OA preclinical studies using BMMSCs.
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"webinar-introduction-to-open-science-wednesday-18-may-1-pm-cest-20220518",title:"Webinar: Introduction to Open Science | Wednesday 18 May, 1 PM CEST"},{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"}]},book:{item:{type:"book",id:"10236",leadTitle:null,fullTitle:"Plasmodium Species and Drug Resistance",title:"Plasmodium Species and Drug Resistance",subtitle:null,reviewType:"peer-reviewed",abstract:"As teachers of parasite biology, we are becoming increasingly aware of the lack of detailed information and experimental approaches about drugs and drug resistance in many medical schools and undergraduate courses. Therefore, this book discusses parasite biology, antimalarial drugs and their mechanism of action, and the dynamic situation of evolving drug resistance of parasites, which has become a pressing issue. It provides insight into the plasmodium species, the role of cytokines in activating immune response during malaria infection, the importance of antimalarials as a therapeutic option, issues of drug resistance and co-resistance, and validation of evolved resistance in humanized mouse models. It is a timely addition to the existing literature on malaria parasite biology and a useful resource for students, researchers, and those working in the field of parasite biology, drugs, drug resistance of infectious diseases in general, and human malaria parasites in particular and beyond.",isbn:"978-1-83969-256-7",printIsbn:"978-1-83969-255-0",pdfIsbn:"978-1-83969-257-4",doi:"10.5772/intechopen.91077",price:119,priceEur:129,priceUsd:155,slug:"plasmodium-species-and-drug-resistance",numberOfPages:286,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"964a389525d1147af3e527c056ac1a73",bookSignature:"Rajeev K. Tyagi",publishedDate:"November 10th 2021",coverURL:"https://cdn.intechopen.com/books/images_new/10236.jpg",numberOfDownloads:2491,numberOfWosCitations:0,numberOfCrossrefCitations:3,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:6,numberOfDimensionsCitationsByBook:0,hasAltmetrics:0,numberOfTotalCitations:9,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"November 23rd 2020",dateEndSecondStepPublish:"December 21st 2020",dateEndThirdStepPublish:"February 19th 2021",dateEndFourthStepPublish:"May 10th 2021",dateEndFifthStepPublish:"July 9th 2021",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"269120",title:"Dr.",name:"Rajeev",middleName:"K.",surname:"Tyagi",slug:"rajeev-tyagi",fullName:"Rajeev Tyagi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRaBqQAK/Profile_Picture_1644331884726",biography:'Dr. Rajeev K. Tyagi earned Ph.D. degree at Biomedical Parasitology Unit, Institute Pasteur, Paris, France in June 2011 on a very challenging and interesting topic of malaria immunology/parasitology. He developed a long lasting, stable and straightforward laboratory animal model (humanized mouse model: a versatile mouse model) to study biology and immunology of infectious diseases and beyond. Dr. Tyagi worked as postdoc fellow in the laboratory of Dr. John Adams, University of South Florida, USA and received training to explore the potential of the developed “humanized mouse” to characterize attenuated asexual blood stage falciparum parasite to understand the innate immune response of the attenuated parasite (growth mutant). Also, he developed small laboratory human liver chimeric mice by transplanting the human hepatocytes in transgenic/immunodeficient mice (TK/NOG) at USF to study the least known liver stage infection of P. falciparum. Later on, he discovered novel dendritic like cell population called “pathogen differentiated dendritic cells (PDDCs)” when incubated with P. gingivalis and tracking of monocyte derived dendritic cells (MoDcs) in a reconstituted immunodeficient NOD.PrkdcscidIl2rg-/- (NSG) mice was carried out at Augusta University, USA to understand the host-pathogen interaction. Dr. Tyagi at the Department of Medicine, Division of Gastroenterology, Hepatology and Nutrition Vanderbilt University Medical Centre (VUMC), USA deployed his efforts to understand the role of IL-23R in the modulation of functioning of regulatory T cells and its role in the pathogenesis of colitis in an experimental humanized mouse. Currently, Dr. Tyagi has been leading a group at CSIR-Institute of Microbial Technology, Chandigarh, India and his lab is focused to:\r\n 1. Developing human-liver chimeric mice for huHep transplantation to study liver stage infection of P. falciparum and transition to asexual blood stage infection to test antimalarial drugs and vaccine candidates in one host. \r\n2. Study of drug resistance against Plasmodium falciparum\r\n3. Dendritic cells as "therapeutic vaccines" playing a crucial role in translational biomedical research.\r\n4. Formulation and characterization of nanoscale drug carriers to deliver methotrexate (MTX) and aceclofenac to address Rheumatoid Arthritis, cancer and other inflammatory diseases as well as candidate vaccines.',institutionString:"CSIR - Institute of Microbial Technology, India",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"2",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"1195",title:"Drug Discovery",slug:"pharmacology-toxicology-and-pharmaceutical-science-pharmacology-drug-discovery"}],chapters:[{id:"76981",title:"Finding Novel Strategies to Overcome the Impact of Malaria Vector Resistance in Limited-Resources Settings. The Case of Cameroon as a Basis for Reflection",doi:"10.5772/intechopen.98318",slug:"finding-novel-strategies-to-overcome-the-impact-of-malaria-vector-resistance-in-limited-resources-se",totalDownloads:111,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Malaria remains one of the most important and deadliest diseases in many countries in Africa, in the Americas, in South-East Asia, in the Eastern Mediterranean and in the Western Pacific regions, with high morbidity and mortality, despite important successes for the control of this disease borne by the vector Anopheles mosquitoes. Malaria elimination relies on different strategies including early diagnosis, improved drug therapies and better health infrastructure, and mainly the use of long-lasting insecticidal nets (LLINs) and indoor residual sprayings (IRS) of insecticide. In Cameroon, a country composed of several ethnic groups, malaria transmission is endemic in some regions, while it is seasonal in others; children and pregnant women are most vulnerable. Progress has been made towards malaria control, considering these specificities, and led to a reduction in both morbidity and mortality, but these accomplishments are under threat, mainly due to the development of resistance to insecticides among mosquitoes, targeting the 4 commonly used insecticide classes. To continue our route towards malaria control and elimination, it is urgent to have more knowledge about resistance mechanisms, in the objective of elaborating new strategies with the involvement of the community; these strategies should take into consideration socio-ecological factors such as the young age of the population, low literacy rate especially among women, population’s beliefs, traditions, and customs. Forest ecosystems with abundant rains, humidity and hot temperature, lower access to water for populations living in rural areas, and poverty level are other factors to consider when elaborating malaria control approaches.",signatures:"Benjamin Jr Fouda Abougou",downloadPdfUrl:"/chapter/pdf-download/76981",previewPdfUrl:"/chapter/pdf-preview/76981",authors:[{id:"342228",title:"M.D.",name:"Benjamin Jr",surname:"Fouda Abougou",slug:"benjamin-jr-fouda-abougou",fullName:"Benjamin Jr Fouda Abougou"}],corrections:null},{id:"77286",title:"Plasmodium Species and Drug Resistance",doi:"10.5772/intechopen.98344",slug:"plasmodium-species-and-drug-resistance",totalDownloads:185,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Malaria is a leading public health problem in tropical and subtropical countries of the world. In 2019, there were an estimated 229 million malaria cases and 409, 000 deaths due malaria in the world. The objective of this chapter is to discuss about the different Plasmodium parasites that cause human malaria. In addition, the chapter discusses about antimalarial drugs resistance. Human malaria is caused by five Plasmodium species, namely P. falciparum, P. malariae, P. vivax, P. ovale and P. knowlesi. In addition to these parasites, malaria in humans may also arise from zoonotic malaria parasites, which includes P. inui and P. cynomolgi. The plasmodium life cycle involves vertebrate host and a mosquito vector. The malaria parasites differ in their epidemiology, virulence and drug resistance pattern. P. falciparum is the deadliest malaria parasite that causes human malaria. P. falciparum accounted for nearly all malarial deaths in 2018. One of the major challenges to control malaria is the emergence and spread of antimalarial drug-resistant Plasmodium parasites. The P. vivax and P. falciparum have already developed resistance against convectional antimalarial drugs such as chloroquine, sulfadoxine-pyrimethamine, and atovaquone. Chloroquine-resistance is connected with mutations in pfcr. Resistance to Sulfadoxine and pyrimethamine is associated with multiple mutations in pfdhps and pfdhfr genes. In response to the evolution of drug resistance Plasmodium parasites, artemisinin-based combination therapies (ACTs) have been used for the treatment of uncomplicated falciparum malaria since the beginning of 21th century. However, artemisinin resistant P. falciparum strains have been recently observed in different parts of the world, which indicates the possibility of the spread of artemisinin resistance to all over the world. Therefore, novel antimalarial drugs have to be searched so as to replace the ACTs if Plasmodium parasites develop resistance to ACTs in the future.",signatures:"Sintayehu Tsegaye Tseha",downloadPdfUrl:"/chapter/pdf-download/77286",previewPdfUrl:"/chapter/pdf-preview/77286",authors:[{id:"344290",title:"M.Sc.",name:"Sintayehu",surname:"Tsegaye Tseha",slug:"sintayehu-tsegaye-tseha",fullName:"Sintayehu Tsegaye Tseha"}],corrections:null},{id:"76582",title:"Recent Advances in Antimalarial Drug Discovery: Challenges and Opportunities",doi:"10.5772/intechopen.97401",slug:"recent-advances-in-antimalarial-drug-discovery-challenges-and-opportunities-1",totalDownloads:211,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Malaria is a global health problem that needs attention from drug discovery scientists to investigate novel compounds with high drug efficacy, safety and low cost to encounter the malaria parasites that are resistant to existing drug molecules. Antimalarial drug development follows several approaches, ranging from modifications of existing agents to the design of novel agents that act against novel targets. Most of market and clinical drugs act on blood schizonticide are in current therapy for malaria reduction. This chapter will intend to highlight the currently available drugs including various novel agents. In addition, emphasis has been given on the prospective pharmacophores that are likely to emerge as effective clinical candidates in the treatment of malaria. Besides all aspects, some alternative approaches will also be highlight.",signatures:"Imrat, Ajeet Kumar Verma and Pooja Rani Mina",downloadPdfUrl:"/chapter/pdf-download/76582",previewPdfUrl:"/chapter/pdf-preview/76582",authors:[{id:"320004",title:"Dr.",name:"Pooja",surname:"Mina",slug:"pooja-mina",fullName:"Pooja Mina"},{id:"414260",title:"Dr.",name:"Imrat",surname:null,slug:"imrat",fullName:"Imrat null"},{id:"414261",title:"Dr.",name:"Ajeet",surname:"Kumar Verma",slug:"ajeet-kumar-verma",fullName:"Ajeet Kumar Verma"}],corrections:null},{id:"77047",title:"Adaptive Drug Resistance in Malaria Parasite: A Threat to Malaria Elimination Agenda?",doi:"10.5772/intechopen.98323",slug:"adaptive-drug-resistance-in-malaria-parasite-a-threat-to-malaria-elimination-agenda-",totalDownloads:167,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Malaria is a global disease of importance, especially in the sub-Saharan African region, where malaria accounts for great losses economically and to life. Fight to eliminate this disease has resulted in reduced disease burden in many places where the diseases is endemic. Elimination strategies in most places is focus on the use of treated nets and drug application. Exposure of malaria parasites to anti-malaria drugs have led to the evolution of drug resistance in both parasites and host. Development of drug resistance vary but, studies on adaptive drug resistance has implications and consequences. Our knowledge of this consequences are limited but important for the pursuit of an uninterrupted malaria elimination agenda. This chapter draws our attention to this risks and recommends interventions.",signatures:"Moses Okpeku",downloadPdfUrl:"/chapter/pdf-download/77047",previewPdfUrl:"/chapter/pdf-preview/77047",authors:[{id:"344467",title:"Assistant Prof.",name:"Moses",surname:"Okpeku",slug:"moses-okpeku",fullName:"Moses Okpeku"}],corrections:null},{id:"77119",title:"Treatment of Malaria Infection and Drug