ESSP V8E1

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Do not miss the new issue of EPSA Newsletter!


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Table of contents

Dear readers,

4 Identifying novel naturallyoccurring chemical scaffolds as potential inhibitors of Poly(ADPribose) polymerase (PARP)

In front of you is the newest EPSA Students’ Scientific Publication of this academic year – Volume 8bEdition 1. For those of you who are not familiar with this project, ESSP allows students to publish their research abstract, improve their writing skils and get feedback by professionals from the European Federation for Pharmaceutical Sciences (EUFEPS) who review each abstract.

6 Synthesis and characterization of chloroquine click derivatives with potential antimalarial activity 8 Overview on Targeted Drug Delivery In Treatment of Brain Tumour 12 Pharmacists And Patients Perceptions Over Deprescribing In Albania 14 Pleiotrophin And Midkine As Biomarkers And Possible Drug Targets In Dementias

I am very happy to present you five abstracts from various fields of pharmaceutical sciences. By reading the abstracts, you can see how amazing research projects are doing students around Europe. It was a great pleasure to collaborate with such talented students who are brave enough to submit their abstracts. Thank you very much, I have learned a lot by reading your abstracts. I want to thank EUFEPS for their collaboration and the hard work they have put into this edition, supporting this project and setting it on a high professional level. Also I would like to thank the EPSA Team especially to the Public Relations Department and the Educational Departmen for the hard work, effort and everything they have done to make this ESSP edition possible and great as it is.

Yours in science,

Ognjen Ivetić, Science Coordinator 2020/2021


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European Pharmaceutical Students’ Association

IDENTIFYING NOVEL NATURALLY-OCCURING CHEMICAL SCAFFOLDS AS POTENTIAL INHIBITORS OF POLY(ADP-RIBOSE) POLYMERASE (PARP) Author: Zrinka Duvnjak, Maria Eznarriaga Gutierrez, Jack Greenhalgh Scientific Coordinator: Dr. Taufiq Rahman - university lecturer, group leader Institution:University of Cambridge, Department of Pharmacology

INTRODUCTION: Introduction: The poly(ADP-ribose) polymerase (PARP) proteins catalyze the polymerization of poly(ADP-ribose) (PAR) and their covalent attachment to proteins (PARylation), and as such play important role in base excision repair, homologous recombination, and nonhomologous end joining. The discovery that loss of PARP (PARP-1 in particular) activity triggers cytotoxicity in cells deficient in homologous recombination (for example, lacking BRCA1/2) has sparked a decade of translational research efforts that culminated in the FDA approval of an oral PARP1 inhibitor - Olaparib for clinical use in patients with ovarian cancer and defective homologous recombination. Historically, nature has always been a rich source of diverse chemical scaffolds, some of which have been used directly as drugs whilst most others serve as hits and leads for further development into modern medicines. AIM: Using published structures of inhibitorbound PARP1, we aimed to identify novel naturally-occurring small molecular scaffolds that could potentially inhibit PARP1. MATERIALS AND METHODS: Structurebased virtual screening of Molport Natural ProductTM library by FREDTM and then rescoring by GOLDTM gave 65 hits which were again rescored using AutoDockVinaTM and LeDockTM docking software. After additional in silico assessment of ADME properties, 9 hits were purchased and subjected to wet screening using In Cell WesternTM. Inhibition of PARP-1 is reflected by decreased levels of PARylation and levels of H202 induced PARylation in A549 cells were measured. Spectrally-distinct infrared dye conjugates were used to quantify PAR (at 680 nm) and PARP-1 (at 800 nm). PARylation signal was normalized to total PARP-1. Positive control was Olaparib (100% inhibition), and negative control was 0,5% DMSO (solvent). RESULTS: 2 out of 9 purchased hits seemed to reduce H2O2-induced PARylation (Caffeic acid phenethyl ester and Psoralidin). Possible

binding models with PARP-1 show the interactions of ligands with 3-4 amino acid residues which are in the interaction with registered PARP inhibitors too. CONCLUSION: Our in silico screening protocol has identified few natural products that appear to be significantly reducing PARylation in wet experimental validation. Future study should involve enzyme kinetic essay to prove impairment of catalytic function of recombinant PARP-1, biophysical assays to prove physical engagement of compounds and target, and further characterisations (selectivity for PARP-1 over PARP-2, effect on PARP trapping etc.).


