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Mechanisms of cancer dissemination along nerves

Opinion | Published: 06 May 2016

Mechanisms of cancer dissemination along nerves

Nature Reviews Cancer volume16, pages399–408 (2016) | Download Citation

Abstract

The local extension of cancer cells along nerves is a frequent clinical finding for various tumours. Traditionally, nerve invasion was assumed to occur via the path of least resistance; however, recent animal models and human studies have revealed that cancer cells have an innate ability to actively migrate along axons in a mechanism called neural tracking. The tendency of cancer cells to track along nerves is supported by various cell types in the perineural niche that secrete multiple growth factors and chemokines. We propose that the perineural niche should be considered part of the tumour microenvironment, describe the molecular cues that facilitate neural tracking and suggest methods for its inhibition.

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Acknowledgements

C. Cohen is thanked for her editorial assistance. N. Rada is thanked for her artistic work. Supported by the Israeli Science Foundation, Binational US–Israel Science Foundation, Israeli Cancer Research Found, Israel Cancer Association, Rappaport Institute at the Technion and the Clinical Research Institute at Rambam.

Author information

Affiliations

  1. Laboratory for Applied Cancer Research, Department of Otolaryngology Head and Neck Surgery, Head and Neck Center, Rambam Healthcare Campus, Clinical Research Institute at Rambam, Rappaport Institute of Medicine and Research, The Technion-Israel Institute of Technology, Haalia Street No. 8, Haifa, Israel.
    • Moran Amit
    • , Shorook Na’ara
    •  & Ziv Gil

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ziv Gil.

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  1. 1.Supplementary informationSupplementary information S1 (table)

Glossary

Desmoplastic reaction

Also known as desmoplasia, the desmoplastic reaction is the growth of fibrous tissue secondary to an insult such as a tumour or surgery.Dorsal root ganglia

(DRG). Also known as spinal ganglia, DRG are clusters of nerve cell bodies (a ganglia) in a posterior root of a spinal nerve.Endoneurial space

The anatomical space between the deepest layer of nerve covering, called the endoneurium, and the peripheral nerve fibres.Euclidean velocity

Directional vector of velocity defined not only by magnitude, but also by direction.Pancreatic afferents

These afferent nerve fibres are sensory neurons extending far from the nerve cell body in the coeliac ganglia. They conduct pain sensation by carrying nerve impulses from sensory receptors towards the central nervous system.Parasympathetic cholinergic fibres

These components of the autonomic nervous system are responsible for the body’s activities when it is at rest. They are called cholinergic after the main neurotransmitter, acetylcholine.Perineural space

The anatomical space between the most superficial nerve covering, also known as the epineurium layer, and the middle layer, called the perineurium, in peripheral nerves.Perineurium

Peripheral fibres are each wrapped in a protective sheath known as the endoneurium. These are bundled together into fascicles, each surrounded by a protective sheath known as the perineurium.Peripheral glial cell

Schwann cells are the principal peripheral glial cells that function to support neurons in the peripheral nervous system.Sensory fibres

Nerve fibres that deliver sensory information (for example, pain), from a peripheral organ to the central nervous system.Sympathetic nervous system

A component of the autonomic nervous system responsible for maintaining homeostasis and stimulating the body for flight-or-fight response. In peripheral nerves, the main postganglionic sympathetic neurotransmitter is noradrenaline, which activates α- and β-adrenergic receptors.Visceral hypersensitivity

Cancer-associated altered visceral perception caused by hyperexcitability of the neurons in the visceral afferent nervous system. Characterized by a lowered threshold for abdominal pain and discomfort.Wallerian degeneration

A process that results after a nerve injury, in which the part of the axon separated from the cell body of the neuron degenerates distal to the injury.

