Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
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Barely three months into the new year and we are happy to announce a monumental milestone reached - 150 million downloads.
\n\nThis achievement solidifies IntechOpen’s place as a pioneer in Open Access publishing and the home to some of the most relevant scientific research available through Open Access.
\n\nWe are so proud to have worked with so many bright minds throughout the years who have helped us spread knowledge through the power of Open Access and we look forward to continuing to support some of the greatest thinkers of our day.
\n\nThank you for making IntechOpen your place of learning, sharing, and discovery, and here’s to 150 million more!
\n\n\n\n\n'}],latestNews:[{slug:"intechopen-supports-asapbio-s-new-initiative-publish-your-reviews-20220729",title:"IntechOpen Supports ASAPbio’s New Initiative Publish Your Reviews"},{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"}]},book:{item:{type:"book",id:"6317",leadTitle:null,fullTitle:"Rediscovery of Landraces as a Resource for the Future",title:"Rediscovery of Landraces as a Resource for the Future",subtitle:null,reviewType:"peer-reviewed",abstract:"In recent years, all over the world, the attention paid to local and traditional productions is growing, especially in the agro-food sector. Maybe, it is not only due to the impact of globalization and the social and economic changes but also due to the increased consideration to health and nutritional aspects of food. Hence, for economic, social, historical, and nutritional reasons, this trend has led to the rediscovery and reuse of landraces of many different crops, responding to requests for more and more demanding market. This volume collects examples of local crops and old landraces of different areas of the planet that testify the extreme importance of the relation existing among a land, the local productions, the historical traditions, the conservation of biodiversity, the health benefits, the environmental impact and the local economies, also including the significance to dedicate resources to scientific researches in local crops.",isbn:"978-1-78923-725-2",printIsbn:"978-1-78923-724-5",pdfIsbn:"978-1-83881-396-3",doi:"10.5772/intechopen.69576",price:119,priceEur:129,priceUsd:155,slug:"rediscovery-of-landraces-as-a-resource-for-the-future",numberOfPages:204,isOpenForSubmission:!1,isInWos:null,isInBkci:!1,hash:"b081917230f78f4420809fb47ef52713",bookSignature:"Oscar Grillo",publishedDate:"September 12th 2018",coverURL:"https://cdn.intechopen.com/books/images_new/6317.jpg",numberOfDownloads:11712,numberOfWosCitations:21,numberOfCrossrefCitations:35,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:63,numberOfDimensionsCitationsByBook:0,hasAltmetrics:1,numberOfTotalCitations:119,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"May 11th 2017",dateEndSecondStepPublish:"June 1st 2017",dateEndThirdStepPublish:"November 25th 2017",dateEndFourthStepPublish:"December 25th 2017",dateEndFifthStepPublish:"February 25th 2018",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"51992",title:"PhD.",name:"Oscar",middleName:null,surname:"Grillo",slug:"oscar-grillo",fullName:"Oscar Grillo",profilePictureURL:"https://mts.intechopen.com/storage/users/51992/images/1749_n.jpg",biography:"Dr. Oscar Grillo is a food technologist with an international PhD in applied and environmental botany. Since 2003 he has been working as a researcher at the Stazione Sperimentale di Granicoltura per la Sicilia, a governmental institute of agronomic research, mainly working with computer vision applied to food matrices and plant structures. Currently, he is collaborating with the Sardinian Germplasm Bank of the Biodiversity Conservation Centre of the University of Cagliari on projects devoted to wild plant seed characterization and identification by image analysis. He also works as a supervisor for many MSc and PhD students. He is the author of about 50 research works published in many peer-reviewed journals and about 70 international conference papers. Dr. Grillo is a referee for a few peer-reviewed journals, and many times was invited as a visiting professor by national and international universities and research centres. In 2011 he was the co-editor of five volumes published by InTech, and in 2014 the editor of the last one.",institutionString:null,position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"1",totalChapterViews:"0",totalEditedBooks:"7",institution:null}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"311",title:"Plant Genetics",slug:"agronomy-plant-genetics"}],chapters:[{id:"61116",title:"Landraces and Crop Genetic Improvement",doi:"10.5772/intechopen.75944",slug:"landraces-and-crop-genetic-improvement",totalDownloads:2178,totalCrossrefCites:22,totalDimensionsCites:33,hasAltmetrics:1,abstract:"Landraces are repository of gene pool that enrich biodiversity and maintain and stabilize ecosystem in a sustainable way to make it functional. Cultivation of traditional crops in different regions of the world, aside maintaining biodiversity in agriculture, also avails humanity of regulatory services such as nutrient cycling, carbon sequestration, control of soil erosion, reduction of greenhouse gas emission and control of hydrological processes. However, man through over-exploitation of some plant species with utter neglect to some other either deliberately or otherwise through modern agricultural systems that promote cultivation of a few high-input and high-yielding crop species caused disaffection to biodiversity with consequences of reduction in its regulatory services. In this chapter, different landraces of crops are examined, their usefulness in the maintenance of genetic diversity is explored, and implications of their depletion are discussed.",signatures:"Musibau A. Azeez, Amos O. Adubi and Felicia A. Durodola",downloadPdfUrl:"/chapter/pdf-download/61116",previewPdfUrl:"/chapter/pdf-preview/61116",authors:[{id:"228835",title:"Dr.",name:"Musibau",surname:"Azeez",slug:"musibau-azeez",fullName:"Musibau