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What was the biggest challenge whilst carrying out the research and how did you overcome it?

Questions & answers Please, tell us a little bit more about yourself.

The first part of my research was computational chemistry – structure-based screening and docking. There is numerous software for this, and they all work in a different way - one software will prefer partial charges overlapping for a good score (result), other will suggest that you have the best overlapping of the structures when there is a pi-stacking present, etc. Different software will give you different results so I needed to use 4 different software and to look at all the results at the same time to choose which molecules we will buy for wet screening. Additionally, I used 3 different conformations of PARP protein for all the docking. To succeed not to mix up everything I needed to be very organized and careful with naming files and putting them in the right folder. Another thing you should keep in mind is that these software are not flawless – each result I needed to check by looking it in software for visualization.

My name is Zrinka Duvnjak and I’m a fifthyear student from Zagreb, Croatia. You may know me as a former Twinnet Coordinator for Zagreb or a former Pharmaceutical Sciences Coordinator at IPSF. At the moment, I’m an intern at Xellia Pharmaceuticals (R&D), and next semester you can meet me in Helsinki where I’ll be doing my master’s thesis. In my free time, I’m playing modern board games, checking off my list of escape rooms in Zagreb, preparing myself for some running race (or being disappointed when it is canceled a few weeks before the race due to the pandemic), playing volleyball, In your opinion, what is the benefit scratching my world map, playing guitar, or just of joining ESSP and what advice do enjoying life with my friends and family. you have for students undertaking

research in the future? Tell us a bit more about your research Writing for ESSP is a great way of practicing your and its significance. abstracts writing skills because except from the My research has been done at the University of Cambridge during 2,5 months of my summer internship. It is actually a side project of one Ph.D. topic funded by Astra Zeneca. Existing PARP inhibitors showed promising in practice and they are broadening its indications, so why not to try to find a new one, since we will always need new, better and different anti-cancer drugs? Another indicator of importance of this research is that with this work I won the prize for the best poster presentation at the Pharmacology Away Day, University of Cambridge.

feedback you get, you have an opportunity to present yourself and your work to other students from other countries interested in research.


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European Pharmaceutical Students’ Association

SYNTHESIS AND CHARACTERIZATION OF CHLOROQUINE CLICK DERIVATIVES WITH POTENTIAL ANTIMALARIAL ACTIVITY Author: Marko Dužević Scientific Coordinator: doc. dr. sc. Ivana Perković Institution: Faculty of Pharmacy and Biochemistry at University of Zagreb

Malaria is one of the most prevalent parasitic diseases in the world, ranked by the WHO in 2016 as the 6th most common cause of death in low-developed countries. Although positive progress has been made in its treatment and prevention over the past decade, there is still a great need for the development of new antimalarials due to the emergence and spread of strains resistant to conventional drugs. Until the advent of newer molecules, in the past, due to its good safety profile, efficacy, and cost-effective synthesis, chloroquine was used very often and is still used today as a model drug for the development of new alternative antimalarials. To enhance its antiplasmodial activity on resistant strains, four new quinoline-1H-1,2,3-triazole hybrids with harmine, an alkaloid of plant origin that also has antimalarial activity, were synthesized using method of copper-catalysed azide–alkyne cycloaddition. The reactions of organic azides and alkynes catalysed by copper species represent the prototypical examples of click chemistry. This paper presents the procedures for their synthesis and the results of structural characterization by analytical and spectroscopic techniques. All synthesized compounds have shown the potential for good oral bioavailability, and further research, which goes beyond the scope of this paper, will examine their antiparasitic effects on species of the genus Plasmodium.

Newly synthesised molecules presented in the paper


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Questions & answers Please, tell us a little bit more about yourself.

conventional analytical techniques such as nuclear magnetic resonance, IR, and mass spectroscopy. In the scientific paper are adduced methods and materials used for their synthesis. Furthermore, it contains ADME properties prediction carried out using SwissADME online tool. This research could be important if further in vitro assays would prove compounds’ antimalarial activity. If that happens, one of these molecules could be used as a lead compound and its optimization could lead to the invention of new antimalarial for Plasmodium strains resistant to conventional therapy.