Resistance",doi:"10.5772/intechopen.98373",slug:"treatment-of-malaria-infection-and-drug-resistance",totalDownloads:184,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Malaria is a public health challenge that requires prompt treatment for those infected to make a full recovery. Treatment of malaria infection is to be started as soon as a diagnosis is confirmed. Antimalarial medications are administered to prevent and also to treat malaria. The type of medication used and the duration of therapy is dependent on the type of malaria-causing plasmodium species, the severity of the symptoms, geographical area where malaria infection occurred and the medication used to prevent malaria and whether there is pregnancy. Treatment of malaria from public health perspective is to reduce transmission of the infection to others, by reducing the infectious reservoir and to prevent the emergence and spread of resistance to antimalarial medicines. Medications used in the treatment of malaria infection come from the following five groups of chemical compounds: quinolines and aryl amino alcohols, antifolate, artemisinin derivatives, hydroxynaphthoquinones and antibacterial agents. The treatment of malaria is not initiated until the diagnosis has been established through laboratory testing. Artemisinin-based Combination Therapy (ACTs) has been used for the treatment of uncomplicated malaria. ACTs are also to enhance treatment and protect against the development of drug resistance. IV artesunate is used in the treatment of severe malaria, regardless of infecting species.",signatures:"Bernard Kofi Turkson, Alfred Ofori Agyemang, Desmond Nkrumah, Reinhard Isaac Nketia, Michael Frimpong Baidoo and Merlin Lincoln Kwao Mensah",downloadPdfUrl:"/chapter/pdf-download/77119",previewPdfUrl:"/chapter/pdf-preview/77119",authors:[{id:"342313",title:"Dr.",name:"Bernard Kofi",surname:"Turkson",slug:"bernard-kofi-turkson",fullName:"Bernard Kofi Turkson"},{id:"344502",title:"Mr.",name:"Michael",surname:"Frimpong Baidoo",slug:"michael-frimpong-baidoo",fullName:"Michael Frimpong Baidoo"},{id:"344503",title:"Mr.",name:"Alred",surname:"Ofori Agyemang",slug:"alred-ofori-agyemang",fullName:"Alred Ofori Agyemang"},{id:"344504",title:"Mr.",name:"Desmond",surname:"Nkrumah",slug:"desmond-nkrumah",fullName:"Desmond Nkrumah"},{id:"344505",title:"Mr.",name:"Reinhard Isaac",surname:"Nketia",slug:"reinhard-isaac-nketia",fullName:"Reinhard Isaac Nketia"},{id:"344507",title:"Prof.",name:"Merlin Lincoln Kwao",surname:"Mensah",slug:"merlin-lincoln-kwao-mensah",fullName:"Merlin Lincoln Kwao Mensah"}],corrections:null},{id:"77461",title:"P. falciparum and Its Molecular Markers of Resistance to Antimalarial Drugs",doi:"10.5772/intechopen.98372",slug:"-em-p-falciparum-em-and-its-molecular-markers-of-resistance-to-antimalarial-drugs",totalDownloads:190,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"The use of molecular markers of resistance to monitor the emergence, and the spread of parasite resistance to antimalarial drugs is a very effective way of monitoring antimalarial drug resistance. The identification and validation of molecular markers have boosted our confidence in using these tools to monitor resistance. For example, P. falciparum chloroquine resistance transporter (PfCRT), P. falciparum multidrug resistance protein 1 (PfMDR1), P. falciparum multidrug kelch 13 (pfk13), have been identified as molecular markers of resistance to chloroquine, lumefantrine, and artemisinin respectively. The mechanism of resistance to antimalarial drugs is mostly by; (1) undergoing mutations in the parasite genome, leading to expelling the drug from the digestive vacuole, or (2) loss of binding affinity between the drug and its target. Increased copy number in the pfmdr1 gene also leads to resistance to antimalarial drugs. The major cause of the widespread chloroquine and sulfadoxine-pyrimethamine resistance globally is the spread of parasites resistant to these drugs from Southeast Asia to Africa, the Pacific, and South America. Only a few mutations in the parasite genome lead to resistance to chloroquine and sulfadoxine-pyrimethamine arising from indigenous parasites in Africa, Pacific, and South America.",signatures:"Peter Hodoameda",downloadPdfUrl:"/chapter/pdf-download/77461",previewPdfUrl:"/chapter/pdf-preview/77461",authors:[{id:"344545",title:"M.Sc.",name:"Peter",surname:"Hodoameda",slug:"peter-hodoameda",fullName:"Peter Hodoameda"}],corrections:null},{id:"78631",title:"A Double Line of Defense: Heat Shock Proteins and Polyamines Act as Contributing Factors to Drug Resistance of some Plasmodium Parasites",doi:"10.5772/intechopen.98852",slug:"a-double-line-of-defense-heat-shock-proteins-and-polyamines-act-as-contributing-factors-to-drug-resi",totalDownloads:103,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Malaria remains a threat to human life worldwide with children under the age of 5 being the most vulnerable. Plasmodium falciparum, known as the causative agent of the deadliest malaria, survives both in the mosquito vector and human host. The sudden temperature change seems to not affect the parasite’s cellular system. Heat shock proteins and polyamines are the major house-keepers of the parasite’s cellular system to remain viable, despite the temperature changes that the parasite gets exposed to. While heat shock proteins protect newly synthesized proteins until they are properly folded polyamines are needed for cell differentiation, proliferation, and cell growth. In plants for example, polyamines have been reported to act as molecular chaperones when cells are exposed to unfavorable conditions that could be detrimental to cells. In this review, the role of heat shock proteins and polyamines in plasmodium parasite drug resistance and their role in parasite survival are discussed. The current drugs against malaria as well as the alternative future approach towards malarial drug development are reviewed.",signatures:"Xolani Henry Makhoba",downloadPdfUrl:"/chapter/pdf-download/78631",previewPdfUrl:"/chapter/pdf-preview/78631",authors:[{id:"342340",title:"Dr.",name:"Xolani Henry",surname:"Makhoba",slug:"xolani-henry-makhoba",fullName:"Xolani Henry Makhoba"}],corrections:null},{id:"77697",title:"Molecular Approaches for Malaria Therapy",doi:"10.5772/intechopen.98396",slug:"molecular-approaches-for-malaria-therapy",totalDownloads:187,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Malaria is a potentially fatal blood disease spread by mosquitos. Malaria is preventable, but it is more prevalent in developing countries where prevention is difficult and prophylaxis is often inaccessible. Malaria remains one of the world’s most serious public health problems, according to the World Health Organisation (WHO). The development of resistance is a current problem that poses a danger to the environment. Resistance is a current problem that could jeopardise the use of well-established and cost-effective antimalarials. The World Health Organisation recommends an artemisinin-based drug combination (ACT) to avoid or postpone the development of resistance. This book’s chapter discusses current medicines as well as potential and rational possibilities for finding new drugs to treat malady. There were also WHO recommendations for both complicated and non-complicated malaria. Other preventive measures such as ITN and IPT are listed in the manuscript in addition to routine care. While a brief overview of the vaccine tested so far has been included, there is currently no vaccine available to treat malaria.",signatures:"Mitali Mishra, Vikash Kumar Mishra, Varsha Kashaw and Sushil Kumar Kashaw",downloadPdfUrl:"/chapter/pdf-download/77697",previewPdfUrl:"/chapter/pdf-preview/77697",authors:[{id:"345127",title:"Dr.",name:"Sushil",surname:"Kashaw",slug:"sushil-kashaw",fullName:"Sushil Kashaw"},{id:"350673",title:"Dr.",name:"Vikash",surname:"Mishra",slug:"vikash-mishra",fullName:"Vikash Mishra"},{id:"350674",title:"Mrs.",name:"Mitali",surname:"Mishra",slug:"mitali-mishra",fullName:"Mitali Mishra"},{id:"350757",title:"Dr.",name:"Varsha",surname:"Kashaw",slug:"varsha-kashaw",fullName:"Varsha Kashaw"}],corrections:null},{id:"75927",title:"Regulation of T-reg/Th-17 Balance: One Step Closer Towards Immunotherapy Against Malaria Infection",doi:"10.5772/intechopen.97045",slug:"regulation-of-t-reg-th-17-balance-one-step-closer-towards-immunotherapy-against-malaria-infection",totalDownloads:135,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"According to World Malaria Report 2020, the rate of decline in malaria case incidence and deaths caused by malaria has ceased in latter half of the past decade. Though Artemisinin Combination Therapy (ACT) is still the major therapeutic approach globally to treat malaria patients, increased resistance of Plasmodium sp. to artemisinin can be looked upon as a major factor responsible for the rate of decline. In the present world, immunotherapeutic approaches are in the limelight to treat several infections, autoimmune disorders, cancers but application of such therapeutic measures in case of malaria are yet not available. Among different immune cells, T-regulatory cells (T-reg) and Th-17 cells and the balance between them, helps in determining the outcome of the immune response in host during both lethal and non-lethal malaria. TGFβ and IL-6 are two major cytokines that play important role in fine tuning the Treg/Th-17 balance by modulating dendritic cell responses, specially by regulating the ratio between myeloid DC and plasmacytoid DC (mDC/pDC). Studies in rodent malaria models have revealed that neutralization of IL-6 by using anti IL-6 monoclonal antibodies in-vivo has been found effective in declining the parasitemia, malaria induced deaths and also in reverting back the altered T-reg/Th-17 balance to normal levels. Apart from these, autophagy is one of the major factors which also contributes to regulate the T-reg/Th-17 balance. In malaria infected mice, autophagy induction has been found to normalise the dysregulated T-reg/Th-17 ratio and promote anti-inflammatory Th-2 pathway by supressing pro-inflammatory Th-1 pathway. So, Treg/Th-17 balance and its associated regulators can be important immunotherapeutic targets for malaria prevention in near future.",signatures:"Saikat Mukherjee, Soubhik Ghosh and Arindam Bhattacharyya",downloadPdfUrl:"/chapter/pdf-download/75927",previewPdfUrl:"/chapter/pdf-preview/75927",authors:[{id:"343432",title:"Prof.",name:"Arindam",surname:"Bhattacharyya",slug:"arindam-bhattacharyya",fullName:"Arindam Bhattacharyya"},{id:"343434",title:"Mr.",name:"Soubhik",surname:"Ghosh",slug:"soubhik-ghosh",fullName:"Soubhik Ghosh"},{id:"343435",title:"Mr.",name:"Saikat",surname:"Mukherjee",slug:"saikat-mukherjee",fullName:"Saikat Mukherjee"}],corrections:null},{id:"76204",title:"A Comprehensive Review of 4(1H)-Quinolones and 4(1H)-Pyridones for the Development of an Effective Antimalarial",doi:"10.5772/intechopen.97084",slug:"a-comprehensive-review-of-4-1-em-h-em-quinolones-and-4-1-em-h-em-pyridones-for-the-development-of-an",totalDownloads:214,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Malaria is a global public health issue. Despite the efforts in malaria prevention, nearly half the world’s population is at risk of infection. Until present-day, researchers are struggling to design and discover an efficacious antimalarial. In comparison to most common antimalarial chemotypes that eliminate erythrocytic stages of P. falciparum, 4(1H)-quinolones and 4(1H)-pyridones exhibit antimalarial activity against multiple stages of the parasite. They have potential to treat blood stages of multidrug resistant P. falciparum malaria, eradicate dormant exoerythro stages of relapsing malaria species (P. vivax), and prevent transmission of infectious gametocytes to mosquitoes. However, thus far, the advancement of these chemotypes towards pre-clinical and clinical development has been impeded due to poor physicochemical properties, poor oral bioavailability, and poor dose-proportionality limiting preclinical safety and toxicity studies. Despite all these challenges, 4(1H)-quinolones and 4(1H)-pyridones continue to be at the forefront for the development of the next-generation antimalarials as they would have tremendous global public health impact and could significantly enhance current malaria elimination efforts.",signatures:"Ami H. Asakawa and Roman Manetsch",downloadPdfUrl:"/chapter/pdf-download/76204",previewPdfUrl:"/chapter/pdf-preview/76204",authors:[{id:"334739",title:"Associate Prof.",name:"Roman",surname:"Manetsch",slug:"roman-manetsch",fullName:"Roman Manetsch"},{id:"345559",title:"Dr.",name:"Ami H.",surname:"Asakawa",slug:"ami-h.