Azeez"},{id:"240210",title:"MSc.",name:"Felicia",surname:"Durodola",slug:"felicia-durodola",fullName:"Felicia Durodola"},{id:"240213",title:"MSc.",name:"Amos",surname:"Adubi",slug:"amos-adubi",fullName:"Amos Adubi"}],corrections:null},{id:"62756",title:"Phenolic Fingerprinting and Glumes Image Analysis as an Effective Approach for Durum Wheat Landraces Identification",doi:"10.5772/intechopen.79595",slug:"phenolic-fingerprinting-and-glumes-image-analysis-as-an-effective-approach-for-durum-wheat-landraces",totalDownloads:873,totalCrossrefCites:1,totalDimensionsCites:1,hasAltmetrics:0,abstract:"In the last decade, encouraged by economic, social and nutritional reasons, the trend towards the rediscovery and reuse of durum wheat landraces moved on in Sicily. This growing attention in local wheat landraces made necessary to design new effective and objective identification methods that are able to distinguish landraces. Considering the difficulties coming from the genetic and morphological heterogeneity of a landrace, in this chapter a multidisciplinary approach for durum wheat landraces identification is proposed. Nine Sicilian wheat landraces were investigated from the genotypic and phenotypic point of view, studying their polyphenolic profile, and analyzing the glumes morpho-colorimetric traits, in search of similarities and/or differences. In particular, hydro-alcoholic extracts from whole wheat grains were analyzed by means of HPLC/DAD and HPLC/ESI-MS, revealing 13 metabolites mainly belonging to the classes of hydroxycinnamic acids and flavones C-glycosides. The quantitative pattern of the 13 phenolic markers allowed to perfectly identify all the wheat samples, confirming a specific and genotype-dependent pattern of phenolics concentration. Moreover, computerized image analysis techniques were applied to compare the wheat samples on the basis of 138 quantitative morpho-colorimetric variables descriptive of glumes size, shape, color and texture, confirming the possibility to undoubtedly identify wheat samples belonging to local landraces.",signatures:"Oscar Grillo, Marisol Lo Bianco, Sebastiano Blangiforti, Laura\nSiracusa, Gianfranco Venora and Giuseppe Ruberto",downloadPdfUrl:"/chapter/pdf-download/62756",previewPdfUrl:"/chapter/pdf-preview/62756",authors:[{id:"51992",title:"PhD.",name:"Oscar",surname:"Grillo",slug:"oscar-grillo",fullName:"Oscar Grillo"},{id:"54656",title:"Dr.",name:"Gianfranco",surname:"Venora",slug:"gianfranco-venora",fullName:"Gianfranco Venora"},{id:"62599",title:"Dr.",name:"Marisol",surname:"Lo Bianco",slug:"marisol-lo-bianco",fullName:"Marisol Lo Bianco"},{id:"214308",title:"Dr.",name:"Sebastiano",surname:"Blangiforti",slug:"sebastiano-blangiforti",fullName:"Sebastiano Blangiforti"},{id:"214309",title:"Dr.",name:"Laura",surname:"Siracusa",slug:"laura-siracusa",fullName:"Laura Siracusa"},{id:"214311",title:"Dr.",name:"Giuseppe",surname:"Ruberto",slug:"giuseppe-ruberto",fullName:"Giuseppe Ruberto"}],corrections:null},{id:"59698",title:"Rice Biodiversity in Cold Hill Zones of Kashmir Himalayas and Conservation of Its Landraces",doi:"10.5772/intechopen.74591",slug:"rice-biodiversity-in-cold-hill-zones-of-kashmir-himalayas-and-conservation-of-its-landraces",totalDownloads:1069,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Jammu & Kashmir is an agri-horticulture state (in India) where a large population is economically dependent to agriculture and horticulture, directly or indirectly for livelihood, food and nutritional security. Rice, the staple food of majority population, is cultivated in diverse agro-ecological situations extending from subtropical area (<1000 m amsl) of Jammu, through temperate valley to cold high altitudes regions (1650–2400 m amsl) of Kashmir, and therefore rice biodiversity is rich. Some of the landraces fall into indica type and thrive well in temperate regions of valley, while others fall into japonica type and are prevalent in hilly areas. Cold tolerance is a special feature in most of these peculiar landraces, which are different from rest of the country. However, with the advent of High Yielding Varieties the local biodiversity got neglected and remained confined to seed banks. With new emerging challenges like climate change, population explosion, limited land and water resources, demand for organic products, local landraces have assumed tremendous importance, either for direct exploitation or indirect use. In this chapter, we attempt to bring out information about these landraces in a comprehensive manner and discuss the issues pertaining to their conservation, utilization, cultivation and revival through approaches like participatory plant breeding, participatory varietal selection or plant biotechnology.",signatures:"Amjad M. Husaini and Sofi NR",downloadPdfUrl:"/chapter/pdf-download/59698",previewPdfUrl:"/chapter/pdf-preview/59698",authors:[{id:"224846",title:"Dr.",name:"Amjad",surname:"Husaini",slug:"amjad-husaini",fullName:"Amjad Husaini"},{id:"238242",title:"Dr.",name:"Najeeb",surname:"Sofi",slug:"najeeb-sofi",fullName:"Najeeb Sofi"}],corrections:null},{id:"57368",title:"Morpho-Agronomic Variation among Phaseolus vulgaris Landraces: A Review",doi:"10.5772/intechopen.71359",slug:"morpho-agronomic-variation-among-phaseolus-vulgaris-landraces-a-review",totalDownloads:838,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Phaseolus vulgaris L. of the family Fabaceae is widely grown for essential nutrients in its edible leaves, immature pods, and mature seeds. Landraces are local crops with wide morphological and genetic diversity. Morpho-agronomically, P. vulgaris landraces vary exceptionally in their vegetative and reproductive traits. These landraces vary in their germination rate and final percentage. Their growth form varies from bushy to vining type. Flowers range in their time to flowering, color, and size. Pods also vary widely in their time to pod formation; pod size, color, and shape; number of pods per plant; and time to pod maturity. Seeds also vary in their size, shape, color, and mass, as well as their number per pod and per