Curricular training report: 7 months as a study coordinator at Blueclinical LTD

The present report describes in detail the activities undertaken under the coordination of clinical and observational studies during the curricular internship at Blueclinical Ltd., inserted in the Master of Pharmaceutical Biomedicine. Blueclinical Ltd.company operates in three different areas: R&D consultancy, management and coordination of trial centers, and a phase I unit. The curricular internship had the duration of seven months during which I was able to perform different tasks relating to coordination of clinical trials in Centro Hospitalar do Baixo Vouga, E.P.E., (CHBV) in Aveiro, Portugal. This academic internship allowed me to develop theoretical and practical skills in the field of clinical trials and observational studies. I also had the opportunity to further the knowledge I gained throughout my academic journey. During this internship, I had the opportunity to interact with different health professionals and develop my knowledge in the field of several therapeutic indications. I also could interact with distinct monitors and sponsors. This experience allowed me to improve time management, communication and problems resolution skills.

Agentes etiológicos de infecções urinárias em ambulatório

As infeções do trato urinário (ITU), depois das infeções respiratórias, são as mais comuns na comunidade, sendo a Escherichia coli o principal agente etiológico. Afeta predominantemente o sexo feminino e, anualmente, estima-se que ocorram em todo o Mundo cerca de 150 milhões de episódios de ITU, sendo responsável por 15% dos antibióticos prescritos em ambulatório. Os objetivos deste estudo foram caracterizar os agentes etiológicos das ITU e determinar o seu padrão de resistência aos antimicrobianos na região litoral norte de Portugal, de modo a contribuir para o uso racional na terapêutica empírica. Foi realizado um estudo observacional, descritivo e transversal, sendo obtidos 80 967 resultados de uroculturas de um Laboratório de Análises Clínicas de prestação de serviços à comunidade, relativos ao período entre Abril de 2007 e Março de 2015. Registaram-se 13 541 bacteriúrias positivas (16,72%). Escherichia coli foi o microrganismo mais isolado (71,62%), seguida de Klebsiella pneumoniae (12,41%), Proteus mirabilis (7,84%), Enterococcus. faecalis (3,97%) e Pseudomonas aeruginosa (1,42%), tendo-se observado diferenças estatisticamente significativas entre sexos e idades. Verificou-se uma diminuição da resistência aos antimicrobianos a partir do ano de 2012. E. coli apresentou em 2015 a menor taxa de resistência respetivamente de 4,46% e 12,37% para a fosfomicina e nitrofurantoína. A combinação de amoxicilina+ácido clavulânico registou uma taxa de resistência superior a 20% (22,03%). O baixo nível de resistência à fosfomicina permite que este antibiótico se apresente como a opção terapêutica de primeira linha no tratamento empírico de ITU não complicada na mulher em ambulatório, pelo que, estes resultados permitem corroborar as indicações de 2011 da Direção Geral de Saúde sobre a substituição de fluoroquinolonas por fosfomicina.

Curricular training report: clinical studies coordination in a clinical research organization vs an investigational site perspective

This report describes my experience of nine months as a trainee of a CRO (Eurotrials, Scientific Consultants), as well as a trainee of a clinical research site (Clinical Academic Center – Braga, Association). This document describes the European framework about clinical research and the Portuguese situation compared to similar countries. The activities developed during this internship are also described. These activities are divided in two phases. The first one occurred in Eurotrials, Scientific Consultants, a CRO specialized in clinical research and scientific advice. The first weeks were dedicated to intensive self-training needed to perform CTA tasks. These tasks included qualification, initiation and monitoring activities related to clinical trials, as well as the development of a quality management system. The second phase took place on 2CA-Braga, a clinical research center located in Hospital of Braga. Clinical studies coordination was the main focus of this second phase of my internship, as well as negotiation of clinical studies agreements. I had also the opportunity to participate in “1as Jornadas de Investigação Clínica e Inovação” (1st Clinical Investigation and Innovation Conference) organized by 2CA-Braga. Globally, this internship was a great opportunity to get knowledge and experience in the implementation and management of clinical trials, in a CRO and clinical research site perspectives. These two perspectives provided an interesting overview about the scientific needs of different players involved in clinical research. To conclude, this internship strengthened the knowledge acquired from my academic background, which make me able to face and overcome new challenges in the clinical research area.