I was born on March 29, 1998, in the capital of Croatia Zagreb. In 2016 I enrolled at the Faculty of Pharmacy and Biochemistry at the University of Zagreb and now I am in my fifth-year. Immediately at the beginning of my studies, I have become a member of the Croatian Pharmaceutical Students’ Association (CPSA), within which I regularly participate in activities and events related to the pharmaceutical profession. In the academic year 2018/19, I was elected Secretary of the Association for a term of one year. In the same year, I had become a demonstrator at the Department of Organic Chemistry and one of the organizers of the CPSA’s National Congress. As an educational coordinator, I was responsible for choosing lectures’ topics and finding lecturers. In my fourth year, I decided to make a run for a member of the Student Union of the University of Zagreb to represent the students, fighting for their rights, and raising the students’ standard. I was elected to this position for a term of 2 years. In the same year, I joined the preparation of this scientific paper because of my interest in the development and synthesis of new drugs. The main motive for joining the research group at the Department of Medicinal Chemistry on my home faculty was a desire to acquire new knowledge and skills in the field of synthetic pharmaceutical chemistry and to start a scientific career. For this paper, I was awarded the Rector’s Award in 2020.

What was the biggest challenge whilst carrying out the research and how did you overcome it?

Tell us a bit more about your research and its significance.

For me, the biggest benefit of joining ESSP is the possibility of this platform to bring your work to a wider audience. By sharing our knowledge we enrich the community and make knowledge accessible to everyone. Also, by publishing our work we help others solve or avoid problems that we were struggling with during our research. Just like any other passion, research also demands huge dedication and effort, but the final results and joy you feel are something that one lives for.

My research was conducted in the Department of Medicinal Chemistry and was part of the Department’s project entitled “Harmine derivatives as potential antimalarials”. It was planned for me to synthesize seven new compounds, but, due to lockdown in March, research lasted only 5 months and it encompassed synthesis and characterization of only four imaginary compounds. Structures of all the newly-synthesized molecules were confirmed using

The biggest challenge was to perform faculty duties parallelly throughout the duration of the research. Since my lectures, seminars, and laboratory exercises were obligatory, I couldn’t skip teaching to have more time for synthesis. Unfortunately, I wasn’t able to overcome this problem, so I just got used to it. Ten hours at the faculty was my everyday life and the only time when I could do quality learning was on weekends. Another problem was the fact that you can’t leave the laboratory until you finish synthesis or previously started the compound purification process. The workday ends when you pack your final product for NMR analysis. Fortunately, one of the assistants and I had an agreement: some days he was finalizing my compounds and the other days it was my turn to help him. Although this research was a very stressful period for me, I can tell that it was also a wonderful period because I learned incredibly much in those 5 months.

In your opinion, what is the benefit of joining ESSP and what advice do you have for students undertaking research in the future?


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European Pharmaceutical Students’ Association

OVERVIEW ON TARGETED DRUG DELIVERY IN TREATMENT OF BRAIN TUMOR KONSTANTINOS PEFANIS, Dr, AHMED FAHEEM, University of Sunderland

INTRODUCTION: Nowadays, treatment of malignant brain tumors remains a challenge. Pharmacological interventions are inhibited by the Blood Brain Barrier (BBB), which has brain endothelial cells that line the cerebral microvasculature, that act as a guardian. Targeted drug delivery method seems positive for overcoming limitations of patient compliance, the BBB and side effects; however, effectiveness relies not only on the therapeutic effect but also on early detection of tumors. Conjugation of nanoparticles with ligands of specific tumor biomarkers is a potent therapeutic approach to deal effectively with brain cancer. AIMS AND OBJECTIVES: Currently, treatment for brain cancer, especially glioblastoma multiforme, focuses on chemotherapy, radiation and surgery providing limited survival rates and numerous adverse effects. Research is currently focused on targeted delivery drug methods that are going to provide patient compliance, less adverse reactions and prolonged release medication. This review will evaluate the effectiveness of controlled targeted delivery of anticancer therapy to glioblastoma through the BBB using nanoparticles. Moreover, it will evaluate the potential use of imaging agents as a successful diagnostic tool for detecting brain tumors in early stage, increasing the possibilities for higher survival rates. Furthermore, each study will investigate different type of nanoparticles and ligands in combination with desirable drugs or peptides. Ligands selected due to their overexpression in carcinogenic cells, increasing the specificity.

