contribution of jak-stat signaling pathways and …

www.wjpps.com │ Vol 10, Issue 7, 2021. │ ISO 9001:2015 Certified Journal │

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Shinde. World Journal of Pharmacy and Pharmaceutical Sciences

CONTRIBUTION OF JAK-STAT SIGNALING PATHWAYS AND

NOVEL APPROACHES IN SITE SPECIFIC DRUG DELIVERY FOR

MALIGNANT TUMOURS: A SYSTEMATIC OVERVIEW

Snehal Gajanan Shinde*

Final year B. Pharmacy of Shree Saraswati Institute of Pharmacy, Tondavali, Kankavali,

Sindhudurg, Maharashtra.

Dr. Babasaheb Ambedkar Technological University, Lonere, Raigad, Maharashtra.

ABSTRACT

Cancer is prevalent cause of mortality around the world. As we know

JAK STAT signaling pathway regulates cellular processes like cell

division, cell death and immune regulation. They also control cell

survival, proliferation, differentiation and hematopoiesis. Aberrated

activation of JAK and STAT signaling pathway promote tumour

growth or tumorigenesis. Dysregulation of this signaling pathway also

cause numerous immune inflammatory diseases. As the JAK and

STAT3 play an important role in the signaling pathway is the target

strategy for intracellular drug development. The therapeutic approaches

like JAK and STAT inhibitor, natural agents including phytochemicals

which exhibit potent anti-cancer activity via various mechanisms are

mentioned in this topic. Based on comprehensive analysis of literature several chemical as

well as phytochemical exerts therapeutic and cancer preventive effect through regulation of

JAK and STAT signaling pathway. Future perspective related to preclinical and clinical

research is necessary to completely comprehend the capability of modulating JAK and STAT

signaling to achieve efficient cancer control and treatment. This topic includes structural

morphology of JAK and STAT domain, regulation signaling pathway of JAK and STAT,

pathological or aberrant signaling of JAK and STAT, effect of mutagen or mutative agent in

the JAK STAT signaling pathway, current approaches in the treatment of malignancy related to

JAK STAT and future strategies which control and prevent malignancy associated with JAK -

STAT signaling pathway.

WORLD JOURNAL OF PHARMACY AND PHARMACEUTICAL SCIENCES

SJIF Impact Factor 7.632

Volume 10, Issue 7, 983-1001 Review Article ISSN 2278 – 4357

*Corresponding Author

Snehal Gajanan Shinde

Final year B. Pharmacy of

Shree Saraswati Institute of

Pharmacy, Tondavali,

Kankavali, Sindhudurg,

Maharashtra.

Article Received on

10 May 2021,

Revised on 30 May 2021,

Accepted on 20 June 2021

DOI: 10.20959/wjpps20217-19389


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KEYWORDS:- Malignancy, JAK-STAT, Signaling pathway, JAK mutation, STAT3

inhibitor, SBDD and computational drug design.

INTRODUCTION

Cancer or malignancy is a significant medical issue which driving mortality throughout the

world.[1] It is an uncontrolled or unscheduled cell multiplication or cell growth at the

particular part of body. Tumors associated with viral or bacterial infection and genetic

mutation are able to influence cancer growth rate.[2] Several risk factors such smoking,

chewing tobacco, alcohol, obesity, chronic inflammation, age, ethnicity and geographical

location will also contribute in development of cancer recent researches suggest the majority

of cancer are brought about by malfunction of numerous protein coded genes, such as anti-

apoptotic Proteins, growth factors, receptor of growth factors and transcript of factors.[3] This

factors also constitute as a target for cancer prevention and treatment .When tumors are

formed, their abnormal cells obtain at least 10 common characteristics that describe the

malignant tumor cell’s complexity, including proliferation, resistance to growth suppressors,

avoidance of programmed cell death (apoptosis), unlimited ability to replicate, growth of fresh

blood vessels, tissue invasion with risk of metastatic growth, genetic instability and mutation

of high frequency, tumor-driven inflammation, altered metabolism, and compromised

immunological surveillance.[4,5] During tumor advancement and malignant conversion,

abnormal cells evade the mechanisms of host defense. Targeting and inhibiting the previously

mentioned characteristics has been perceived as potential approaches to cancer treatment.