O médico na indústria farmacêutica: contributo para o enquadramento da atividade

Ao longo desta dissertação de mestrado pretendemos analisar e discutir o papel do Médico na Indústria Farmacêutica, contribuindo para um melhor enquadramento de uma atividade ainda não muito conhecida. A partir da análise da implementação da Indústria Farmacêutica em Portugal, descrevemos o seu contributo para a Sociedade aliado ao valor do medicamento. Descrevemos a Medicina Farmacêutica, o treino da atividade e alguns dos órgãos relevantes nesta área, como a Competência em Medicina Farmacêutica da Ordem dos Médicos e a Associação dos Médicos Portugueses da Indústria Farmacêutica. De uma forma detalhada caraterizamos as atividades e competências do Médico nesta indústria que reforçamos com uma análise de um questionário efetuado com as opiniões de colegas Portugueses e estrangeiros com experiência nesta área do conhecimento. Concluímos, reconhecendo a importância da atividade, da sua caraterização e dos seus desafios futuros.

Optimization of a multielectrode array (MEA)-based approach to study the impact of Aβ on the SH-SY5Y cell line

The human brain stores, integrates, and transmits information recurring to millions of neurons, interconnected by countless synapses. Though neurons communicate through chemical signaling, information is coded and conducted in the form of electrical signals. Neuroelectrophysiology focus on the study of this type of signaling. Both intra and extracellular approaches are used in research, but none holds as much potential in high-throughput screening and drug discovery, as extracellular recordings using multielectrode arrays (MEAs). MEAs measure neuronal activity, both in vitro and in vivo. Their key advantage is the capability to record electrical activity at multiple sites simultaneously. Alzheimer’s disease (AD) is the most common neurodegenerative disease and one of the leading causes of death worldwide. It is characterized by neurofibrillar tangles and aggregates of amyloid-β (Aβ) peptides, which lead to the loss of synapses and ultimately neuronal death. Currently, there is no cure and the drugs available can only delay its progression. In vitro MEA assays enable rapid screening of neuroprotective and neuroharming compounds. Therefore, MEA recordings are of great use in both AD basic and clinical research. The main aim of this thesis was to optimize the formation of SH-SY5Y neuronal networks on MEAs. These can be extremely useful for facilities that do not have access to primary neuronal cultures, but can also save resources and facilitate obtaining faster high-throughput results to those that do. Adhesion-mediating compounds proved to impact cell morphology, viability and exhibition of spontaneous electrical activity. Moreover, SH-SY5Y cells were successfully differentiated and demonstrated acute effects on neuronal function after Aβ addition. This effect on electrical signaling was dependent on Aβ oligomers concentration. The results here presented allow us to conclude that the SH-SY5Y cell line can be successfully differentiated in properly coated MEAs and be used for assessing acute Aβ effects on neuronal signaling.

Curricular trainig report as study coordinator in Blueclinical Ltd.

The present report describes in detail the activities and knowledge aquired during my internship as study coordinator in Blueclinical – Investigação e Desenvolvimento em Saúde, Ltd., in order to obtain the master degree in Pharmaceutical Biomedicine. According to the type of services provided, Blueclinical is formed by three business units: Blueclinical Clinical Research Partnership, Blueclinical Phase I and Blueclinical Research and Development. The fact of belonging to such a company gave me the opportunity to be in touch with different areas of pharmaceutical development and to contact with different research teams, which for me was an added advantage to the integration and consolidation of knowledge, as well as in the development and improvement of soft and hard skills. The main activity developed was the coordination of clinical studies, in Unidade Local de Saúde de Matosinhos, E.P.E., which was one of the institutions that established a partnership with Blueclinical, Ltd. During my internship I was able to contact with various stages of development and coordination of clinical trials, which will be reported in this report.

Curricular internship report in medical writing at Blueclinical, Portugal

The contents of this report are a summary of the activities carried out during the 8-month internship as an Associate Medical Writer at Blueclinical Ltd, Matosinhos, Portugal. Mainly my activities were related to medical writing, particularly writing the clinical research protocols, clinical study reports, writing manuscript and preparing poster presentations. In addition to these activities, I also participated in performance of a clinical trial from beginning to end. During the period of its realization, I was able to familiarize myself with all the steps of the Phase I clinical trial.