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06 May 2016

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´´A thorough, logical and reflective analysis of a sentence thought and/or described by a particular person can significantly influence the way they see and reflect the world around them´´. Rodrigo Nunes Cal ´´A análise minuciosa, lógica e reflexiva de uma frase pensada e/ou descrita por uma determinada pessoa pode influenciar significativamente no modo de ver e refletir o mundo ao seu redor´´. Rodrigo Nunes Cal “Para uma ideia que não parece insana à primeira vista, não há esperança.” Albert Einstein -- “For an idea that does not first seem insane, there is no hope.” ― Albert Einstein - - “A verdadeira lógica deste mundo está no cálculo de probabilidades.” James Clerk Maxwell “The true logic of this world is in the calculus of probabilities.” —James Clerk Maxwell - Virtual Induction Into The Human Mind = Indução Virtual Na Mente Humana #Probability #probabilidade(s) #Internet - Virtual Induction Of The Human Mind = Indução Virtual Da Mente Humana @ #probability #probabilities #RealFacts #RealFact #vision #thinking #Thoughts #NegativeFacts #PositiveFacts #analysis #research #researches #reference #people #communication #person #law #countries #country #Internet #work #team #pionner #pionners #blog #videos #video #photo #photos #information #knowledge #money #price #intelligence #TrueFacts #FalseFacts #HumanEvolution I N T E R N E T #Intenções #Imaginations #Thoughts #Pensamento(s) #Imaginações #Influences #Influência(s) -- Nem sempre o que fazemos na Internet com seus vários tipos de influências, faremos no ´´Mundo Real´´, obviamente. - Not always what we do on the Internet with its various types of influences, we will do in the ´´Real World´´, obviously. - “The true logic of this world is in the calculus of probabilities.” —James Clerk Maxwell * Nothing is better than reading and gaining more and more knowledge.” — Stephen Hawking #time #data #messages #information #knowledge #intentions #reading #probability #people #mind #photo #name #image #video #influences #actions #health #person #life #speak #write #researches #reference #type #listen #InternetHistory #objectives #improvement #longevity #imaginations #thinking #reality #Internet #ScientificDiscoveries #books #journals #importance #websites #analysis #SocialNetworks #links #blogs #countries #innovations #graphics #feedbacks #facts #science #technologies #ScienceEvents #poster #abstract #methodology #article #publications #team #DirectInvitations #speaker #Delegate #cities #feelings #energy #pionner #lives #work #contribuitions #pionners #minds #WorldHistory #ranking #economy ´´The world people need to have very efficient researches and projects resulting in very innovative drugs, vaccines, therapeutical substances, medical devices and other technologies according to the age, the genetics and medical records of the person. So, the treatment, diagnosis and prognosis will be very efficient and better, of course´´. Rodrigo Nunes Cal ´´O mundo precisa ter pesquisas e projetos muito eficientes que resultem em medicamentos, vacinas, substâncias terapêuticas, dispositivos médicos e outras tecnologias muito inovadoras de acordo com a idade, a genética e o prontuário da pessoa. Assim, o tratamento, o diagnóstico e o prognóstico serão bem mais eficientes e melhores, é claro´´. Rodrigo Nunes Cal ´´As you know, the world needs to have very efficient researches resulting new therapeutical substances, medical devices, prevention, diagnostic and prognostic methods, drugs and vaccines, for example. Very detailed researches are fundamental in this process. So, high impact innovations are essential to the world people!!´´ Rodrigo Nunes Cal  ´´Como você sabe, o mundo precisa de pesquisas muito eficientes que resultem em novas substâncias terapêuticas, aparelhos médicos, métodos de prevenção, de diagnósticos e de prognósticos, medicamentos e vacinas, por exemplo. Pesquisas muito detalhadas são fundamentais neste processo, obviamente. Portanto, inovações de grande impacto são essenciais para as pessoas do mundo todo!!