensive endeavor encompasses various stages, including target identification, preclinical studies, clinical trials, regulatory approval, and post-market surveillance. It involves multidisciplinary collaboration among scientists, researchers, clinicians, regulatory experts, and pharmaceutical companies to bring innovative therapies to market and address unmet medical needs.
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!
Knee anatomy and clinical tests 2024.pdfvimalpl1234
This includes all relevant anatomy and clinical tests compiled from standard textbooks, Campbell,netter etc..It is comprehensive and best suited for orthopaedicians and orthopaedic residents.
NVBDCP.pptx Nation vector borne disease control programSapna Thakur
NVBDCP was launched in 2003-2004 . Vector-Borne Disease: Disease that results from an infection transmitted to humans and other animals by blood-feeding arthropods, such as mosquitoes, ticks, and fleas. Examples of vector-borne diseases include Dengue fever, West Nile Virus, Lyme disease, and malaria.
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
Tom Selleck Health: A Comprehensive Look at the Iconic Actor’s Wellness Journey
Pharmacogenomics implication of risk SNPs in diabetes
1. Pharmacogenomic implications
of risk SNPs in type 2 diabetes mellitus
Dr Muhammad Huzaimi Haron
Trainee Lecturer in Pharmacology
Pharmacology CME
28 March 2011
3. Introduction
Genetic component to diabetes
High concordance rate between monozygotic twins
Different prevalence between populations
Different effect of traditional risk factors
Single nucleotide polymorphisms (SNPs)
Common
Functional
Heritable?
8. T2DM: Back home…
Increasing prevalence
6.3% in 1986 (NHMS I) 11.0% in 2006 (MyNCDS-1)
NHMS II (1996): 8.3% (>30 yrs old)
NHMS III (2008): 11.6% (>18)
14.9% (>30)
39% did not know they were diabetic!
83% of 18-30yr old diabetic newly diagnosed!
Ethnic discrepancy (NHMS III)
Indian highest (19.9%)
Malay (11.9%) and Chinese (11.4%)
9. Worrying signs in NHMS III
High prevalence of undiagnosed DM in younger age
group (18 – 30 years old)
Increasing prevalence despite:
1. Health awareness campaigns
2. Increasing education and information levels
Need for a better screening program?
11. Implication of
SNPs
DNA seq
change
Coding region
Non-coding
region
mRNA
mRNA seq
change
Intronic
transcription
alteration
Exonic
mRNA
processing
altered
AA seq change
Changes in
protein
12. How SNPs confer risk?
Variations in how body handles glucose
Absorption
Rate of emptying of stomach
Distribution
Action of insulin
Metabolism
Alteration in metabolic pathways
Disposition
Excretion of excess
14. TCF7L2 and T2DM
Protein: transcription factor 7-like-2
Gene on long arm of chromosome 10
Nuclear
Wnt pathway
Controls expression of downstream genes
Proglucagon (Ni et al, 2003) – promote expression in intestinal
L-cells
mRNA silencing of TCF7L2: apoptosis of beta-cells
(Shu et al, 2008)
proliferation, GSIS
Reduced levels lead to defective insulin granule exocytosis
(da Silva Xavier et al, 2009)
15. TCF7L2 SNPs
Multiple SNPs in multiple population
rs7903146
rs12255372
rs4506565
rs11196205
rs7901695
rs290487
Intronic
16. TCF7L2 SNPs and T2DM
Effect of SNPs on:
Expression of TCF7L2 gene
Increased in pancreatic beta-cells (Lyssenko et al, 2007)
Expression of other genes
Proglucagon – reduced in pancreatic L-cells (Yi et al, 2008)
Impaired GLP-1 synthesis
Its protein levels: unknown
Glucose handling
Blunting of incretin effect (Lyssenko et al, 2007; Schafer et al, 2007)
Reduction in pro-insulin conversion (Stancakova et al, 2009)
Increased hepatic gluconeogenesis (Pilgaard, 2009)
17. Impact on T2DM risk
Icelandic carriers of SNPs at increased risk of T2DM
(Grant et al, 2006)
Dose-dependent
Heterozygous carrier of T allele of rs7903146: OR 1.5
Homozygous carrier: OR 2.1
Replicated in various Caucasian and Asian populations
However with differing impact due to different allele
frequencies
18. Impact on T2DM risk
Malaysian population
No large scale data
Known data collected from UMMC 2009-2010 from
Malay, Chinese and Indian patients and non-diabetic
volunteers
Case-control study of 800 people
19. Type 2 DM Risk Analysis
TCF7L2
SNP
Subject
rs7903146
rs12255372
rs11196205
rs4506565
rs7901695
Minor allele
frequency
p-value
Diabetic
Non-diabetic
0.16
0.10
0.0061
Diabetic
Non-diabetic
0.13
0.06
0.0010
Diabetic
Non-diabetic
0.81
0.88
0.0047
Diabetic
Non-diabetic
0.16
0.08
0.0013
Diabetic
Non-diabetic
0.85
0.92
0.0025
OR [95% CI] *
of wildtype vs mutant allele
1.73
[1.17-2.58]
2.14
[1.35-3.40]
0.61
[0.43-0.86]
2.11
[1.33-3.36]
0.49
[0.31-0.79]
* Statistical test used: chi-square test
21. Summary from Malaysian data
1. TCF7L2 SNPs increase the risk of T2DM in a
Malaysian population
2. The minor allele frequencies observed are:
much lower than in Caucasian and Indian population
(Grant et al, 2006; Chandak et al, 2007)
higher than in Japanese population (Miyake et al, 2008)
Impact?