CONCLUSION: Most of the evidence successfully proved the beneficial clinical effect of drugs and targeting ligands when they were attached to multifunctional nanoparticles for accurate detection. However, an absolute comparison between each ligand and nanoparticles was not applicable due to different conditions and unique characteristics such as morphology, zeta potential, size and composition. Evidently, results indicated that drugs should be preferable hydrophobic, unionised and the nanoparticles should be characterised by highly controlled size, appropriate surface properties and chemical functionaliMETHODS: In this review, 8 research articles sation. and studies were included from the databases ScienceDirect, PubMed and Medline by following the PRISMA guidelines. Studies were assessed and the inclusion or exclusion of them followed criteria and standards. In this review, in vivo and in vitro glioma model, such as transfected cells U87 and mice’s brains, were used while no human trials were included.


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What was the biggest challenge whilst carrying out the research and how did you overcome that?

The biggest challenge I faced during my research project was time. The project was carrying out during the third year of pharmacy simultaneously with the lectures and the seminars. I had to find the balance between the studying time and the research time. Planning early and organising effectively were the keys Please, tell us a little bit more about to success.

Questions & answers

yourself.

My name is Konstantinos Pefanis and I am currently a student on the 4th year Master of Pharmacy in University of Sunderland. I have already graduated as an Optometrist from Technological Education Institute of Athens. As a professional, I worked in a community pharmacy for over 5 years as a dispenser.

In your opinion, what is the benefit of joining ESSP and what advice do you have for students undertaking research in the future?

Joining ESPA was extremely useful, as a pharmacy student i have ample accessibility in research papers and events. Definitely is an opportunity that nobody should miss out as it Tell us a bit more about your research is pushing the profession to the right direction. and its significance. It is great opportinuty to meet other colleagues My research is investigating the effectiveness from all over the world and exchange opinions of targeted drug delivery in brain tumors, and knowledge. especially glioblastoma. Glioblastoma has limitations in phramcological approach as well as in early detection. Being able to prolong and expand the quality of life, it will be clearly a unique benefit for people’s lives. Tumor cells in brain could associate with numerous complications being obstacle in appropiarte treatment. Ideally, the cytotoxic drug needs to be delivery on the site of action causing the minimum toxicity, not affecting the healthy cells and shrink completely the tumor cells. The discovery and development of nanoparticles has given the ability to target cancer cells, minimising the damage in the healthy cells while is reducing the toxic effects, too. Different types of nanoparticles could enhance different characteristics providing a wide range of treatments or detective methods.


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European Pharmaceutical Students’ Association


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European Pharmaceutical Students’ Association

PHARMACIST’S AND PATIENT’S PERCEPTIONS OVER DESCRIBING IN ALBANIA Msc. Ledi Shehi, Dr. Shk. Klejda Harasani, Msc. Jonida Talanaj University of Medicine Tirana, Faculty of Medicine, Department of Pharmacy Farmaci.al, Tirana, Albania

INTRODUCTION: Polypharmacy is defined as the use of five or more medications simultaneously by one patient, however inappropriate polypharmacy represents one of the current potentially avoidable problems of the healthcare system. A therapy review resulting in the reduction of drugs’ number and/or dose, known as deprescribing, can be performed when drugs are unnecessary, harmful or excessive. OBJECTIVE: To assess the perception of Albanian pharmacists and patients on therapy review, polypharmacy and reduction of unnecessary medications.

CONCLUSION: Based on our results, pharmacists are willing to help reduce medications but there are many obstacles related to perceived lack of competence and patients´ expectations. On the other hand, patients have a positive attitude towards deprescribing when doctors are involved. Specific training on deprescribing for pharmacists, increasing awareness on the adverse reactions caused by superfluous medications, and close collaboration with doctors and patients are recommended.

