Atherosclerosis
vulnerable plaque. A plaque rupture may result in thrombus
Atherosclerosis (ath"er-o-skleh-RO'sis) comes from the Greek
words athero (meaning gruel or paste) and sclerosis
(hardness). It's the name of the process in which deposits of
fatty substances, cholesterol, cellular waste products, calcium
and other substances build up in the inner lining of an artery.
This buildup is called plaque. It usually affects large and
medium-sized arteries.  Some hardening of arteries often
occurs when people grow older.
Plaques can grow large enough to significantly
reduce the blood's flow through an artery. But most of the
damage occurs when they become fragile and rupture.
Plaques that rupture cause blood clots to form that can block
blood flow or break off and travel to another part of the
body. If either happens and blocks a blood vessel that feeds
the heart, it causes a heart attack. If it blocks a blood vessel
that feeds the brain, it causes a stroke. And if blood supply to
the arms or legs is reduced, it can cause difficulty walking and
eventually lead to gangrene.
Circulating monocytes infiltrate the intima of the vessel wall,
and these tissue macrophages act as scavenger cells, taking
up LDL cholesterol and forming the characteristic foam cell of
early atherosclerosis.
Hemodynamic factors interact with the activated vascular
endothelium. Microscopy reveals lipid-laden macrophages, T
lymphocytes, and smooth muscle cells in varying proportions.
The fatty streak may progress to form a fibrous plaque, the
result of progressive lipid accumulation and the migration
and proliferation of smooth muscle cells.
Platelet-derived growth factor, insulin like growth factor,
transforming growth factors alpha and beta, thrombin, and
angiotensin II are potent mitogens that are produced by
activated platelets, macrophages, and dysfunctional
endothelial cells that characterize early atherogenesis,
vascular inflammation, and platelet-rich thrombosis at sites of
endothelial disruption.
The relative deficiency of endothelium-derived nitric oxide
further potentiates this proliferative stage of plaque
maturation.
Growth of the fibrous plaque results in vascular remodeling,
progressive luminal narrowing, blood-flow abnormalities, and
compromised oxygen supply to the target organ. The plaque
rupture occurs due to weakening of the fibrous cap.
Inflammatory cells localize to the shoulder region of the
formation, partial or complete occlusion of the blood vessel,
and progression of the atherosclerotic lesion due to
organization of the thrombus and incorporation within the
plaque.
Atherosclerosis is a slow, complex disease that typically starts
in childhood and often progresses when people grow older.
In some people it progresses rapidly, even in their third
decade. Many scientists think it begins with damage to the
innermost layer of the artery.
symptoms:
Unfortunately, atherosclerosis produces no symptoms until
the damage to the arteries is severe enough to restrict blood
flow.
Restriction of blood flow to the heart muscle due to
atherosclerosis can cause angina pectoris or a myocardial
infarction (a heart attack).
-Restriction of blood flow to the muscles of the legs causes
intermittent claudication (pains in the legs brought about by
walking and relieved by rest).
-Narrowing of the arteries supplying blood to the brain may
cause transient ischemic attacks (symptoms and signs of
a stroke lasting less than 24 hours) and episodes of dizziness,
or ultimately, to a stroke itself.
Manage Stress
Research shows that the most commonly reported "trigger"
for a heart attack is an emotionally upsetting event—
particularly one involving anger. Also, some of the ways
people cope with stress, such as drinking, smoking, or
overeating, aren't healthy.
Learning how to manage stress, relax, and cope with
problems can improve your emotional and physical health.
Having supportive people in your life with whom you can
share your feelings or concerns can help relieve stress.
Physical activity, medicine, and relaxation therapy also can
help relieve stress. You may want to consider participating in
a stress management program.
Medicines
To slow the progress of plaque buildup, your doctor may
prescribe medicines to help lower your cholesterol level or
blood pressure or to prevent blood clots from forming.
For successful treatment, take all medicines as your doctor
prescribes.
Medical Procedures and Surgery
-Angioplasty is a procedure that's used to open blocked or
narrowed coronary (heart) arteries.
-Coronary artery bypass grafting (CABG) is a type of surgery.
In CABG, arteries or veins from other areas in your body are
used to bypass (that is, go around) your narrowed coronary
arteries.
-Caratid endarteroctomy(END-ar-ter-EK-to-me), or carotid
artery surgery, removes plaque buildup from the carotid
arteries in the neck. This procedure opens the arteries and
improves blood flow to the brain, which can help prevent
a stroke.
Gene therapy
 Gene therapy is ‘the use of genes as medicine’. It
involves the transfer of a therapeutic or working
gene copy into specific cells of an individual in order
to repair a faulty gene copy. Thus it may be used to
replace a faulty gene, or to introduce a new gene
whose function is to cure or to favorably modify the
clinical course of a condition.