plant. These landraces also vary in their resistance to pests and diseases from seed germination, plant growth and yield, and seed storage duration. A review on variation among P. vulgaris landraces forms basis for their future breeding as they are a good source of genetic diversity. This enables a possible selection for leaf, pod, and seed consumption, as well as resistance toward pests and diseases during the entire growth.",signatures:"Nontuthuko R. Ntuli",downloadPdfUrl:"/chapter/pdf-download/57368",previewPdfUrl:"/chapter/pdf-preview/57368",authors:[{id:"211715",title:"Dr.",name:"Nontuthuko",surname:"Ntuli",slug:"nontuthuko-ntuli",fullName:"Nontuthuko Ntuli"}],corrections:null},{id:"57756",title:"Agronomic Performance, Nutritional Phenotyping and Trait Associations of Okra (Abelmoschus esculentus) Genotypes in South Africa",doi:"10.5772/intechopen.70813",slug:"agronomic-performance-nutritional-phenotyping-and-trait-associations-of-okra-abelmoschus-esculentus-",totalDownloads:1073,totalCrossrefCites:3,totalDimensionsCites:5,hasAltmetrics:0,abstract:"Okra, Abelmoschus esculentus L. (Moench), is an important fruit vegetable crop which belongs to the family Malvaceae. It is a good source of protein, carbohydrates, vitamins, minerals, and enzymes that are often consumed in small quantities in developing country. Okra is a highly nutritious underutilized fruit vegetable crop in South Africa. However, despite its importance for food, nutritional, and health benefits, the crop is rarely produced in some areas of South Africa. The study was carried out to assess the genetic diversity using agro-morphological traits and nutritional contents towards future use in the okra breeding programme. The experiment was carried out at the Roodeplaat research farm of the Agricultural Research Council in a randomized complete block design replicated three times. Agro-morphological traits and selected nutrients were determined. The analysis of variance for both showed highly significant differences for most traits recorded. The multivariate analysis showed a wide genetic diversity among the okra genotypes, which could be exploited in selecting suitable and potential parents when breeding for high yield and nutritional qualities. The present study revealed the genetic potential of the genotypes studied and their importance for use in the breeding programme aimed toward addressing malnutrition, food security, and poverty alleviation by breeding for increased yields, and nutritional contents in South Africa.",signatures:"Abe Shegro Gerrano",downloadPdfUrl:"/chapter/pdf-download/57756",previewPdfUrl:"/chapter/pdf-preview/57756",authors:[{id:"190921",title:"Dr.",name:"Abe",surname:"Gerrano",slug:"abe-gerrano",fullName:"Abe Gerrano"}],corrections:null},{id:"57526",title:"Genetic Potential and Usefulness of Native Maize Populations in Developing Novel Germplasm for Current and Upcoming Goals",doi:"10.5772/intechopen.71360",slug:"genetic-potential-and-usefulness-of-native-maize-populations-in-developing-novel-germplasm-for-curre",totalDownloads:1081,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"Traditional agricultural system is referring to the maize production based on indigenous or farmers knowledge and practices that have been developed through many generations. In the area of study, genetic maize diversity was explored by the expression of quantitative traits of the ear and the race classification approach. Evaluation results indicated that the native populations adapted to the transition and highland (above 2000 masl) areas, showed a contrasting yield response when they were evaluated at the intermediate environment; whereas, those populations adapted to the lowland and intermediate altitudes showed a satisfactory yield performance in both environments. The above performance pattern is essential because it may be useful to identify favorable alleles that, in a local population per se or through genetic combination, results in population changes in allele frequencies that could mitigate the effects of climate changes, particularly in maize populations adapted to highland altitudes. Selection procedures applied to a local adapted population can be managed attending different goals, including the conservation of genetic diversity (per se selection), and to develop novel germplasm. The introgression of foreign germplasm into a local population and the application of three selection cycles resulted in a novel variety (JAGUAN) adapted to a regional northeast Mexico environmental conditions.",signatures:"Froylan Rincon-Sanchez and Norma A. Ruiz-Torres",downloadPdfUrl:"/chapter/pdf-download/57526",previewPdfUrl:"/chapter/pdf-preview/57526",authors:[{id:"212335",title:"Dr.",name:"Froylan",surname:"Rincon",slug:"froylan-rincon",fullName:"Froylan Rincon"},{id:"212336",title:"Dr.",name:"Norma",surname:"Ruiz",slug:"norma-ruiz",fullName:"Norma Ruiz"}],corrections:null},{id:"57534",title:"Lessons from Common Bean on How Wild Relatives and Landraces Can Make Tropical Crops More Resistant to Climate Change",doi:"10.5772/intechopen.71669",slug:"lessons-from-common-bean-on-how-wild-relatives-and-landraces-can-make-tropical-crops-more-resistant-",totalDownloads:1131,totalCrossrefCites:4,totalDimensionsCites:9,hasAltmetrics:0,abstract:"Warming is expected to lead to drier environments worldwide, especially in the tropics, and it is unclear how crops will react. Drought tolerance often varies at small spatial scales in natural ecosystems, where many of the wild relatives and landraces of the main crops have been collected. Through a series of examples, we will show that collections of wild relatives and landraces, many of those deposited at germplasm banks, may represent this desired source of variation, as they are genetically diverse and phenotypically variable. For instance, using a spectrum of genotyping and phenotyping approaches, we have studied the extent of genetic and phenotypic diversity for drought tolerance in wild and landraces of common bean (Phaseolus vulgaris L.) and compared it with the one available at cultivated varieties. Not surprisingly, most of the naturally available variation to cope with drought in the natural environments was lost through domestication and recent plant breeding. It is therefore imperative to exploit the reservoir of wild relatives and landraces to make crops more tolerant. Yet, it remains to be seen if the rate at which this naturally available variation can be incorporated into the cultivated varieties may keep pace with the rate of climate change.",signatures:"Andrés J. Cortés and Matthew W. Blair",downloadPdfUrl:"/chapter/pdf-download/57534",previewPdfUrl:"/chapter/pdf-preview/57534",authors:[{id:"190729",title:"Dr.",name:"Andrés",surname:"Cortés",slug:"andres-cortes",fullName:"Andrés Cortés"},{id:"216535",title:"Dr.",name:"Matthew W.",surname:"Blair",slug:"matthew-w.