-asakawa",fullName:"Ami H. Asakawa"}],corrections:null},{id:"78959",title:"Stable Artesunate Resistance in A Humanized Mouse Model of Plasmodium falciparum",doi:"10.5772/intechopen.100381",slug:"stable-artesunate-resistance-in-a-humanized-mouse-model-of-em-plasmodium-falciparum-em-",totalDownloads:101,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Plasmodium falciparum, the most devastating human malaria parasite, confers higher morbidity and mortality. Although efforts have been made to develop an effective malaria vaccine, stage- and species-specific short-lived immunity crippled these efforts. Hence, antimalarial drug treatment becomes a mainstay for the treatment of malaria infection in the wake of the unavailability of an effective vaccine. Further, there has been a wide array of antimalarial drugs effective against various developmental stages of P. falciparum due to their different structures, modes of action, and pharmacodynamics as well as pharmacokinetics. The development of resistance against almost all frontline drugs by P. falciparum indicates the need for combination therapy (artemisinin-based combination therapy; ACT) to treat patients with P. falciparum. A higher pool of parasitemia under discontinuous in vivo artemisinin drug pressure in a developed humanized mouse allows the selection of artesunate resistant (ART-R) P. falciparum. Intravenously administered artesunate, using either single flash doses or a 2-day regimen, to the P. falciparum-infected human blood chimeric NOD/SCID.IL-2Rγ−/− immunocompromised (NSG) mice, with progressive dose increments upon parasite recovery, was the strategy deployed to select resistant parasites. Parasite susceptibility to artemisinins and other antimalarial compounds was characterized in vitro and in vivo. P. falciparum has shown to evolve extreme artemisinin resistance as well as co-resistance to antimalarial drugs. Overall, the present information shall be very useful in devising newer therapeutic strategies to treat human malaria infection.",signatures:"Sheetal Saini, Rajinder Kumar and Rajeev K. Tyagi",downloadPdfUrl:"/chapter/pdf-download/78959",previewPdfUrl:"/chapter/pdf-preview/78959",authors:[{id:"269120",title:"Dr.",name:"Rajeev",surname:"Tyagi",slug:"rajeev-tyagi",fullName:"Rajeev Tyagi"},{id:"426960",title:"Dr.",name:"Sheetal",surname:"Saini",slug:"sheetal-saini",fullName:"Sheetal Saini"},{id:"426961",title:"Mr.",name:"Rajinder",surname:"Kumar",slug:"rajinder-kumar",fullName:"Rajinder Kumar"}],corrections:null},{id:"77444",title:"Drug Design for Malaria with Artificial Intelligence (AI)",doi:"10.5772/intechopen.98695",slug:"drug-design-for-malaria-with-artificial-intelligence-ai-",totalDownloads:196,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Malaria is a deadly disease caused by the plasmodium parasites. Approximately 210 million people get affected by malaria every year resulting in half a million deaths. Among several species of the parasite, Plasmodium falciparum is the primary cause of severe infection and death. Several drugs are available for malaria treatment in the market but plasmodium parasites have successfully developed resistance against many drugs over the years. This poses a serious threat to efficacy of the treatments and continuing discovery of new drug is necessary to tackle the situation, especially due to failure in designing an effective vaccine. People are now trying to design new drugs for malaria using AI technologies which can substantially reduce the time and cost required in classical drug discovery programs. In this chapter, we provide a comprehensive overview of a road map for several AI based computational techniques which can be implemented in a malaria drugs discovery program. Classical computers has limiting computing power. So, researchers are also trying to harness quantum machine learning to speed up the drug discovery processes.",signatures:"Bhaswar Ghosh and Soham Choudhuri",downloadPdfUrl:"/chapter/pdf-download/77444",previewPdfUrl:"/chapter/pdf-preview/77444",authors:[{id:"343436",title:"Dr.",name:"Soham",surname:"Choudhri",slug:"soham-choudhri",fullName:"Soham Choudhri"},{id:"346210",title:"Dr.",name:"Bhaswar",surname:"Ghosh",slug:"bhaswar-ghosh",fullName:"Bhaswar Ghosh"}],corrections:null},{id:"76742",title:"Plasmodium vivax and Drug Resistance",doi:"10.5772/intechopen.97320",slug:"-em-plasmodium-vivax-em-and-drug-resistance",totalDownloads:212,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Resistance to antimalarial drugs is a threat to global efforts to eliminate malaria by 2030. Currently, treatment for vivax malaria uses chloroquine or ACT for uncomplicated P. vivax whereas primaquine is given to eliminate latent liver stage infections (a method known as radical cure). Studies on P. vivax resistance to antimalarials and the molecular basis of resistance lags far behind the P. falciparum as in vitro cultivation of the P. vivax has not yet been established. Therefore, data on the P. vivax resistance to any antimalarial drugs are generated through in vivo studies or through monitoring of antimalarial treatments in mixed species infection. Indirect evidence through drug selective pressure on the parasites genome, as evidenced by the presence of the molecular marker(s) for drug resistance in areas where P. falciparum and P. vivax are distributed in sympatry may reflect, although require validation, the status of P. vivax resistance. This review focuses on the currently available data that may represent the state-of-the art of the P. vivax resistance status to antimalarial to anticipate the challenge for malaria elimination by 2030.",signatures:"Puji Budi Setia Asih and Din Syafruddin",downloadPdfUrl:"/chapter/pdf-download/76742",previewPdfUrl:"/chapter/pdf-preview/76742",authors:[{id:"216332",title:"Dr.",name:"Puji",surname:"Budi Setia Asih",slug:"puji-budi-setia-asih",fullName:"Puji Budi Setia Asih"},{id:"239838",title:"Prof.",name:"Din",surname:"Syafruddin",slug:"din-syafruddin",fullName:"Din Syafruddin"}],corrections:null},{id:"77452",title:"rRNA Platform Technology for Drug Discovery Methods for Identifying Ligands That Target Plasmodium RNA Structural Motifs",doi:"10.5772/intechopen.98776",slug:"rrna-platform-technology-for-drug-discovery-methods-for-identifying-ligands-that-target-plasmodium-r",totalDownloads:107,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Determining the structure of the P. falciparum40s leads to better understanding of the structural basis for its protein-synthesizing roles in the cell. This enables researchers in the field of drug development to run in silico ligand screening experiments using the solved P. falciparum 40S structure as a target against a library of potential anti-malarial compounds. Drug leads identified through this method can lead to further biochemical and In vitro binding studies with the ultimate goal of developing new class of anti-malarial drugs. The use of structure prediction and modeling technologies in this study dramatically reduces the time it takes from target identification to drug lead determination. Furthermore, very many compounds that were previously incapable of being experimentally tested can now be tested in silico against the generated structure. Owing to the increasing utility of bioinformatics and three dimensional structural modeling software, one can accurately build physical models solely from sequence data by unwrapping the information therein on probable motif sites capable of being anchored onto available compounds or aptamers.",signatures:"Harrison Ndung’u Mwangi and Francis Jackim Mulaa",downloadPdfUrl:"/chapter/pdf-download/77452",previewPdfUrl:"/chapter/pdf-preview/77452",authors:[{id:"343043",title:"Prof.",name:"Francis",surname:"Jackim Mulaa",slug:"francis-jackim-mulaa",fullName:"Francis Jackim Mulaa"},{id:"343049",title:"Dr.",name:"Harrison",surname:"Ndung’u Mwangi",slug:"harrison-ndung'u-mwangi",fullName:"Harrison Ndung’u Mwangi"}],corrections:null},{id:"77404",title:"Malaria: Introductory Concepts, Resistance Issues and Current Medicines",doi:"10.5772/intechopen.98725",slug:"malaria-introductory-concepts-resistance-issues-and-current-medicines",totalDownloads:190,totalCrossrefCites:0,totalDimensionsCites:1,hasAltmetrics:0,abstract:"Malaria continues to be the main community health problem in numerous nations. Six species of Plasmodium are documented as the cause of human malaria infection. Among others, Plasmodium falciparum and Plasmodium vivax parasites produce an immense challenge in the public health. Anopheles funestus and Anopheles gambiae are the major transimmiter of the disease (malaria) from one person to another. The disease parasite has a complicated cycle of life that occurs in human and mosquitoes. In general, malaria diagnosis is divided into parasitological and clinical diagnosis. Internationally, the death rate of malaria becomes reduced although few records from Ethiopia describe the presence of raised prevalence of malaria in certain areas. Apart from reduction in incidence and prevalence, transmission of malaria is continued throughout the globe. Hence, its control needs a combined approach comprising treatment with effective antimalarial agents. A lot of novel compounds are under pre-clinical and clinical studies that are triggered by the occurrence of resistance among commonly used antimalarial drugs. In addition to the already known new compounds and targets for drug discovery, scientists from all corner of the world are in search of novel targets and chemical entities.",signatures:"Dejen Nureye",downloadPdfUrl:"/chapter/pdf-download/77404",previewPdfUrl:"/chapter/pdf-preview/77404",authors:[{id:"343470",title:"Mr.",name:"Dejen",surname:"Nureye",slug:"dejen-nureye",fullName:"Dejen Nureye"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"7663",title:"Role of Novel Drug Delivery Vehicles in Nanobiomedicine",subtitle:null,isOpenForSubmission:!1,hash:"e3fc1c64277dcc5702828fc74a423eea",slug:"role-of-novel-drug-delivery-vehicles-in-nanobiomedicine",bookSignature:"Rajeev K. 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Agents",doi:null,correctionPDFUrl:"https://cdn.intechopen.com/pdfs/76505.pdf\r\n",downloadPdfUrl:"/chapter/pdf-download/76505",previewPdfUrl:"/chapter/pdf-preview/76505",totalDownloads:null,totalCrossrefCites:null,bibtexUrl:"/chapter/bibtex/76505",risUrl:"/chapter/ris/76505",chapter:{id:"76353",slug:"the-ghanaian-flora-as-a-potential-source-of-anthelmintic-and-anti-schistosomal-agents",signatures:"Evelyn Asante-Kwatia, Abraham Yeboah Mensah, Lord Gyimah and Arnold Donkor Forkuo",dateSubmitted:"February 24th 2021",dateReviewed:"March 25th 2021",datePrePublished:"April 20th 2021",datePublished:"May 11th 2022",book:{id:"10356",title:"Natural Medicinal Plants",subtitle:null,fullTitle:"Natural Medicinal Plants",slug:"natural-medicinal-plants",publishedDate:"May 11th 2022",bookSignature:"Hany A. El-Shemy",coverURL:"https://cdn.intechopen.com/books/images_new/10356.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"54719",title:"Prof.",name:"Hany",middleName:null,surname:"El-Shemy",slug:"hany-el-shemy",fullName:"Hany El-Shemy"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"217045",title:"Dr.",name:"Arnold Forkuo",middleName:null,surname:"Donkor",fullName:"Arnold Forkuo Donkor",slug:"arnold-forkuo-donkor",email:"forkuo3@gmail.com",position:null,institution:null},{id:"303360",title:"Dr.",name:"Evelyn",middleName:null,surname:"Asante-Kwatia",fullName:"Evelyn Asante-Kwatia",slug:"evelyn-asante-kwatia",email:"emireku@yahoo.com",position:null,institution:null},{id:"309974",title:"Prof.",name:"Abraham Yeboah",middleName:null,surname:"Mensah",fullName:"Abraham Yeboah Mensah",slug:"abraham-yeboah-mensah",email:"aymensah@yahoo.com",position:null,institution:{name:"Kwame Nkrumah University of Science and Technology",institutionURL:null,country:{name:"Ghana"}}},{id:"347910",title:"Mr.",name:"Lord",middleName:null,surname:"Gyimah",fullName:"Lord Gyimah",slug:"lord-gyimah",email:"lordgyimah36@gmail.com",position:null,institution:{name:"Kwame Nkrumah University of Science and Technology",institutionURL:null,country:{name:"Ghana"}}}]}},chapter:{id:"76353",slug:"the-ghanaian-flora-as-a-potential-source-of-anthelmintic-and-anti-schistosomal-agents",signatures:"Evelyn Asante-Kwatia, Abraham Yeboah Mensah, Lord Gyimah and Arnold Donkor Forkuo",dateSubmitted:"February 24th 2021",dateReviewed:"March 25th 2021",datePrePublished:"April 20th 2021",datePublished:"May 11th 2022",book:{id:"10356",title:"Natural Medicinal Plants",subtitle:null,fullTitle:"Natural Medicinal Plants",slug:"natural-medicinal-plants",publishedDate:"May 11th 2022",bookSignature:"Hany A. 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This enormous availability of genomic information, in addition to its data availability, enables analysis of the complete genome of the species and imposes a growing demand for the understanding of several complex biological phenomena. Initially, the GWAS approach was applied in human genome studies involving entire sets of DNA from numerous individuals to find gene variations related to diseases such as asthma, diabetes, cancers, heart disease, and mental disorders. Nowadays the impact of GWS studies is not restricted only to the human genome to advances in the understanding of diseases. With the genome sequencing of several species and the availability of their complete genomes in large databases, other complex aspects can be investigated today by GWAS, such as evolutionary and phylogenetic relationships, characteristics of relevance for biodiversity conservation, and genetic improvement of plants and animals. Included in this book there are original and relevant works involving GWAS studies, carefully selected for the academic public. This book has been carefully designed to provide current and quality information to students and researchers of all levels who have an interest in Genome-Wide Association Studies and its applications.