Target Cell
1.Somatic cell= most cells of the body, non reproductive.
Ex Vivo
In Vivo
2.Germline cell= eggs or sperm, can reproduce
 All gene therapy to date on humans has been
directed at somatic cells, whereas germline
engineering in humans remains controversial and
prohibited in for instance the European Union.
Ex Vivo
Ex vivo, which means exterior (where cells are modified
outside the body and then transplanted back in again). In
some gene therapy clinical trials cells from the patient’s blood
or bone marrow are removed and grown in the laboratory.
The cells are exposed to the virus that is carrying the
desired gene. The virus enters the cells and inserts the
desired gene into the cells’ DNA. The cells grow in the
laboratory and are then returned to the patient by injection
into a vein.
In Vivo
In vivo, which means interior (where genes are changed in
cells still in the body). This form of gene therapy is called in
vivo, because the gene is transferred to cells inside the
patient’s
A gene can be delivered to a cell using a carrier known as a
“VECTOR.” The most common types of vectors used in gene
therapy are viruses. Viruses have evolved a way of
encapsulating and delivering their genes to human cells in a
pathogenic manner. Scientists have tried to harness this
ability by manipulating the viral genome to remove disease-
causing genes and insert therapeutic ones
Kinds of Vector used in Gene Therapy
1.Retroviruses
2.Adenoviruses
3.Adeno-associated viruses
4.Herpes Simplex viruses
5.Lenti-viruses
What factors have kept gene therapy from becoming an
effective treatment for genetic disease?
Short-lived nature of gene therapy 
Before gene therapy can become a permanent cure for any
condition, the therapeutic DNA introduced into target cells
must remain functional and the cells containing the
therapeutic DNA must be long-lived and stable. Problems
with integrating therapeutic DNA into the genome and the
rapidly dividing nature of many cells prevent gene therapy
from achieving any long-term benefits. Patients will have to
undergo multiple rounds of gene therapy.
Immune response 
Anytime a foreign object is introduced into human tissues,
the immune system is designed to attack the invader. The risk
of stimulating the immune system in a way that reduces gene
therapy effectiveness is always a potential risk. Furthermore,
the immune system's enhanced response to invaders it has • Phenylalanine is a large, neutral amino acid (LNAA).
seen before makes it difficult for gene therapy to be repeated LNAAs compete for transport across the blood brain
in patients. barrier (BBB) via the large neutral amino acid
transporter (LNAAT). Excessive phenylalanine in the
Problems with viral vectors  blood saturates the transporter. Since these amino
acids are required for protein and neurotransmitter
Viruses, while the carrier of choice in most gene therapy
synthesis, phenylalanine accumulation disrupts brain
studies, present a variety of potential problems to the patient
development in children, leading to mental
-toxicity, immune and inflammatory responses, and gene
retardation (Pietz et al. 1999). There is also a lack of
control and targeting issues. In addition, there is always the
dopamine and other neurotransmitters whose
fear that the viral vector, once inside the patient, may
synthesis traces to tyrosine.
recover its ability to cause disease.
• Phenylalanine Hydroxylase
Multigene disorders 
• This enzyme helps degrade phenylalanine by
Conditions or disorders that arise from mutations in a single
converting it to tyrosine.
gene are the best candidates for gene therapy. Unfortunately,
some the most commonly occurring disorders, such as heart • If this enzyme is defective, phenylalanine is
disease, high blood pressure, Alzheimer's disease, arthritis, converted to phenylpyruvate (a ketoacid)
and diabetes, are caused by the combined effects of
variations in many genes. Multigene or multifactorial • Phenylpyruvate
disorders such as these would be especially difficult to treat
effectively using gene therapy. • Accumulates in the body and inhibits the conversion
of pyruvate to acetyl coA.
Phenylketonuria
• Thus depriving the cells of energy via the common
• Hereditary defects in amino acid catabolism. pathway. This is most important in the brain, which
gets its energy from the utilization of glucose
• Absence of the enzyme phenylalanine hydroxylase in resulting to MENTAL RETARDATION.
normal catabolism.
• This genetic defect can be detected early because
• Phenylketonuria is an autosomal recessive genetic phenylpyruvic acid appears in the urine.
disorder. This means that a child must inherit
abnormal genes from both parents to develop PKU • It can be prevented by restricting the intake of
(Longe 2006). People with one gene are carriers phenylalanine in the diet.
because they do not have the disease, but can pass it
on to their children. • Patients with PKU should avoid artificial sweetener
aspartame.
