The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15
years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we
present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it
is time to embrace the central role of epigenetics in cancer.
Majority of cancer lead by point mutation in p53 gene. which is also known as "guardian of genome". this mutation leads conversion of normal cell into cancerous cell.
The epigenetic regulation of DNA-templated processes has been intensely studied over the last 15
years. DNA methylation, histone modification, nucleosome remodeling, and RNA-mediated targeting regulate many biological processes that are fundamental to the genesis of cancer. Here, we
present the basic principles behind these epigenetic pathways and highlight the evidence suggesting that their misregulation can culminate in cancer. This information, along with the promising clinical and preclinical results seen with epigenetic drugs against chromatin regulators, signifies that it
is time to embrace the central role of epigenetics in cancer.
Majority of cancer lead by point mutation in p53 gene. which is also known as "guardian of genome". this mutation leads conversion of normal cell into cancerous cell.
Cancer is mainly caused by the conversion of proto-oncogenes into oncogenes. The process is known as oncogenesis.
This slide will help to get an idea about oncogenesis and also the proto-oncogenes which get converted.
p53 has been described as “GUARDIAN ANGEL OF THE GENOME”
because it performs following mechanism:
DNA Repair
Cell growth arrest
Apoptosis (programmed cell death)
P53 is also known as cellular tumour antigen Ag, phosphoprotein
P53 or tumour suppressor p53.
P53 protein is encoded by TP53.
Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathway s
Different types of diseases and infections have always threatened man.However, one disease that is considered almost deadly and has a very high rate of recurrence is cancer.Know more by visiting https://www.plus100years.com
Cancer is mainly caused by the conversion of proto-oncogenes into oncogenes. The process is known as oncogenesis.
This slide will help to get an idea about oncogenesis and also the proto-oncogenes which get converted.
p53 has been described as “GUARDIAN ANGEL OF THE GENOME”
because it performs following mechanism:
DNA Repair
Cell growth arrest
Apoptosis (programmed cell death)
P53 is also known as cellular tumour antigen Ag, phosphoprotein
P53 or tumour suppressor p53.
P53 protein is encoded by TP53.
Cellular Signaling Pathways have direct implications on our understanding of tumor cell behavior. A general overview is presented here followed by a brief discussion of some of the major pathways currently implicated in cancer progression : Ras/RAF/MAP kinase pathway and PI3K/AKT/mTOR pathway s
Different types of diseases and infections have always threatened man.However, one disease that is considered almost deadly and has a very high rate of recurrence is cancer.Know more by visiting https://www.plus100years.com
HEC-RAS is a computer program that models the hydraulics of water flow through natural rivers and other channels. The program is one-dimensional, meaning that there is no direct modeling of the hydraulic effect of cross section shape changes, bends, and other two- and three-dimensional aspects of flow. The program was developed by the US Department of Defense, Army Corps of Engineers in order to manage the rivers, harbors, and other public works under their jurisdiction; it has found wide acceptance by many others since its public release in 1995.
ONCOGENE AND PROTOONCOGENE
P53 GENE AND ITS APPLICATION IN CANCER ETIOLOGY
TUMOUR SUPPRESSOR GENE AND BCA AND BAC GENE AND ITS APPLICATION ON THE APOPTOSIS AND DEATH RECEPTORS
Cancer (Concept of oncogenes and tumor suppressor genes with special referenc...RubinSahu5
Cancer (Concept of oncogenes and tumor suppressor genes with special referencetop53, Retinoblastoma and Ras and APC)
Cancer is a non-infectious disease. It starts at the molecular level of the cell and, ultimately affects the cellular behavior.
It can be defined as uncontrolled proliferation of cells without any differentiation.
Cancer is a genetic disease because it can be traced to alterations within specific genes.
Most cancer cells experience a breakdown in all of these regulatory influences that protect the body from chaos and self‐destruction.
Cancer cells proliferate uncontrollably, producing Malignant tumors that invade surrounding healthy tissue.
