EGFR Kinase Mechanisms Targeted Cancer Therapy

Anilinoquinazoline Mechans Of Egfr
Specifically the genetic alteration of epidermal growth factor receptor (EGFR) and anaplastic
lymphoma kinase (ALK) genes encodes targetable tyrosine kinases, involved in growth factor
receptor signaling and these genes has changed the way these cancers are diagnosed and treated. As
gefitinib and erlotinib are competitive inhibitors of the EGFR tyrosine kinase, in the last decade
several clinical trials of advanced–stage lung cancer.
Covalent inhibitors are a class of kinase inhibitors, which forming covalent bond to the active site of
kinase, most commonly by reacting with a nucleophilic cysteine residue (Cohen et al., 2005; Kwak
et al., 2005). The most clinically using advanced irreversible kinase inhibitors of the (EGFR) are
HKI–272 ... Show more content on Helpwriting.net ...
Polier et al. 2013 identified a new mode of action for ATP–competitive kinase inhibitors, is a
significant class of anticancer agents, these inhibitors are used in the clinic (Polier et al., 2013). This
discovery of new inhibitory mechanism of action exposes the interactions among the chaperone
protein heat shock protein 90 (HSP90), its co–chaperone CDC37 (a scaffold protein) and the protein
kinases that they regulate. However, the inhibition of Hsp90 in vivo cause in degradation of kinase
clients, with a curative effect in dependent cancers. Result of this study shows that the Cdc37
binding to protein kinases is itself disturbed by ATP–competitive kinase inhibitors (vemurafenib and
lapatinib). Polier et al used the commonly mutated BRAF kinase model to perform their
investigations.
Malignant pleural mesothelioma (MPM) is a disease with few therapeutic options. Protein kinase C
beta (PKCß) is involved in important cellular functions. It was highly expressed in the majority of
MPM cells. Enzastaurin (LY317615.HCl) is a novel inhibitor of PKC, which has preclinical activity
against MPM, and exhibited synergism with cisplatin. PKCß inhibition in MPM might be able to
reduce the invasiveness of MPM by affecting cytoskeletal function (Faoroa et al., 2008).
At least 40 kinases are known to be
... Get more on HelpWriting.net ...

Phenylketonuria Essay
Phenylketonuria is an autosomal recessive error that leads to a mutation of the enzyme
phenylalanine hydroxylase (PAH). This disease, more commonly known as PKU, is characterized
by a deficiency in the enzyme needed to process the amino acid called phenylalanine (Mayo Clinic
Staff, 2014). The mutated PAH is crucial in the degradation of amino acids. The amino acids we
intake are from food, which makes PKU a metabolic disorder (Okan, 2011). The body's inability to
break down phenylalanine leads to a build up of it in the body. The excess of this amino acid
negatively impacts the cognitive function of the individual. Phenylketonuria is the most common
inborn error of amino acid metabolism (Arnold, 2014). Approximately 1 in 10,000 caucasian babies
are born with PKU (Baulny, 2007). In order for a person to inherit phenylketonuria, the mother and
father both must have and pass down the defective gene. The parents of someone afflicted by this
disease may have the gene but not have PKU. This parent would ... Show more content on
Helpwriting.net ...
Many times when babies are initially screened for the disease they are not yet showing any of the
symptoms. As a child grows, the signs begin to emerge (Mayo Clinic Staff, 2014). Due to modern
medicine, PKU, if spotted early can now be treated. However, if PKU goes untreated, permanent
damage to the body will be evident (Williams, 2008). People with PKU will have many visible
symptoms such as growth failure, fair pigmentation of the skin, hair loss, and skin rashes (Arnold,
2014). There are other symptoms that are warning signs of PKU that are less noticeable. For
example, people suffering from phenylketonuria often have a musty body odor and their urine is
characterized by strange coloring and an odd, musty odor as well. Many times these are the main
warning signs for the illness in people that were not detected for PKU in the newborn screenings
(Williams,

Oxidative Stress Key Research Data and Analysis
Key Research Data and Analysis Study 1: Ipc1 controls the Pkc1 activation by modulation of DAG
Regulation of DAG and phytoceramide by Ipc1. When Wild type and GAL7::IPC1 strains were
exposed to galactose and glucose, DAG (activator of PKC1) levels in the GAL7::IPC1 strain
increased when IPC1 was induced by galactose, and decreased when IPC1 was repressed by
glucose. Furthermore, phytoceramide levels were increased when IPC1 was down regulated by
glucose in the GAL7::IPC1 strain. In both wild type strains, no change was seen when IPC1 was up
or down regulated, as expected (Fig. 2). PKC1 activity in relation to DAG and Phytoceramide
exposure. Since IPC1 regulates DAG and phytoceramide levels, the authors wanted to explore if
DAG or phytoceramide can control PKC1 activity. DAG or phytoceramide were delivered in Triton
x–100 lipid micelles and histone phosphorylation by recombinant PKC1 was measured in absence
or presence of lipids. Without lipids, Pkc1 activity was 31.5 pmol/min/mg. When DAG subspecies
were added, Pkc1 activity increased up to two fold (Fig. 3A). In order to make sure kinase activity
measured was specific to Pkc1, APP1 activity was measured when exposed to DAG subspecies and
as expected, did not cause phosphorylation of histone, which was expected (Fig. 3B). When
phytoceramide lipids were added, Pkc1 activity decreased by about 50% compared to no
phytoceramide, which was expected because phtyoceramide is an inhibitor of Pkc1 (Fig. 3C). Study
2:

Drug Development Of The Drug Imatinib
TRM6002 Essay 2 – Drug Development
State what the target for the drug imatinib is, and why that target was a good choice for a drug
discovery project.
Summary/Abstract:
Until the 1990's, drug discovery relied on forward pharmacology where trial and error produced
medications that were usually involved in changing DNA synthesis and/or cell division. These
medications were efficacious, but had issues with systemic toxicities due to their non–selectivity of
diseased cells or disease causing proteins. With the discovery of specific genetic changes that occur
in Chronic Myeloid Leukemia, a haematological malignancy, a target was identified which was only
seen in diseased cells; thus, rational drug design came about. Imatinib is the first medication of
rational drug design with action only in diseased cells.
Introduction:
Historically, drug discovery projects were aimed at developing drugs that were involved in changing
DNA synthesis and/or cell division. These medications included alkylating agents which were very
effective but due to the large range of non targeted action within the body, had multiple side effects
and toxicities. Since the discovery of specific and varied genetic changes that can occur within
cancerous cells, the approach to drug development has changed significantly. Imatinib was one of
the first drugs developed where its site of action was only on diseased but not on non–diseased cells.
Discussion:
Drug discovery programs start when there is a

Stc Case Study
1) The Philadelphia chromosome is chromosome 22, which has undergone a reciprocal translocation
with chromosome 9, such that the long arm of chromosome 22 has been replaced with the long arm
of chromosome 9. This chromosome is relevant to cancer because the long arm of chromosome 9
contains human c–abl oncogene, which becomes fused to the breakpoint cluster region (bcr) in the
Philadelphia chromosome, following translocation. Presence of this bcr–abl gene fusion produces a
poorly regulated tyrosine kinase, which results in a much higher level of cell proliferation. The
action of this tyrosine kinase results in chronic myelogenous leukemia (CML) symptoms, such as
overproduction of white blood cells.
2) Opposed to structural data alone, NMR ... Show more content on Helpwriting.net ...
This will result in the substrate concentration remaining relatively constant, while only the
concentration of the enzyme changes over time. These conditions result in the kinetic order to be the
same with respect to enzyme concentration and with time; thus, mimicking first–order kinetics.
3b) A non–linear response is observed here because the binding of enzyme to substrate does not
follow simple pseudo–first–order kinetics, but instead there is a two–step process involving rate–
limiting changes in protein conformation. These findings support the previously proposed model of
substrate binding, in that there is a fast step of enzyme binding to substrate, followed by a slow
conformational change in the enzyme once bound to substrate. The plateau in the observed rates
indicates the maximal rate at which enzyme can bind to substrate, with Abl binding with a maximal
rate of 20 s–1 and Src binding with a maximal rate of 2 s–1.
4) For Abl, the indicated residues are within the C lobe of the enzyme, and are not in direct contact
with Gleevec when it is bound. For Src, the indicated residues are within the N lobe of the enzyme,
and within the Gleevec binding site, such that they may be making direct contact with Gleevec.
Since these residues are within the Gleevec binding region, they demonstrate the complex, two–step,
fast and slow exchange that is occurring with Src; whereas, the residues indicated in Abl are not