• Phenylketonuria is the inability to metabolize
phenylalanine. • ASPARTAME-yields phenylalanine when yields in the
stomach.
• Phenylalanine
• Tyrosine
• An a-amino acid that is found in many proteins (such
as hemoglobin), is essential in the human diet, and • (abbreviated as Tyr or Y) or 4-hydroxyphenylalanine.
normally is readily converted to the amino acid
• is an important production of neurotransmitters that
tyrosine in the human body.
function in the brain.
• Also classified as an “essential amino acid” since it
• One of the 20 amino acids that are used by cells to
cannot be sythesized by the human body from other
synthesize proteins.
compounds through chemical reactions and thus has
to be taken in with the diet.

• •

• Metabolic Pathways
• L-phenylalanine can be converted into L-tyrosine,
another one of the DNA-encoded amino acids. L-
tyrosine, in turn, is converted into L-DOPA, which is
further converted into dopamine, norepinephrine
(noradrenaline), and epinephrine (adrenaline).
Dopamine, norepinephrine, and epinephrine are
known as catecholamines. Catecholamines are any
of a group of amines (nitrogen-contain organic
compounds) derived from the amino acid tyrosine
and containing a catechol group (aromatic chemical
compound consisting of a benzene ring with two
hydroxyl groups). Catecholamine are important as
neurotransmitters and hormones.
• Metabolic Pathways
• The basic synthetic pathway shared by all
cathecolamines involves the following series of
enzymatic steps:
• Tryosine, one of the main precursors of
catecholamines, is created from phenylalanine by
hydroxylation via the enzyme phenylalanine
hydroxylase. (Tyrosine also is ingested directly from
dietary protein).
• Tyrosine is oxidized into dihydroxyphenylalanine (L-
DOPA).
• This is followed by decarboxylation into the
neurotransmitter dopamine.
• The basic synthetic pathway shared by all
cathecolamines involves the following series of
enzymatic steps:
• Next is β-oxidation into norepinephrine by dopamine
beta hydroxylase.
• Epinephrine then is synthesized from
norepinephrine via methylation of the primary distal
amine of norepinephrine by phenylethanolamine N-
methyltransferase (PNMT).
The enzyme phenylalanine hydroxylase (PAH) is fundamental
to the process through conversion of amino acid
phenylalanine into the amino acid tyrosine. This is the only
known role of PAH in the human body (Krapp and Wilson
2005).
• CANCER
• What is Cancer?
• Medical term – malignant neoplasm
• A class of diseases in which a group of cells display
uncontrolled growth, invasion, and sometimes
metastasis (spread to other locations in the body via
lymph or blood).
• The branch of medicine concerned with the study,
diagnosis, treatment, and prevention of cancer is
oncology.
Mutation: Chemical Carcinogens
• Cancer pathogenesis is traceable back to DNA
mutations that impact cell growth and metastasis.
• Substances that cause DNA mutations are known as
mutagens
• Mutated genes that cause cancer are called
oncogenes.
• Any agent that causes cancer is called a carcinogen
and is described as carcinogenic.
• Some mutagens are carcinogenic.
•
Mutation: ionizing radiation
• Prolonged exposure to ultraviolet radiation from the
sun can lead to melanoma and other skin
malignancies.
• Viral or Bacterial Infection
• Some cancers can be caused by infection with
pathogens. Many cancers originate from a viral
infection; viruses are responsible for 15% of human
cancers worldwide.
• The main viruses associated with human cancers are
human papilloma virus, hepatitis B and hepatitis C
virus.
 • Hereditary
• Most forms of cancer are sporadic, meaning that
there is no inherited cause of the cancer. There are,
however, a number of recognised syndromes where
there is an inherited predisposition to cancer, often
due to a defect in a gene that protects against tumor
formation.
• Example: Down syndrome patients, who have an
extra chromosome 21, are known to develop
malignancies such as leukemia and testicular cancer,
though the reasons for this difference are not well
understood.
• •
Other Factors Increasing Risk for Cancer
• Age
• Body weight, diet, physical activity
• Day to day environment
• Immune System
• Types of Cancer Cells
• Carcinoma: Malignant tumors derived from
epithelial cells. This group represents the most
common cancers, including the common forms of
breast, prostate, lung and colon cancer.
• Sarcoma: Malignant tumors derived from connective
tissue, or mesenchymal cells.
• Lymphoma and leukemia: Malignancies derived from
hematopoietic (blood-forming) cells
• Germ cell tumor: Tumors derived from totipotent
cells.
• Blastic tumor or blastoma: A tumor (usually
malignant) which resembles an immature or
embryonic tissue. Many of these tumors are most
common in children.