Malignant tumors tend to metastasize, that is, to spawn renegade cells that break away from the parent mass, enter the lymphatic or vascular circulation, and spread to distant sites in the body where they establish lethal secondary tumors that are no longer amenable to surgical removal.
All types of cancer can result from uncontrolled Cell Growth And Division of any of the different kinds of cells in the body.
The uncontrolled cell growth produces a mass of cells which are called tumors or neoplasm tumors may be Benign or Malignant.
Oncogenes encode proteins that promote the loss of growth control and the conversion of a cell to a malignant state and Cell Proliferation.
Oncogenes may lead to genetic instability, prevent a cell from becoming a victim of apoptosis, or promote metastasis.
Tumor‐suppressor genes act as a cell’s brakes; they encode proteins that restrain cell growth and prevent cells from becoming malignant.
The first tumor suppressor gene to be studied and eventually cloned is associated with a rare childhood cancer of the retina of the eye, called Retinoblastoma.
The gene responsible for this disorder is named RB .
RAS refers to a family of genes that encode proteins involved in cell signaling pathways regulating cell growth and differentiation.
APC stands for Adenomatous Polyposis Coli.
It's a tumor suppressor gene that plays a critical role in regulating cell proliferation and maintaining the integrity of the epithelial lining of the colon and rectum.
Mutations in the APC gene are associated with familial adenomatous polyposis (FAP), an inherited condition characterized by the development of numerous polyps in the colon and rectum, leading to a significantly increased risk of colorectal cancer.
The cells of patients with this condition were found to contain a deletion of a small portion of chromosome 5, which was subsequently identified as the site of a tumor‐suppressor gene called Adenomatous Polyposis Coli, or APC .
APC is known to suppress the Wnt pathway, which activates the transcription of genes, that promote cell proliferation.
Loss of APC function could therefore lead directly to abnormal chromosome segregation and aneuploidy.
An oncovirus is a virus that can cause cancer. This term originated from studies of acutely transforming retroviruses in the 1950–60s, often called oncornaviruses to denote their RNA virus origin. It now refers to any virus with a DNA or RNA genome causing cancer and is synonymous with "tumor virus" or "cancer virus".
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
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.
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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
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.
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.
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
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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.
Title: Sense of Taste
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 structure and function of taste buds.
Describe the relationship between the taste threshold and taste index of common substances.
Explain the chemical basis and signal transduction of taste perception for each type of primary taste sensation.
Recognize different abnormalities of taste perception and their causes.
Key Topics:
Significance of Taste Sensation:
Differentiation between pleasant and harmful food
Influence on behavior
Selection of food based on metabolic needs
Receptors of Taste:
Taste buds on the tongue
Influence of sense of smell, texture of food, and pain stimulation (e.g., by pepper)
Primary and Secondary Taste Sensations:
Primary taste sensations: Sweet, Sour, Salty, Bitter, Umami
Chemical basis and signal transduction mechanisms for each taste
Taste Threshold and Index:
Taste threshold values for Sweet (sucrose), Salty (NaCl), Sour (HCl), and Bitter (Quinine)
Taste index relationship: Inversely proportional to taste threshold
Taste Blindness:
Inability to taste certain substances, particularly thiourea compounds
Example: Phenylthiocarbamide
Structure and Function of Taste Buds:
Composition: Epithelial cells, Sustentacular/Supporting cells, Taste cells, Basal cells
Features: Taste pores, Taste hairs/microvilli, and Taste nerve fibers
Location of Taste Buds:
Found in papillae of the tongue (Fungiform, Circumvallate, Foliate)
Also present on the palate, tonsillar pillars, epiglottis, and proximal esophagus
Mechanism of Taste Stimulation:
Interaction of taste substances with receptors on microvilli
Signal transduction pathways for Umami, Sweet, Bitter, Sour, and Salty tastes
Taste Sensitivity and Adaptation:
Decrease in sensitivity with age
Rapid adaptation of taste sensation
Role of Saliva in Taste:
Dissolution of tastants to reach receptors
Washing away the stimulus
Taste Preferences and Aversions:
Mechanisms behind taste preference and aversion
Influence of receptors and neural pathways
Impact of Sensory Nerve Damage:
Degeneration of taste buds if the sensory nerve fiber is cut
Abnormalities of Taste Detection:
Conditions: Ageusia, Hypogeusia, Dysgeusia (parageusia)
Causes: Nerve damage, neurological disorders, infections, poor oral hygiene, adverse drug effects, deficiencies, aging, tobacco use, altered neurotransmitter levels
Neurotransmitters and Taste Threshold:
Effects of serotonin (5-HT) and norepinephrine (NE) on taste sensitivity
Supertasters:
25% of the population with heightened sensitivity to taste, especially bitterness
Increased number of fungiform papillae
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The prostate is an exocrine gland of the male mammalian reproductive system
It is a walnut-sized gland that forms part of the male reproductive system and is located in front of the rectum and just below the urinary bladder
Function is to store and secrete a clear, slightly alkaline fluid that constitutes 10-30% of the volume of the seminal fluid that along with the spermatozoa, constitutes semen
A healthy human prostate measures (4cm-vertical, by 3cm-horizontal, 2cm ant-post ).