22. Other SNPs
KCNJ11
Codes for component of ATP-sensitive K+ channels on
beta-cells (Kir6.2 subunit)
Mutations caused monogenic forms of DM
SNP (rs5215) cause defect to subunit
K+ channels fail to open in response to rising ATP:ADP ratio
Failed exocytosis of insulin granules (reviewed by Florez, 2008)
23. Other SNPs
KCNQ1
Encodes for a voltage-gated K+ channels
needed for repolarisation phase of cardiac
action potential
This channel also found on intestinal L-cells
SNPs (rs231362, rs163184) cause impaired
incretin effect
Reduction in GLP-1 secretion by L-cells (Tan et al, 2009)
24. Other SNPs
PPAR 2
Codes for nuclear receptor
Involved in lipid and glucose
homeostasis, differentiation of lipocytes, FA storage
SNP confers protection against T2DM
Increased insulin sensitivity
Lower BMI
Higher HDL
Lower BP
Reduced MI risk
25. Pharmacogenomics
Different DNA sequence, different response!
Drug-metabolizing enzymes
Cytochrome-p450 family, eg CYP2C9 and sulfonylureas
Statement 1:
SNPs conferring risk affect glucose handling
Statement 2:
Glucose handling modified by drugs
Can risk SNPs alter drug response?
26. TCF7L2 SNPs and Sulfonylurea
GoDARTs study (Pearson et al, 2007)
900 patients on a sulfonylurea
Treatment failure: HbA1c >7% after 3 – 12 months of
initiation
Adequate control of confounder
SNP carrier 2 times more likely to encounter treatment
failure – even after adjusting for baseline HbA1c
29. KCNJ11 SNPs and Sulfonylurea
Sesti et al, 2006
525 patients treated with sulfonylurea, either alone or
combination with metformin
Secondary failure: those requiring insulin therapy
despite combination therapy
Adequate control of confounders
SNP carrier more likely to get secondary failure with
sulfonylurea therapy
Sulfonylurea-stimulated insulin secretion lower in
pancreatic islets carrying the SNP
30. KCNJ11 SNP and Repaglinide
He et al, 2008
100 newly diagnosed Chinese patients, treated with
repaglinide over 24 weeks
SNP carriers had greater reduction in FPG and HbA1c
levels
SNP carriers had better improvements of HOMA-B
31. PPAR 2 SNP and
Kang et al (2005)
Improved response to rosiglitazone in heterozygous
SNP carriers
Greater drops in FPG and HbA1c
32. The future
is still uncertain
Identification of risk SNPs
Need cohort studies, long term follow-up
Involvement of epigenetics, CNVs
Pharmacogenomics
Better-designed clinical trials, controlling for confounder
Promise of personalised medicine in DM?
33. Take home message
Importance of genetic factors/variations in conferring
risk to T2DM is evident
Response to antidiabetic medications is heavily
influenced by genetic variations as well!
However, the specifics are still missing/unclear
– lots of “research holes” yet to be filled…
36. Incretins and GSIS
Glu
Glu
Glu
GSIS and Incretins:
An Overview
Small intestine
Pancreatic
β-cells
• GSIS: glucose stimulated insulin secretion
lumen
• Accounts for majority of postprandial insulin release
GLP
• Earliest defect leading up to T2DM
-1
Ins
• Incretins
• Intestinal peptide hormones
• Released upon detection of glucose in GIT
GIP
• Glucagon-like peptide-1 (GLP-1)
• Glucose-dependent insulinotropic polypeptide (GIP)
Cell
Glu
Glu
Vasculature
Done
Re-analyse – examine those achive hba1c target only
Entrance of oral glucose stimulates production of GLP-1 and GIP.These in turn will stimulate the release of insulin from the betacells – which accounts for 70% of insulin released during hyperglycemic spikes post-meals.Insulin in turn stimulates glucose uptake by cells