Apart from conventional treatment, an additional area of interest among researchers is the

utilization of alternative therapy, particularly using dietary sources to regulate these key

mechanisms.[6] The JAK and STAT are intracellular pathways connect signaling from

extracellular cytokines, hormone and growth factor with the nuclear transcription

machinery.[7] The cascade consists tyrosine kinase, transcriptional factors and different

regulatory proteins.[8]

JAK-STAT signaling control cellular responses, immune responses,

cell proliferation, cell migration, cell survival, cell apoptosis according to signal. These event

play crucial role in various biological functions such as hematopoiesis, immune development,

inflammatory responses, adipogenesis and angiogenesis.[9,10,11] Under normal physiological

conditions JAK STAT pathway is strictly regulated. However, in pathological state the

aberrant regulation of JAK STAT can cause cancer, atherosclerosis, rheumatoid arthritis,

diabetes, etc.[11] Generally increasing JAK mutation promotes STAT activation which

triggers tumorigenesis.[12] The prominence uses of JAK inhibitor mainly in the treatment of


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JAK mutation is one of the important aspect of treatment relief from

malignancy/cancer.[13,14,15,16]

Dysregulation of a protective mechanism or immune checkpoints used by a number of

malignancies to escape from the immune surveillance allowing for cancer development.[17]

This has inspired the idea of boosting the host immune response as an anti-cancer therapy. The

blockade of immune checkpoints such as programmed cell death 1 ligand 1 (PD-L1) and

cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) will remains untreatable.[18,19,20] In

order to expand the area of research of treatable cancers as well as increase the number of

patients that respond to the therapy, novel therapeutic targets and new molecules/strategies

should be urgently identified and developed for immunotherapy appropriate for the clinical

use.[21] The JAK/STAT pathway regulates embryonic development and is involved in the

control of processes such as stem cell maintenance, hematopoiesis and the inflammatory

response. The pathway transduces signals from cytokines, interleukins and growth factors that

act through a number of transmembrane receptor families.[22] These includes two types of

receptors as follows:

1) Type I receptors -

I. Erythropoietin receptor

II. Granulocyte colony stimulating factor (G-CSF)

2) Type II receptors -

I. Type IIa - Granulocyte-macrophage colony-stimulating factor

II. Type IIb - Interleukin-6 and leukemia inhibitory factor

These receptors are associated with inactive kinases called as JAK kinases intracellularly.[98]

Binding of ligand with receptor cause alteration in alignment of receptor associated JAK,

enable phosphorylation of specific tyrosine residues that convert inactive JAK to active

tyrosine kinase.[22] In some cases, STAT can be activated by receptor with intrinsic tyrosine

kinase activity such as epidermal growth factor receptor and platelet derived growth factor

receptor.[22]

JAKs (Janus kinases)

JAK protein-are non-receptor tyrosine kinase that are useful for activation of signaling

mediated by receptor for cytokine, hormone and several growth factor. This receptor includes

four proteins weighing 120-130k Da. This family of receptor includes JAK1, JAK2, JAK3 and

TYK2 with seven defined region of homology called JAK homology domain.[Fig. 1, 10] In


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this domain C terminal contains kinase and pseudo kinase connected to activation loop of

domain essential for JAK activation. The pseudo kinases domain act as catalyst.[23] The FH2

domain mediate JAK associated phosphorylation while N terminal called as FERM involved

in the associated between JAK and cytokine receptor.[23,24]

Figure 1: JAK Domain.[29]

STATs (Signal transducer and activator of transcription proteins)

The STAT family has seven members named as STAT1 toSTAT4, STAT5a STAT5b and

STAT6.This are light in weight approximately 80-100 k Da. The STAT domain contain 7

regions which includes N terminal domain, purple domain, DNA binding domain, SH2 domain

and a transactivation domain at C terminals.[12 Fig. 2] The N terminal is implicated in

STAT dimer-dimer and other protein interaction which is less conserved among Statute spiral

or coiled domain is responsible for protein-protein interaction.[11] The DNA binding domain

defines STAT dimer to recognize 8-10 base pair of DNA element. The SH2 domain is

responsible for specific tyrosine phosphorylated peptide sequences within binding molecule

for intracellular signaling function. The transactivation domain holds two amino acids (tyrosine

and serine) essential for STAT activity so that JAK can promote phosphorylation of tyrosine

which lead to STAT dimerization whereas STAT phosphorylated serine by MAPK (mitogen

activated protein kinases) which enhance transcriptional activity.[12,25] These all domain of

STAT essential for its biological functions to respond extracellular stimuli.