A Report On Gleevec ( Imatinib Mesylate )
Gleevec (imatinib mesylate)
Antineoplastic
MW = 589.7 g/mol pKa = 5.5
Chemical Formula = C29H31N7O ● CH4SO3
IUPAC name: N–(4–methyl–3–{[4–(pyridine–3–yl) pyrimidin–2–yl]amino}phenyl)–4–((4–
methylpiperazin–1–yl) methyl]benzamide
Description
Imatinib mesylate is a protein tyrosine kinase (RTK) inhibitor that exhibits high specificity and
potency for ABL, c–kit, and PDGF receptors, which often harbor activating mutations and are
typically mutually exclusive of each other and within specific cancer types.2 The compound has
been approved as a targeted chemotherapy for Philadelphia chromosome positive chronic and acute
myeloid leukemia (Ph+ CML and AML), Ph+ acute lymphoblastic leukemia (ALL), platelet–derived
growth factor receptor (PDGFR) aberrancy–related myelodysplastic or myeloproliferative
pathologies, kit+ expressing advanced gastrointestinal stromal tumors (GIST), and for FIP1L1–
PDGFRα gene fusion expressing hypereosinophilic syndrome (HES) or chronic eosinophilic
leukemia (CEL).1 Imatinib is available in 100 mg and 400 mg tablets for case–dependent single
agent or adjunct therapy1. Therapeutic doses range from 100 mg to 800 mg/day, depending on
diagnosis, age, and hepatic function.1 The drug exhibits pH–dependent solubility in aqueous
solutions (soluble at pH ≤ 5.5), varying solubility in polar protic solvents, and is immiscible in polar
aprotic liquids.1
Mechanism of Action
Imatinib is a competitive antagonist that exhibits specific activity for ABL, c–kit, and PDGFR

Tanning Pills
Tanning pills are available in two major varieties, which are dependent on the type of major
ingredients. One type is rich in tyrosine as discussed here (To open Top Tan Enhancing Tablets on
the Tinning Tablets article) while the other is rich in specific pigments that form a golden–brown
color on the epidermis once they are introduced in the body. Tyrosine supplements optimize the
natural tanning of the body because it is an amino acid that is converted into melanin, the brown
skin pigment of the body. On the other hand, the pigment variety consists of beta carotene and
canthaxanthin based tanning pills. These two main varieties will help you achieve a toned skin
without using any synthetic material.
Melanin –The skin tan determined
Melanin ... Show more content on Helpwriting.net ...
Beta carotene–based tanning pills
They are best alternative for Canthaxanthin–based tanning pills because they don't have the
Canthaxanthin retinopathy side effect. Instead of the side effect, they give a bright brown color in
the epidermis that gives the tan that we are always looking for.
Tyrosine–based tanning pills
These supplements are very effective because they are rich in amino acids which are required by the
body to synthesis melanin. Using these pills leaves a deeper and long lasting tan. In addition, some
tyrosine pills contain copper which is vital in the conversion of tyrosine to melanin. The levels of
copper in the body are usually low which implies that copper supplements in tyrosine makes the
pills more

Cancer
Cancer is defined as a "disease cause by the uncontrolled division of abnormal cells inside a part of
the body." Mutations to specific genes or regions of DNA contribute to the presentation of these
abnormal cells as well as the ability for these cells to divide uncontrollably throughout the body. For
many years, the standard route of treatment for those who have been diagnosed with cancer is to use
chemotherapy or radiation therapy. Although these therapies have been considered to be the standard
of care for cancer treatment for many decades, the toxic side effects that are also associated with
these therapies can be just as devastating as the disease itself. The onset of targeted therapy for the
treatment of cancer has brought on a new ... Show more content on Helpwriting.net ...
Other formulations of TKIs include erlotinib (Tarceva), canertinib, vatalanib, dasatinib, and
sorafenib to name a few. This manuscript will be discussing Imatinib Mesylate in further detail and
reviewing many of the pharmacological and antitumor and anticancer properties of the drug in more
detail. The use and increased acceptance towards targeted cancer therapies is not without its
imperfections. As with any medication or therapy, not every individual is the same and the overall
response rates may change from person to person and from population to population. As more
research is done, the introduction of new inhibitors as well as the improvement of current inhibitors
will help to increase the overall response rate in patients as well as help to increase the ability for
patients to receive even more selective and specific care for their disease.
To gain a better understanding and overall appreciation for the creation and implementation of
targeted therapies, it is important to look at previous standards of care for the treatment of cancers
and tumors. Conventional chemotherapy, when directed in the direction of specific cells in the body,
does not do a very good job at being able to discriminate between normal, healthy dividing cells and
tumorigenic cells. This can lead to many different toxic side effects ranging from fatigue and anemia
to excessive vomiting, hair loss and in some

Short-term in vitro Inhibition of Glycogen
Introduction:
Overt type 2 diabetes mellitus is the most prevalent form of diabetes, accounting for approximately
90% of the 20.8 million cases in the United States. Unlike type 1 diabetes mellitus, type 2 diabetes
mellitus is most commonly caused by a defect in insulin action on cells rather than by a defect in the
insulin itself1. It has recently been shown that overactivity of glycogen synthase kinase 3 (GSK–3)
may be implicated in the impaired insulin action2. Although GSK–3 is a distal element of the insulin
signaling pathway (which includes insulin receptor substrate 1 or IRS–1), when it is overactive, this
affects both insulin signaling and the removal of glucose from the blood stream by skeletal muscle.
Firstly, when ... Show more content on Helpwriting.net ...
In addition, the tyrosine–phosporylated IR and IRS–1 measured using the same method used to
assess insulin signaling.
Results:
3.1 GSK–3 serine phosphorylation in soleus muscle from lean Zucker and ZDF rats.
3.2 Effects of GSk–3 inhibition in glucose transport activity
3.3 Effects of GSK–3 inhibition on insulin signaling functionality
3.1 GSK–3 serine phosphorylation in soleus muscle from lean Zucker and ZDF rats.
In order to evaluate the activity state of GSK–3 in the skeletal muscle of ZDF rats, the
phosphorylation of the GSK–3β Ser9 was measured. This information was then compared to the
data obtained from lean Zucker rats. The first test was conducted in the absence of insulin and
showed that the GSK–3β Ser9 phosphorylation of the ZDF rats was significantly less [36%] than
that of the lean Zucker rats. The second test performed between the lean Zucker and ZDF rats was
identical to the first minus one aspect: the presence of insulin. When given insulin, the
phosphorylation of the GSK–3β Ser9 in ZDF rats was considerably less [35%] than the
phosphorylation in lean Zucker rats. These findings were expected because type 2 diabetes lowers
an organism's ability to phosphorylate GSK–3β Ser9. This lowered ability is inversely related to
GSK–3 activity. Thus, the ZDF rats, which have type 2 diabetes, had a higher activity rate of GSK–3
in their skeletal muscles than the lean Zucker rats. Finally,

Phenylketonuria Research Paper
Phenylketonuria (PKU) is a metabolic disorder caused by the deficiency of the enzyme
phenylalanine hydroxylase (PAH). It is the most dangerous disease in the class of
hyperphenylalaninemia, which is a class of diseases that contains high levels of phenylalanine in the
blood. PKU is an autosomal recessive disorder that occurs on the twelfth chromosome. It is caused
by alterations of the genetic code of the PAH enzyme. This can involve many different changes such
as deletions and insertions in the DNA that codes for PAH. The normal PAH gene is dominant to its
mutation counterpart. There is up to 400 types of PKU mutations, with the more sever the mutation
the greater effect of physiological development and performance. It has been found that ... Show
more content on Helpwriting.net ...
PKU is positive when bacteria is found around the high concentrations of phenylalanine treatment is
recommended for babies with a PAH level of 7–10 mg/dl. The treatment options all depend on the
lifestyle and genetic factors of the infant. If the treatment is given early enough PKU patients can
live a close to normal life. A specialized diet is the key for PKU patients. Preventing PAH from
entering the diet can be bland and frustrating, even being in women's breast milk, but is the most
reliable source for PKU treatment. PAH is an amino acid which means it is in a lot of food, because
people cannot produce the substance on their own. Almost all proteins cannot be consumed, as well
as sugar–free food(They contain aspartame which contain PAH). The range for PKU patients of
PAH before 12 is 2–6 mg/dl, but over that age is 2– mg/dl. The specialized diet can cause some
abnormalities, like with tyrosine; this can lead to some doctors recommending PKU patients also
taking a tyrosine supplement. Researchers are trying to synthesize a new enzyme for the breakdown
of PAH that will make the lives of PKU patients easier. Pregnant mothers with PKU should take
special care before and during pregnancy. Their children can have a higher risk of having
microcephaly, congenital heart disease, stunted growth, mental impairment, and psychomotor
difficulties. They can