• Malignant tumors are usually named using
-carcinoma, -sarcoma or -blastoma as a suffix, with
the Latin or Greek word for the organ of origin as the
root.
For instance, a cancer of the liver is called
hepatocarcinoma; a cancer of the fat cells is called
liposarcoma. For common cancers, the English organ name is
used. For instance, the most common type of breast cancer is
called ductal carcinoma of the breast or mammary ductal
carcinoma. Here, the adjective ductal refers to the
appearance of the cancer under the microscope, resembling
normal breast ducts.
• Benign tumors (which are not cancers) are named
using -oma as a suffix with the organ name as the
root. For instance, a benign tumor of the smooth
muscle of the uterus is called leiomyoma.
Unfortunately, some cancers also use the -oma
suffix, examples being melanoma and seminoma.
• Malignant or Benign?
Benign tumours - do not spread from their site of
origin, but can crowd out (squash) surrounding cells.
ex: brain tumour, warts.
• Malignant tumours - can spread from the original
site and cause secondary tumours. This is called
metastasis. They interfere with neighbouring cells
and can block blood vessels, the gut, glands, lungs
etc.
• Carcinogen
• Substances and exposures that can lead to cancer
are called carcinogens.
• Carcinogens do not cause cancer in every case, all
the time. Substances labeled as carcinogens may
have different levels of cancer-causing potential.
Some may cause cancer only after prolonged, high
levels of exposure.
•
Who determines how carcinogens are classified?
• IARC
• National Toxicology Program
• Environmental Protection Agency
• CDC's National Institute for Occupational Safety and
Health (NIOSH)
• Food and Drug Administration (FDA)
• California Environmental Protection Agency (CalEPA)
The International Agency for Research on Cancer (IARC)
 is part of the World Health Organization (WHO). Its major
goal is to identify causes of cancer.
• The most widely used system for classifying
carcinogens comes from the IARC. In the past 30
years, the IARC has evaluated the cancer-causing
potential of more than 900 likely candidates, placing
them into one of the following groups:
• Group 1: Carcinogenic to humans
• Group 2A: Probably carcinogenic to humans
• Group 2B: Possibly carcinogenic to humans
• Group 3: Unclassifiable as to carcinogenicity in
humans
• Group 4: Probably not carcinogenic to humans
• Stages
• Staging is the process of finding out how much
cancer there is in the body and where it is located.
Doctors use this information to plan treatment and
to help find out a person's outlook (prognosis).
Cancers with the same stage usually have similar
outlooks and are often treated the same way. The
cancer stage is also a way for doctors to describe the
extent of the cancer when they talk with each other
about a person's case.
• For most cancers, the stage is based on 3 main
factors:
• the original (primary) tumor's size and whether or
not the tumor has grown into nearby areas
• whether or not the cancer has spread to the nearby
lymph nodes
• whether or not the cancer has spread to distant
areas of the body
• Treatment
• Chemotherapy
-the treatment of disease by means of chemicals that have a
specific toxic effect upon the disease-producing
microorganisms or that selectively destroy cancerous tissue.
• Radiotherapy
-also called radiation oncology, and sometimes abbreviated
to XRT, is the medical use of ionizing radiation as part of
cancer treatment to control malignant cells (not to be
confused with radiology, the use of radiation in medical
imaging and diagnosis). Radiotherapy may be used for
curative or adjuvant cancer treatment. It is used as palliative
treatment (where cure is not possible and the aim is for local
disease control or symptomatic relief) or as therapeutic
treatment (where the therapy has survival benefit and it can
be curative)
• Surgical
-Surgery is a medical specialty that uses operative manual
and instrumental techniques on a patient to investigate
and/or treat a pathological condition such as disease or
injury, to help improve bodily function or appearance, or
sometimes for some other reason.
• Immunotherapy
-treatment designed to produce immunity to a disease or
enhance the resistance of the immune system to an active
disease process, as cancer.
• Monoclonal antibody therapy
-is the use of monoclonal antibodies (or mAb) to specifically
bind to target cells. This may then stimulate the patient's
immune system to attack those cells. It is possible to create a
mAb specific to almost any extracellular/ cell surface target.
mAb therapy can be used to destroy malignant tumor cells
and prevent tumor growth by blocking specific cell receptors.
• Molecular mechanisms of Cancer Metastasis
• Metastasis, the spread of cancer cells from the
primary tumor to distant organs, is the most
dreadful development of
neoplastic diseases. Although metastasis contributes
to over 90% of human cancer mortality, the
molecular mechanism
of this process remains largely unknown. Our
laboratory applies a multidisciplinary approach to
analyze the molecular
basis of cancer metastasis, combining molecular
biology and genomics tools with animal models and
advanced in vivo
imaging technologies.