´´ Rodrigo Nunes Cal ´´Ter grandes metas, muitas das quais ditas como impossíveis é muito importante porque pode induzir de várias maneiras em diferentes intensidades na sociedade científica mundial o surgimento de grandes descobertas científicas para toda a humanidade, beneficiando significativamente a vida das pessoas e fazendo com que a expectativa de vida humana aumente significativamente. Dessa forma, doenças conhecidas hoje como sendo fatais e incuráveis, podem se tornar doenças curáveis, com a obtenção de novas tecnologias altamente eficazes de prevenção, diagnóstico, prognóstico e de tratamento´´. Rodrigo Nunes Cal ´´Having big goals, many of which are said to be impossible, is very important because it can induce, in different ways, in different intensities in the world scientific society, the emergence of great scientific discoveries for all of humanity, significantly benefiting people's lives and causing the increase of human life expectancy significantly. Thus, diseases known today as being fatal and incurable, can become curable diseases, with the achievement of highly effective prevention, diagnosis, prognosis and treatment technologies´´. Rodrigo Nunes Cal * ´´The very unknown path may be the best path to take in life´´. Rodrigo Nunes Cal ´´O caminho muito desconhecido pode ser o melhor caminho a seguir na vida´´. Rodrigo Nunes Cal ´´A Ciência abre um leque de possibilidades dos mais variados assuntos e dos mais variados níveis de dificuldades. Sendo assim, a compreensão total dos mecanismos fisiológicos envolvidos na patogênese das doenças, destacando-se as doenças fatais que ocorrem em humanos, é de suma importância para a humanidade, com toda certeza. Quem sabe num futuro próximo essa compreensão seja muito bem entendida e quem sabe, como muitas pessoas sonham na imortalidade física, dentre elas cientistas, essa grande conquista pode ser adquirida. Como você sabe, a humanidade necessita urgentemente de novas descobertas científicas, destacando-se a aquisição de medicamentos e vacinas altamente eficazes contra um grande número de doenças, dentre elas as doenças desconhecidas e silenciosas, a obtenção de aparelhos médicos muito eficientes de diagnóstico, prognóstico e tratamento de doenças, entre outros. Com certeza, precisamos ter esperança e motivação para a realização de ótimos trabalhos e para uma qualidade de vida bem melhor e uma expectativa de vida cada vez maior´´. Rodrigo Nunes Cal ´´Science opens up a range of possibilities for the most varied subjects and the most varied levels of difficulties. Therefore, the full understanding of the physiological mechanisms involved in the pathogenesis of diseases, highlighting the fatal diseases that occur in humans, is of paramount importance for humanity, for sure. Maybe in the near future this understanding will be very well understood and who knows, as many people dream of physical immortality, among them scientists, this great achievement can be acquired. As you know, humanity urgently needs new scientific discoveries, highlighting the acquisition of highly effective medicines and vaccines against a large number of diseases, including unknown and silent diseases, obtaining very efficient medical devices for diagnosis, prognosis and treatment of diseases, among others. Certainly, we need to have hope and motivation to do great work and for a much better quality of life and an ever-increasing life expectancy´´. Rodrigo Nunes Cal - Very important note: The statistics on the number of people who visited this blog in 2018 were not entirely based on real visitors. - Observação muito importante: As estatísticas sobre número de pessoas que acessaram este blog no ano de 2018 não foram totalmente baseadas em visitantes reais. ´´Great difficulties may have come, but it is of great importance to have in mind the possibility of great victories in the future, bringing happiness and health for a long time´´. Rodrigo Nunes Cal ´´O caminho muito desconhecido pode ser o melhor caminho a seguir na vida´´. Rodrigo Nunes Cal ´´Understanding the great difficulties of a given subject can be a very long process, however, of great value for the progress of Science in all aspects´´. Rodrigo Nunes Cal ´´Entender as grandes dificuldades de um determinado assunto pode ser um processo muito longo, mas de grande valor para o progresso da Ciência em todos os seus aspectos´´. Rodrigo Nunes Cal My Curriculum Lattes: http://buscatextual.cnpq.br/buscatextual/visualizacv.do?id=K4240145A2 My Facebook Page: www.facebook.com/scientificblog IT´S A VERY EASY, FAST AND PRACTICAL WAY TO KNOW EXCELLENT INFORMATION ABOUT SCIENCE, TECHNOLOGY AND INNOVATION, AS AN EXAMPLE, APPLYING THE SEARCH MECHANISM Ctrl + F IN THIS BLOG FOR A WORD OR WORDS. SO, THIS BLOG SHARING IS VERY IMPORTANT TO THE WORLD SOCIETY! I hope in some way with this blog to help significantly in the socio-economic and technical-scientific development of the countries. My E-mail Accounts: rodrigoncal1984@gmail.com rodrigonunescal@yahoo.com rodrigoncal1984@yahoo.com ´´NÃO VÁ PARA ONDE O CAMINHO PODE TE LEVAR. VÁ ONDE