Describe The Structure Of Methanogenesis
Methanogens are prokaryotes. A prokaryote cell does not contain a membrane–bound nucleus; they
range from 0.1 to 10 µm in total cell size. Methanogens are usually either coccoid (spherical) or
bacilli (rod shaped). Each cell is surrounded by a plasma membrane. The cell has no subcellular
organelles, only infoldings of the plasma membrane called mesosomes. The deoxyribonucleic acid
(DNA) is condensed within the cytosol to form the nucleoid. The cell walls of Methanogens, like
other Archaea, lack peptidoglycan. Some prokaryotes have tail–like flagella. By rotation of their
flagella, they have the ability to move through their surrounding media in response to chemicals or
better known as 'chemotaxis'. The flagella are made of the protein flagellin that forms a long
filament, which is attached to the flagellar motor by the flagellar hook.
Methanogens are anaerobic unicellular organisms that release methane as a waste product of cellular
metabolism. All of the methanogens are lithotrophs that can make their own energy only by
Methanogenesis, or the production of methane. ... Show more content on Helpwriting.net ...
They are responsible for the methane in the belches of ruminants, as in, the flatulence in humans,
and the marsh gas of wetlands. Methanogenic archaea, are an important group of microorganisms
that remove excess hydrogen and fermentation products produced by other forms of anaerobic
respiration produce methane as a metabolic by–product under anaerobic conditions ecosystem.
Because of this, methanogens thrive in environments in which all electron acceptors other than CO2
(such as oxygen, nitrate, trivalent iron, and sulphate) have been depleted. In spite of this, since the
process of methanogenesis also produces methane, which has a global warming potential 21 times
greater than that of carbon dioxide. This effect can fortunately be offset through the use of methane
as a

A Research Study On Protein Arginine And C Met Are...
Specific aims: EGFR and c–Met are receptor tyrosine kinases (RTKs), and tyrosine kinase inhibitors
(TKIs) against these receptors have been initially effective when prescribed to patients in
combination with traditional chemotherapy or radiation. However, the overall efficacy of TKIs is
limited due to the development of resistance as seen through clinical trials in NSCLC. Epithelial
Mesenchymal Transition (EMT) is a process by which epithelial cells undergo phenotypic and
morphological changes to acquire mesenchymal characteristics including increased motility and
invasiveness. Currently, the role of EMT in TKI drug resistance is poorly understood. EMT results
in loss of tight junction proteins such as E–cadherin and upregulation of transcriptional repressors of
these proteins such as ZEB1. Recently, protein arginine methyl transferase 1 (PRMT1) has been
shown to be an important regulator of EMT, cancer cell migration and metastasis. However, the role
of PRMT1 in TKI resistance is not known. In this study, we propose to evaluate the role of EMT
proteins in TKI resistance using H2170 and H358 cell lines (wild type EGFR) that were made
resistant to an EGFR inhibitor, erlotinib and a c–Met inhibitor, SU11274 and a combination of both.
H3255 cell line (with L858R EGFR mutation), and H1975 cell line with L858R and T790M EGFR
mutations which we have made resistant to erlotinib will also be used. Our recent in vitro studies
indicate that TKI resistance may be due to the activation

Targeted Therapy
Targeted therapy in the treatment of cancer Student ID – 39298 Class – HAS–3 Word count–
Targeted therapy, which first became available in the late 1990s, has had a significant impact on the
treatment of cancer. Currently, because of advancement in the field of technology, various types of
therapies are discovered to treat cancer. In this essay, targeted therapy is defined as a therapy in
which various drugs or other substances are used to recognize and kill the cancerous cells without
harming the normal cell (National cancer institute, 2014). Effectiveness refers to the degree in ...
Show more content on Helpwriting.net ...
One of them is Gleevec (Imatinib mesylate), a tyrosine kinase inhibitor, was called a "magical
bullet". This was the first targeted therapy drug used to treat cancer. It was invented in the late
1990's, to treat "chronic myeloid leukemia and gastrointestinal stromal growth". Imatinib is tyrosine
kinase inhibitors. Tyrosine kinase is a protein that cells use to signal to each other to grow (Iqbal and
Iqbal, 2014, p.1). It works by preventing a tyrosine kinase enzyme and therefore inhibits growth
factor–induced receptor phosphorylation and blocks the PDGF/PDGFR and P13–k/Akt pathway
(Kheradmand, et.al.2016, p.83). According to Richardson (2010, p.679), the drug Velcade was also
known as "Bortezomib" is useful in the treatment of multiple myelomas. The main goal of this drug
is to lower the tumor growth significantly. The American cancer society (2013, para.20) studies
show Bortezomib is a "proteasome inhibitor". It works by blocking or slowing down the action of
proteosome is to break down protein in both healthy and cancerous cells. When proteosome activity
is blocked, proteins in the cells accumulate. This accumulation may cause cells to stop growing and
multiplying, and cause them to die and Sutent (Sunitinib) is a drug used to treat metastatic renal cell
carcinoma. It is currently approved as a second–line treatment of MRCC. Sunitinib inhibits the
vascular endothelial growth factor receptor and stops the growth of tumors (Kolesar, et.al. 2008,
pp.123 131). It is considered as a multi– targeted kinase inhibitor because it is a type of VEGF
inhibitor, an angiogenesis inhibitor, and it blocks an enzyme called tyrosine kinase. By doing all of
this, it slows cancer growth and keeps tumors from making their own blood vessels to help them
grow and spread (American

Cd117 Dako Research Paper
Cell Pathology Assignment 5 – CD117 – Dako Structure, function and distribution of this protein:
CD117 is a membrane tyrosine kinase receptor (Type III receptor tyrosine kinase family), encoded
by the c–kit proto–oncogene. The Type I transmembrane glycoprotein locates on chromosome 4q11
and 4q12 and has a total length of 90 kb. It has a molecular mass of 145 kDa. The extra–cellular
domain consists of 519 amino acids. It contains 5 Ig–like domains. D1–D3 are responsible for c–kit
binding to stem cell factor, and D4 and D5 are the dimerization domains. The transmembrane region
consists of 23 amino acids and the juxta–membrane domain is made up of 433 amino acids. The
tyrosine kinase domain is inserted by approximately 80 amino acid residues.