-blair",fullName:"Matthew W. Blair"}],corrections:null},{id:"57390",title:"Critical Aspects on the Use of Microsatellite Markers for Assessing Genetic Identity of Crop Plant Varieties and Authenticity of their Food Derivatives",doi:"10.5772/intechopen.70756",slug:"critical-aspects-on-the-use-of-microsatellite-markers-for-assessing-genetic-identity-of-crop-plant-v",totalDownloads:1157,totalCrossrefCites:1,totalDimensionsCites:5,hasAltmetrics:0,abstract:"A total of 90 original articles concerning the varietal characterization and identification by means of SSR analysis of the five most economically relevant crops in Italy (i.e., Olea europaea L., Solanum lycopersicum L., Vitis vinifera L., Triticum spp. and Malus × domestica Borkh.) have been selected and reviewed. Since the genetic traceability of processed products may result more complex, wine and olive oil have been considered too. Specifically, this chapter deals with three main aspects: (i) the criteria adopted for the selection of the most appropriate number, type, and distribution of SSR marker loci to be employed for varietal genotyping, (ii) the use of genetic statistics and parameters for the evaluation of the discriminant ability and applicability of SSR marker loci, and (iii) how to make different experimental works on the same species that are standardized, reliable, and comparable. What emerges from the studies reviewed here is a lack of wider consensus among the authors regarding the strategy to design and to adopt for genotyping plant varieties with SSR markers. This finding highlights the urgent need to establish a common procedure, especially for characterizing and preserving landraces, and for supporting its rediscovery and valorization locally.",signatures:"Fabio Palumbo and Gianni Barcaccia",downloadPdfUrl:"/chapter/pdf-download/57390",previewPdfUrl:"/chapter/pdf-preview/57390",authors:[{id:"176837",title:"Prof.",name:"Gianni",surname:"Barcaccia",slug:"gianni-barcaccia",fullName:"Gianni Barcaccia"},{id:"214689",title:"MSc.",name:"Fabio",surname:"Palumbo",slug:"fabio-palumbo",fullName:"Fabio Palumbo"}],corrections:null},{id:"59806",title:"Wild Soybeans: An Opportunistic Resource for Soybean Improvement",doi:"10.5772/intechopen.74973",slug:"wild-soybeans-an-opportunistic-resource-for-soybean-improvement",totalDownloads:1215,totalCrossrefCites:4,totalDimensionsCites:10,hasAltmetrics:0,abstract:"Reduced genetic diversity in cultivated soybean coupled with changing dietary expectations, climate change, and increase in population demands expansion of current gene pool. Wild soybeans are an opportunistic resource and a rational choice to discover novel genes and gene families for alternative crop production systems and to improve soybean. Multiple agronomic traits, lineage-specific genes, and domestication-related traits have been studied in wild soybeans in contrast to cultivated soybeans, and it has been proved that wild soybeans are an essential genomic resource containing unique and useful genetic resources that have been lost during domestication to expand the gene pool in order to improve soybean. Wild soybean is very often a plant of disturbed habitats of Southeast Asia. The vulnerability of these habitats to agriculture systems and urban expansion causes a reduction in the area of distribution and hence the diversity. To capture the wild soybean genetic diversity in its main distribution areas, a unique and comprehensive germplasm collection, characterization, and conservation platform is direly needed. Chung’s Wild Legume Germplasm Collection is preserving and maintaining a representative wild soybean germplasm collection guided by the principles of conservation genetics. These wild legumes and particularly wild soybean is a promising genetic resource for soybean breeders.",signatures:"Muhammad Amjad Nawaz, Seung Hwan Yang and Gyuhwa Chung",downloadPdfUrl:"/chapter/pdf-download/59806",previewPdfUrl:"/chapter/pdf-preview/59806",authors:[{id:"91315",title:"Prof.",name:"Gyuhwa",surname:"Chung",slug:"gyuhwa-chung",fullName:"Gyuhwa Chung"},{id:"206330",title:"Mr.",name:"Muhammad Amjad",surname:"Nawaz",slug:"muhammad-amjad-nawaz",fullName:"Muhammad Amjad Nawaz"},{id:"228347",title:"Prof.",name:"Seung Hwan",surname:"Yang",slug:"seung-hwan-yang",fullName:"Seung Hwan Yang"}],corrections:null},{id:"58931",title:"Genetic Variation of Landraces of Common Bean Varying for Seed Coat Glossiness and Disease Resistance: Valuable Resources for Conservation and Breeding",doi:"10.5772/intechopen.73425",slug:"genetic-variation-of-landraces-of-common-bean-varying-for-seed-coat-glossiness-and-disease-resistanc",totalDownloads:1100,totalCrossrefCites:0,totalDimensionsCites:0,hasAltmetrics:0,abstract:"In this chapter, we outline the significance of landraces of common bean (Phaseolus vulgaris L.) for unraveling novel morphological, biochemical and genetic variation that could be integrated to breeding programs, related to seed coat color and glossiness and disease resistance. Moreover, we emphasize how important the conservation of such genetic resources is in small-farming areas, the prevailing system for bean cultivation. A particular Brazilian landrace referred as Serro Azul by local farmers is highlighted to show new evidences of the genetic control of seed glossiness in common bean and