Influence of substrates composition on immunomodulation by MSCs

Mesenchymal stem cells (MSCs) are non-hematopoietic multipotent stem cells capable to self-renew and differentiate along different cell lineages. MSCs can be found in adult tissues and extra embryonic tissues like the umbilical cord matrix/Wharton’s Jelly (WJ). The latter constitute a good source of MSCs, being more naïve and having a higher proliferative potential than MSCs from adult tissues like the bone marrow, turning them more appealing for clinical use. It is clear that MSCs modulate both innate and adaptive immune responses and its immunodulatory effects are wide, extending to T cells and dendritic cells, being therapeutically useful for treatment of immune system disorders. Mechanotransduction is by definition the mechanism by which cells transform mechanical signals translating that information into biochemical and morphological changes. Here, we hypothesize that by culturing WJ-MSCs on distinct substrates with different stiffness and biochemical composition, may influence the immunomodulatory capacity of the cells. Here, we showed that WJ-MSCs cultured on distinct PDMS substrates presented different secretory profiles from cells cultured on regular tissue culture polystyrene plates (TCP), showing higher secretion of several cytokines analysed. Moreover, it was also shown that WJ-MSCs cultured on PDMS substrates seems to possess higher immunomodulatory capabilities and to differentially regulate the functional compartments of T cells when compared to MSCs maintained on TCP. Taken together, our results suggest that elements of mechanotransduction seem to be influencing the immunomodulatory ability of MSCs, as well as their secretory profile. Thus, future strategies will be further explored to better understand these observation and to envisage new in vitro culture conditions for MSCs aiming at distinct therapeutic approaches, namely for immune-mediated disorders.

LAP1 interactome and its functional features throughout spermatogenesis

The lamina-associated polypeptide 1 (LAP1) is a type II transmembrane protein of the inner nuclear membrane encoded by the human gene TOR1AIP1. LAP1 is involved in maintaining the nuclear envelope structure and appears be involved in the positioning of lamins and chromatin. In the nuclear envelope, LAP1 is suggested to exist as a complex with A-type and B-type lamins, torsins and emerin. The presence of such complexes suggests that LAP1 may cooperate functionally with these proteins in tissues where they play a critical role. Therefore, the identification of LAP1 binding partners and the signalling pathways where LAP1 participates, is crucial for a better understanding of LAP1 functions. The work described in this thesis addresses novel human LAP1 associated proteins found through bioinformatic tools. Public databases allowed for the discovery of the LAP1 interactome, which was manually curated, identifying several functionally relevant proteins. Subsequently, the integration of multiple bioinformatic tools established novel functions to LAP1 such as DNA damage response and telomere association. In conjunction, bioinformatic results also reinforced the association of LAP1 with mitosis, and the already identified role of LAP1 in nuclear morphology. Interestingly, this association of LAP1 with the regulation of the nuclear envelope structure and mitosis progression, shares functional elements with spermatogenesis. Therefore, this work additionally described the localization of LAP1 and some of its interactors throughout the spermatogenic cycle, in mouse and human testis. The results established that the activity of LAP1 during the mouse spermatogenic cycle is most evident from stage VIII until the end of spermiogenesis, which is characteristic of manchette development. Concomitantly, some LAP1 interactors studied in this work share a similar localization, namely, PP1γ2, Lamin B1 and Lamin A/C. The results obtained from the study of LAP1 throughout different periods of the male reproductive system attributed potential new biological functions to LAP1. Thereby, this work can be the foundation of future studies regarding LAP1 and the regulation of multiple cellular processes and disease conditions.

Perspetiva atual e futura da nova regulamentação da investigação clínica

A investigação clínica na Europa, e em particular em Portugal, tem vindo a perder competitividade, uma situação preocupante face aos benefícios que a investigação representa para os doentes, instituições, profissionais de saúde e comunidade científica. O quadro regulamentar da investigação clínica em Portugal sofreu alterações significativas em 2014 com a implementação da Lei n.º 21/2014. Adicionalmente, o Regulamento UE n.º 536/2014, publicado no mesmo ano, será implementado a partir de maio de 2016, entrando diretamente em vigor nos países membros. Esta nova regulamentação contribuiu positivamente para o desenvolvimento da investigação clínica em Portugal. No entanto é fundamental colocar em prática todas a medidas promulgadas para que haja um crescimento sustentado do número de estudos clínicos em Portugal.