",isbn:null,printIsbn:"979-953-307-X-X",pdfIsbn:null,doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"006916e730c66d3b84d3ec036f769e00",bookSignature:"Prof. Rafael Trindade Trindade Maia, Dr. Magnólia De Araújo Campos and Dr. Marco Antônio Alves Schetino",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11805.jpg",keywords:"Disorders, Deleterious Mutations, Association Mapping, Complex Diseases, Mega-Scale Genome Sequencing, Adaptative Fitness, Disease Resistance, Adaptative Alleles, Patterns of Inbreeding, Genome Phylogeny, Population Genetics, Population Structure",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"April 15th 2022",dateEndSecondStepPublish:"May 13th 2022",dateEndThirdStepPublish:"July 12th 2022",dateEndFourthStepPublish:"September 30th 2022",dateEndFifthStepPublish:"November 29th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"a month",secondStepPassed:!0,areRegistrationsClosed:!1,currentStepOfPublishingProcess:3,editedByType:null,kuFlag:!1,biosketch:"Professor honoured as an academic reviewer with an interest in the areas of genetics, evolution, bioinformatics, and biotechnology. Academic editor of books and journals and author of 3 patents and 1 software registration. Dr. Rafael Trindade Maia received a master´s degree in Genetics, Conservation, and Evolutionary Biology from the National Institute of Amazonian Research, Brazil, in 2008, and a Ph.D. in Animal Biology from the Federal University of Pernambuco, Brazil, in 2013.",coeditorOneBiosketch:"Dr. Magnólia A. Campos is a researcher with experience in the Genetics and Plant genomics and the author of books and patents. She has a master's in Agronomy / Plant Breeding from the Federal University of Pelotas and a Ph.D. in Biological Sciences / Molecular Biology from the University of Brasília. Since 2008, she has been a Professor at the Federal University of Campina Grande (UFCG).",coeditorTwoBiosketch:"Dr. Marco Antônio Alves Schetino studied biological sciences at the Federal University of Viçosa (UFV), Brazil, he received a master´s degree in Genetics, Conservation, and Evolutionary Biology from the National Institute of Amazonian Research (INPA), Brazil, and a Ph.D. in Genetics from the Federal University of Minas Gerais (UFMG), Brazil. He is a researcher with experience in Genetics (with emphasis on Animal Genetics, Evolution, and major health areas) and philosophy of science areas.",coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"212393",title:"Prof.",name:"Rafael",middleName:"Trindade",surname:"Trindade Maia",slug:"rafael-trindade-maia",fullName:"Rafael Trindade Maia",profilePictureURL:"https://mts.intechopen.com/storage/users/212393/images/system/212393.jpg",biography:"Dr. Rafael Trindade Maia studied biological sciences at the Federal Rural University of Pernambuco, Brazil (2005). He received a master´s degree in Genetics, Conservation, and Evolutionary Biology from the National Institute of Amazonian Research, Brazil, in 2008, and a Ph.D. in Animal Biology from the Federal University of Pernambuco, Brazil, in 2013. He is currently an adjunct professor at the Center for the Sustainable Development for Semiarid (CDSA) at Federal University of Campina Grande (UFCG), Brazil. He has experience with population genetics, bioinformatics, molecular docking, and modeling and molecular dynamics of proteins. He works in science and biology education. 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The gender also seems to play a major role, where the majority of OA patients are women and higher prevalence has been liked to menopause. Radiological evidence suggests that about 70% of women above the age of 65 years are affected by OA [2, 3]. Other factors such as genetic predisposition, extrinsic environmental factors, nutrition, and lack of exercise are reasons for the increased prevalence of OA. It has been reported by the World Health Organization (WHO) that 10–15% of the populations aged >60 years exhibit a certain degree of OA [4]. It has been reported by the National Health Portal of India that 22–39% of the Indian population are affected by OA. As reported by the United Nations Organization (UNO), 130 million people will be affected by OA with over 40 million people with severe disability due to disease progression [3].
The etiology of OA is believed to be multifactorial. Some of the main reasons include the biomechanical disease progression due to the narrowing of space in the joints, bone hypertrophy, and formation of new osteophytes in the articular margins causing stiffness and pain in the joints. In addition, an imbalance in the synthesis and release of cytokines by chondrocytes in the disease state could be the main reason for the continual inflammatory state in the joint. During the initial stages of OA, catabolic interleukins (IL) such as IL-1α and IL-1β and tumor necrosis factor α (TNFα) increase inflammation affecting cartilage metabolism and homeostasis. TNFα is a proinflammatory cytokine implicated in the degradation of matrix proteins synthesized by chondrocytes and synoviocytes [5]. Further, increase in the levels of interferon γ (IFNγ) in the joint worsens the inflammatory state and structure of the joint leading to degradation of proteoglycans such as sulfated glycosaminoglycans (sGAG) [5, 6].
Currently, pain in OA is pharmacologically managed using nonsteroidal anti-inflammatory drugs (NSAIDS), opioids, and analgesics. Corticosteroid injections have also been used for relieving severe pain in OA patients. Recent attempts have been made to use TNFα blockers as recent studies have proven the significant role of TNFα in contribution to the pathogenesis of OA [7]. Research by several groups has implicated the role of nerve growth factor (NGF) and its binding to tropomyosin receptor kinase A (trk A) which leads to downstream signaling and activation of peripheral and central pain molecules causing severe pain. The therapeutic efficiency of anti-NGF antibodies to block NGF or its antagonists has been studied by several groups for relieving pain. The pain-relieving effects of anti-NGF antibodies fasinumab and fulranumab manufactured by Regeneron Pharmaceuticals and Janssen Pharmaceutica, respectively, have been evaluated in phase III clinical trials [8]. In addition to pain relief, efforts have been made to halt further cartilage damage using slow-acting symptomatic drugs such as chondroitin sulfate and glucosamine sulfate. Orally administered chondroitin and glucosamine have shown to relieve joint pain equivalently compared to NSAIDs. These molecules, intact or broken, could be absorbed into the matrix of the joint and prevent cartilage degeneration. Although glucosamine and chondroitin sulfate have been clinically proven to be safe, their therapeutic efficacy in protecting the cartilage matrix was found to the variable [9]. In grade 4 OA (Kellgren and Lawrence classifications), patients are advised to opt for total knee replacement surgery [10]. Alternatively, autologous chondrocyte implantation (ACI) has been suggested and reported to be successful. In the ACI method, the chondrocytes from patients are taken, culture-expanded in vitro, and then implanted back into the knees of patients. This procedure is invasive and has a lesser success rate than total knee replacement surgeries [11].
Apart from ACI, the efficacy of autologous platelet-rich plasma (PRP) in providing pain relief and promoting cartilage regeneration has been recently investigated by several groups [12]. The PRP is rich in platelets that secrete several growth factors and cytokines such as platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF-1), vascular endothelial growth factor (VEGF), and prostaglandin E2 (PGE-2) [13]. Several research groups have reported that intra-articular injections of PRP primarily reduced inflammation mediated by PGE-2, HGF, and IGF-1. IGF-1 synthesized and secreted by platelets is shown to prevent leukocyte infiltration into the joint space, thereby reducing the levels of IL-1β and TNFα in the synovial fluid [13]. Overall intra-articular injection of PRP has been shown to maintain joint homeostasis. However, clinical trial data suggest that the effect of PRP seems to last for only 3 weeks and thereafter reduces. The symptoms of OA were seen to relapse after a period of 1 year. Although promising results were observed using PRP in the hydrogel, chitosan, or hyaluronic acid (HA) scaffolds [14], efficacy is yet to be shown in elaborate randomized clinical trials (RCTs).
The history of mesenchymal stromal/stem cells (MSCs) dates back to 1960 when seminal studies conducted by Friedenstein showed the isolation of MSCs from bone marrow (BM) which were capable of forming ectopic bone in vivo. This was found to be a non-hematopoietic fibroblast-like, colony-forming cell which primarily supported hematopoietic stem cells in the perivascular niche [15]. Owen and Friedenstein discovered that these cells were capable of differentiating into the osteogenic lineage [16]. Subsequently, the multipotent plasticity of that bone marrow MSCs (BMMSCs) was identified and shown that they were capable of differentiating into osteocytes, chondrocytes, and adipocytes in vitro [17]. In addition to the abovementioned three lineages, Caplan and colleagues demonstrated that these cells were capable of differentiating into cells of the muscle, tendons/ligaments, and connective tissue after which he coined the term “mesenchymal stem cells” [18]. Bianco and Gehron Robey deduced that
The pathophysiology of OA is characterized by degradation of hyaline cartilage causing narrowing of joint space leading to subchondral sclerosis, subchondral cysts, hypertrophic chondrocytes, and formation of osteophytes. The friction caused by the rubbing of joints results in chronic pain in OA patients [24]. Degeneration of cartilage extracellular matrix (ECM) may be caused due to the increase in the levels of proteolytic enzymes such as matrix metalloproteases (MMPs) and aggrecanases mediated by IL-1β and TNFα [25]. BMMSCs express a wide range of properties that are anticipated to be beneficial for treating genetic, mechanical, and age-related degeneration in diseases such as OA. In our previous publication, we have in detail attempted to deduce the possible mechanism of action (MoA) of allogeneic pooled BMMSC population [25]. Briefly, BMMSCs are known to be immunomodulatory in nature, primarily because of their potential to significantly suppress the proliferation of inflammatory T cells, monocytes, and dendritic cells either by direct cell-to-cell contact. In addition, they secrete a wide range of anti-inflammatory molecules such as PGE-2, IDO, IL1Ra, and IL-10 [26, 27]. BMMSCs influence the local osteoarthritic microenvironment by stimulating resident chondrogenic progenitor cells and promote their differentiation into mature chondrocytes mediated by secretion of bone morphogenetic proteins (BMPs) and TGFβ1 [28]. BMMSCs are known to differentiate into chondrocytes in vitro using differentiation cues such as BMP-7 and TGFβ1. A similar mechanism could be involved in the differentiation of BMMSCs in vivo. With the increase in the levels of BMP-7 and TGFβ1 in the local joint milieu, mediated by a change in expression of master regulatory genes such as Sox9, HoxA, HoxD, and Gli3, BMMSCs could differentiate into chondrogenic progenitor cells (CPCs) in vivo. The CPCs further differentiate into chondroblasts characterized by definitive upregulation of collagen types II B, IX, and XI. Subsequently, the CPCs differentiate into mature chondrocytes regulated by balanced expression of collagen X (Col X) and synthesize the secretion of collagen II which is made of sGAG building blocks which maintain the structural integrity of hyaline cartilage [25]. Very high expression of collagen X has been linked to hypertrophy of chondrocytes and formation of fibrous cartilage, and thus a regulated expression of Col X would likely result in deposition of hyaline cartilage [29]. From the above-described multimodal MoA, it is clear that BMMSCs are an ideal cell population which could contribute significantly for an effective treatment of OA.
In the current therapeutic scenario, the common practice is to screen several individual donors, isolate MSCs, and characterize them based on their key characteristics such as their surface marker expression, tri-lineage differentiation potential, and immunomodulatory and paracrine properties [30, 31, 32]. It is inevitable that a product that is manufactured using a master cell bank (MCB) made from a single donor will result in exhaustion. Successively, a product that is made using another single donor MSC bank, although presumably similar in basic characteristics qualifying the identity and safety criteria, may not have the same functional attributes which may lead to varied therapeutic outcomes. Eminent scientific groups have demonstrated donor-to-donor variability in properties of MSCs such as their clonogenicity, growth kinetics, and differentiation potential [33]. A comparative analysis of five different BMMSC populations showed significant variation in the proteomic profile of these cells. Only 13% similarity in the proteomic profile which included transcriptional and translational regulators, kinases, receptor proteins, and cytokines between the five BMMSC populations was found. A maximum of 72% similarity in the proteome was observed between two of the five analyzed cell populations [34]. Disparities in clinical trial outcomes have been reported where BMMSCs derived from single donors have been used. A steroid-refractory acute graft-versus-host disease (SR-aGvHD) clinical trial conducted in both children (n = 25) and adults (n = 30) using BMMSC products derived from 92 HLA-matched and HLA-mismatched donors resulted in only 50% overall durable complete response, while the remaining patients did not respond or partially responded to the treatment [35]. Similar variations with limited response rates were observed in a phase III GvHD trial conducted by Osiris Therapeutics using Prochymal® with only 35% complete response rate compared to 30% in the placebo arm [36]. It has been suggested that improper selection of a BM donor and making a single donor-derived cell product could lead to substantial variations in therapeutic outcomes [37]. In order to challenge this issue, some scientific groups have suggested pooling of BMMSCs from two or more donors in order to compensate for the variation and balance the properties between different donor cell populations. Samuelsson et al. showed that a two- or three-donor pooled BMMSC product could optimize the immunosuppressive properties of these cells in vitro [38]. Later, Kuçi et al. showed substantial variability in the immunosuppressive properties of individual donor-derived BMMSCs (n = 8). On the contrary, a mesenchymal end product (MEP) made by pooling BMMNCs from eight donors resulted in a cell population that consistently suppressed an MLR in vitro [39]. Subsequently, they went on to conduct a multicentric SR-aGvHD clinical trial in 51 children and 18 adults using MEP/MSC Frankfurt am Main (MSC-FFM, Obnitix®) cells and observed 83% overall response (complete response, 32%; partial response, 51%) [40]. At Stempeutics Research Pvt. Ltd., we were the first group to develop an allogeneic pooled human BMMSC product called Stempeucel® using an established, robust pooling protocol and a two-tier manufacturing and banking system as previously described [41, 42]. Recently, we have published our comprehensive studies including in vitro chondrogenic properties and preclinical and clinical findings establishing the efficacy and safety of using Stempeucel® for the treatment of OA of the knee joint [43]. In this study, we found that several manufactured batches of Stempeucel®, when differentiated into the chondrocyte lineage, downregulated the expression of the gene Sox9 and upregulated the expression of collagen type 2A (Col2A) gene confirming their differentiation into the chondrogenic lineage. The same Stempeucel® batches synthesized substantial levels of sGAG (30 ± 1.8 μg/μg GAG/DNA) which were estimated using a dimethylmethylene blue-based biochemical assay kit (Figure 1). These properties indicate that Stempeucel® could be a potential treatment option for treating OA.