how it implicates in the seed protection against diseases and insects. Moreover, new findings presented here give insights into a remarkable anthracnose resistance of one of the variants of Serro Azul, which also presents seed coat glossiness. The potential benefits for human health after consuming beans with glossy seed coat are also discussed. This is one among the various landraces that need better understanding for strengthening the knowledge of the genetic diversity of common bean. Such knowledge is important for conducting conservation actions and performing new crosses for providing genetic materials with desirable combinations for farmers, breeders and consumers.",signatures:"Enéas Ricardo Konzen and Siu Mui Tsai",downloadPdfUrl:"/chapter/pdf-download/58931",previewPdfUrl:"/chapter/pdf-preview/58931",authors:[{id:"90489",title:"Prof.",name:"Siu Mui",surname:"Tsai",slug:"siu-mui-tsai",fullName:"Siu Mui Tsai"},{id:"196963",title:"Dr.",name:"Enéas Ricardo",surname:"Konzen",slug:"eneas-ricardo-konzen",fullName:"Enéas Ricardo Konzen"}],corrections:null}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},subseries:null,tags:null},relatedBooks:[{type:"book",id:"1369",title:"Changing Diversity in Changing Environment",subtitle:null,isOpenForSubmission:!1,hash:"a9f3c1cbb7119a88079a1c07838455f8",slug:"changing-diversity-in-changing-environment",bookSignature:"Oscar Grillo and Gianfranco Venora",coverURL:"https://cdn.intechopen.com/books/images_new/1369.jpg",editedByType:"Edited by",editors:[{id:"51992",title:"PhD.",name:"Oscar",surname:"Grillo",slug:"oscar-grillo",fullName:"Oscar Grillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1366",title:"Biodiversity Loss in a Changing Planet",subtitle:null,isOpenForSubmission:!1,hash:"d325a1437cd12bf8823408657080ee8a",slug:"biodiversity-loss-in-a-changing-planet",bookSignature:"Oscar Grillo and Gianfranco Venora",coverURL:"https://cdn.intechopen.com/books/images_new/1366.jpg",editedByType:"Edited by",editors:[{id:"51992",title:"PhD.",name:"Oscar",surname:"Grillo",slug:"oscar-grillo",fullName:"Oscar Grillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3821",title:"Biodiversity",subtitle:"The Dynamic Balance of the Planet",isOpenForSubmission:!1,hash:"7233b40924b0a40793d6f2bd6db38356",slug:"biodiversity-the-dynamic-balance-of-the-planet",bookSignature:"Oscar Grillo",coverURL:"https://cdn.intechopen.com/books/images_new/3821.jpg",editedByType:"Edited by",editors:[{id:"51992",title:"PhD.",name:"Oscar",surname:"Grillo",slug:"oscar-grillo",fullName:"Oscar Grillo"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"394",title:"Ecosystems Biodiversity",subtitle:null,isOpenForSubmission:!1,hash:"49d03ba9ec3a70c20364366827d63cbf",slug:"ecosystems-biodiversity",bookSignature:"Oscar Grillo and Gianfranco Venora",coverURL:"https://cdn.intechopen.com/books/images_new/394.jpg",editedByType:"Edited by",editors:[{id:"51992",title:"PhD.",name:"Oscar",surname:"Grillo",slug:"oscar-grillo",fullName:"Oscar 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2017",dateReviewed:"August 22nd 2017",datePrePublished:"December 20th 2017",datePublished:"January 24th 2018",book:{id:"6165",title:"Entrepreneurship",subtitle:"Development Tendencies and Empirical Approach",fullTitle:"Entrepreneurship - Development Tendencies and Empirical Approach",slug:"entrepreneurship-development-tendencies-and-empirical-approach",publishedDate:"January 24th 2018",bookSignature:"Ladislav Mura",coverURL:"https://cdn.intechopen.com/books/images_new/6165.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"85474",title:"Associate Prof.",name:"Ladislav",middleName:null,surname:"Mura",slug:"ladislav-mura",fullName:"Ladislav Mura"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"181601",title:"Prof.",name:"Er'El",middleName:null,surname:"Granot",fullName:"Er'El Granot",slug:"er'el-granot",email:"erelgranot@gmail.com",position:null,institution:{name:"Ariel University",institutionURL:null,country:{name:"Israel"}}}]},book:{id:"6165",title:"Entrepreneurship",subtitle:"Development Tendencies and Empirical Approach",fullTitle:"Entrepreneurship - Development Tendencies and Empirical Approach",slug:"entrepreneurship-development-tendencies-and-empirical-approach",publishedDate:"January 24th 2018",bookSignature:"Ladislav Mura",coverURL:"https://cdn.intechopen.com/books/images_new/6165.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"85474",title:"Associate Prof.",name:"Ladislav",middleName:null,surname:"Mura",slug:"ladislav-mura",fullName:"Ladislav Mura"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},ofsBook:{item:{type:"book",id:"11638",leadTitle:null,title:"Meat Science and Nutrition - Recent Advances and Innovative Processing Technologies",subtitle:null,reviewType:"peer-reviewed",abstract:"
\r\n\tHealth is usually the physical or mental fitness of the person. The activity of the body is possible at times when the human consumes a nutrient-rich diet. There is a direct relationship between diet and health. Nutrition is the biochemical and physiological process by which a human uses food to support its life. A nutrient is a substance consumed by an organism to survive, grow and reproduce. There are different sources of nutrient consumption and animal meat is one of them. Meat is a perishable food and a rich source of protein. It is also composed of PUFAs, zinc, iron, selenium, and phosphorus followed by vitamin A and B-complex vitamins. Therefore meat is a good source of nutrient and bioactive compounds. During processing, some reactions are started such as oxidation. Plant bioactive compounds including antioxidants, polyphenols, and vitamins are added to meat for protection from oxidation and improving nutrition values. Plant sources also contain components that inhibit microbe growth and make meat safer for human health. Irradiated meat is free from bacteria but during processing, the oxidation process is started. To protect from oxidation, natural antioxidants sources are used. However, advanced processing technologies are used to improve the quality and nutritional value of meat and meat products.