It surrounds the urethra just below the urinary bladder. It has anterior, median, posterior and two lateral lobes
It’s work is regulated by androgens which are responsible for male sex characteristics
Generalised disease of the prostate due to hormonal derangement which leads to non malignant enlargement of the gland (increase in the number of epithelial cells and stromal tissue)to cause compression of the urethra leading to symptoms (LUTS
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!
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
Cancer and genetic influences
1. Cancer and geneticCancer and genetic
influencesinfluences
1. overview & oncogenes1. overview & oncogenes
Lec 24Lec 24
2. What is cancer?What is cancer?
A name used to describe a form ofA name used to describe a form of neoplasianeoplasia
Uncontrolled cell proliferation leading to a mass or tumorUncontrolled cell proliferation leading to a mass or tumor
(neoplasm)(neoplasm)
Occurs due to imbalance between cellular proliferation andOccurs due to imbalance between cellular proliferation and
cellular deathcellular death
Normal growthNormal growth NeoplasmNeoplasm
Mutations in genesMutations in genes
controllingcontrolling
-prolif or cell cycle.-prolif or cell cycle.
-cytoskeletal-cytoskeletal
inv’ed with contactinv’ed with contact
inhibitioninhibition
-programmed cell-programmed cell
deathdeath
-detecting and-detecting and
repairing DNArepairing DNA
damagedamage
3. What is cancer?What is cancer?
In addition, the neoplasm must alsoIn addition, the neoplasm must also be malignantbe malignant
NOTE: Tumors that do not invade or spread are not cancerous, butNOTE: Tumors that do not invade or spread are not cancerous, but
referred to asreferred to as benignbenign
growth no longergrowth no longer
controlled and can nowcontrolled and can now
invade neighboringinvade neighboring
tissues and/or spread totissues and/or spread to
more distant sitesmore distant sites
(metastasis)(metastasis)
4. Major types of cancerMajor types of cancer
CarcinomaCarcinoma
Derived from epithelial cells, which line surface of skin andDerived from epithelial cells, which line surface of skin and
organs, digestive tract, airways and mammary ductsorgans, digestive tract, airways and mammary ducts
Most common cancer type (89-90% of all reported cases)Most common cancer type (89-90% of all reported cases)
SarcomaSarcoma
Derived from mesenchymal tissue – muscle, bone, cartilage, fat,Derived from mesenchymal tissue – muscle, bone, cartilage, fat,
connective tissuesconnective tissues
HematopoieticHematopoietic
Leukemia – derived from white blood cells or their precursorsLeukemia – derived from white blood cells or their precursors
Lymphoma – involves cells of the lymphatic systemLymphoma – involves cells of the lymphatic system
Myelomas – involves white blood cells responsible for theMyelomas – involves white blood cells responsible for the
production of antibodies (B lymphocytes or B-cells)production of antibodies (B lymphocytes or B-cells)
6. Stages of tumor progressionStages of tumor progression
more growth – abnormalmore growth – abnormal
cellular appearance; maycellular appearance; may
become disorganizedbecome disorganized
uncontrolled cell
division leading to
an excess of cells
cells become primitive incells become primitive in
capability – invasivecapability – invasive
potential existspotential exists
ability to invadeability to invade
&/or metastasize&/or metastasize
7. Characteristics of cancer cellsCharacteristics of cancer cells
Cytoskeletal changesCytoskeletal changes
Cell adhesion altered – cells able to moveCell adhesion altered – cells able to move
Changes in structure of nucleusChanges in structure of nucleus
Secretion of enzymes that enable them to invadeSecretion of enzymes that enable them to invade
neighboring tissuesneighboring tissues