Potential Therapeutics For Treating Type 2 Diabetes Mellitus
Bromophenols have been identified as potential therapeutics for treating type 2 diabetes mellitus
(T2DM) due to their suspected tyrosine phosphatase 1B (PTP1B) inhibitory activity. A new series of
bromophenol analogues will be synthesised and their PTP1B inhibitory activity will be tested in in
vitro enzymatic assays to elucidate their mechanism of action as PTP1B inhibitors.
Background and Introduction
Type 2 diabetes mellitus (T2DM) is a metabolic disease that is caused by insulin resistance of the
peripheral tissues and impaired insulin secretion of the pancreatic β cells.1 Both conditions result in
reduced glycemic control, which can lead to hyperglycemia. Despite the availability of a wide range
of anti–diabetic drugs to treat T2DM, ... Show more content on Helpwriting.net ...
Bromophenols have attracted much attention as potential PTP1B inhibitors due to their suspected
anti–diabetic activity.4 Bromophenols occur naturally in marine organisms such as algae, mollusks
and jellyfish. (±)–Polysiphenol (1, figure 1) is an example of a bromophenol that can be extracted
from the marine algae Polisiphonia Ferulecea.5 After the Braddock group successfully achieved the
first total synthesis of (±)–polysiphenol and the separation of its enantiomers, they collaborated with
the Woscholski group to test their inhibitory activity in PTP1B enzymatic assays.6,7 Both
enantiomers of polysiphenol were essentially found to be identical in PTP1B inhibitory activity.
Thus polysiphenol, as single enantiomers, cannot be responsible for the observed inhibition. This
implicates a chemical change of polysiphenol into a non–chiral form is likely to take place under the
conditions of the assay. One possibility is the formation of a para–quinone methide species (4, figure
1), which in turn can tautomerise into an ortho–quinone methide species (5, figure 1). Thus there are
various possible reactive species that might be responsible for the observed inhibition of PTP1B.
The formation of quinones highlights a red flag in drug discovery due to their highly reactive nature.
Quinones are Michael acceptors that are known to cause toxicity in vivo by covalently binding to
nucleophilic sites on proteins and DNA.8 Consequently, quinones

Dopaminergic Pathway Analysis
The pathways of dopaminergic called dopaminergic projections; has a group of neurons located in
the brain that produces and releases the dopamine defined as a neurotransmitter (Le Moal, 2013).
The neurons present in the dopamine have axons that run through the whole extent of the pathway
and it named as dopamine neurons. Sometimes, mesocortical and mesolimbic pathways can be
mentioned as the mesocorticolimbic pathway or system.The mesolimbic pathway has dopaminergic
projections which release dopamine from the ventral tegmental area present in the midbrain to the
ventral striatum (has nucleus accumbens and olfactory tubercle). This pathway has a role in emotion
and reward systems. However, dopamine produces in the mesolimbic brings about pleasure ... Show
In this pathway, dopamine plays in cognitive and emotional behavior. An amount of dopamine
produced in this pathway, specifically from the prefrontal cortex, assist in enhanced effective
memory and kindness. Nevertheless, it would be a fragile equilibrium and as the quantity of
dopamine enhances or reduces to irregular levels, memory endures [Malenka RC, 2009, Björklund
A, 2007, Paulus W, 2006).There is significant confirmation, from animal models and recently from
humans, which total drugs of abuse unite on a circuitry in the brain's limbic system (1–5). Utmost
consideration has been specified to the mesolimbic dopamine pathway, which has dopaminergic
neurons in the ventral tegmental area (VTA) of the midbrain and their intentions in the limbic
forebrain, particularly the nucleus accumbens (NAc). This VTA–NAc pathway is unique of the
essential substrates meant for the severe rewarding effects of the abuse of every drug, unrelatedly its
different mechanism of action, joins on the VTA and NAc with usual severe practical effects.The
entire drug stimulates dopaminergic transference in the NAc and several yields dopamine–like, so
far dopamine–independent results on the similar NAc neurons, in some cases through indirect,
circuit–level movements (1–8). Additionally, numerous drugs appear to trigger the endogenous
opioid and cannabinoid systems in the brain in the VTA–NAc pathways, as illustrated by decreased
drug results in cannabinoid and opioid receptor knockout mice, has the common acute action of
mechanisms of a drug. A recent study has recognized that some further brain areas that interrelate
with VTA and NAc are too important for severe drug reward and long–lasting variations in reward–
related with addiction. These areas comprise the amygdala, hippocampus, hypothalamus and
numerous areas of the

Chronic Myeloid Leukaemia (CML)
Chronic myeloid leukaemia (CML) is one of the most dangerous bone marrow diseases with an
initial chronic stage lasting for 3–5 years. It changes to a very fast phase called accelerated phase
and then to the blast phase in which it leads later to death1. Besides (CML) is a type of cancer that
affects the blood cells by raising the level of the immature white blood cells (leukocytes) in the bone
marrow and which leads later to circulate in the blood stream. These crowded immature blood cells
do not perform their vital role in defending the body against infectious organisms properly, and that
leads to leukaemia disease progression.2, 3 On the other hand leukaemia is classified into four
kinds: acute lymphocytic leukaemia (ALL), acute ... Show more content on Helpwriting.net ...
14 CML attacks 1 to 2 cases per 100,000 people per year which is about 15% of adult, and the
patients are between 45 and 55 years and about 85% of the patients are in chronic phase. On the
other hand the symptoms that appear in chronic myelogenous leukaemia patients are fatigue, weight
loss, abdominal fullness, bleeding, purpura, splenomegaly, leukocytosis, anaemia, and
thrombocytosis.

A Study On Meeting Receptor
MET RECEPTOR Met is a tyrosine kinase receptor, which binds to HGF (Hepatocyte Growth
Factor), causing effects through several pathways (including anti–apoptotic mechanisms and
cytoskeletal changes), being one of the most important processes during embryogenesis, organ
regeneration and tumour invasion (TRUSOLINO; BERTOTTI; COMOGLIO, 2010). MET GENE
AND STRUCTURE The c–Met gene is present on chromosome 7q21–31, has 21 exons and 20
introns, with a total length of 120kb. The transcription of this proto–oncogene produces a
polypeptide, which after glycosylation, is cleaved in a 50 kD α chain and a 140kD β chain
(CIPRIANI, 2009). The mature c–Met receptor is a heterodimer, with a complete extracellular α
subunit and a large β subunit, presenting the following extracellular domains: sema (semaphoring
domain), PSI (also called MET–Related Sequence – MRS), four IPT domains (immunoglobulin –
plexin – transcription domains), and 3 intracellular regions: juxtamembrane (containing tyrosine
1003, which negatively regulates c–MET by inducing its ubiquitination), a tyrosine kinase domain
(with tyrosines Y1234 and Y1235, which positively modulate the receptor function) and a carboxy–
terminal tail region (containing tyrosines Y1356 and Y1349, responsible for the recruitment of
adaptors during the activation of c–MET) (CECCHI; RABE; BOTTARO, 2012; ORGAN; TSAO,
2011). HEPATOCYTE GROWTH FACTOR Hepatocyte Growth Factor (HGF), the main ligand of
the c–Met receptor, is a secretory product,

Acute Lymphoblastic Leukemia Research Papers
LEUKEMIA 2 Abstract This paper discusses Leukemia. The paper gives a detailed description of
Leukemia which will include signs and symptoms of the disease and a review of how bone marrow
and the circulatory system normally work to give a better understanding of what leukemia does to
the body. The paper will also discuss risk factors and causes of the disease as well as prevention
techniques. This paper will also go over how the disease is diagnosed and a description of what the
diagnostic procedures actually include. The paper also reviews treatments for Leukemia including
drugs that are commonly used for treatment. The expected outcome of the disease will also be
reviewed as well as special side effects of Leukemia that will change how someone ... Show more
content on Helpwriting.net ...
A lot of Leukemia patients are at risk of developing other forms of Leukemia or cancer in general
because of the extremely high levels of radiation they areLEUKEMIA 6 exposed to during
treatment. Exposure to certain pesticides as a kid or even in the womb has been statistically tied to
higher chances of developing Leukemia. If a mother drinks alcohol, smokes cigarettes, or does illicit
drugs while she is pregnant, her child has increased chances of developing Leukemia. A family
history of Leukemia can increase your chances of developing Leukemia. The biggest prevention of
Leukemia is do not smoke, drink, or do drugs during pregnancy, stay away from areas with high
levels of radiation, like old nuclear bomb sites, stay away from pesticides that are bad for the health,
and do not smoke or drink alcohol after birth (Belson, M., Kingsley, B., & Holmes, A., 2007).
Diagnosing Leukemia The diagnosis of Acute Myelogenous Leukemia is made through
immunophenotyping which detects the antigens made by white blood cells. Each white blood cell
produces certain antigens so the type of white blood cell being tested is