Figure 2: STAT Domain.[29]


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Signaling pathway of JAK/STAT

When external stimuli i.e. cytokine, growth factor binds to cellular membrane which activate

JAK associated receptor after auto phosphorylation of JAK. These triggers conformational

change in structure of JAK which binds to substrate and exert kinase activity.[Fig. 5] JAK

binding site then expose to cytoplasm where STAT recruited their area for phosphorylated

JAK. Due to this reaction single STAT monomer convert into homodimer i

e.STAT1,STAT3,STAT4, and STAT5a STAT5b or heterodimer i e.stat1-stat2 and stat1-

STAT3.[29] These active STAT dimer translocate into nucleus and binds to DNA lead to

activation of their target gene In the non-canonical signaling other tyrosine kinases different

from JAK can activate stat factor including epidermal growth factor (EGF) and platelet

derived growth factor (PDGF)and non- receptor tyrosine kinases (e.g.proto-oncogene tyrosine

kinase Src and Dcr-Abl).[8,11,35,97] STAT also having ability to form a dimer and exert

biological activity in absence of canonical JAK tyrosine phosphorylation. Some studies show

that JAK 2 can enter into nucleus and mediate modification in histone.[12,25]

Figure 3: JAK-STAT Signaling pathway.[99]

Regulation of JAK/STAT

The JAK/STAT pathway is regulated endogenously in tight and precise manner. Since,

dysregulation of JAK/STAT can lead to various pathological disorders including malignancies,

most of JAK/STAT modulators are assessed as interesting therapeutic approaches.[29] Most

common and conventional JAK/STAT modulators is protein tyrosine phosphatases (PTPs)

which negatively regulates JAK/STAT signaling pathway by dephosphorylating the associated

receptors of JAK and JAK itself. Another classical group of JAK/STAT negative modulators


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is protein inhibitors of activated STATs (PIAS). These proteins can inhibit STAT signaling

function directly by inhibiting attachment of STAT with DNA or indirectly inhibiting STAT

dimerization.[26,27] Furthermore, most studied family of negative modulators is suppressor of

cytokines signaling (SOCS) proteins.[28] It is a family of eight members consists SOCS 1-7 and

CIS. All members of this family shows different domain structure consists N-terminal domain,

central Src homology Region include extension of SH2 Sequence that leads to binding of SOCS

to tyrosine phosphorylated residue in JAK associated receptors and a C-terminal domain which

is also known as SOCS box.[30] The SOCS1-3 consists a small kinase inhibitory region (KIR)

near the N-terminal region which inhibits catalytic activity of JAK receptors. These family of

proteins work on base of negative feedback mechanism where activated STATs induce

expression of SOCS which controls STATs transduction signaling.[29] The suppression of

JAK/STAT signaling by SOCS include following mechanism:

Figure 4: JAK-STAT Regulation.[29]

Dysregulation/overactivity of JAK/STAT-

The multifactorial process of tumorigenesis is characterized by cellular failure in sensing and

repairing DNA damage, loss of regulation of cell cycle progression and apoptosis and

expression of aberrant pattern of growth signaling and angiogenesis.[31,32] Numerous studies

have strong evidence that JAK kinases play important role in cancer genesis and

progression.[33,34]

Overactivity or gain in function of JAK, cognate JAK tyrosine kinase or JAK

associate receptor leads to generation of fusion protein or the loss of negative feedback

regulation of JAK signaling which ultimately effect on the STAT signaling results into