Unlimited number of cell divisionsUnlimited number of cell divisions
Growth in the absence of “go” signalsGrowth in the absence of “go” signals
Avoidance of cell deathAvoidance of cell death
Tumors stimulate the growth of blood vesselsTumors stimulate the growth of blood vessels
(angiogenesis)(angiogenesis)
8. Cancer in familiesCancer in families
Many forms have higher incidence in relatives thanMany forms have higher incidence in relatives than
in general populationin general population
Nearly 50 mendelian disorders where risk ofNearly 50 mendelian disorders where risk of
cancer is very high among relativescancer is very high among relatives
For other cancers, the increased incidence is 2-3For other cancers, the increased incidence is 2-3
fold higher for 1fold higher for 1
oo
relatives – complex disorderrelatives – complex disorder
9. Cancer as a genetic diseaseCancer as a genetic disease
whether sporadic or familial, cancer is fundamentally duewhether sporadic or familial, cancer is fundamentally due
to mutation in various genes controlling cell growth or cellto mutation in various genes controlling cell growth or cell
deathdeath
once initiated, the cancer evolves by accumulatingonce initiated, the cancer evolves by accumulating
additional mutations in other genesadditional mutations in other genes
leads to an ever-worsening cascade of mutationsleads to an ever-worsening cascade of mutations
Original clone of neoplastic cells can evolve intoOriginal clone of neoplastic cells can evolve into
numerous sublineages with different but overlappingnumerous sublineages with different but overlapping
mutationsmutations
Tumor suppressor geneTumor suppressor gene ProtooncogeneProtooncogene
10. Classifying the genes involvedClassifying the genes involved
in cancerin cancer
OncogenesOncogenes –– mutant forms of genes (proto-mutant forms of genes (proto-
oncogenes) that positively regulate cell proliferationoncogenes) that positively regulate cell proliferation
and cell survivaland cell survival -usu dominant, gain-of-fn mutations-usu dominant, gain-of-fn mutations
Tumor suppressorsTumor suppressors – genes which function to block– genes which function to block
tumor development by negatively regulating cellulartumor development by negatively regulating cellular
growth-growth-usu need loss of both copiesusu need loss of both copies
Cellular maintenance genesCellular maintenance genes – responsible for the– responsible for the
detection and repair of genetic damage in cellsdetection and repair of genetic damage in cells
11. OncogenesOncogenes
in altered (mutated) form, gene expression leads toin altered (mutated) form, gene expression leads to
abnormal stimulation of cell division and proliferationabnormal stimulation of cell division and proliferation
have a dominant effect at the cellular level – a singlehave a dominant effect at the cellular level – a single
mutant allele is enough to change cellular phenotypemutant allele is enough to change cellular phenotype
from normal to malignant (gain of function)from normal to malignant (gain of function)
Mutations: gene, regulatory region, copy #Mutations: gene, regulatory region, copy #
normalnormal mutantmutant
12. OncogenesOncogenes
in its normal form, thein its normal form, the
gene is called agene is called a
proto-oncogeneproto-oncogene
Most proto-oncogenesMost proto-oncogenes
are components ofare components of
signal transductionsignal transduction
pathways:pathways:
translate extracellulartranslate extracellular
signals into changes insignals into changes in
gene expressiongene expression
Increase blood supplyIncrease blood supply
to the tumor or inhibitto the tumor or inhibit
apoptosisapoptosis
13. RET, METRET, MET
Receptor tyrosine kinasesReceptor tyrosine kinases
-transduce an extracellular-transduce an extracellular