",isbn:"978-1-80356-297-1",printIsbn:"978-1-80356-296-4",pdfIsbn:"978-1-80356-298-8",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,isSalesforceBook:!1,isNomenclature:!1,hash:"3923d89fcf837fac59c906f9694ab1f8",bookSignature:"Dr. Muhammad Sajid Arshad",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/11638.jpg",keywords:"Composition, PUFAs, Nutrients, Antioxidants, Polyphenols, Oxidation, Shelf Life, Sonication, Irradiation, Quality, Safety, Health",numberOfDownloads:4,numberOfWosCitations:0,numberOfCrossrefCitations:0,numberOfDimensionsCitations:0,numberOfTotalCitations:0,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 15th 2022",dateEndSecondStepPublish:"April 20th 2022",dateEndThirdStepPublish:"June 19th 2022",dateEndFourthStepPublish:"September 7th 2022",dateEndFifthStepPublish:"November 6th 2022",dateConfirmationOfParticipation:null,remainingDaysToSecondStep:"4 months",secondStepPassed:!0,areRegistrationsClosed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Assistant Professor at Government College University Faisalabad, Pakistan whose area of research is food science particularly meat science and halal foods. Author of 55 publications and 10 book chapters and recipient of several national and international awards in his field.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"192998",title:"Dr.",name:"Muhammad Sajid",middleName:null,surname:"Arshad",slug:"muhammad-sajid-arshad",fullName:"Muhammad Sajid Arshad",profilePictureURL:"https://mts.intechopen.com/storage/users/192998/images/system/192998.jpg",biography:"Dr. Muhammad Sajid Arshad is currently working as Assistant Professor at Department of Food Science, Government College University Faisalabad, Pakistan. He served as visiting research scholar at the University of Illinois, Urbana Champaign, the USA for a period of six months. He received his doctoral degree from the University of Agriculture, Faisalabad, Pakistan in 2013. From 2016-2017, he worked as postdoctoral fellow at Kyungpook National University, South Korea for one year. He worked with Iowa State University, the USA for 3 weeks. Later on, he got training from the University of Melbourne, Australia for 2 weeks. Dr. Arshad is author of about 65 publications and 10 book chapters to his credit. He has presented his papers in different national and international conferences in USA, Canada, Australia, South Korea, Thailand, and Turkey. He received several national and international awards in his field. His area of research is food science particularly functional foods, non-thermal processing technologies, muscle foods, and halal foods.",institutionString:"Government College University, Faisalabad",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"6",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"5",title:"Agricultural and Biological Sciences",slug:"agricultural-and-biological-sciences"}],chapters:[{id:"82512",title:"Antimicrobial Residues in Meat and Meat Products",slug:"antimicrobial-residues-in-meat-and-meat-products",totalDownloads:4,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"347258",firstName:"Marica",lastName:"Novakovic",middleName:null,title:"Ms.",imageUrl:"//cdnintech.com/web/frontend/www/assets/author.svg",email:"marica@intechopen.com",biography:null}},relatedBooks:[{type:"book",id:"6669",title:"Meat Science and Nutrition",subtitle:null,isOpenForSubmission:!1,hash:"bca2d87ed258a60a9c92c5c6056d1465",slug:"meat-science-and-nutrition",bookSignature:"Muhammad Sajid Arshad",coverURL:"https://cdn.intechopen.com/books/images_new/6669.jpg",editedByType:"Edited by",editors:[{id:"192998",title:"Dr.",name:"Muhammad Sajid",surname:"Arshad",slug:"muhammad-sajid-arshad",fullName:"Muhammad Sajid Arshad"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10637",title:"Functional Foods",subtitle:"Phytochemicals and Health Promoting Potential",isOpenForSubmission:!1,hash:"a4aa0abf066e78deed1f65312ff24b22",slug:"functional-foods-phytochemicals-and-health-promoting-potential",bookSignature:"Muhammad Sajid Arshad and Muhammad Haseeb Ahmad",coverURL:"https://cdn.intechopen.com/books/images_new/10637.jpg",editedByType:"Edited by",editors:[{id:"192998",title:"Dr.",name:"Muhammad Sajid",surname:"Arshad",slug:"muhammad-sajid-arshad",fullName:"Muhammad Sajid Arshad"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"6418",title:"Hyperspectral Imaging in Agriculture, Food and Environment",subtitle:null,isOpenForSubmission:!1,hash:"9005c36534a5dc065577a011aea13d4d",slug:"hyperspectral-imaging-in-agriculture-food-and-environment",bookSignature:"Alejandro Isabel Luna Maldonado, Humberto Rodríguez Fuentes and Juan Antonio Vidales Contreras",coverURL:"https://cdn.intechopen.com/books/images_new/6418.jpg",editedByType:"Edited by",editors:[{id:"105774",title:"Prof.",name:"Alejandro Isabel",surname:"Luna Maldonado",slug:"alejandro-isabel-luna-maldonado",fullName:"Alejandro Isabel Luna Maldonado"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"10359",title:"Landraces",subtitle:"Traditional Variety and Natural Breed",isOpenForSubmission:!1,hash:"0600836fb2c422f7b624363d1e854f68",slug:"landraces-traditional-variety-and-natural-breed",bookSignature:"Amr