METHODOLOGY: Firstly, we carried out a literature review on the topic focusing on studies reporting strategies for drug therapy review by health professionals, including pharmacists, aiming to reduce redundant medication, as well as the obstacles and opportunities associated with the process of deprescribing. Two questionnaires were designed and distributed online to registered KEY WORDS: therapy review, deprescribing, pharmacists and patients regarding their polypharmacy, pharmacists, patients perception and evaluation of drug therapy review and deprescribing. RESULTS: Pharmacists and patients showed to be generally aware of the problem of polypharmacy. Among 64 pharmacists who participated in the study, 90.6 % of them reported that many prescribed medications are not necessary. Out of 100 patients who participated, 73.1 % of them opine that it is necessary to reduce the number of prescribed drugs. Most patients expressed strong preference indicating doctors as health professionals who should perform deprescribing and therapy review. Just 8.3 % of patients thought they were capable of doing it themselves and only 3.6 % of them would trust a pharmacist to conduct this process.


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taking a high number of drugs, some of them potentially unnecessary. A specific objective is to measure patients´ and pharmacists´ perception regarding deprescribing and the role of healthcare professionals.

Questions & answers

What was the biggest challenge whilst carrying out the research and how did you overcome that?

Please, tell us a little bit more about The research was conducted during the Covid-19 pandemic while Albania was in yourself. My name is Ledi Shehi and I am 25 years old. I have recently graduated from the University of Medicine, Tirana (Albania) with a Masters degree in Pharmacy and I currently work as a licensed community pharmacist. During my university years I studied different foreign languages and now I can speak fluently English, French, Italian, Spanish while also learning German. I am really interested in developing my professional career and in order to achieve that I am following different online courses and also carrying out pharmacy-related research. My future goal is to get a postgraduate degree in pharmaceutical management. People describe me as hard-working, calm and precise. Additionally, I would say that I am really eager to expand my knowledge and become more accomplished in my field.

Tell us a bit more about your research and its significance.

I carried out this research study in collaboration with my professor Ph.D. Klejda Harasani and pharmacy student Jonida Talanaj. I chose this particular topic because it is timely and has a strong impact in patients´ treatment and well-being. As a community pharmacist I am in everyday contact with patients which often report negative feedback related to polypharmacy and sometimes experience drug adverse effects, drug interactions and high financial burden. The aim of our research is to explore the concept and process of deprescribing, the reduction of the number and/ or dose of one or more drugs of the therapeutic regimen, especially among older patients

lockdown, therefore we had to communicate remotely about the study and were limited in its implementation. It was also difficult because it felt innapropriate to ask pharmacy patients to fill out the questionnaire due to the physical distance and the aggravated mental condition. However, we overcame this obstacle by sending the questionnaire via email and on social networks.

In your opinion, what is the benefit of joining ESSP and what advice do you have for students undertaking research in the future?

The pharmacist´s profession evolves continously and it is our responsibility to constantly use our skills and knowledge to improve patient care. Joining ESSP is a great opportunity to have our scientific research professionally reviewed. It also teaches valuable skills which every one of us young researchers should gain for their following papers and projects. The advice I have for students is to have the courage to try new projects without having fear of failure. I learned that through hard work and with the support of right people we can be a step closer to our objectives.


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European Pharmaceutical Students’ Association

PLEIOTROPHIN AND MIDKINE AS BIOMARKERS AND POSSIBLE DRUG TARGETS IN DEMENTIAS Author: Sara Martín Martínez. Scientific Coordinators: Gonzalo Herradón Gil-Gallardo, Marta del Campo Milán. Institution: University CEU-San Pablo (Madrid, Spain).