signal inwardsignal inward
-bind a ligand, conformational-bind a ligand, conformational
change that results in kinasechange that results in kinase
activity, leading to phosphor-activity, leading to phosphor-
lation of cellular proteinslation of cellular proteins
-pt mut’s cause receptors to-pt mut’s cause receptors to
be constitutively activebe constitutively active
RET mut-multiple endocrineRET mut-multiple endocrine
neoplasianeoplasia
MET mut-hereditary papillaryMET mut-hereditary papillary
renal carcinomarenal carcinoma
Ras, AblRas, Abl
MycMyc
14. RAS family of proto-oncogenesRAS family of proto-oncogenes
One of the first activated oncogenes discovered by theOne of the first activated oncogenes discovered by the
DNA transformation assayDNA transformation assay
Encodes a small guanosine triphosphate (GTP) –Encodes a small guanosine triphosphate (GTP) –
binding protein (G-protein)binding protein (G-protein)
3 members of this family; H-RAS, K-RAS, N-RAS3 members of this family; H-RAS, K-RAS, N-RAS
Serves as an “on/off” switch to activate or inhibitServes as an “on/off” switch to activate or inhibit
downstream molecules when bound to GTPdownstream molecules when bound to GTP
The protein’s effect is ended by self-directed cleavageThe protein’s effect is ended by self-directed cleavage
of GTPof GTP
15. RAS family of proto-oncogenesRAS family of proto-oncogenes
Ras associates with the plasma membraneRas associates with the plasma membrane
Ras relays signals from the cell surface receptors toRas relays signals from the cell surface receptors to
the nucleus, functioning as athe nucleus, functioning as a switchswitch
‘‘Active’ when GTP is boundActive’ when GTP is bound
‘‘Inactive when the hydrolyzed GDP is boundInactive when the hydrolyzed GDP is bound
16. RAS mutation in humanRAS mutation in human
cancerscancers
H-RAS mutated in 10% of all bladder cancer
K-RAS mutations in about 50% of
colorectal cancers, 70-90% of pancreatic
cancers and 30% of lung adenocarcinomas as
well as in ovarian, breast skin liver and kidney
N-RAS mutations have been detected in 20-
30% of acute nonlymphocytic leukemias
17. RAS oncogene activation byRAS oncogene activation by
nucleotide substitutionnucleotide substitution
Conversion to oncogene usually due to a pointConversion to oncogene usually due to a point
mutation in the gene where:mutation in the gene where:
the ras protein is able to signal continuously, even inthe ras protein is able to signal continuously, even in
absenceabsence of GTPof GTP
the ras protein isthe ras protein is unable to hydrolyze GTPunable to hydrolyze GTP toto
turn “off” the signalturn “off” the signal
Leads to the continuous activation of multipleLeads to the continuous activation of multiple
downstream signaling pathways inducing celldownstream signaling pathways inducing cell
proliferationproliferation
Mutations in the 3 RAS genes are found in 10-15% ofMutations in the 3 RAS genes are found in 10-15% of
all human cancersall human cancers
18. Oncogenes are also activatedOncogenes are also activated
by chromosome translocationsby chromosome translocations
Breakpoint can occur withinBreakpoint can occur within
introns of two genes: chimericintrons of two genes: chimeric
protein with novel properties –protein with novel properties –
Chronic MyelogenousChronic Myelogenous
Leukemia-Leukemia-UncontrolledUncontrolled
proliferation of white bloodproliferation of white blood
cellscells
Arises in a bone marrow stemArises in a bone marrow stem
cell that is a precursor to thecell that is a precursor to the
granulocytes andgranulocytes and
megakaryocytesmegakaryocytes
These cells contain a chr 9;22These cells contain a chr 9;22
translocation – “Philadelphiatranslocation – “Philadelphia
Chromosome”Chromosome”
Protooncogene ABL, a tyrosine
kinase, is moved from its normal
position on 9 to 22.