Types Of Cell Surface Receptors And The Mitogen Activated...
Introduction–
Cell–surface receptors are integral membrane proteins that play a major role in signal transduction,
allowing the function of Neurons, muscles and sensory organs to occur. Their basic function is to
carry out the process of signal transduction by binding to an extracellular signalling molecule. Cell–
surface receptors regulate gene transcription, ion flux in the neurons and growth factors. This
regulation allows the human body to function with little error. They detect the smallest of changes
and respond with a cascade of signalling events appropriately. I am going to describe the four main
types of cell–surface receptors and the Mitogen–activated protein cascade in receptor tyrosine
kinases.
G–Protein Coupled Receptors– ... Show more content on Helpwriting.net ...
GPCRs consist of alpha–helical segments separated by these intracellular and extracellular loops
(Figure 1) Figure 1 Structure of G–protein–coupled receptor, showing alpha–helical proteins
attached to the three subunits of the G–protein.
GPCRs are associated with a G protein, which is heterotrimeric i.e. they consist of three different
subunits: an alpha subunit, a beta subunit, and a gamma subunit (Figure 1). (Scitable by nature) G
proteins are specialized proteins with the ability to catalyse the exchange of guanosine triphosphate
(GTP) and guanosine diphosphate (GDP). (Scitable by nature)
The G–protein receptor is coupled to a trimeric G protein and controls the effector protein. The
receptors activate cytosolic or nuclear transcription via several pathways. They are involved in
signal transduction pathways such as MAP kinase pathway. (Lodish et al.).
When a signalling molecule such as Epinephrine, serotine and adenosine is released and binds to the
extracellular receptor site of the GPCR, the G protein changes conformation and GTP replaces the
GDP on the alpha subunit of the G–protein (Figure 2). This activated alpha subunit then parts from
the beta and gamma subunits. The alpha subunit becomes inactive when the ligand leaves the
receptor site and the receptors own phosphorylase activity removes a phosphate from the GTP
molecule, therefore leaving GDP bound to the alpha–subunit and the reformation of the 3 subunits.
Figure

The Therapeutic Challenge Essay
DISSEMINATED GERMINOMAS The Therapeutic Challenge INTRODUCTION The prospect of
tumours in the paediatric population is heart wrenching for parents and caregivers alike. The
instinctive need for humans to care and protect their offspring leads to emotions of despair, anguish
and hopelessness. Neurosurgeons are familiar with these emotions, as brain tumours represent the
second most common paediatric tumour(1). Germinomas, even though rare, are unique to the
paediatric population and adequate treatment of these tumors tend to have a good prognosis. In a
few patients, there can be spread of the tumour, usually along the cerebrospinal fluid pathways with
distant metastases being rare(2). Patients with this disseminated disease tend to present a unique
challenge in managing the disease process. CASE A 16 year girl presented to the Accident and
Emergency department of the University Hospital of the West Indies with a history of worsening
headaches, vomiting and drowsiness. She had a history of having a suprasellar lesion resected one
year previously that was diagnosed histologically to be a germinoma. A ventriculoperitoneal shunt
had been placed to treat her postoperative hydrocephalus and she received conformational
radiotherapy post operatively and was during well until the time of presentation. On presentation she
was completely blind, and had no history of fever, seizures or weakness. On examination she had a
Glasgow Coma score of 15 with no motor

Transfer RNA Synthesis Lab Report
Aminoacyl transfer RNA synthetases catalyze the formation of "charged" transfer RNA. This means
the Aminoacyl transfer RNA synthtaseses attach an amino acid to the transfer RNA. A specific
aminoacyl transfer RNA synthestase binds a specific amino acid and a molecule of Adenosine
triphosphate to the active site. The bond is broken between the amino acid and Adeonsine
monophosphate and the Adenosine monophosphate is then released. At the same time, a covalent
bond is formed between the amino acid and the 3' end of the transfer RNA. A specific transfer RNA
has an anticodon that corresponds to the amino acid then binds to the synthetase. The RNA sequence
in the anticodon region, as well as other parts of the transfer RNA molecule, are important ... Show
The first being, the attachment of a given amino acid to a specific transfer RNA establishes the
translation of the genetic code. The genetic code has several important properties, without these
properties life could not exist. When an amino acid is linked to a transfer RNA, it will be assimilated
into a growing peptide chain at a location ordained by the anticodon of the transfer RNA. The
second reason the linkage of an amino acid to a transfer RNA is so important is, the formation of a
peptide bond between amino acids is not thermodynamically favorable. The amino acids need to be
activated for the reaction to continue, once activated they are amino acid esters. These intermediates
have the carboxyl group linked to either the 2′– or the 3′–hydroxyl group of the ribose unit at the 3′
end of tRNA. This is called the aminoacyl–tRNA synthetase. Tyrosyl tRNA synthetase is a dimeric
enzyme, that is comprised of two indistinguishable sub–units. Tyrosyl transfer RNA synthetase
catalyzes the formation of tyrosyl transfer RNA in a two–step reaction. Tyrosine is first activated by
reaction with Adenosine triphosphate. This forms the enzyme bound intermediate, tyrosine
adenylate. Although the enzyme is a dimer, only one molecule of tyrosine is bound per

Cell And Breast Cancers And Colorectal Cancer
An antimetabolite, 5FU is a pyrimidine analog that irreversibly inhibits TS. Thymidine is a
nucleoside and a major component of the DNA and is hence required by cells for proliferation.
Deoxyuridine monophostate (dUMP) upon methylation by TS generates thymidine monophostate
(dTMP). 5FU interrupts the activity of TS and creates a shortage in the levels of dTMP. Thus the
rapidly proliferating cells undergo death due to lack of thymidine nucleoside. The drug has
successful applications in colorectal and breast cancers and is used in various combination therapies
with methotrexate (Maddur et al., 2009). The concentration used for the experiments is 10 µM
Oxaliplatin is an antineoplastic platinum drug. Platinum drugs target DNA synthesis by ... Show
215 cells have high proliferating rates as compared to 253 cells. To generate metformin resistant
cells, 215 and 253 were cultured 4–8 weeks in the presence of 3mM of metformin. Cells were
considered resistant after 3 serial passages in vitro.
For the generation and enrichment of cancer stem cells, PDAC cells at 106 cells/ml concentration
were grown in a serum free Dulbecco's Modified Eagle's Medium (DMEM–F12) complemented
with B–27 and FGF. The cells were seeded in ultra–low attachment flasks. This aids in the
development and the expansion of the PDAC spheres (cancer stem cells). Metformin was added (at
1:1000 dilution) in case of culturing metformin resistant spheres. All the cells were contained in a
T–75 flask and incubated at 37°C.
The regular cancer cells were seeded at 106 cells/ml concentration in RPMI containing 10% (v/v)
FBS. The cells were cultured in regular attachment T–75 flasks. Metformin at 1:1000 dilutions was
added in case of culturing metformin resistant PDAC cells.
After incubating for 7 days, spheres increase in size and range from 40–120 µm. For serial
passaging, spheres were harvested using 40 µm cell strainers (filters), trypsinised to dissociate into
single cells and then grown again for 4 days in the same conditions.
Growth media was aspirated and the flask was washed with PBS. The cells were trypsinised and
kept in an incubator at 37°C until the cells

Essay On Silico Analysis Of FLT3 Gene
In silico analysis of single nucleotide polymorphism (SNP) in human FLT3 gene
ABSTRACT
FLT3 is a member of extracellular receptors on hematopoietic precursors and belongs to the class 3
tyrosine kinase receptor. The FLT3 receptor is receptor gene encodes a 993–amino acid protein. Its
location on the chromosome is 13q12. FLT3 receptor ligand , FL–like tyrosine kinase poisoning 3
receptor interaction works to maintain, spread and differentiate from the normal hematopoietic stem.
The damaging mutations for FLT3 gene have not been predicted in silico. The current work was
done to determine the harmful single nucleotide polymorphisms in FLT3 gene of Homo sapiens by
Several bioinformatics tools to identify functional SNPs, predict damaging ... Show more content on
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In addition, FMS–like tyrosine kinase–3 receptor expressed in most acute lymphoblastic leukemia
cells and acute myeloid leukemia(Drexler, Meyer et al. 1999). FMS–like tyrosine kinase–3 receptor
mutations are identified in about 30% of the adult with acute myeloid leukemia, and leukocytosis
and poor prognosis(Rasko, Metcalf et al. 1995, Kiyoi and Naoe 2002, D Kottaridis, Gale et al. 2003,
Levis and Small 2003, Stirewalt and Radich 2003, Naoe and Kiyoi 2004, Kiyoi, Yanada et al. 2005).
In normal bone marrow, expression appears to be restricted to early progenitors, includingCD34_
cells with high levels of expression of CD117 (c–KIT)(Rasko, Metcalf et al. 1995, Drexler 1996,
Kiyoi, Yanada et al. 2005). FMS–like tyrosine kinase–3 receptor is also expressed at high levels in a
spectrum of hematologic malignancies including 70% to 100% of myelogenous leukemia of all
French–American British subtypes–precursor cell acute lymphoblastic leukemia , a fraction of T–
cell acute lymphoblastic leukemia, and chronic myelogenous leukemia in lymphoid blast
crisis(Mackarehtschian, Hardin et al. 1995, Kiyoi, Yanada et al. 2005).
Targeted disruption of FMS–like tyrosine kinase–3 receptor in healthy adult mice with normal
mature hematopoietic populations(Savvides, Boone et al. 2000). However, there are deficiencies in
primitive B–lymphoid progenitors, and bone marrow transplantation experiments that show reduced
ability of stem cells lacking FMS–like tyrosine kinase–3