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oncogenesis.[35] Recent studies discover that JAK point somatic mutation is a most common

cause for JAK dysregulation in the malignancy related to JAK2 mutation. Other JAK mutations

are associated to hematological malignancy and down syndrome, hence the discovery of potent

drug which avoid JAK proteins mutation is major approach of drug design in malignancy

related to JAK STAT dysregulation.[36,29]

Role of mutations - JAK1 mutation

It plays important role in lymphopoiesis. JAK1 activating mutations found in several lymphoid

neoplasms with highest frequency (7-25%)in T- ALL (T acute lymphoblastic leukemia) but

also in B- ALL and T cell prolymphocytic leukemia. It rarely found in acute myeloid leukemia

(AML).[14] Most of the JAK 1 mutations occurs within pseudo kinase domain. JAK1A634D

mutation in adult T-ALL leads to JAK 1 activation and results into overexpression of JAK 1

receptor. The somatic JAK 1 mutation cause modification in AML since they do not directly

induce cell transformation but modify activation of downstream signaling pathway in response

to external stimuli.[37,38]

JAK2 Mutation

Myeloproliferative disorders (MPD) are the group of chronic clonal malignancies arise from

expansion of matured hematopoietic progenitor cells.[39] These are of two types-

a) Chronic myelogenous leukemia (CML)-CML involved Philadelphia(Ph) chromosome

associated to BCR - ABL fusion oncoprotein.

b) Ph negative MPD Syndrome-These referred as polycythemia vera (PV), essential

thrombocythemia (ET) and idiopathic myelofibrosis (IMF).[40] These are caused due to

hypersensitivity of numerous cytokines. JAK2 single point somatic mutation at

chromosome 9p24, exon14 cause genetic abnormality in stem cell nature affect myeloid

lineage.[41,42]

JAK2V617F mutation effect on B lymphocytes and T lymphocytes will

cause Ph negative MPD's. This results into differentiation of stem cell origin in lymphoid

and myeloid.[43]

JAK3 mutation

JAK3 involved in lymphocytes development and carry out its function after interacting with

interleukin receptor. JAK3 mutation cause lymphoproliferative disorders.[44,45,46] JAK 3

mutation occurs at FERM domain and cause defect in gamma chain of receptor involved in

JAK 3 signaling pathway.[47] JAK3A572V mutation responsible for STAT 5 activation due to


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that pseudo kinase is negatively regulates which results into acute megakaryoblastic leukemia

(AMKL).[29] JAK3A572V and JAK3A573V mutation damage exon12 in JH2 domain will

cause non-Hodgkin lymphoma and natural killer/T-cell lymphoma (NKTCL)due to

overagrresion of natural killer/T lymphocytes.[45,48]

Novel approaches for site specific drug delivery in malignancies - JAK Inhibitors -

In 1996 AG490 JAK inhibitor had ability to treat recurrent B cell leukemia based on

experimental studies.[49] Since then natural components like Curcumin, lavoperidol have been

preclinical examine to inhibit anti-inflammatory pathway.[50] These pathways inhibit STAT3

phosphorylation through decrease production of cytokines after direct bind with JAK.[51,52] The

research says that JAK inhibitor and its development continue with discovery of driver

mutation and myeloproliferative leukemia virus oncogene that produce JAK 2 activation and

cause aberrant JAK STAT signaling.[53,54,55] JAK inhibitors classified into four different groups

depending upon their region of target as follows-

a) Type 1 Inhibitor-They target ATP binding site of JAK in active confirmation of kinase

domain.[56] These compounds are different according to their specificity. Most of JAK

inhibitors target JAK 1, JAK 2 and other kinases like TYK2 and JAK 3. Some of them

can inhibit all JAK (e.g. gandotinib) and less frequently they specifically target JAK 2 (e

g. pacritinib), JAK1(e.g. filgotinib) or JAK 3 (e.g. JANEX 1).[56,57,58] Type1 JAK 2

inhibitors are commonly use in MPN such as myelofibrosis, polycythemia vera, essential

thrombocythemia whereas type 1 JAK inhibitors target JAK 1 and JAK 3 used to treat

inflammation and autoimmune disease.[59,60,61,62,63]

b) Type 2 Inhibitors-Type 2 JAK2 inhibitors have been developed recently in which NVP-