Sistemas de avaliação de tecnologias de saúde: dispositivos médicos

As tecnologias de saúde, nomeadamente medicamentos, dispositivos médicos (DM), procedimentos médicos ou cirúrgicos, entre outros, têm ocupado uma posição de destaque no setor da saúde, e na vida dos seus utilizadores. A inovação e utilização de tecnologias de saúde, e consequente aumento das despesas fizeram emergir a necessidade de avaliação das tecnologias de saúde. Surge assim, a avaliação de tecnologias de saúde (ATS), que tem por objetivo abordar os impactos clínicos, económicos, organizacionais, sociais, legais e éticos de uma tecnologia de saúde, considerando o seu contexto médico específico, bem como as alternativas disponíveis. A ATS pretende que os processos sejam feitos de forma rigorosa, transparente, valorizando e garantindo a sustentabilidade do acesso aos cuidados em saúde. Seguindo a tendência europeia de implementação de políticas e modelos de ATS, Portugal criou o seu próprio sistema de avaliação de tecnologias. O Decreto-Lei nº 97/2015, de 1 de junho veio oficializar a criação do Sistema Nacional de Avaliação de Tecnologias de Saúde (SiNATS). O SiNATS vai permitir uma avaliação não só de medicamentos, mas também de DM e outras tecnologias tendo em consideração a avaliação técnica, terapêutica e económica das tecnologias de saúde com base em fatores sociais, políticos, éticos e a participação de entidades, como, a indústria, as instituições de ensino, as instituições de saúde, os investigadores, os profissionais de saúde, os doentes e as associações dos doentes. O SiNATS vai emitir recomendações e decisões sobre o uso das tecnologias de saúde e possibilitar o ganho em saúde e contribuir para a sustentabilidade do Serviço Nacional de Saúde (SNS). O SiNATS vem permitir a avaliação de DM. O sector dos DM é um sector caracterizado pela inovação, crescimento e também competitividade. A complexidade e especificidade deste sector devem por isso ser tidas em consideração aquando da sua análise. A implementação do SiNATS permitirá avaliar e reavaliar preços, comparticipações, recomendações, contratos ao longo do ciclo de vida de cada DM. No presente momento, ainda é difícil expor os processos através dos quais esta avaliação vai ser processada, uma vez que se aguarda a publicação de despachos e portarias referidos no Decreto-Lei nº 97/2015, de 1 de junho. Tendo em consideração a partilha de informação sobre políticas, métodos, procedimentos de ATS aplicada aos DM na Europa, foram analisados os casos de França e do Reino Unido com o objetivo de alargar o conhecimento acerca do que já é feito a nível Europeu e explorar se os mesmos poderiam ser adaptados à realidade portuguesa. Em França, a ATS está diretamente relacionada com a comparticipação de DM, já no Reino Unido, o National Institute and Centre of Excellence (NICE) tem a responsabilidade de avaliar os DM segundo procedimentos de ATS, mas não está diretamente relacionado com comparticipação. O NICE publica normas de orientação que auxiliam a decisão de aquisição ou não de um DM. Tendo em consideração a informação reunida e descrita, este trabalho também propõe um modelo hipotético sobre o sistema português de avaliação de DM. Este modelo aborda, ainda que não de forma exaustiva, os possíveis processos e procedimentos para a avaliação de DM. Este sistema caracteriza-se pela importância dada ao envolvimento dos stakeholders e partilha de informação com os mesmos, mas também na agilização dos processos, isto é, uma redução e simplificação dos processos de avaliação de DM. A reavaliação de DM durante a sua comercialização também ganha destaque, apontando que cada grupo genérico de dispositivos ou DM inovador dever ser reavaliado a cada cinco anos, ou sempre que informação emergente o justifique. Este modelo representa uma abordagem experimental sobre o futuro do SiNATS aplicado aos DM. A partilha de informação, os fóruns de discussão e o envolvimento da sociedade serão uma mais-valia para que a implementação do SiNATS aos DM seja feita de forma gradual e com a máxima transparência possível.