Chondrogenic potency assessment using quantification of sGAG in 16 batches of Stempeucel® cryopreserved in PlasmaLyte A-based cryopreservation solution and 4 batches of Stempeucel® cryopreserved in CS 5.
The US Food and Drug Administration (USFDA) describes potency assays as “The specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result” (US-FDA, 21 CFR 600). For any cell therapy product (CTP) intended to be used for a particular indication, a specific, quantifiable, potency test or array must be developed. The development of a potency assay must begin with in vitro and preclinical studies based on the MoA of the CTP. The confirmation of the assay or the identified marker must be evaluated in every large-scale manufactured batch of the CTP during the progress of the phase I and phase II clinical studies. A quantifiable range for the potency test must be defined and implemented during the course of phase III clinical trial [44]. In order to predict the efficacy of a CTP, either in vitro biochemical assays or biological assays or in vivo biological assessment could be implemented. For example, a company called TiGenix (Leuven, Belgium) has developed and adopted an assay matrix where an ex vivo polymerase chain reaction (PCR) array for autologous chondrocytes (ChondroCelect) is performed and ectopic cartilage formation is correlated to the histology sections of an orthotopic goat model where ChondroCelect is implanted [45, 46]. Jeong et al. have demonstrated that thrombospondin-2 (TSP-2) could be an effective marker to predict the chondrogenic efficiency of umbilical cord-derived MSCs (UC-MSCs). They demonstrated that UC-MSCs, through the TSP-2 secretion, can promote chondrogenesis via PKCa, ERK, P38/MAPK, and Notch signaling pathways [47]. Recently, another group estimated the levels of TSP-2 to evaluate the chondrogenic potency of a UC-MSC product (Cellistem®OA, Cells for Cells, Brazil) intended to be used in phase I/phase II RCT for knee OA [48]. Other scientific groups have shown that autologous culture-expanded chondrocytes could be embedded in collagen-1 and injected subcutaneously in nude mice to predict the potency of several bioactive molecules in promoting chondrogenesis [49]. For the first time, we have developed a chondrogenic potency assay for an allogeneic pooled bone marrow-derived MSC product (phBMMSCs, Stempeucel®). Preliminarily, we culture-expanded and differentiated several Stempeucel® batches into the chondrogenic lineage using commercially available differentiation assay kits (Thermo Fisher Scientific, USA). To confirm the differentiation, we evaluated the Col2A mRNA expression in differentiated cells and compared them with the undifferentiated control cells. After observing a significant increase in the Col2A expression of differentiated cells, we enzymatically digested both the differentiated and undifferentiated cells to quantify the levels of sGAG synthesized by these cells using a 1,9-dimethylmethylene blue (DMMB)-based assay kit (Blyscan, Biocolor, UK). We further normalized the levels of sGAG with the amount of DNA from the same number of cells. We evaluated the sGAG levels in 20 batches of Stempeucel® of which 16 batches were cryopreserved in our older formulation (10% dimethyl sulfoxide (DMSO), 5% human serum albumin (HSA) and PlasmaLyte A) and also four batches of Stempeucel® cryopreserved in a new cGMP grade CryoStor 5 solution (CS5, BioLife Solutions). We observed a significant and consistent increase in the levels of sGAG in the differentiated cells compared to the undifferentiated cells (undifferentiated, 11.9 ± 4.6 GAG/DNA (μg/μg); differentiated, 31 ± 8.6 GAG/DNA (μg/μg; P < 0.0001; n = 20)) (Figure 1). Based on our results, we propose that the sGAG assay is a simple, quantifiable, and robust potency assay which could also be a part of a bigger potency assay matrix to predict the chondrogenic potency of therapeutic cells intended to treat cartilage defects.
Many studies have demonstrated that MSCs are nontoxic and non-tumorigenic when tested in various animal models [50, 51]. Prior to evaluating the efficacy of Stempeucel® in an appropriate preclinical model of OA, we had earlier evaluated the preclinical safety and toxicity of Stempeucel® in rodent and non-rodent models. In the same study, we evaluated the feasibility of multiple routes of cell injection. Tumorigenic analysis in severe combined immunodeficient (SCID) mice showed that Stempeucel® is non-tumorigenic. In addition, the biodistribution kinetics of CM-DiI labeled Stempeucel® in the systemic circulation and also in muscle tissue were studied in both rats and mice [51].
It is important to demonstrate the efficacy of any cell therapy product in an animal model of disease before administrating the product in humans with the same disease. It is imperative to determine the suitability of using animal stem cells in animals or human stem cells in immunocompromised/immunocompetent animals. A common regulatory requirement is to have animal data for the same test product that is intended to be tested in humans. In our recently published work, we evaluated the efficacy of Stempeucel® in a monosodium iodoacetate (MIA)-induced OA model in Wistar rats. We demonstrated the dose-dependent efficacy of two Stempeucel® doses of 0.65 × 106 (25 × 106 human equivalent dose, HED) and 1.3 × 106 (50 × 106 HED) followed by an injection of hyaluronic acid (HA). A significant dose-dependent reduction in pain scores was observed in both low and high Stempeucel® doses compared to the HA alone and disease control group. Histological evaluation of joint tissue sections in all study groups showed significant improvement in proteoglycan staining in both low and high Stempeucel® administered groups indicating significant regeneration of the cartilage in both groups compared to the HA alone and disease control groups [43].
Similar to the animal model we used, other scientific groups have created articular cartilage defects in small animals, such as mice [52], rats [43, 53, 54], and rabbits [55, 56]. Smaller animal models are cost-effective and easy to house, and rodents are available in a variety of genetically modified strains with minimal biological variability [57, 58]. However, the small joint size, thin cartilage, altered biomechanics, and increased spontaneous intrinsic healing hamper the study of the regenerative capacity of stem cells and these mechanisms of healing which cannot be fully extrapolated to human cartilage repair [59, 60]. Rodents have mainly been used to assess the chondrogenesis of cell-based therapies by subcutaneous, intramuscular, and intra-articular implantations of cells [60]. Of all small animals, the rabbit model is the most utilized model in cartilage regeneration studies because of the slightly larger knee joint size than rodents [55, 56]. Despite their limited translational capacity, small animals can be very useful as a proof-of-principle study and to assess therapy safety before moving on to preclinical studies using larger animals [60].
Large animal models play a more substantial role in translational research because of a larger joint size and thicker cartilage; however, their preclinical use is often hindered by high costs and difficulties in animal handling. A variety of large animal models have been used to investigate cartilage repair strategies, including horses [61], dogs [62], sheep [63, 64], goats [65], and pigs [66], each with their own strengths and limitations. We have listed some relevant published studies which have used autologous, allogeneic, or xenogeneic BMMSCs to treat OA induced by various methods (Table 1).
Author/year | Animal | OA model | Cell type and dose | Vehicle | Study duration time points | Reference |
---|---|---|---|---|---|---|
Murphy et al. (2003) | Goat | ACLT-meniscectomy | 10 × 106 Autologous (goat) BMMSC + HA | HA | 12 and 26 weeks | [65] |
Frisbie et al. (2009) | Horse | Arthroscopic surgery | 10.5 × 106 Autologous (horse) BMMSC | Saline | 10 weeks | [61] |
Sato et al. (2012) | Pig | Spontaneous | 7 × 106 Xenogeneic (human) BMMSC | HA/PBS | 1, 3, and 5 weeks | [66] |
Song et al. (2014) | Sheep | ACLT-meniscectomy | 10 × 106 Autologous (sheep) BMMSC | PBS | 8 weeks | [63] |
Delling et al. (2015) | Sheep | Bilateral meniscectomy | 20 × 106 Autologous (sheep) BMMSC | PBS | 0, 1, 4, 8, and 12 weeks | [64] |
Singh et al. (2014) | Rabbit | ACLT | 1 × 106 Autologous (rabbit) BMMSC | Culture medium | 4 and 6 weeks | [55] |
Chiang et al. (2016) | Rabbit | ACLT | 1 × 106 Allogeneic (rabbit) BMMSC | HA | 6 and 12 weeks | [56] |
Diekman et al. (2013) | Mouse | Closed tibial plateau fracture | 1 × 105 Allogeneic (mice) BMMSC | Saline/mouse albumin | 8 weeks | [52] |
Suhaeb et al. (2012) | Rat | MIA injection | 3.5 × 106 Allogeneic (rat) BMMSC | HA | 3 and 9 weeks | [67] |
Kim et al. (2014) | Rat | ACLT-meniscectomy | 1 × 106 Allogeneic (rat) BMMSC | Culture medium | 3 and 6 weeks | [53] |
Yang et al. (2015) | Rat | ACLT-meniscectomy | 0.5 × 106 Autologous (rat) BMMSC | PBS | 3 weeks | [54] |
Gupta et al. (2016) | Rat | MIA injection | 0.6 × 106 or 1.3 × 106 Xenogeneic (human) pooled BMMSC | PlasmaLyte A | 4, 8, and 12 weeks | [43] |
OA preclinical studies using BMMSCs.
Based on the positive efficacy outcomes of our preclinical study, subsequently, we demonstrated the safety and optimal dose for efficacy in a phBMMSC product, Stempeucel®, in a randomized, double-blind, placebo-controlled dose-finding phase II clinical trial in Indian patients [43].
Lalu MM et al. conducted a systematic review of clinical trials that examined the use of MSCs to evaluate their safety [68]. A total of 36 studies having 1012 participants with different clinical conditions was evaluated. Eight studies were randomized control trials (RCTs) and enrolled 321 participants. Only prospective clinical trials that used the intravenous or intra-arterial route of administration in different age groups were analyzed. Meta-analysis did not detect an association with MSC administration and acute infusional toxicity, organ system complications, infection, and death. There was a significant association between MSCs and transient fever at or shortly after MSC administration which was not associated with long-term sequelae. Most importantly, the meta-analysis showed no serious adverse event due to the administration of MSCs and specifically found no association between MSCs and tumor formation. In another study, Peeters et al. [69] did a systemic review of the safety of intra-articular administration of culture-expanded stem cells. A total of 844 procedures (mean follow-up of 21 months) was analyzed. Four SAEs were reported—one infection following bone marrow aspiration (BMA) that resolved with antibiotics, one pulmonary embolism after 2 weeks of BMA, and two adverse events not related to the therapy. Other adverse events documented were increased pain/swelling and dehydration after BMA. In another review, a recent analysis of adverse events (AEs) in 2372 orthopedic patients treated with autologous stem cell therapies and followed up for 2.2 years has been published [70]. The common AEs reported included post-procedure pain and pain due to progressive degenerative joint disease in under 4% of the population. Hence, we can conclude that the systemic administration of MSC including intra-articular administration is safe.
Several clinical trials have been conducted using bone marrow mononuclear cells, adipose tissue-derived stromal vascular fraction (AD-SVF), adipose tissue-derived mesenchymal stromal cells (AD-MSCs), or bone marrow-derived mesenchymal stromal cells (BMMSCs) in OA of the knee joint. The list of the published clinical trials in chronological order is given in Table 2. Administration of the cells has been fairly standardized, with the cells being administered either directly intra-articularly or under ultrasound guidance. Few trials have been conducted using the arthroscopic method of administration with direct implantation of the cells alone or with a scaffold at the site of cartilage injury.