Philadelphia Chromosome And Leukemia Essay
Essay 88: The Philadelphia Chromosome and Leukemia The so called Philadelphia chromosome is
an abnormal chromosomal structure present in most cases of chronic myelogenous leukemia (CML)
and to a lesser extent in other types of leukemia, most notably acute lymphocytic leukemia (ALL).
The origin of the term Philadelphia chromosome simply reflects the fact that a research team first
identified this abnormality in a blood sample from a leukemia patient in Philadelphia, PA.
CML vs. Acute Leukemias Unlike acute forms of leukemia, in which the cardinal manifestations
(fever, weight loss, and fatigue) appear abruptly, patients with CML may be asymptomatic for
months or even years prior to diagnosis. Even after diagnosis, many patients with chronic forms of
leukemia survive 5–10 years or longer. In approximately 90% of CML patients an abnormal
structure known as the Philadelphia chromosome results from an event known as a chromosomal
translocation. ... Show more content on Helpwriting.net ...
In CML, a chromosomal translocation occurs between chromosomes 9 and 22. Geneticists
abbreviate this event t9:22. The result of this t9:22 translocation is the juxtaposition of the c–abl
tyrosine kinase gene on chromosome 9 with the bcr (breakpoint cluster region) on chromosome 22.
The product is an abnormal fusion gene that encodes a constitutively active tyrosine kinase called
bcr–abl. The bcr–abl protein is a perpetually active version of a cell proliferation signal. The normal
versions of these intracellular tyrosine kinases are generally inactivated unless the cell is responding
to growth factors or cytokines that promote cell proliferation. The bcr–abl protein is a different
story. It acts like a broken record, continuously telling the cell to copy its DNA and undergo cell
division. Consequently, lymphocytes that undergo the t9:22 translocation begin to proliferate out of

Spleen Tyrosinse
Spleen tyrosine kinase (SYK) is a cytoplasmic non–receptor tyrosine kinase that has been shown to
be involved in intracellular signaling pathways of a number of diverse cell types. Structurally, SYK
is a 72k Da protein with two SRC homology 2 domains and a kinase domain. It has a well–
documented and crucial role in intracellular signaling of adaptive immune cells via immunoreceptor
tyrosine–based activation motifs (ITAMs) of the classical immunoreceptors; B cell receptors, T cell
receptors and Fc receptors. Activation of these receptors leads to the phosphorylation of the ITAMs'
cytoplasmic tyrosine residues resulting in the recruitment and activation of SYK. For activation,
both of SYK's SH2 domains needs to bind to the phosphorylated ITAMs of the receptor, or
phosphorylation can occur at a tyrosine residue in either of the interdomains. This initial
phosphorylation leads to the autophosphorylation of other tyrosine residues in the interdomains or
the kinase domain, resulting in ITAM release and sustained activation.
Following ITAM activation, SYK has been shown to complex with several different intermediate
molecules. This results in the triggering of varying responses including phagocytosis, Ca2+
signaling, cytoskeletal rearrangement, reactive oxygen species (ROS) production, and protein ...
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These PRRs include hemITAM containing C–type lectins resulting in ROS production,
phagocytosis, and gene transcription. SYK has been shown to activate the ERK signaling cascade
and activate NF– κB resulting in proinflammatory responses. This includes the SYK dependent and
NF– κB mediated production of pro–IL–1β and the its proteolytic processing by Caspase 1 in
inflammasomes, a multiprotein complex. The inflammasome activation is also regulated by the SYK
dependent activation of nod–like receptor family pyrin domain–containing 3 (NLRP3) reported in
antifungal immune

Acute Lymphoblastic Leukemia
Acute lymphoblastic leukemia(ALL), also known as lymphoblastic leukemia/lymphoma in the
WHO classification, is a malignant expansion of immature lymphoid cells that results from multi–
step genetic changes in a single lymphoid progenitor cell. Its incidence peaks between the ages of 2
and 4 years(1(.
Acute lymphoblastic leukemia (ALL) is the most common malignancy in children (2). ALL causes
77% of children leukemia, and acute myeloblastic leukemia (AML) counts for 11% (3). ALL is
categorized based on cytogenetic and molecular criteria into a few subgroups for diagnosis,
prognosis and treatment (4–6).
There is not any comprehensive information available in Iran about the prevalence of leukemia;
however research indicates a high prevalence (7). Research showed that the prevalence of leukemia
is 16.2% in Iran, which is a higher prevalence compared with skin, lung and breast cancers (8).
Acquired genetic changes that are likely to contribute to development of ALL include the
dysregulation ... Show more content on Helpwriting.net ...
Two different forms are identified for ROR1 (13). One form lack all the out of cellular domains,
which is called shortened or truncated– ROR1 (t– ROR1) (13). The second form lake the intra–
cellular, and transmembrane domains. However most of studies have been performed on the long
form (13). Some studies indicated that the intra–cellular domain lacks biologic activity, while others
showed its vital role in transforming signal (11).
Many functions have been described for ROR; they are involved in cell polarity and tumor like
behavior like migration and invasion (14, 15). The increased expression of ROR1 had been reported
in acute and chronic lymphoblastic leukemia (16–18) and mantle cell lymphoma (19). Though the
high expression of ROR2 is reported in osteosarcoma (15) and renal cell carcinoma (20). ROR1 also
had been known as a diagnostic marker in chronic lymphoblastic leukemia (CLL)

The JAK/STAT Pathway
A) Post–translational modifications (PTMs) are the addition of biochemical molecules to proteins
after translation in order to modulate intracellular mechanisms1. PTM modulation is only possible
through proteins called readers, writers, and erasers1. Readers are proteins (most likely protein
domans) that bind to PTMs, writers are proteins (most likely enzymes) add PTMs to other proteins
or itself, and erasers (again, most likely enzymes) remove PTMs off other proteins or itself1. One
example of a signalling pathway modulated by PTMs is the JAK/STAT pathway2,3. This pathway is
mediated by a very common PTM in mammalian cells – phosphoptyrosines2. The JAK/STAT
pathway is involved in initiating gene transcription leading to cell proliferation, differentiation, and
apoptosis2. ... Show more content on Helpwriting.net ...
This signaling cascade starts with an extracellular ligand (most likely a growth factor or cytokine)
binding to JAK receptors which causes dimerization3. The JAK receptor monomers are bound to
inactive JAK (Janus kinase which is a tyrosine kinase therefore, it only phosphorylates tyrosine
residues) but when dimerized JAK is activated and trans–phosphorylates the receptor which leads to
protein recruitment2,3. This is an example of a writer protein (JAK) add a PTM (phosphate) onto
another protein (JAK receptor) and as a result, moves the pathway forward by recruiting other
proteins. JAK also phosphorylates the recruited proteins including a transcription factor called
STAT3. Once active, STAT dimerizes with another activated STAT protein then enters the nucleus3.
Dimerization occurs via the SH2 (Src Homology 2) domain which can recognize and bind to
phosphotyrosines3. This is an example of a reader protein domain (SH2) recognizing and binding to
a PTM (phosphate) on another protein (STAT) and as a result, moves the pathway forward by
causing dimerization. Then the dimer binds to specific gene elements to influences