Result: increased activity
19. Chronic MyelogenousChronic Myelogenous
Leukemia (CML)Leukemia (CML) Proto-oncogene ABLProto-oncogene ABL
(tyrosine kinase) moves(tyrosine kinase) moves
from 9q to thefrom 9q to the
“breakpoint cluster region“breakpoint cluster region
(BCR) on 22q(BCR) on 22q
Chimeric protein hasChimeric protein has
increased tyrosine kinaseincreased tyrosine kinase
activity but alteredactivity but altered
structure and functionstructure and function
Requires secondaryRequires secondary
mutation to move intomutation to move into
crisis phasecrisis phase
Effective drug therapyEffective drug therapy
developed to target noveldeveloped to target novel
proteinprotein
20. Oncogenes are also activatedOncogenes are also activated
by chromosome translocationsby chromosome translocations
Breakpoint can occur withinBreakpoint can occur within
introns of two genes: chimericintrons of two genes: chimeric
protein with novel properties –protein with novel properties –
Chronic MyelogenousChronic Myelogenous
LeukemiaLeukemia
Alternately, translocation mayAlternately, translocation may
place proto-oncogeneplace proto-oncogene
downstream of a strongdownstream of a strong
constitutive promoter fromconstitutive promoter from
another gene – proto-another gene – proto-
oncogene is now expressed atoncogene is now expressed at
inappropriate time/place –inappropriate time/place –
Burkitt LymphomaBurkitt Lymphoma
21. Burkitt LymphomaBurkitt Lymphoma
B-cell tumorB-cell tumor
MYC proto-oncogeneMYC proto-oncogene
(transcription factor)(transcription factor)
translocated from 8q24translocated from 8q24
to 14q32, distal of the Igto 14q32, distal of the Ig
heavy chain locusheavy chain locus
Ig enhancers orIg enhancers or
activating sequences actactivating sequences act
on MYC – allowing foron MYC – allowing for
unregulated expressionunregulated expression
and uncontrolled celland uncontrolled cell
growthgrowth
22. http://tooldoc.wncc.edu/Infections/lymphoma.JPG
• Solid tumor of B-lymphocytes
• Predominantly affecting young children
in Africa,
• one of the fastest growing malignancies
in humans.
• manifested most often as a large jaw
lesion expands rapidly over a period of
a few weeks to invade the orbit.
• Visceral involvement, usually an
abdominal mass
• Treatment of the jaw and eye areas is by
radiotherapy,while visceral involvement
requires systemic chemotherapy.
In all cases, translocation of MYC is the cause
Editor's Notes
Cancer is abnormal cellular
Oncogenes in it’s normal form the gene is called proto-oncogene. Most proto-oncogene are components of signal transduction pathways. ,translate extracellular signals into changes in gene expression by increasing the blood supply to the tumor or inhibit apoptosis.
One of the the first activated oncogenes discovered by DNA Transformation process , encodes a small guanosine triphosphate binding protein 3 members of the family the H-RAS , K-RAS And N-RAS , Serves as on / off switch to activate or inhibit molecules when bound to GTP , the effect of protein effect is ended by self directed cleavage of GTP.
RAS associated with plasma membrane
RAS activation is done by another mechanism which is done via neclueotide substitution Note the conversion of oncogene to proto-oncogene is
Proto-Oncogenes are converted to oncogenes by means of : 1-Point mutation. 2- chromosome translocation ( breakpoint can occur within 2 introns of 2 genes producing chimeric protein with novel properties ) .
B lymphocytes are one of the fastest growing malignancies (B cell solid tumor ) Slid tumors are type of cancer intiated in the tissues The outer surfaces is dealt with radiotherapy whilst the vesrical is dealt with chemotherapy