Author/year | Sample size | Study design | Grade of OA | Cell type and dose | Control group | Outcome measures | Outcomes | Follow-up period | Reference |
---|---|---|---|---|---|---|---|---|---|
Wakitani (2002) | 24 | A single-arm control study | Stage I to stage II Ahlback changes | Auto BMMSC, 13 × 106 cells embedded in soluble collagen (n = 12) | High tibial osteotomy (n = 12) | Hospital for Special Surgery knee rating scale, arthroscopy and histology | No significant difference in clinical evaluations between the two groups, arthroscopy and histology showed partially hyaline cartilage-like tissue | 16 months | [71] |
Centeno et al. (2008) | 1 | Case study | — | Auto BMMSC, 2.4 × 106 cells + 1 ml NC + 1 ml PRP | Nil | VAS, ROM, and MRI | Decreased VAS pain scores; increased the range of motion; MRI, statistically significant cartilage and meniscus growth | 6 months | [72] |
Haleem et al. (2010) | 5 | Case series | Outerbridge grade III or grade IV | Auto BMMSC + PR-FG, 15 × 106 cells | Nil | Lysholm and RHSSK scores and X-rays and MRI | Lysholm and RHSSK scores showed statistically significant improvement, MRI of three patients revealed complete defect fill | 12 months | [73] |
Nejadnik et al. (2010) | 72 | Cohort study | Lesion grade 3 or grade 4 | Auto BMMSC | n = 12 each in BMMSC and chondrocyte group | ICRS, SF-36, IKDC, Lysholm knee scale and Tegner activity level scale | SF-36 showed physical role functioning improvement in the BMMSC group, no difference in other outcome measures | 24 months | [74] |
Davatchi et al. (2011) | 4 | Single-arm study | Moderate to severe OA | Auto BMMSC, 8–9 × 106 cells | Nil | VAS pain score, time to walk and number of stairs to climb to produce pain, the resting time to induce the gelling pain, ROM and patellae crepitus | Walking time for the pain to appear improved for three patient, VAS pain score and number of stairs to climb improved for all patients, improvement in crepitus | 6 months | [75] |
Saw et al. (2011) | 5 | Single-arm study | ICRS grade 3 or grade 4 | Auto PBPC (8 ml) + HA/weekly injection × 5 | Nil | Arthroscopy and histology | Arthroscopy showed articular cartilage regeneration and histologically showed hyaline cartilage | 26 months | [76] |
Koh et al. (2012) | 25 | Case–control study | KL grade 3 or grade 4 | Arthroscopic debridement + Auto AD-MSC, 1.89 × 106 cells + PRP | Arthroscopic debridement + PRP | Lysholm score, Tegner activity scale, and VAS scores | The clinical scores preoperatively were significantly poorer than those of the control group but at the last follow-up visit were similar and not significantly different between the two groups | 18 months | [77] |
Orozco et al. (2013) | 12 | Case series | KL grade 2 to grade 4 | Auto BMMSC, 40 × 106 cells | Nil | VAS score, Lequesne indexes, WOMAC scores, MRI T2 mapping | All clinical scores decreased significantly, MRI T2 mapping showed improvement of cartilage quality | 12 months | [78] |
Koh et al. (2013) | 18 | Case series | KL grade 3 or grade 4 | Auto AD-MSC, 1.18 × 106 cells + PRP | Nil | WOMAC score, Lysholm score, Tegner activity scale, and VAS scores, MRI (WORMS score) | WOMAC, Lysholm, Tegner, and VAS scores improved significantly, WORMS score in MRI improved significantly | 26 months | [79] |
Van Pham et al. (2014) | 21 | Case series | KL grade 2 or grade 3 | Auto SVF | Nil | VAS, Lysholm score, and MRI | VAS scores improved, Lysholm scores increased, MRI showed increased cartilage thickness | 8.5 months | [80] |
Koh et al. (2014) | 37 knees (35 patients) | Case series | KL grade 1 or grade 2 | Auto AD-MSC, 3.8 × 106 cells | Nil | IKDC score, Tegner activity scale, and cartilage repair assessed using ICRS grading | IKDC and Tegner activity scale scores significantly improved, ICRS grades showed 2 of the 37 lesions (5%) were grade I (normal) and 7 (19%) were grade II (near normal) | 26.5 months | [81] |
Koh et al. (2015) | 30 | Case series | KL grade 2 or grade 3 | Auto SVF + PRP, 42 × 106 cells | Nil | Lysholm score, KOOS, VAS score, arthroscopic evaluation (n = 16) | Significant improvement in all clinical outcomes, 87.5% of patients (14/16) improved or maintained cartilage status | 24 months | [82] |
Munar et al. (2015) | 50 | Case series | KL grade 2 to grade 4 | Auto BMMSC, 40 × 106 cells | Nil | VAS, Lequesne and WOMAC indices, MRI (T2 mapping) | All clinical scores improved, T2 mapping, PCI decreased significantly | 12 months | [83] |
Davatchi et al. (2016) | 4 | Case series | Moderate to severe OA | Auto BMMSC, 8–9 × 106 cells | Nil | VAS pain score, time to walk and number of stairs to climb to produce pain, the resting time to induce the gelling pain, ROM and patellae crepitus | All parameters still better than baseline at 5 years follow-up for three patients | 60 months | [84] |
Soler et al. (2016) | 15 | Single-arm, open-label phase I/phase II trial | KL grade 2 or grade 3 | Auto BMMSC, 41 × 106 cells | Nil | VAS score, questionnaire, QOL SF-36 questionnaire, Lequesne functional index and WOMAC score, MRI (T2 mapping) | The clinical scores improved, SF-36 showed improvement of parameters, T2 mapping showed signs of cartilage regeneration | 12 months | [85] |
Sampson et al. (2016) | 125 | Retrospective case series | KL grade 3 or grade 4 | Auto BMC + PRP (8 weeks apart) | Nil | VAS score, patient satisfaction scale | VAS score and patient satisfaction score improved in all patients | 4.8 months | [86] |
Fodor and Paulseth (2016) | 6 patients (8 knees) | Case series | KL grade 1 to grade 3 | Auto SVF, 14.1 × 106 cells | Nil | VAS score, WOMAC score, ROM, TUG test, and MRI | VAS and WOMAC scores significantly improved, ROM and TUG improved, MRI showed no detectable structural differences | 12 months | [87] |
Kim et al. (2016) | 20 patients (24 knees) | Case series | KL grade 1 or grade 2 | Auto AD-MSC, 4.4 × 106 cells | Nil | IKDC score, Tegner activity scale, MRI MOAKS and MOCART score | Clinical outcomes significantly improved, MOAKS and MOCART score significantly improved | 24 months | [88] |
Pak et al. (2016) | 3 | Case reports | KL grade 3 | Auto AD-SVF + HA + PRP, PRP repeated weekly × 3 | Nil | FRI, ROM and VAS score, MRI | All clinical scores improved in three patients, MRI showed cartilage-like tissue regeneration | 4.5 months | [89] |
Pers et al. (2016) | 18 | Open-label, phase I study | KL grade 3 or grade 4 | Auto AD-MSC, low (2 × 106), medium (10 × 106), and high dose (50x106), 6 patients each | Nil | Safety, WOMAC, VAS, PGA, SAS and KOOS index, MRI, dGEMRIC in 6 patients | Safety established, low dose most effective, and all parameters improved as compared to baseline, dGEMRIC improved in three patients | 6 months | [90] |
Koh et al. (2016) | 80 | RCT | ICRS grade 3 or grade 4 | Auto AD-MSC + fibrin glue + microfracture, 5 × 106 cells (group 1) | n = 40 (group 2) (microfracture) | Lysholm score, KOOS, VAS score, MRI, cartilage repair tissue scoring system, arthroscopy and histology | MRI, better signal intensity for repair tissue in group 1 (80%) as compared to 72.5% in group 2; KOOS pain and symptom subscores, significantly greater for group 1; arthroscopy and histology, no significant difference | 24 months | [91] |
Gupta et al. (2016) | 60 | Double-blind, phase II, RCT | KL grade 2 or grade 3 | Allo BMMSC + HA, four doses (25, 50, 75, 150 × 106 cells) | n = 20 (placebo + HA) | Safety, VAS, ICOAP, WOMAC, MRI, WORMS score | Safety established; AE were predominant in the higher-dose groups; VAS, ICOAP, and WOMAC scores best in the lowest dose; MRI, no significant difference | 24 months | [43] |
Lamo-Espinosa et al. (2016) | 30 | Phase I/phase II, RCT | KL grade 2 to grade 4 | Auto BMMSC + HA, two doses (10 and 100 × 106 cells) | n = 10, (HA) | Safety, VAS score, WOMAC, MRI, WORMS | Safety established. VAS, WOMAC, and WORMS scores significant in high-dose group at 12 months follow-up | 12 months | [92] |
de Windt et al. (2017) | 10 | Phase I/phase II single-center study | Modified Outerbridge grade 3 or grade 4 | Allo BMMSCs +10 or 20% autologous chondrons | Nil | Safety, KOOS, VAS, MRI, second-look arthroscopy, histology | No SUSAR; KOOS and VAS scores improved significantly; MRI, showed complete filling of the defect; arthroscopy, effective defect fill, and integration in the surrounding tissue; histology, positive staining for both type I and type II collagen and proteoglycan | 12 months | [93] |
Turajane et al. (2017) | 60 | RCT, single-center study | KL grade 1 to grade 3 | 3 groups, 20 each; first group (AAPBSC + PRP + G-CSF+ HA + MCS); second group (AAPBSC + PRP + HA + MCS); third group (control) (all given weekly × 3 injections) | 20 patients, IA, HA alone | Avoidance of TKA intervention and WOMAC scores | TKA done in three patients in the control group but not in the cell group; WOMAC, all groups reached statistically significant improvements within the individual (intra) groups | 12 months | [94] |
Shapiro et al. (2017) | 25 patients, 50 knees | RCT, single-blind, placebo-controlled | Bilateral OA, KL grade 1 to grade 3 | 25 knees; 5 ml of Auto BMAC +10 ml of platelet-poor bone marrow plasma | 25 knees; sterile saline, 15 ml | ICOAP, VAS scores, MRI, T2 mapping | No SAE, patients had a similar decrease in scores in VAS and ICOAP scores in both BMAC- and saline-treated arthritic knees | 6 months | [95] |
Park et al. (2017) | 7 | Open-label, single-arm, phase I/phase II | KL grade 3 and ICRS grade 4 | Two doses; Allo hUCB MSCs and HA hydrogel | Nil | ICRS cartilage repair, VAS, IKDC, MRI, histological findings | VAS and IKDC improved at 24 weeks and stable till 7 years; histology at 1 year showed hyaline-like cartilage; MRI at 3 years showed the persistence of regenerated cartilage | 7 years | [96] |
Nguyen et al. (2017) | 30 | Placebo-controlled trial | KL grade 2 or grade 3 | 15 patients; AM + Auto AD (SVF + PRP; 107 SVF cells/ml) | 15 patients, AM | Safety, WOMAC, Lysholm, and modified VAS scores, MRI | Safety established, WOMAC scores not significant between two arms at 6 and 12 months but significant at 18 months; increased Lysholm and VAS scores in the treatment group compared with the placebo; MRI, MRI demonstrated cartilage layer was thicker in the treatment group | 18 months | [97] |
Pintat et al. (2017) | 19 | Single-arm study | Patellofemoral OA | IA AD-MSC + PRP | Nil | WOMAC, MRI, T2 mapping | WOMAC scores significantly lower in treatment arm than baseline; MRI, no change | 12 months | [98] |
Russo et al. (2017) | 30 | Single-arm study | KL grade 1 to grade 3, grade > II (ICRS classification) | Auto microfragmented adipose tissue | Nil | VAS, KOOS, IKCD, subjective, Tegner Lysholm knee | IKDC and KOOS, improvement of 20 points; VAS and Tegner Lysholm score, improvement in 24 and 31 points, respectively | 12 months | [99] |
Yokota et al. (2017) | 13 | Single-arm study | KL grade 3 or grade 4 | IA Auto AD- SVF; 2.5 ml SVF containing 3 × 107 SVF cells/knee | Nil | VAS, JKOM, WOMAC | Scores improved by an average of 35% over baseline for JKOM, 32% improvement in WOMAC, and 40% for pain (VAS) | 6 months | [100] |
Jo et al. (2017) | 18 | Single-arm study | Knee OA | Auto AD-MSC; 3 doses (10 × 106, 50 × 106, and 100 × 106 AD-MSCs) | Nil | WOMAC, KSS, KOOS, VAS, MRI, size and depth of the cartilage defect, the signal intensity of regenerated cartilage and cartilage volume | No TEAE; WOMAC, KSS, and KOOS, improved knee function; VAS, improved pain (statistical significance in high dose); MRI, improvements in all parameters | 24 months | [101] |
Garay Mendoza et al. (2017) | 61 | Open-label, phase I/phase II controlled trial | Knee OA | Cell group, BM stimulation with subcutaneous administration of G-CSF (n = 30) | Control group, oral acetaminophen (n = 31) | VAS and WOMAC scores | BM-SC group showed significant improvement in knee pain and quality of life | 6 months | [102] |
Kuah et al. (2018) | 20 | RCT, double-blind, placebo-controlled | KL grade 1 to grade 3 | Randomized 4:1; Progenza (PRG) (Allo AD-MSC + culture supernatant); 2 groups, 8 pts. each, 3.9 or 6.7 million cells | 4 patients, placebo administered | Safety, WOMAC, VAS, AQoL-4D, biomarkers (urine, C2C and CTX-II; serum, MIF and CTX-I; MRI, MOAKS score) | All patients experienced at least one TEAE; VAS and WOMAC, statistically significant within-group reduction from baseline in PRG group, no statistically significant differences at any time point between placebo and PRG groups; MRI, no decrease in lateral tibial cartilage volume while the placebo group showed a statistically significant cartilage loss | 12 months | [103] |
Matas et al. (2018) | 29 | Phase I/phase II RCT, triple-blind trial | KL grade 1 to grade 3 | Allo UC-MSC, single (20 × 106) or repeat dose (20 × 106 baseline and 6 months), 10 pts. each | 9 patients, HA (baseline and 6 months) | VAS, WOMAC, MRI, WORMS score | No SAEs, repeat dose group had a significant decrease in VAS and WOMAC scores as compared to HA group, no changes in function subscale, SF36, and MRI | 12 months | [48] |
Emadedin et al. (2018) | 43 | RCT, phase I/phase II, placebo-controlled, triple-blind | KL grade 2 to grade 4 | Auto BMMSC, 40 × 106 cells (n = 19) | 5 ml normal saline (placebo) (n = 24) | VAS, WOMAC, walking distance, painless walking distance, standing time and knee flexion compared | WOMAC, significant improvements in total score, pain, and physical function subscales and improvement in painless walking distance compared with placebo | 6 months | [104] |
Khalifeh Soltani et al. (2019) | 20 | RCT, double-blind, placebo-controlled | KL grade 2 to grade 4 | Placental-derived MSC, 50–60 x 106 cells (n = 10) | Normal saline (n = 10) | VAS, KOOS, knee flexion range of motion (ROM), MRI | No SAEs; significant knee ROM improvement at 2 and 24 weeks; VAS, no change; KOOS, improvement till 8 weeks; MRI, chondral thickness improved in about 10% of the total knee joint area AT 24 weeks | 24 weeks | [105] |
Chronological list of publications of stem cell application for cartilage repair.