Chemokines impact in Alzheimer’s disease

Alzheimer’s Disease (AD) is a neurodegenerative disorder neuropathologically characterized by the presence of extracellular senile plaques, intracellular neurofibrillary tangles and synaptic loss. Neuroinflammation has been associated with some neurodegenerative diseases, such as AD. In AD, increased Aβ production and aggregation, have a fundamental role in the activation of the inflammatory process. In turn, this could be fundamental in the early stages of this pathology, regarding the Aβ clearance and brain protection. However, chronic inflammation leads to an increase of the inflammatory mediators, such as cytokines, released by activated microglia, astrocytes, and neurons. The excessive production of these inflammatory components promotes alterations in both amyloid precursor protein (APP) expression and processing, stimulating the increase of Aβ accumulation and abnormal tau phosphorylation. This results in neurotoxic effects, irreversible damage and neuronal loss. Chronic inflammation is a feature of AD however, little is known about the effects of some chemokines on its pathogenesis. Thus, the main aim of this thesis was to study the impact of the interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) on apoptosis, APP and tau. The both studied chemokines resulted in small alterations regarding the cytotoxicity on SH-SY5Y differentiated cells, being a significant increase in apoptosis observed only for the MCP-1 at the highest concentration. For the APP processing no significant differences were obtained, although a tendency to increase at different concentrations and periods was registered for both IL-8 and MCP-1. With respect to tau and other cytoskeleton-associated proteins, it was possible to observe a tendency to increase in the phosphorylated residue (Ser396) at the higher concentrations, as well as alterations on actin and tubulin with an increase on acetylated-α tubulin. This effect can be translated by neuronal architectural and survival alterations. Therefore additional studies could contribute to a better understanding of the way that these chemokines act on AD pathogenesis.

From genes to radioresistance in head and neck squamous cell carcinoma

Head and Neck Cancers (HNC) are a group of tumours located in the upper aero-digestive tract. Head and Neck Squamous Cell Carcinoma (HNSCC) represent about 90% of all HNC cases. It has been considered the sixth most malignant tumour worldwide and, despite clinical and technological advances, the five-year survival rate has not improved much in the last years. Nowadays, HNSCC is well established as a heterogeneous disease and that its development is due to accumulation of genetic events. Apart from the majority of the patients being diagnosed in an advanced stage, HNSCC is also a disease with poor therapeutic outcome. One of the therapeutic approaches is radiotherapy. However, this approach has different drawbacks like the radioresistance acquired by some tumour cells, leading to a worse prognosis. A major knowledge in radiation biology is imperative to improve this type of treatment and avoid late toxicities, maintaining patient quality of life in the subsequent years after treatment. Then, identification of genetic markers associated to radiotherapy response in patients and possible alterations in cells after radiotherapy are essential steps towards an improved diagnosis, higher survival rate and a better life quality. Not much is known about the radiation effects on cells, so, the principal aim of this study was to contribute to a more extensive knowledge about radiation treatment in HNSCC. For this, two commercial cell lines, HSC-3 and BICR-10, were used and characterized resorting to karyotyping, aCGH and MS-MLPA. These cell lines were submitted to different doses of irradiation and the resulting genetic and methylation alterations were evaluated. Our results showed a great difference in radiation response between the two cell lines, allowing the conclusion that HSC-3 was much more radiosensitive than BICR-10. Bearing this in mind, analysis of cell death, cell cycle and DNA damages was performed to try to elucidate the motifs behind this difference. The characterization of both cell lines allowed the confirmation that HSC-3 was derived from a metastatic tumour and the hypothesis that BICR-10 was derived from a dysplasia. Furthermore, this pilot study enabled the suggestion of some genetic and epigenetic alterations that cells suffer after radiation treatment. Additionally, it also allowed the association of some genetic characteristics that could be related to the differences in radiation response observable in this two cell lines. Taken together all of our results contribute to a better understanding of radiation effects on HNSCC allowing one further step towards the prediction of patients’ outcome, better choice of treatment approaches and ultimately a better quality of life.