NÃO HÁ CAMINHO E DEIXE UMA TRILHA. ´´ ´´DON'T GO WHERE THE PATH CAN TAKE YOU. GO WHERE THERE IS NO PATH AND LEAVE A TRAIL. ´´ @ KNOWING THE UNKNOWN.. CONHECENDO O DESCONHECIDO.. The world needs very innovative ideas to people live better and longer more and more. I have been invited as a Speaker/Delegate in numerous International Conferences and Congresses. * DISCOVERING HOW THE INITIAL STAGES OF A CERTAIN DISEASES WORK, SUCH AS A FATAL DISEASES, IS OF HUGE IMPORTANCE FOR SCIENCE, FOR SURE. THERE ARE SEVERAL BIOLOGICAL FACTORS CONNECTED IN THE HUMAN BODY THAT ACTING IN A VERY COMPLEX FORM. THEREFORE, IT IS OF GREAT NECESSITY TO CARRY OUT NEW SCIENTIFIC RESEARCHES MUCH MORE DETAILED AND MODERN, WITH A HIGH DEGREE OF PRECISION, EVEN IF THERE IS NO SIGNIFICANT STATISTICAL DIFFERENCE BETWEEN CERTAIN FACTORS. * DESCOBRIR COMO FUNCIONA OS ESTÁGIOS INICIAIS DE DETERMINADAS DOENÇAS, TAIS COMO AS DOENÇAS FATAIS, É DE ENORME IMPORTÂNCIA PARA A CIÊNCIA , COM CERTEZA. HÁ VÁRIOS FATORES BIOLÓGICOS INTERLIGADOS NO CORPO HUMANO QUE ATUAM DE FORMA MUITO COMPLEXA. PORTANTO, É DE GRANDE NECESSIDADE A REALIZAÇÃO DE NOVAS PESQUISAS CIENTÍFICAS MUITO MAIS MINUCIOSAS E MODERNAS, COM ALTO GRAU DE PRECISÃO, MESMO QUE NÃO HAJA DIFERENÇA ESTATÍSTICA SIGNIFICATIVA ENTRE DETERMINADOS FATORES. * The discussion of certain facts in science envolving stastistics is fundamental to the scientific community, for example, the analysis and interpretation of very important, innovative and interesting graphics with no statistical difference between them can have a big value to the researches and to the future researches. So, the quality and efficiency of researches can increase so much in a little time, increasing the possiblities of excellent references and new scientific discoveries. The facts veracity and the disclosure of them are essential for the scientific community, of course. Reconhecer o(s) erro(s) cometido(s) e não praticá-lo(s) novamente é um ato de grande sabedoria e importância para si mesmo e para a(s) outra(s) pessoa(s). Acknowledging mistakes and not doing them again is an act of great wisdom and importance for yourself and to the other person or people. ´´O IMPOSSÍVEL PODE SER POSSÍVEL´´. ´´THE IMPOSSIBLE CAN BE POSSIBLE´´. I have received positive feedbacks about this blog by LinkedIn, Twitter, Facebook, E-mails and Instagram. ´´EVERYONE DIES. THE GOAL IS NOT TO LIVE FOREVER. THE GOAL S TO CREATE SOMETHING THAT WILL´´ # time #time #internet #technologies #HighTechnologies #Cell Phones #Computer #Notebook  # Television #radio #communication #tempo  #InternetSociety # Society #person # people # age #ages #genetics #longevity #investigations #researches #efficiency #projects #ideas #reference #references #article #articles #journal # journals #magazines #websites #blogs #sites #links #SocialNetworks #energy #graphics #dissertation #monograph #citations #ImpactFactor #pesquisa #pesquisas #tecnologias #DiferentesPercepções #DifferentPerceptions #mind #mente #minds #MentesHumanas #emails #email e-mails reading #MenteHumana leitura mensagem mensagens probabilidade(s) probabilities messages message importance importância relevância assunto(s) subject subjects issue tema reflexão reflections vision visão pioneirismo pionners prêmio(s) prizes awards innovations inovações Grupos de Estudo Grupos Controle saúde doença(s) nome(s) tempo(s) Início da doença - Momento inicial da doença - Momento(s) inicial(ais) da(s) doença(s) humana(s) - Semelhança genética com camundongos - Mice researches - vaccines - drugs - eficiência - medicamento(s) - vacina(s) - High efficiency - Fatal diseases - Doenças fatais - Investments - investimentos - laboratórios - industries - indústrias - laboratories - Centros de Pesquisa - Países - cidades - cities - longevidade - desafio(s) - challenges - gráficos detalhados - interações biológicas - fatores biológicas - análise minuciosa - Very detailed analysis @ Initial moment of disease - Initial moments of human diseases - No Name @ discussion - discussão científica - science facts - detailed graphics - fatos científicos - publicação de trabalhos científicos - publications - hard work - better results - better science - diagnóstico - prognósticos - Diferença Estatística Significativa 100 Diferença Estatística Significativa @ Significant Statistical Difference - V X I Interpretations interpretações intenções intenions countries EU 100 gene Sem genes Cem genes 1 0 0 gene(s) time(s) times 100 limites limite(s) limits 1 0 0 limit NO LIMIT 10 0 @ 100 genes @ 100 gene & NO GENE NO TEMPO NOS TEMPOS NO(S) TEMPO(S) NOS TIMES NO TIME 100 GENE No Time # no time @ nos genes no(s) gene(s) * no(s) limite(s) - words- palavra(s) - listen - write - type - fala - escuta - ler - virtualidade - virtuality - reality - realidade - mundo real - mundo virtual - vida real - virtual life - real life - vida virtual - imaginations - thoughts - pensamento(s) - imaginações - melhoria - improvement - respect - respeito - speak - nome(s) - trabalho(s) - dinheiro - money - team - equipe - objetivo(s) - Best Universities of the World - Scientific Discoveries - Brazil - World - RNA - Cell - DNA - Idade biológica - biological age - pessoas - idade - idade(s) - pessoa - História da Computação Mundial - Harvard - Names - Places - City - researches - scientists - professors - pesquisador(es) - cientistas - professores - professor(es) - Produção científica - Fatores de Impacto - feelings - logic - sentimento(s) - lógica - história - world history - difficulties - dificuldades - Scientific community - comunidade científica mundial - vidas humanas - vida(s) humana(s) - trabalho(s) - human lives - life - human life - única - one life - person people @ momentos - moments memories memory memória longevidade energias energia(s) Many people liked my Twitter and Facebook comments that I informed this blog like great professors, scientists and researchers around the world who work in human health area! Many data about it aren´t in this blog. #database #system #time #data #search #information #InternetHistory #contribuitions #improvement #analysis #intentions Intenções @ #person #people #age #longevity #work #reading #probabilities #energy #money #price #clicks #jobs #country #city #countries #cities #knowledge #HumanInterdependence #WorldHistory #communication #HumanRelations #websites #e-mails #SocialNetworks #ranking #links #images #photos #texts #messages #videos #writing #typing #speak #listen #think #feelings #ideas #ScientificDiscoveries #investigations #researches #articles #ImpactFactors #journals #citations #influence #dissertations #monographs #ScientificWorks #Inventions #graphics #subjects #books #references #blogs ´´Compreender as grandes dificuldades de um determinado assunto pode ser um processo muito demorado, porém, de grande valia para o progresso da Ciência em todos os aspectos´´ Rodrigo Nunes Cal Observação/Note: I won a scholarship by FAPEMIG during the period of ´´my´´ monograph in Uberaba. Ganhei bolsa de estudo pela FAPEMIG durante o período da ´´minha´´ monografia em Uberaba. During the period that I participated of ´´my´´ dissertation at FAMERP, I didn't win a scholarship. Já durante o mestrado que fiz na FAMERP, não ganhei bolsa de estudo. ´´Os gráficos baseados em dados da ´´minha´´ dissertação que fiz podem ser uma excelente referência para muitos tipos de pesquisas e projetos, é claro !! Por exemplo, para pesquisas e projetos que tenham como objetivo analisar os tipos de influências das idades em camundongos e humanos (estudos genéticos, por exemplo) em relação a diferentes estágios de determinadas doenças, como aquelas em que a comunidade científica desconhece (doenças desconhecidas) e que poderão surgir no mundo. Outros tipos de pesquisas e projetos que podem ser feitos são aqueles que analisam a eficácia de diversos tipos de substâncias terapêuticas em camundongos e humanos nos diversos tipos de doenças com o objetivo de saber qual a melhor substância terapêutica para cada doença, levando em consideração a idade e genética, com certeza. Contudo, realizar pesquisas com o objetivo de avaliar qual é a influência da idade e da genética na eficiência terapêutica em animais de experimentação e em humanos, consequentemente, possui um grande valor, já que muitas pessoas adoecem e acabam falecendo mesmo sendo submetidas à ótimos sistemas de diagnóstico, tratamento e prognóstico, dependendo da doença que possui e do estágio da mesma´´. ´´A partir daí, ao comprovar que há influência significativa da idade e da genética, consequentemente, no processo de patogênese de doenças nos animais de experimentação e nos humanos, seria muito mais conveniente e lógico um grupo de indivíduos de certa faixa etária e histórico familiar e individual de doenças adquiridas e possíveis de serem adquiridas no decorrer do tempo serem tratados com outros tipos de medicamentos, substâncias terapêuticas, vacinas, dentre outros. Com certeza, para a realização destes tipos de pesquisa deve haver grande investimento financeiro nos laboratórios a fim de aquisição de aparelhos científicos altamente eficientes. Com certeza, pesquisas à nível genético e com relação à influência da idade do ser vivo na patogênese de doenças, até das