BBT594 was effective in MPN.[64] Type 2 JAK 2 inhibitors are more powerful and

effective than Type 1 inhibitors. They target ATP binding pockets of kinase domain in

inactive conformation.[56]

c) Allosteric inhibitor -In this group of inhibitors there are two types of inhibitor which are

type 3 and type 4. Type 3 inhibitors binds to a site close to ATP binding site (e.g.LS104)

whereas type 4 inhibitors bind to Allosteric site distant from ATP binding site (e.g.

ON044580).[65,66]

since they do not target ATP pockets, they are more specific than Type 1

and type 2. hence this group of inhibitors particularly used in MPN related to JAK

mutation.[56]


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STAT Inhibitors

The main target for STAT inhibitors is STAT3 receptor which is an ideal binding site like

double stranded DNA for intratumoral or intravenous injection.it prevents STAT 3 dimer from

binding to its target by isolating into STAT3.[67,68,69,70] preclinical studies show that

phosphorylation of STAT3 cause due to STAT 3 decoy in neck and head squamous cell

carcinoma. The significant level of phosphorylated STAT3 result in cancer cell apoptosis,

results in lower tumor growth. Currently STAT 3 decoy is studied in patients with neck and

head cancer which is less intrusive and radially assessable with local injection.[6] Direct STAT

3 inhibitors are designed to influence SH2 domain by restricting STAT3 phosphorylation or

dimerization. STAT3 inhibitors such as peptidomymetics act by inhibiting phosphorylation of

STAT3 intracellularly, DNA binding and DNA transcription.[71] Peptidomymetics mainly

associated with monomeric proteins of stat 3 which are non-phosphorylated in nature via pY-

SH2 domain binding to create a complex which results into decrease amount of free non-

phosphorylated STAT3 monomer use in the phosphorylation and denovo activation. These

agents also use to decrease progression of cancer.[71,72,73] For example, nifuroxazide a drug

used to treat diarrhea could effectively use to inhibit JAK2 and TYK2 while it also uses in

decreasing the p-STAT3 level in multiple myeloma. The antimalarial drug named as

pyrimethamine also use as STAT 3 inhibitor and myeloma growth inhibitor to treat

lymphocytic leukemia hence tyrosine and non-tyrosine phosphorylated STAT3 performs a

significant role in cancer cell development and this knowledge can be used to develop a

potential anticancer agent.[74,75]

Phytochemicals inhibiting the JAK STAT Signaling pathway

Several bioactive photocompounds demonstrated that JAK STAT pathway is inhibited by

various mechanism. Phytochemicals can target more than one site of JAK STAT pathway.[6]

These agents can able to block signaling pathway by decreasing level of cytokines or growth

hormones which triggers JAK STAT protein activation. These can also act by stopping JAK

phosphorylation before STAT activation. JAK STAT signaling control can achieve by

inhibiting STAT dimerization and stop translocation of STAT dimer from cytoplasm to

nucleus.[76,77] This results into avoid STAT-DNA binding which directly inhibit JAK STAT

regulated gene transcription. These can be combine with JAK STAT pathway inhibitor such as

SHP (Src Homology 2 (SH2) domain containing protein tyrosine phosphatase). Recent

experiment shows that phytochemicals can specifically block one target site.[78,79]


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Table 1: Examples of phytoconstituents used in malignancies.[6]

Name Mechanism of action Anticancer effect

Curcumin STAT3 inhibition, decrease

gene expression

Lung cancer

T cell leukemia

Indirubin STAT3 inhibition Prostate and breast cancer

Ergosterol peroxide JAK2 inhibition Multiple myeloma

Dihydroartemisinin JAK2 and STAT3 inhibition Head and neck cancer , liver

cancer, colon cancer, tongue

cancer

β- caryophyllene oxide JAK1/2 and STAT3

inhibition

Multiple myeloma, prostate

and breast cancer

Future perspectives regarding to treatment of malignant tumours - Advances in Anti-