BRCA2 And Breast Cancer
BRCA 2 INFORMATION
BRCA1 and BRCA2 share a lot of similarities. BRCA2 is also a cause for hereditary breast cancer
and is also responsible for tumor suppressor proteins. BRCA2 is located on chromosome thirteen.
BRCA2 can repair breaks within DNA, such as DSBs and can regulate cytokinesis. Cytokinesis is a
process during cell division where the cytoplasm, the fluid inside the cells that is enclosed by the
cell membrane, of one parent cells splits into two daughter cells. BRCA2 mutations are more
commonly found in people of Jewish and French–Canadian backgrounds.
MUTATIONS THAT LEAD TO BREAST CANCER THAT DON'T INVOLVE BRCA
Mutations in the BRCA1 and BRCA2 genes are the only cause for breast cancer. A mutation in the
human epidermal growth

Mir-193a-5p Essay
In this article, we aimed to research the diagnostic value of peripheral blood and tissue miR–193a–
5p. And we also tend to illuminate the underlying molecular modulatory mechanism of miR–193a–
5p in lung cancer. Hereby, we comprehensively retrieve the eligible microarrays and performed
meta–analysis to explore the clinical diagnostic significance. Then we adopted bioinformatics
analysis to lucubrate the potential molecular mechanism. We collected predicted and validated target
genes of miR–193a–5p and further acquired the overlapping genes. GO, KEGG and PPI network
analysis were further performed for the overlapping genes. We hope what we obtained might offer
references for future researches.
Up to now, there is no study illuminating the ... Show more content on Helpwriting.net ...
Therefore, it is worthy to notice such special expression difference of miR–193a–5p in lung cancer.
The reasons causing such inverse peripheral blood and tissue miR–193a–5p expression remain
unclear yet. It still needs additional larger samples studies to validate and provide exact explanation.
Still, peripheral blood and tissue miR–193a–5p could provide a certain reference value for clinical
lung cancer diagnosis.
Since miR–193a–5p exerts its regulative functions through specifically targeting certain target
genes, we here collected the possible targets of miR–193a–5p and further uncover the underlying
regulatory pathways. We found that the top enriched items in BP, CC and MF were regulation of
neuron apoptosis; organelle outer membrane and tubulin–tyrosine ligase activity, respectively.
Mitochondria is the basic and important organelle in most of the eukaryocyte. Mitochondria outer
membrane permeabilization has been reported to be involved in cancer and be a promising
therapeutic target. [26–27] Thereby, miR–193a–5p might be also involved in lung cancer through
similar approach. Recently, Tubulin tyrosine ligase widespread loss has been found during the tumor
growth, which suggests tubulin tyrosine ligase activity may be involved in the regulation of tumor
cells [28]. As a result, tubulin tyrosine ligase activity might be related miR–193a–5p, which might
exert effects in lung cancer. Nevertheless, more studies are needed in the future. In KEGG

Activation of Protein Kinases by Means of Stochastic...
Short overview The current technology is based on protein kinase activation by means of stochastic
resonance mediated through pulsed electrical fields of very low signal strength. The mode of action
reveals how even small pulsed electrical fields can have a major influence on cellular function and
physiological consequences. It is well known that biological sensory systems transform analog
quantities such us pressure, temperature, electric fields (E–fields) etc. into trains of information. All
the features of systems exhibiting stochastic resonance were found to be present in cell signaling
systems which are intrinsically noisy, nonlinear threshold systems. We observed the effects of
pulsed electrical fields of intensity near that of ... Show more content on Helpwriting.net ...
We visualize the mechanism as that of a working Brownian ratchet where transitions into a different
activated state can be favored. We observed that changing frequencies of E–fields causes enhanced
activation from 2 to 100 Hz and that higher frequencies cause reduced activation. Thus the system
fulfills the requirements of a stochastic resonance system with a '∩' shaped curve. Introduction:
Stochastic resonance (SR) occurs in a system with a threshold or barrier such as in a protein when a
correct input of information transfer (changes in specific electrical fields effecting charged particles
and signal–to–noise ratio) is maximized in the presence of a specific non–zero level of stochastic
input noise (such as randomly fluctuating electrical fields) thereby lowering the response threshold.
The system will then resonate at a particular noise level. Thus, stochastic resonance is a term which
describes that one time scale is established by the period of the external stimulus and the other by
the position to position switching rate induced by the stochastic process or noise. By this effect a
synchronization of a nonlinear system to a weak periodic signal can be enhanced by the presence of
random fluctuations. A weak periodic signal is one which cannot by itself produce switchin g
between positions in protein subunits. In such systems the essence of the signal enhancing effect of
SR can be understood in following way: In the absence of stimuli there are few and random

Essay On Dopamine
Taking a look inside of the basal ganglia specifically within the substantia nigra and ventral
tegmental space, the production of dopamine occurs. Dopamine is a neurotransmitter that effects
provide both excitatory and inhibitory responses with axon networks. Within the substantia nigra
amino acids known as tyrosine reacts with tyrosine hydroxylase in order to produce L–Dopa which
is then reacted with L–Dopa decarboxylase in order to finally produce dopamine. Once produced
dopamine has been found responsible for initiating movement, helpful in attention and learning.
Therefore, the synthesis of dopamine occurs within the substantia nigra, but this is only where the
cell bodies are located. The neurons project onto the ventral tegmental area ... Show more content on
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Unfortunately, when this hyperactivity occurs and Dopamine continuously binds to D2 receptors
thendopamine acts to cause schizophrenic type behaviors. It has been thought that such a
hyperactivity, which can cause hallucination are the primary reason for schizophrenia but in recent
studies there may be other factors that cause schizophrenia. These factors are still unclear. However,
for now tyrosine an amino acid is converted into L–Dopa which then is converted into dopamine.
Dopamine is then released into a synapse which can influence an individuals thought processes
specifically it can cause one to experience severe hallucinations a and delusions of people and
objects that do not exist ultimately linking dopamine and schizophrenia. However it should be
known that the "Dopamine Hypothesis of Schizophrenia" is currently being disputed but for now the
scientific community believes that schizophrenia may be caused by hyperactivity of dopamine likely
due to the inability to inactivate and reuptake dopamine in the synapse and repeated binding to D2

Experiment Results Predict Questions: Metabolic Rate Of Rat
Experiment Results Predict Question: Predict Question 1: Make a prediction about the basal
metabolic rate (BMR) of the remaining rats compared with the BMR of the normal rat you just
measured. Your answer : b. The hypophysectomized (Hypox) rat's BMR will be higher than the
normal rat's BMR. Predict Question 2: What do you think will happen after you inject thyroxine into
the three rats? Your answer : c. The hypophysectomized rat will become hyperthryoidic and develop
a goiter. Predict Question 3: What do you think will happen after you inject TSH into the three rats?
Your answer : a. The normal rat will become hyperthyroidic and develop a goiter. Predict Question
4: Propylthiouracil (PTU) is a drug that inhibits the production of thyroxine ... Show more content
on Helpwriting.net ...
Now that you have calculated the oxygen consumption per hour for this rat, you can calculate the
metabolic rate per kilogram of body weight with the following equation (note that you need to
convert the weight data from grams to kilograms to use this equation). Metabolic rate = (ml
O2/hr)/(weight in kg) = ml O2/kg/hr Enter the metabolic rate in the field below and then click
Submit to display your results in the grid.
02/03/13
page 1
You answered: 1536.6 ml O2/kg/hr 3h. Calculate the oxygen consumption per hour for this rat
using the following equation. ml O2 consumed/1 minute x 60 minutes/hour = ml O2/hour Enter the
oxygen consumption per hour in the field below and then click Submit to display your results in the
grid. You answered: 384 ml O2/hr 3i. Now that you have calculated the oxygen consumption per
hour for this rat, you can calculate the metabolic rate per kilogram of body weight with the
following equation (note that you need to convert the weight data from grams to kilograms to use
this equation). Metabolic rate = (ml O2/hr)/(weight in kg) = ml O2/kg/hr Enter the metabolic rate in
the field below and then click Submit to display your results in the grid. You answered: 1573.8 ml
O2/kg/hr Judging from their basal metabolic rates (an indicator of thyroid function), categorize the
rats as hypothyroid (low thyroid levels; BMR below 1600), euthyroid ("good," or normal, thyroid
levels; BMR = 1650–1750), or hyperthryoid (high thyroid