INTRODUCTION: Pleiotrophin (PTN) and Midkine (MK) constitute a small family of heparin binding factors, with overlapping diverse functions in the maintenance of the central nervous system (CNS). Recent studies highlight the role of these cytokines in the modulation of neuroinflammatory processes on brain damage. Dysregulation of neuroinflammatory mechanisms play a relevant role in the development of different neurodegenerative dementias. AIM: In this project we aimed to study the relation between these cytokines and different dementia types (Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD) and Lewy Bodies Dementia (LBD)) through the neuroinflammatory response, using patients’ cerebrospinal fluid (CSF). MATERIALS AND METHODS: The concentration of PTN, MK and IL-6 was analyzed in CSF from non-demented controls (CON, n = 195), AD (n = 230), FTD (n = 199) and LBD (n = 123) patients using PEA-extension assay (Olink® Proteomics). Correlation of these proteins with the classical AD CSF biomarkers (β-amyloid 1-42 (Aβ142); total concentration of tau (t-Tau) and hyperphosphorylated tau (p-Tau)) and MiniMental State Examination (MMSE) test was also performed. RESULTS: CSF PTN was decreased in AD patients (p < 0.05) compared to controls and correlated with both t-Tau and p-Tau in AD. CSF MK was decreased in FTD patients compared to controls and AD (p < 0.05) and correlated with Aβ1-42 in LBD patients only and with Tau forms in AD and FTD patients. CSF IL-6 remained similar across the different diagnostic groups. PTN and MK levels inversely correlated in all the subjects, suggesting a possible interconnection between them on the development of dementia.

CONCLUSION: Our findings show the possibility that PTN and MK could be involved in specific types of dementias associated to neurodegeneration and neuroinflammation. PTN might be specially related to AD, where might be associated with the development of neurofibrillary tangles (NFTs). MK seems to be specially related to FTD and the development of tau aggregates in this dementia. These data suggest that PTN and MK are involved in the pathophysiology of AD and FTD respectively. Further studies are warranted to analyze their potential as novel targets for the development of therapeutic and/or diagnostic tools.


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Questions & answers

in dementias. Because of that, in this study we did a statistical study where we analyzed the expression of both proteins in selected patients with different dementias, obtaining certain hypothesis which could be interesting to contrast with further statistical and analytical studies in a way to find a possible innovative therapy for these diseases.

What was the biggest challenge whilst Please, tell us a little bit more about carrying out the research and how did yourself. My name is Sara Martín and I am from Madrid, you overcome that? Spain. I am a Graduate in Chemistry specialised in Drug Discovery, and currently I am studying a Master’s Degree in Drug Research and Marketing in Madrid. Since I have started the Bachelor, I have developed a special interest in Organic Chemistry focused on the synthesis of molecules with a therapeutic aim, knowing the chemistry inside the different diseases and how the organism react by the action of drugs. I find this idea it really interesting and complex, specially in Neurodegenerative disorders, in which I would be very pleased to be specialist one day, being part of an investigation group.

All this project supposed a big challenge to me. Everything was new for me, what I found exciting because it gave me the chance to learn new thecniques, concepts and skills that have enriched me for future projects. Although, the biggest challenge was doing the statistical study, because considering the circimstances we are living nowadays, I have to learn Statistics and manage SPSS to manipulate the data by myself. However, I was really enthuastic with the idea, so I put all my effort to do it, using all the resourses that I have. Finally, here is the result.

In your opinion, what is the benefit Tell us a bit more about your research of joining ESSP and what advice do you have for students undertaking and its significance. The centre of this research is around a small research in the future? family of proteins, Pleiotrophin (PTN) and Midkine (MK), proposed as possible new targets for the treatment of neurodegenerative diseases such as Alzheimer’s Disease (AD), Frontotemporal Dementia (FTD) and Lewy Bodies Dementia (LBD). PTN and MK are involved in several organism functions associated with growing and reapairing cells and tissues during embryogenesis, where were highly expressed rather than in adults, which are expressed in specific areas of the brain. Several researchs reported their paper in different Central Nervous System (CNS) diseases such as alcoholism and drug addiction. Furthermore, novel studies show evidences of the implication of PTN and MK in different dementias, as they could participate in several pathways which are associated with the neuroinflammatory response characteristic

Joining ESSP is an excellent oportunity, for me as a novel researcher, to have a publication and, related to that, to make my work know explaining its significnace. It is a useful way to share your work with the rest of the students interested in science, exploring different ways of investigation that are developing actually, adquiring new ideas and amplying your knowledge. My advice is to not give up. Research is not an easy way to follow, it requieres time and a it suppose a big effort, but it is also satisfying when you see your results. So, if you like science, you feel amused with the project and you have a great team which potenciates that feeling and they could give you all the tools to learn all about it, go ahead, because you will learn a lot from them and for yourself.



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