AAPBSC, autologous activated peripheral blood stem cells; AD-MSCs, adipose tissue-derived mesenchymal stromal cells; AEs, adverse events; Auto, autologous; Allo, allogeneic; AM, arthroscopic microfracture; AQoL-4D, assessment of quality of life 4D questionnaire; BMAC, bone marrow aspirate concentrate; BMMSCs, bone marrow-derived mesenchymal stromal cells; C2C, type II collagen C2C peptide; CTX-1, C-terminal telopeptide of type I collagen; CTX-II, C-terminal telopeptide of type II collagen; dGEMRIC, delayed gadolinium-enhanced magnetic resonance imaging of cartilage; FRI, functional rating index; HA, hyaluronic acid; G-CSF, granulocyte colony-stimulating factor; IA, intra-articular; ICOAP, Intermittent and Constant Osteoarthritis Pain; ICRS, International Cartilage Repair Society Cartilage Injury Evaluation Package; IKDC, International Knee Documentation Committee Subjective Knee Evaluation Form; JKOM, Japanese Knee Osteoarthritis Measure; KL grade, Kellgren and Lawrence grade; KOOS, Knee Injury and Osteoarthritis Outcome Scores; KSS, Knee Society clinical rating system; MIF, macrophage migration inhibitory factor; MOAKS, MRI Osteoarthritis Knee Score; MOCART, magnetic resonance observation of cartilage repair tissue; MCS, mesenchymal cell stimulation; MRI, magnetic resonance imaging; NC, nucleated cells; PCI, poor cartilage index; PBPC, peripheral blood progenitor cells; PGA, patient global assessment; PR-FG, platelet-rich fibrin glue; PRP, platelet-rich plasma; QOL, quality of life; RCT, randomized controlled trial; RHSSK, Revised Hospital for Special Surgery knee scores; ROM, range of motion; SAE, serious adverse event; SAS, Short Arthritis Assessment Scale; SF-36, Short Form-36 quality of life questionnaire; SUSAR, suspected unexpected serious adverse reaction; SVF, stromal vascular fraction; TEAE, treatment emergent adverse event; TKA, total knee arthroplasty; TUG, timed up and go; UC-MSC, umbilical cord-derived MSC; VAS, visual analog pain score; WOMAC, Western Ontario and McMaster Universities Osteoarthritis Index; WORMS, whole-organ magnetic resonance imaging score.
The first clinical study has been published way back in 2002 by Wakitani et al. [71]. In this study of 12 patients who underwent high tibial osteotomy, BMMSCs at a dose of 13 million cells were embedded in collagen gel and transplanted into the cartilage defect and covered with autologous periosteum. The clinical improvement was not significantly different from the control group, but the arthroscopic and histological evidence was better in the transplanted group than the control arm. Since then many studies have been published, but still many contentious issues regarding cell therapy in OA are being discussed. We will try to discuss a few burning issues in this chapter:
Recently a meta-analysis was done to evaluate the different endpoints used to see the therapeutic efficacy and safety of MSCs for the treatment of patients with knee osteoarthritis [113]. Five hundred eighty-two patients in 11 randomized controlled trials were included in this meta-analysis. It showed that MSC treatment significantly improved VAS and International Knee Documentation Committee (IKDC) scores after 24 months of follow-up compared to controls. MSC therapy also showed significant improvement in the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), Lequesne algofunctional indices (Lequesne), Lysholm knee scale (Lysholm), and Tegner activity scale (Tegner) at 12 or 24 months of follow-up. Hence, all the endpoints used currently for evaluation of efficacy in OA have shown significant improvement in different clinical trials:
Few clinical trials using autologous or allogeneic MSCs or mononuclear stem cells in OA have been conducted in India. The trials registered in the Clinical Trials Registry of India are the two trials done by Stempeutics (one phase II trial completed and the other phase III trial ongoing). However, one published trial by Bansal et al. [122] for the single-arm study was done in India in which a total of 10 patients were treated with AD-MSCs. The patients were evaluated for safety, WOMAC, 6-minute walk test (6MWT), and MRI for cartilage thickness. The patients were followed up for 2 years. The total WOMAC and its subscale scores and 6MWT were significantly improved at all-time points till 2 years of follow-up. Cartilage thickness as determined by MRI improved by at least 0.2 mm in six patients, was unchanged in two patients, and decreased by at least 0.2 mm in two patients. The authors concluded that the procedure demonstrated a strong safety profile with no severe adverse events or complications reported.
The off-the-shelf allogeneic, pooled BMMSC product developed by Stempeutics has completed one phase II clinical trial [43] and currently ongoing phase III trial in knee OA. In our completed phase II trial, we included patients of idiopathic OA in grade 2 or 3 of Kellgren and Lawrence radiographic criteria; patients who had self-reported difficulty in at least one of the following activities attributed to knee pain, lifting and carrying groceries, walking 400 m, getting in and out of a chair, or going up and down stairs; and patients who had been on stable medication, including nonsteroidal anti-inflammatory drugs/opioid analgesics for the past 3 months and in the age group of 40–70 years. All the criteria have to be present before being included in the study [43].
The phase II results of Stempeucel® in OA patients have been published [43]. Briefly, it was a double-blind, randomized, placebo-controlled, dose-finding study. In this study, 60 OA patients were randomized to receive different doses of Stempeucel®, 25, 50, 75, and 150 million cells or placebo. Stempeucel® was administered intra-articularly (IA) to the knee joint followed by 2 ml of hyaluronic acid (20 mg). The subjects were followed up for 2 years and were evaluated for safety parameters including AEs, and for efficacy parameters, VAS for pain, Intermittent and Constant Osteoarthritis Pain (ICOAP), WOMAC (total score and its subscales), and MRI were done to evaluate the WORMS score. The intra-articular administration of Stempeucel® was safe with knee pain and swelling as the most common AEs. Clinically relevant improvement in a persistent manner was seen in 25 million dose group in all subjective parameters (VAS, ICOAP, and WOMAC scores) (Figures 2–4). WORMS of MRI knee did not reveal any difference from the baseline and placebo group. It was concluded that intra-articular administration of Stempeucel® is safe and 25 million dose may be the most effective among the doses tested.
Visual analog scale values. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively.
WOMAC results. WOMAC: (A, B) composite; (C, D) pain; (E, F) stiffness; and (G, H) physical function. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively; WOMAC = Western Ontario and McMaster Universities Osteoarthritis Index.
ICOAP results. ICOAP: (A, B) total; (C, D) continuous pain; and (E, F) intermittent pain. Data presented as mean value ± SD; C1 = cohort 1; C2 = cohort 2; 25M, 50M, 75M, 150M = 25, 50, 75, 150 million cells, respectively; 1M, 3M, 6M, 12M = 1, 3, 6, 12 months, respectively; ICOAP = Intermittent and Constant Osteoarthritis Pain.
Currently, we are conducting a phase III trial in OA of the knee joint. This is a randomized, double-blind, multicentric, placebo-controlled study assessing the efficacy and safety of intra-articular administration of Stempeucel® in patients with osteoarthritis of the knee joint. One hundred and forty-six patients will be randomized to stem cell and placebo arm in a ratio of 1:1. Seventy-three patients will receive Stempeucel® (25 million) followed by 2 ml of hyaluronan, and 73 patients will receive only intra-articular injection of 2 ml of placebo followed by 2 ml of hyaluronan. The patients will be followed up for a total of 2 years after IMP administration. The details of the study are found in the Clinical Trials Registry of India (CTRI/2018/09/015785).
Osteoarthritis is a common disorder involving damage to synovial joint tissues particularly the cartilage and bone. Current treatments are mostly targeted at end-stage disease, but biological therapies including stem cell therapy show a promise for earlier intervention with a more prolonged benefit. With all the published clinical trial data, it is reasonable to expect that MSCs may prove to be an important therapy for OA. Pooled BMMSCs with their enhanced anti-inflammatory potential, immunomodulatory properties, and secretion of paracrine factors create the optimum environment for a controlled reparative pathway in the affected joint. Pooled BMMSC treatment, perhaps combined with other modalities like a scaffold, would be advantageous in providing treatment in early OA to slow disease progression, thus delaying or avoiding total joint replacement.
We thank Stempeutics Research Pvt. Ltd. and Mr. BN Manohar for proving the required funding for the relevant studies. We would like to thank Dr. Anish S Majumdar and Dr. Sudha Balasubramanian for their critical scientific inputs for potency assay development, preclinical studies, and clinical studies conducted by Stempeutics Research. We also thank Dr. Anoop Chullikana for his valuable inputs in the clinical studies.
The authors declare no conflict of interests.