Radiotherapy's Role In Breast Cancer
Cancer is the main cause of growing mortality all over the world , it is expected that there will be
19.3 million new cancer cases yearly projected for 2025 [1]. Yearly over a million cases of death
worldwide is due to breast cancer [2]. Both environmental and genetic factors play an important role
in cancer susceptibility [3, 4]. The cumulative effects of individual (non–carcinogenic) chemicals
acting on different pathways could produce carcinogenic synergies [5]. Current treatments for
cancer include surgery, hormonal therapy, radiotherapy and targeted therapies. Molecular target
therapies have a great role in the treatment of cancer, they include inhibitors of the tyrosine kinase
enzyme BCR–ABL, inhibitors of vascular endothelial growth factor receptor (VEGFR) and
epidermal growth factor receptor (EGFR) inhibitors ... Show more content on Helpwriting.net ...
Recently, multitherapy are used as it is inexpensive and to avoid causing resistance. [7]. Receptor
tyrosine kinases play a great role in signal transduction pathways that regulate cell division. One of
the most important growth factor receptor kinases that have been identified is epidermal growth
factor receptor (EGFR) [8, 9]. Its role in breast cancer, [10] lung cancer [11–13] and in hormone–
refractory prostate cancer [14] has been studied. EGFR PTK inhibitors were used in the treatment of
malignant epithelial diseases. In cancer clinical trials EGFR kinase inhibitors were evaluated [15–
29]. Some quinazoline derivatives show potent inhibition of epidermal growth factor receptor [15–
25]. Some tyrosine kinase inhibitors (TKIs) were approved by FDA for cancer treatment

Insulin Research Paper
Insulin is a major metabolism regulating hormone. It is secreted by beta cells of the pancreas. Its
function is to counter the concerted actions of a number of hyperglycemiagenerating hormones and
to maintain low blood glucose levels. Insulin also stimulates lipogenesis, diminishes lipolysis, and
increases amino acid transport into cells. Insulin is a member of a family of structurally and
functionally similar molecules that includes the insulinlike growth factors, IGF1 and IGF2, and
relaxin. Insulin modulates transcription and stimulates protein translocation, cell growth, DNA
synthesis, and cell replication, effects that it holds in common with the insulinlike growth factors
and relaxin.
Insulin secretion from beta cells is principally regulated ... Show more content on Helpwriting.net ...
Each IRS molecule has four sequences that are approximately TyrXXMet.
TyrXXMet
is a recurring sequence that is responsible for the IRS molecules' affinity of the receptor tyrosine
kinase. IRS molecules activate when the tyrosine kinase phosphorylates these Tyrosines. An
example is SH2 is a domain present in many signaltransduction proteins. SH2 domains are host to
specific phosphotyrosine sequences, such as those in activated IRS proteins. This is a specific
process, so each SH2 domain has a binding preference to an approximate sequence including
phosphotyrosine. A large group of lipid kinases have SH2 domains that are attracted to IRS proteins.
These lipid kinases react at the 3position of inositol in phosphatidylinositol 4,5bisphosphate
(PIP 2 ) and add a phosphoryl group. By attracting the lipid kinases to IRS proteins, the reaction
moves the kinases to PIP 2 located on the membrane where it can phosphorylate them to
phosphatidylinositol
3,4,5trisphosphate
(PIP 3 )
This causes a cascade which activates the protein kinase PDK1, which phosphorylates the protein
kinase Akt, thus activating it as well. Akt is a free moving kinase inside the

Phenylalanine
and white matter tracts. The lack of tyrosine caused by the non–hydrolysis of Phe leads to a defect in
melanin that can be noticed to a skin and hair very clear in patients who have PKU.
There isn't a true explication of how Phe can affect myelinisation of axons, we just know that it is by
an indirect way. A PKU patient with no treatment is going to have less myelin in the cerebral cortex.
Myelin Sheath increase the speed of nerve messages in the brain. So a patient with PKU will
distribute his nervous messages more slowly than a normal person
Today, we don't know the mechanism who permitted this damages in myelinisation in the brain we
just know that it induces neurological damages.
B) Metabolic Pathways
We are now going to the biochimical part of the desease. Phenylalanine exist in a D–isomer and in a
L–isomer but the important isomer for humans in protein synthesis is the L–isomer. Lphenylalanine
... Show more content on Helpwriting.net ...
When phenylalanine is entered in the body, it can be used to make protein or can be removed by an
enzyme (protein) called phenylalanine hydroxylase.
Enzyme phenylalanine hydroxylase convert Phe into other compounds of the body. In persons who
suffer from PKU, phenylalanine can't be converted in tyrosine, like in normal persons. If
phenylalanine isn't transformed into tyrosine, there is an accumulation of phenylalanine in the body
and a deficiency of tyrosine. There are two other metabolic pathways of phenylalanine : the first one
is the transamination of phenylalanine and the othe one is the decarboxylation to phenylpyruvic acid
but those two are minor in the metabiloc pathways of the phenylalanine, the important one is the
transformation of phenylalanine in

Cray Fish Lab
Introduction
Crayfish (Procambarus clarkii) are crustaceans that are similarly related to crabs, lobsters and
shrimps. They live in partly salty water (brackish water), rivers, ponds and are considered omnivores
because they feed on small fishes, plants, detritus, mollusk, and other small invertebrates. Crayfish
have a hard–calcified exoskeleton which is typically made of structural polysaccharide called chitin.
This calcified exoskeleton must shed for the crayfish to grow (Fitzgerald, 2006). Crayfish can
tolerate different conditions related to temperature, salinity and stress. To survive during loss of
water, they migrate to another area where water is available, or they burrow. During this process,
their heart rate and metabolism is constantly ... Show more content on Helpwriting.net ...
Serotonin was the first neurotransmitter used. A stock solution of 1mM serotonin was obtained from
the refrigerator and with blue tip micropipette, 1ml of solution was transferred to the container. The
container with the crayfish was covered for five minutes to allow the neurotransmitter to equilibrate
between the holding water and the animal's hemolymph. The trace was started and the heart rate was
recorded for five to ten minutes. Afterward the trace was stopped and the start and end of the
serotonin heart rate trace was annotated. With the serotonin experiment finished, the holding water
was replaced with 100ml of freshwater crustacean

JAK/STAT Signaling Pathway Essay
Liz, Choi
AP Biology (8th period)
Mrs. Mast
January 4th, 2017
JAK/STAT Signaling Pathway
As people survived in the Earth, they experienced four different seasons: spring, summer, fall, and
winter. Each season have different weather conditions and our body had to adjust
In order to respond to message from environment, The JAK/STAT signaling pathway has three main
components: receptor, JAK, and STAT. The receptor is on the cell surface waiting for a specific
signals or ligands that fit into it. JAK stands for Janus kinase, Janus is the Greek word for god of
transition and kinase is any type of enzymes that phosphorylate, giving energy by adding phosphate
group, any type of proteins. JAK contains JAK tyrosine kinases which are the enzymes that can
convey a phosphate group from adenosine triphosphate (ATP) to another protein. There are four
different types of JAK proteins: Tyk2 (Tyrosine kinase 2), JAK 1, JAK2, and JAK3. STAT stands for
signal transducers and activator of transcription and it carries ... Show more content on
Helpwriting.net ...
There are three main types of negative regulators. The easiest one is protein tyrosine phosphatases
(PTPs). Their activity is opposite to the JAKs activity; SHP–1 carries two SH2 and it binds to
phosphorylated receptors or JAK in order to capacitate dephosphorylation of signaling molecule
instead of phosphorylation. Another example for PTPs is CD45 and it acts as a regulator through a
portion of receptors. The second type is SOCS proteins (suppressors of cytokine signaling). When
activated STATs initiates transcription on SOCS gene region, the SOCS protein will be made and it
will bind to both receptors and JAK in order to turn off the signaling pathway. The last type is PIAS
proteins and it has a structure of Zinc binding domain in center, a carboxyl domain, and preserved
SAP domain located at terminus–N, which related to binding process. PIAS protein binds to
phosphorylated STAT dimer and prevents it from binding with

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