Elkelish",coverURL:"https://cdn.intechopen.com/books/images_new/10359.jpg",editedByType:"Edited by",editors:[{id:"231337",title:"Dr.",name:"Amr",surname:"Elkelish",slug:"amr-elkelish",fullName:"Amr Elkelish"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophile",surname:"Theophanides",slug:"theophile-theophanides",fullName:"Theophile Theophanides"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"2270",title:"Fourier Transform",subtitle:"Materials Analysis",isOpenForSubmission:!1,hash:"5e094b066da527193e878e160b4772af",slug:"fourier-transform-materials-analysis",bookSignature:"Salih Mohammed Salih",coverURL:"https://cdn.intechopen.com/books/images_new/2270.jpg",editedByType:"Edited by",editors:[{id:"111691",title:"Dr.Ing.",name:"Salih",surname:"Salih",slug:"salih-salih",fullName:"Salih Salih"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"71417",title:"Recent Advances in Mechanochemical Organic Synthesis",doi:"10.5772/intechopen.90897",slug:"recent-advances-in-mechanochemical-organic-synthesis",body:'The use of mechanical energy to promote chemical reactions has become a fast-growing area of green chemistry research in the last decade. With the realization of its practical potentials by chemists and researchers in academia and industry, in recent years, the number of published accounts on mechanosynthesis in various research fields is increasing, ranging from inorganic, metal-organic to organic reactions. Mechanochemistry also become widely exploited for synthesis of drug solid forms [1]. The topic of mechanochemistry was the subject of several review articles [2, 3, 4, 5, 6, 7, 8, 9] and books [10, 11]. In this review, the most recent accounts on the mechanochemical organic synthesis are covered.
Multi-step synthesis is applicable to ball milling solid-state conditions, which is documented by the increasing number of one-pot, multi-step reactions. In the initial milling process, compatible second reagents were added, and milling was continued. Among them are one-pot two-step Negishi C▬C cross-coupling which applies different physical forms of zinc to generate organozinc reagent which was coupled with aryl halide and palladium catalyst in the second milling step. This reaction was also carried out as one-pot one-step reaction [12]. Further examples are one-pot two-step synthesis of thioureas from amines employing thiocarbamoyl benzotriazoles [13], one-pot two-step synthesis of pyrazolones [14], two-step synthesis of paracetamol and procainamide [15], and three-step, two-pot Gabriel synthesis of amines [16]. For illustration, reductive cyclization of fullerene was carried out by three consecutive ball milling reactions (Figure 1) [17]. This solvent-free Michael reaction of fullerene anion to enones (chalkones) was carried out in a two-step, one-pot procedure, starting by zinc reduction of fullerene to carbanion, with water additive used to protonate generated carbanions. The mechanochemical conditions led to the formation of C60-substituted cyclopentanol
Reductive cyclization of C60 with enones by three-step milling.
One-pot, three-step synthesis of pyrroles from amines, alkyne esters, and chalkones saves time and increases the practicality of synthesis (Figure 2) [18]. The first step is reaction of amines with alkyne esters which affords β-enaminoesters
Three-step synthesis of substituted pyrroles.
Some novel variants and reagents were recently applied for reactions which were previously carried out in ball mill such as the formation of peptide bond and imines; Michael, Mannich, and Wittig reactions; porphyrin metalation; halogenations; and various multicomponent reactions. For instance, amide bond formation by one-pot two-step procedure, followed by polymerization in mill [19], application of PhI(OAc)2 cross dehydrogenative coupling for the amidation of aldehydes via C▬H activation [20], formation of phosphinecarboxamides [21], Rh catalyzed amidation [22] or via Ritter reaction [23] and amination to prepare sulfonamides employing Ir catalyst [24] were reported. In addition, a mechanistic study for amide bond formation is published [25].
Some of the traditional transition metal catalysts used in solution reactions can be replaced with elementary metals as catalysts under mechanochemical conditions. For this purpose, different materials for balls and milling vessels were used by Mack, including silver, copper [26], and nickel, even aluminum jars and balls for amorphization [27] and silicon nitride for Scholl reaction [28]. An exemplary reaction is cyclopropenation of alkynes with diazoacetates carried out in ball mill using various materials for vial and balls. Silver foil was found to be a recyclable metal catalyst which does not loose activity and diastereoselectivity after several reaction cycles [29]. The optimal results of [2+1] cycloadditions for internal alkynes were achieved with stainless steel vials and balls, with the addition of silver foil (Figure 3), whereas copper foil showed much better performance in cyclopropanations of terminal alkynes [30]. Silver foil in conjunction with PdCl2(PPh3)2 catalyst was also employed as the effective co-catalyst for mechanochemical Sonogashira coupling of aliphatic alkynes with aryl iodides.