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Thermoplastic starch (TPS), by itself, exhibits poor mechanical properties such as low tensile strength and severe deformations, which limits its application in packaging or films. In addition, TPS presents high hygroscopicity. The use of reinforcing agents in the starch matrix is an effective means to overcome these drawbacks and several types of biodegradable reinforcements, such as cellulosic fibers, whiskers, and nanofibers, have been utilized to develop new and inexpensive starch biocomposites. 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In this regard, optimum conditions of air temperature and humidity are explored and compared on psychrometric charts. Thermodynamic limitations of existing AC systems are discussed from the subject point of view. Consequently, four kinds of low-cost energy-efficient AC systems, namely: (i) direct evaporative cooling (DEC), (ii) indirect evaporative cooling (IEC), (iii) Maisotsenko cycle (M-Cycle) evaporative cooling (MEC), and (iv) desiccant AC (DAC), are investigated for climatic conditions of two cities, that is, Multan (Pakistan) and Fukuoka (Japan). In addition, systems’ fundamentals and principles are explained by means of schematic diagrams and basic heat/mass transfer relationships. According to the results, performance of all systems is influenced by ambient air conditions; therefore, a particular AC system cannot provide optimum AC for all nonhuman applications. However, one or other AC system can successfully provide desired conditions of temperature and relative humidity. It has been concluded that evaporative cooling systems provide low-cost AC for dry climates, whereas DAC system is found energy efficient and viable for humid climates.",book:{id:"5909",slug:"refrigeration",title:"Refrigeration",fullTitle:"Refrigeration"},signatures:"Muhammad Sultan and Takahiko Miyazaki",authors:[{id:"199381",title:"Prof.",name:"Muhammad",middleName:null,surname:"Sultan",slug:"muhammad-sultan",fullName:"Muhammad Sultan"},{id:"199802",title:"Prof.",name:"Takahiko",middleName:null,surname:"Miyazaki",slug:"takahiko-miyazaki",fullName:"Takahiko Miyazaki"}]}],onlineFirstChaptersFilter:{topicId:"771",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"10",title:"Physiology",doi:"10.5772/intechopen.72796",issn:"2631-8261",scope:"Modern physiology requires a comprehensive understanding of the integration of tissues and organs throughout the mammalian body, including the cooperation between structure and function at the cellular and molecular levels governed by gene and protein expression. While a daunting task, learning is facilitated by identifying common and effective signaling pathways mediated by a variety of factors employed by nature to preserve and sustain homeostatic life. \r\nAs a leading example, the cellular interaction between intracellular concentration of Ca+2 increases, and changes in plasma membrane potential is integral for coordinating blood flow, governing the exocytosis of neurotransmitters, and modulating gene expression and cell effector secretory functions. Furthermore, in this manner, understanding the systemic interaction between the cardiovascular and nervous systems has become more important than ever as human populations' life prolongation, aging and mechanisms of cellular oxidative signaling are utilised for sustaining life. \r\nAltogether, physiological research enables our identification of distinct and precise points of transition from health to the development of multimorbidity throughout the inevitable aging disorders (e.g., diabetes, hypertension, chronic kidney disease, heart failure, peptic ulcer, inflammatory bowel disease, age-related macular degeneration, cancer). With consideration of all organ systems (e.g., brain, heart, lung, gut, skeletal and smooth muscle, liver, pancreas, kidney, eye) and the interactions thereof, this Physiology Series will address the goals of resolving (1) Aging physiology and chronic disease progression (2) Examination of key cellular pathways as they relate to calcium, oxidative stress, and electrical signaling, and (3) how changes in plasma membrane produced by lipid peroxidation products can affect aging physiology, covering new research in the area of cell, human, plant and animal physiology.",coverUrl:"https://cdn.intechopen.com/series/covers/10.jpg",latestPublicationDate:"June 20th, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:11,editor:{id:"35854",title:"Prof.",name:"Tomasz",middleName:null,surname:"Brzozowski",slug:"tomasz-brzozowski",fullName:"Tomasz Brzozowski",profilePictureURL:"https://mts.intechopen.com/storage/users/35854/images/system/35854.jpg",biography:"Prof. Dr. Thomas Brzozowski works as a professor of Human Physiology and is currently Chairman at the Department of Physiology and is V-Dean of the Medical Faculty at Jagiellonian University Medical College, Cracow, Poland. His primary area of interest is physiology and pathophysiology of the gastrointestinal (GI) tract, with the major focus on the mechanism of GI mucosal defense, protection, and ulcer healing. He was a postdoctoral NIH fellow at the University of California and the Gastroenterology VA Medical Center, Irvine, Long Beach, CA, USA, and at the Gastroenterology Clinics Erlangen-Nuremberg and Munster in Germany. He has published 290 original articles in some of the most prestigious scientific journals and seven book chapters on the pathophysiology of the GI tract, gastroprotection, ulcer healing, drug therapy of peptic ulcers, hormonal regulation of the gut, and inflammatory bowel disease.",institutionString:null,institution:{name:"Jagiellonian University",institutionURL:null,country:{name:"Poland"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"4",title:"Fungal Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/4.jpg",editor:{id:"174134",title:"Dr.",name:"Yuping",middleName:null,surname:"Ran",slug:"yuping-ran",fullName:"Yuping Ran",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bS9d6QAC/Profile_Picture_1630330675373",biography:"Dr. Yuping Ran, Professor, Department of Dermatology, West China Hospital, Sichuan University, Chengdu, China. Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"302145",title:"Dr.",name:"Felix",middleName:null,surname:"Bongomin",slug:"felix-bongomin",fullName:"Felix Bongomin",profilePictureURL:"https://mts.intechopen.com/storage/users/302145/images/system/302145.jpg",institutionString:null,institution:{name:"Gulu University",institutionURL:null,country:{name:"Uganda"}}},{id:"45803",title:"Ph.D.",name:"Payam",middleName:null,surname:"Behzadi",slug:"payam-behzadi",fullName:"Payam Behzadi",profilePictureURL:"https://mts.intechopen.com/storage/users/45803/images/system/45803.jpg",institutionString:"Islamic Azad University, Tehran",institution:{name:"Islamic Azad University, Tehran",institutionURL:null,country:{name:"Iran"}}}]},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. He also studies the use of medicinal plants for the control of infectious diseases as well as antimicrobial drug resistance.",institutionString:null,institution:{name:"University of Venda",institutionURL:null,country:{name:"South Africa"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"188881",title:"Dr.",name:"Fernando José",middleName:null,surname:"Andrade-Narváez",slug:"fernando-jose-andrade-narvaez",fullName:"Fernando José Andrade-Narváez",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRIV7QAO/Profile_Picture_1628834308121",institutionString:null,institution:{name:"Autonomous University of Yucatán",institutionURL:null,country:{name:"Mexico"}}},{id:"269120",title:"Dr.",name:"Rajeev",middleName:"K.",surname:"Tyagi",slug:"rajeev-tyagi",fullName:"Rajeev Tyagi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRaBqQAK/Profile_Picture_1644331884726",institutionString:"CSIR - Institute of Microbial Technology, India",institution:null},{id:"336849",title:"Prof.",name:"Ricardo",middleName:null,surname:"Izurieta",slug:"ricardo-izurieta",fullName:"Ricardo Izurieta",profilePictureURL:"https://mts.intechopen.com/storage/users/293169/images/system/293169.png",institutionString:null,institution:{name:"University of South Florida",institutionURL:null,country:{name:"United States of America"}}}]},{id:"6",title:"Viral Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/6.jpg",editor:{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:"King George's Medical University",institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"188773",title:"Prof.",name:"Emmanuel",middleName:null,surname:"Drouet",slug:"emmanuel-drouet",fullName:"Emmanuel Drouet",profilePictureURL:"https://mts.intechopen.com/storage/users/188773/images/system/188773.png",institutionString:null,institution:{name:"Grenoble Alpes University",institutionURL:null,country:{name:"France"}}},{id:"188219",title:"Prof.",name:"Imran",middleName:null,surname:"Shahid",slug:"imran-shahid",fullName:"Imran Shahid",profilePictureURL:"https://mts.intechopen.com/storage/users/188219/images/system/188219.jpeg",institutionString:null,institution:{name:"Umm al-Qura University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"214235",title:"Dr.",name:"Lynn",middleName:"S.",surname:"Zijenah",slug:"lynn-zijenah",fullName:"Lynn Zijenah",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSEJGQA4/Profile_Picture_1636699126852",institutionString:null,institution:{name:"University of Zimbabwe",institutionURL:null,country:{name:"Zimbabwe"}}},{id:"178641",title:"Dr.",name:"Samuel Ikwaras",middleName:null,surname:"Okware",slug:"samuel-ikwaras-okware",fullName:"Samuel Ikwaras Okware",profilePictureURL:"https://mts.intechopen.com/storage/users/178641/images/system/178641.jpg",institutionString:null,institution:{name:"Uganda Christian University",institutionURL:null,country:{name:"Uganda"}}}]}]},overviewPageOFChapters:{paginationCount:19,paginationItems:[{id:"82196",title:"Multi-Features Assisted Age Invariant Face Recognition and Retrieval Using CNN with Scale Invariant Heat Kernel Signature",doi:"10.5772/intechopen.104944",signatures:"Kamarajugadda Kishore Kumar and Movva Pavani",slug:"multi-features-assisted-age-invariant-face-recognition-and-retrieval-using-cnn-with-scale-invariant-",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"82063",title:"Evaluating Similarities and Differences between Machine Learning and Traditional Statistical Modeling in Healthcare Analytics",doi:"10.5772/intechopen.105116",signatures:"Michele Bennett, Ewa J. Kleczyk, Karin Hayes and Rajesh Mehta",slug:"evaluating-similarities-and-differences-between-machine-learning-and-traditional-statistical-modelin",totalDownloads:6,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Machine Learning and Data Mining - Annual Volume 2022",coverURL:"https://cdn.intechopen.com/books/images_new/11422.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"81791",title:"Self-Supervised Contrastive Representation Learning in Computer Vision",doi:"10.5772/intechopen.104785",signatures:"Yalin Bastanlar and Semih Orhan",slug:"self-supervised-contrastive-representation-learning-in-computer-vision",totalDownloads:24,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Pattern Recognition - New Insights",coverURL:"https://cdn.intechopen.com/books/images_new/11442.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}},{id:"79345",title:"Application of Jump Diffusion Models in Insurance Claim Estimation",doi:"10.5772/intechopen.99853",signatures:"Leonard Mushunje, Chiedza Elvina Mashiri, Edina Chandiwana and Maxwell Mashasha",slug:"application-of-jump-diffusion-models-in-insurance-claim-estimation-1",totalDownloads:8,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Data Clustering",coverURL:"https://cdn.intechopen.com/books/images_new/10820.jpg",subseries:{id:"26",title:"Machine Learning and Data Mining"}}}]},overviewPagePublishedBooks:{paginationCount:9,paginationItems:[{type:"book",id:"7723",title:"Artificial Intelligence",subtitle:"Applications in Medicine and Biology",coverURL:"https://cdn.intechopen.com/books/images_new/7723.jpg",slug:"artificial-intelligence-applications-in-medicine-and-biology",publishedDate:"July 31st 2019",editedByType:"Edited by",bookSignature:"Marco Antonio Aceves-Fernandez",hash:"a3852659e727f95c98c740ed98146011",volumeInSeries:1,fullTitle:"Artificial Intelligence - Applications in Medicine and Biology",editors:[{id:"24555",title:"Dr.",name:"Marco Antonio",middleName:null,surname:"Aceves Fernandez",slug:"marco-antonio-aceves-fernandez",fullName:"Marco Antonio Aceves Fernandez",profilePictureURL:"https://mts.intechopen.com/storage/users/24555/images/system/24555.jpg",biography:"Dr. Marco Antonio Aceves Fernandez obtained his B.Sc. (Eng.) in Telematics from the Universidad de Colima, Mexico. He obtained both his M.Sc. and Ph.D. from the University of Liverpool, England, in the field of Intelligent Systems. He is a full professor at the Universidad Autonoma de Queretaro, Mexico, and a member of the National System of Researchers (SNI) since 2009. Dr. Aceves Fernandez has published more than 80 research papers as well as a number of book chapters and congress papers. He has contributed in more than 20 funded research projects, both academic and industrial, in the area of artificial intelligence, ranging from environmental, biomedical, automotive, aviation, consumer, and robotics to other applications. He is also a honorary president at the National Association of Embedded Systems (AMESE), a senior member of the IEEE, and a board member of many institutions. His research interests include intelligent and embedded systems.",institutionString:"Universidad Autonoma de Queretaro",institution:{name:"Autonomous University of Queretaro",institutionURL:null,country:{name:"Mexico"}}}]},{type:"book",id:"7726",title:"Swarm Intelligence",subtitle:"Recent Advances, New Perspectives and Applications",coverURL:"https://cdn.intechopen.com/books/images_new/7726.jpg",slug:"swarm-intelligence-recent-advances-new-perspectives-and-applications",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Javier Del Ser, Esther Villar and Eneko Osaba",hash:"e7ea7e74ce7a7a8e5359629e07c68d31",volumeInSeries:2,fullTitle:"Swarm Intelligence - Recent Advances, New Perspectives and Applications",editors:[{id:"49813",title:"Dr.",name:"Javier",middleName:null,surname:"Del Ser",slug:"javier-del-ser",fullName:"Javier Del Ser",profilePictureURL:"https://mts.intechopen.com/storage/users/49813/images/system/49813.png",biography:"Prof. Dr. Javier Del Ser received his first PhD in Telecommunication Engineering (Cum Laude) from the University of Navarra, Spain, in 2006, and a second PhD in Computational Intelligence (Summa Cum Laude) from the University of Alcala, Spain, in 2013. He is currently a principal researcher in data analytics and optimisation at TECNALIA (Spain), a visiting fellow at the Basque Center for Applied Mathematics (BCAM) and a part-time lecturer at the University of the Basque Country (UPV/EHU). His research interests gravitate on the use of descriptive, prescriptive and predictive algorithms for data mining and optimization in a diverse range of application fields such as Energy, Transport, Telecommunications, Health and Industry, among others. In these fields he has published more than 240 articles, co-supervised 8 Ph.D. theses, edited 6 books, coauthored 7 patents and participated/led more than 40 research projects. He is a Senior Member of the IEEE, and a recipient of the Biscay Talent prize for his academic career.",institutionString:"Tecnalia Research & Innovation",institution:null}]},{type:"book",id:"7656",title:"Fuzzy Logic",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7656.jpg",slug:"fuzzy-logic",publishedDate:"February 5th 2020",editedByType:"Edited by",bookSignature:"Constantin Volosencu",hash:"54f092d4ffe0abf5e4172a80025019bc",volumeInSeries:3,fullTitle:"Fuzzy Logic",editors:[{id:"1063",title:"Prof.",name:"Constantin",middleName:null,surname:"Volosencu",slug:"constantin-volosencu",fullName:"Constantin Volosencu",profilePictureURL:"https://mts.intechopen.com/storage/users/1063/images/system/1063.png",biography:"Prof. Dr. Constantin Voloşencu graduated as an engineer from\nPolitehnica University of Timișoara, Romania, where he also\nobtained a doctorate degree. He is currently a full professor in\nthe Department of Automation and Applied Informatics at the\nsame university. Dr. Voloşencu is the author of ten books, seven\nbook chapters, and more than 160 papers published in journals\nand conference proceedings. He has also edited twelve books and\nhas twenty-seven patents to his name. He is a manager of research grants, editor in\nchief and member of international journal editorial boards, a former plenary speaker, a member of scientific committees, and chair at international conferences. His\nresearch is in the fields of control systems, control of electric drives, fuzzy control\nsystems, neural network applications, fault detection and diagnosis, sensor network\napplications, monitoring of distributed parameter systems, and power ultrasound\napplications. 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\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
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