doenças desconhecidas pelo mundo científico. O fato é que este tipo de pesquisa é muito importante porque como todos sabem, há muitas doenças que voltam a se manifestar nas pessoas mesmo depois de excelentes tratamentos, dos mais variados tipos. E outro ponto a ser refletido é a permanência de doenças fatais´´. ´´Assim, este tipo de influência da idade e consequentemente da genética na fisiopatologia das doenças hereditárias ou não hereditárias, um indivíduo de uma determinada idade será submetido a um tratamento terapêutico diferente de outro com a mesma doença mas com idade diferente da de até a pesquisa mostrou uma influência significativa na patogênese da doença, portanto, utilizará outro tipo de substância terapêutica, medicamentos, entre outros. Isso certamente acontecerá se a comunidade científica mundial comprovar cientificamente essas hipóteses por meio de várias pesquisas e projetos científicos. As pessoas precisam ter excelentes inovações para a expectativa de vida humana aumentar muito rapidamente cada vez mais. Portanto, quanto mais a medicina personalizada for, melhor será para cada um de nós´´. Rodrigo Nunes Cal ´´The graphics based on data from ´´my´´ dissertation I did can be an excellent reference for many types of researches and projects, of course!! For example, for researches and projects that the goals are analyse the type of influences of ages in mice and human (genetic studies, for example) in relation to different stages of determined diseases, like those that the scientific community do not know about them (unknown diseases). Other types of researches and projects that can be done is those that analyse the efficiency of many types of therapeutical substances in mice and human in many types of diseases with the objective of knowing which is the best therapeutic substance for each disease, taking into account age and genetics, for sure. For example, to carry out research with the objective of evaluating the influence of age and genetics on therapeutic efficiency in experimental animals and in humans´´. ´´Thus, by proving that there is a significant influence of age and genetics, consequently, in the process of pathogenesis of diseases in experimental animals and in humans, it would be much more convenient and logical to have a group of individuals of a certain age group and family and individual history of acquired diseases and possible to be acquired over time being treated with other types of drugs, therapeutic substances, vaccines, among others. Certainly, to carry out these types of research there must be a large financial investment in laboratories in order to acquire highly efficient scientific devices. Certainly, research at the genetic level and regarding the influence of the age of the living being on the pathogenesis of diseases, even diseases unknown to the scientific world. The fact is that this type of research is very important because as everyone knows, there are many diseases that come back to manifest in people even after excellent treatments, of the most varied types. And another point to be reflected on is the permanence of fatal diseases´´. ´´Taking into account this type of influence of age and consequently genetics on the pathophysiology of inherited or not inherited diseases, an individual of a certain age will be submitted to a different therapeutic treatment from another with the same disease but who has a different age than through the research has shown a significant influence on the pathogenesis of the disease, therefore, will use another type of therapeutic substance, medicine, among others. This will certainly happen if the world scientific community scientifically proves these hypotheses through various research and scientific projects. So, the people need to have excellent innovation to the human expectancy  of life increase so much faster more and more´´. Rodrigo Nunes Cal Note/Obs: I thought each person could do their own friend request permission setting since Facebook's technology is so big. Eu achava que cada pessoa poderia fazer sua própria configuração de permissão de solicitação de amizade já que a tecnologia do Facebook é muito grande. Very important note: I can earn money with this blog if the person do a donation to increase the dissemination of this blog and to recognize the hard work to do it. - Observação muito importante: Posso ganhar dinheiro com este blog se alguém fizer uma doação pra mim para aumentar a divulgação deste blog e pelo reconhecimento de fazer este blog. Foi um trabalho árduo pra fazer este blog.

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