CD81 interacting proteins

Fertilization is a multistep and complex process culminating in the merge of gamete membranes, cytoplasmic unity and fusion of genome. CD81 is a tetraspanin protein that participates in sperm-oocyte interaction, being present at the oocyte surface. CD81 has also been implicated in other biological processes, however its specific function and molecular mechanisms of action remain to be elucidated. The interaction between CD81 and its binding partner proteins may underlie the CD81 involvement in a variety of cellular processes and modulate CD81/interactors specific functions. Interestingly, in a Yeast two Hybrid system previously performed in our lab, CD81 has emerged as a putative interactor of the Amyloid Precursor Protein (APP). In the work here described, bioinformatics analyses of CD81 interacting proteins were performed and the retrieved information used to construct a protein-protein interaction network, as well as to perform Gene Ontology enrichment analyses. CD81 expression was further evaluated in CHO, GC-1 and SH-SY5Y cell lines, and in human sperm cells. Additionally, its subcellular localization was analyzed in sperm cells and in the neuronal-like SH-SY5Y cell line. Subsequently, coimmunoprecipitation assays were performed in CHO and SH-SY5Y cells to attempt to prove the physical interaction between CD81 and APP. A functional interaction between these two proteins was accessed thought the analyses of the effects of CD81 overexpression on APP levels. A co-localization analysis of CD81 and some interactors proteins retrieved from the bioinformatics analyses, such as APP, AKT1 and cytoskeleton-related proteins, was also performed in sperm cells and in SH-SY5Y cells. The effects of CD81 in cytoskeleton remodeling was evaluated in SH-SY5Y cells through monitoring the effects of CD81 overexpression in actin and tubulin levels, and analyzing the colocalization between overexpressed CD81 and F-actin. Our results showed that CD81 is expressed in all cell lines tested, and also provided the first evidence of the presence of CD81 in human sperm cells. CD81 immunoreactivity was predominantly detected in the sperm head, including the acrosome membrane, and in the midpiece, where it co-localized with APP, as well as in the post-acrosomal region. Furthermore, CD81 co-localizes with APP in the plasma membrane and in cellular projections in SH-SY5Y cells, where CD81 overexpression has an influence on APP levels, also visible in CHO cells. The analysis of CD81 interacting proteins such as AKT1 and cytoskeletonrelated proteins showed that CD81 is involved in a variety of pathways that may underlie cytoskeleton remodeling events, related to processes such as sperm motility, cell migration and neuritogenesis. These results deepen our understanding on the functions of CD81 and some of its interactors in sperm and neuronal cells.

APP RERMS enriched matrix as an adhesion substrate for neuritic outgrowth

Specific domains can determine protein structural functional relationships. For the Alzheimer’s Amyloid Precursor Protein (APP) several domains have been described, both in its intracellular and extracellular fragments. Many functions have been attributed to APP including an important role in cell adhesion and cell to cell recognition. This places APP at key biological responses, including synaptic transmission. To fulfil these functions, extracellular domains take on added significance. The APP extracellular domain RERMS is in fact a likely candidate to be involved in the aforementioned physiological processes. A multidisciplinary approach was employed to address the role of RERMS. The peptide RERMS was crosslinked to PEG (Polyethylene glycol) and the reaction validated by FTIR (Fourier transform infrared spectrometry). FTIR proved to be the most efficient at validating this reaction because it requires only a drop of sample, and it gives information about the reactions occurred in a mixture. The data obtained consist in an infrared spectra of the sample, where peaks positions give information about the structure of the molecules, and the intensity of peaks is related to the concentration of the molecules. Subsequently substrates of PEG impregnated with RERMS were prepared and SH-SY5Y (human neuroblastoma cell line) cells were plated and differentiated on the latter. Several morphological alterations were clearly evident. The RERMS peptide provoked cells to take on a flatter appearance and the cytoskeletal architecture changed, with the appearance of stress fibres, a clear indicator of actin reorganization. Given that focal adhesions play a key role in determining cellular structure the latter were directly investigated. Focal adhesion kinase (FAK) is one of the most highly expressed proteins in the CNS (central nervous system) during development. It has been described to be crucial for radial migration of neurons. FAK can be localized in growth cones and mediated the response to attractive and repulsive cues during migration. One of the mechanisms by which FAK becomes active is by auto phosphorylation at tyrosine 397. It became clearly evident that in the presence of the RERMS peptide pFAK staining at focal adhesions intensified and more focal adhesions became apparent. Furthermore speckled structures in the nucleus, putatively corresponding to increased expression activity, also increased with RERMS. Taken together these results indicate that the RERMS domain in APP plays a critical role in determining cellular physiological responses. Here is suggested a model by which RERMS domain is recognized by integrins and mediate intracellular responses involving FAK, talin, actin filaments and vinculin. This mechanism probably is responsible for mediating cell adhesion and neurite outgrowth on neurons.