tumour therapeutics targeting STAT3 -

STAT3 is an essential for various cellular processes which including cell cycle, cell

proliferation, cell apoptosis and tumorigenesis. Normal cell STAT 3 activation is regulated to

prevent uncontrolled gene regulation while abnormal activation of STAT 3 results into

numerous disease development.[83] It also includes disease like cancer such as brain, lung,

pancreatic, renal, colorectal, endometrial, cervical, ovarian, breast and prostate cancer,

melanoma, glioma, head and neck squamous cell carcinoma, lymphoma and

leukemia.[80,81,82,83] Experimental studies say that STAT 3 inhibition will lead to decrease

growth of tumour and their progression.[84] STAT3 also inhibit synthesis of p53 will reduce

binding of STAT 3 with DNA receptor and decrease the probability of gene mutation. It

significantly reduces tolerance of ovarian cancer cell to stress and damage.[85] Research shows

that STAT3 activate miR-608 which inhibits proliferation, migration of lung cancer cell.[86]

Recently researcher have attempt to inhibit STAT3 signaling pathway as a method of cancer.

They also attempt to identify a small inhibitor molecule that directly bind SH2 domain of

STAT 3 which results into prevention of tyrosine phosphorylation, protein dimerization and

transcription activity.[87,88] Recently structure based drug design and computational docking

techniques are used for identification of smaller molecule. e.g. STA-21(deoxytetrangomycin)

which is an analogue of tetrangomycin (non-peptide small molecule STAT3 inhibitor) was

discovered using SBDD and successfully completed phase1/2 clinical trials. This will

inhibit malignant transformation, tumour cell proliferation, migration and invasion.[89,90]

Other small molecules of STAT 3 activation inhibitor under clinical trials are as follows:


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Table 2: Examples of STAT inhibitors.[96]

Inhibitor Name Mechanism Rx Disease

STA-21 SH2 domain inhibition Psoriasis

Pyrimethamine STAT3 inhibition Lymphocytic leukemia

OPB-51602 SH2 domain inhibition Nasopharyngeal carcinoma

Non-Hodgkin lymphoma

OPB-31121 SH2 domain inhibition Leukemia

Hepatocellular carcinoma Non-

Hodgkin lymphoma

Integrating STAT3 in combination cancer immunotherapy

Immunotherapy is currently most prominent approach in the treatment of cancer. This

therapeutic strategy represents as immune check point blockade (ICB) and chimeric antigen

receptor T-cell (CAR-T), as obtained unprecedented result in patient with previously incurable

cancer.[93,21] ICB shows remarkable effectiveness in Melanoma, lung cancer and renal

cancer.[91,92] The previous preclinical and clinical data says combination cancer

immunotherapy have enhanced therapeutic efficacy and reduce drug resistance compare with

monotherapy.[94,95]

Figure 5: combination cancer immunotherapy.[21]


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CONCLUSION

Cancer is a dangerous health risk for people worldwide. The morbidity and the mortality rates

connected with cancer are alarming, despite the existence of multiple treatment modalities for

patients suffering from this disease. JAK/STAT is a vital signaling pathway implicated in the

proliferation, differentiation, apoptosis, evasion, and survival of neoplastic cells. In addition,

its aberrant activation results in cancer-promoting mechanisms. A great effort has been made

by researchers in the last decade to find and characterize novel JAK and STAT3 inhibitors that

might be clinically used, and, in fact, some of them have already reached clinical evaluation.

However, further work is required to establish to what extent the observed activation of

JAK/STAT signaling is driving disease. This may determine the extent to which inhibition of

the pathway brings therapeutic benefits. The near future should see the transition of drugs

that inhibit JAK/STAT signaling from preclinical models into early phase clinical trials.

Targeting drugs that inhibit JAK/STAT activation to these groups of patients is likely to be

particularly promising.

ACKNOWLEDGEMENT

To the best of my knowledge, the material included in this topic is having original sources

which are appropriately Acknowledged and referred. I would like to express my sincere

gratitude to Mr. Chintan Davande student of shree saraswati institute of pharmacy, tondavli

and all teaching staff for their continous guidance, support and motivation.

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