Cyclopropenation of alkenes and alkynes with diazoacetates.
On the other hand, catalysis of [2+2+2+2] cycloaddition of alkynes to cyclooctatetraenes (Figure 4) with Nickel foil was ineffective (SS vial/ball) and with Tungsten carbide balls was moderate, whereas with nickel powder (SS vial/ball), it was moderately active, and pellets were used to obtain high conversion. Nickel vial in combination with nickel balls provided low conversion [31]. Nickel powder generated in situ is responsible for the catalytic activity and, by using the neodymium magnet to separate nickel pellets from crude reaction mixture, makes the catalyst recyclable.
Nickel-catalyzed [2+2+2+2] cycloaddition of alkynes.
Metal catalyst additives such as Pd foil, Cr, and Ni powder showed the activity in alkyne hydrogenation using water as hydrogen source. Efficient mechanochemical hydrogenation method employs SUS304 stainless steel which contains zero-valent Cr and Ni constituents for balls and vial [32]. Alkene and alkyne bonds and nitro, azido, and keto groups were reduced in 62–100% yield by in situ hydrogen generation (Figure 5). Furthermore with SUS304 steel vials as catalyst, alkanes and Et2O were used as hydrogen sources for hydrogenation of aromatic compounds, alkenes, alkynes, and ketones [33].
Nickel-catalyzed hydrogenation reactions.
Novel mechanochemical C▬C bond forming reactions include Friedel-Crafts acylation [34] and alkylation which was also employed in polymer synthesis [35]. Porphyrin synthesis in which mechanochemical procedure was reported earlier was extended to bulkier aromatics [36] and the solventless metalation of porphyrins [37, 38].
Mack has shown that different products could be obtained in enolate addition reactions, when solution procedure was replaced by solvent-free conditions (Figure 6) [39]. Whereas in solution 3-hydroxy-1,3-diphenylbutan-1-one and dypnone were formed by base-catalyzed aldol condensation of acetophenone, in ball mill 1,5-pentadione
Aldol condensation of acetophenone.
Dehydrogenative C▬H/C▬H arylation of oximes and anilides as directing groups was carried out by Xu (Figure 7) [40]. The mechanochemical process is fast (1 h, 6 × (10 min + 1 min break)) and mild, with less amount of arenes, and highly para-selective. A variety of functional groups could be tolerated in LAG (DMF) conditions with TfOH as an additive in conjunction with Pd catalyst and oxidant. Optimal reaction conditions were also applied to olefinic C▬H arylation with simple arenes. Kinetic isotope effects of experiments using deuterated substrates showed KIE data which are consistent with those reported in the similar transformation using arenes as solvents. Slightly different mechanochemical conditions were employed by Su in oxidative C▬H dehydrogenative homocoupling of
Dehydrogenative C▬H/C▬H arylation.
The synthesis of benzo[b]furans by electrophilic cyclization of 2-alkynylanisoles
Synthesis of benzo[b]furans by electrophilic cyclization.
C▬N bond forming reactions were paid larger attention to. Mechanochemical nitration reactions of aromatics are extended to various reagents: NaNO3 in conjunction with MoO3 as an additive [43], BiNO3 with MgSO4 [44], as well as BiNO3 alone was applied for nitration of fullerene C60 [45]. Amine guanylation with
Demethylation of alkaloid
Strecker reaction of benzaldehyde with benzylamine and KCN in simple reaction conditions using unusual material (stones as ball bearings) provided a mixture of α-aminonitrile
Strecker reaction.
Palladium-catalyzed Buchwald-Hartwig amination of aryl chlorides in ball mill has provided moderate to high yields of diarylamine products
Buchwald-Hartwig amination.
Efficient spiroimidazoline synthesis by the reaction of 2-substituted 1H-indene-1,3-(2H)-diones
Synthesis of spiroimidazolines.
Another user and environmentally friendly protocol than isocyanide synthesis via Ugi reaction was the development of solid-state Hofmann reaction (synthesis of isocyanides from amines) (Figure 13) [55]. The implementation of the reaction in mechanochemical conditions significantly reduces the amounts of chloroform, from bulk solvent to 2.1 equivalents. Milling in two 15-minute steps, where chloroform was added each time, afforded better yields than one 30-min milling with all chloroform added at once. The addition of NBu3 was beneficial for sterically more hindered substrates.
Hofmann reaction of amines with chloroform.
Enzymes can tolerate ball milling conditions, and enzymatic reactions were successfully carried out for several transformations: esterification of primary alcohols [56], peptide bond formation [57], ester hydrolysis [58], and cleavage of cellulose [59]. An enzymatic kinetic resolution of racemic secondary alcohols
Acylative kinetic resolution of secondary alcohols.
Similar methodology was applied by Juaristi for the mechanoenzymatic resolution of racemic chiral amines. CALB was applied in the combination of isopropyl acetate as acylating agent and dioxane additive (in agate jars), and amide products were obtained with excellent enantiopurity (ee 66–>99%). Enantiopure chiral amines were used in the synthesis of (
Besides hydrogenation reaction facilitated in SUS304 ss and Strecker reaction, gaseous reagents were also in situ generated in transfer hydrogenation of carbonyls with polymethylhydrosiloxane as hydrogen source [62], reduction of NO2 group by catalytic transfer hydrogenation employing Pd and ammonium formate [15], and synthesis of thioureas by generation of ammonia from NH4Cl and Na2CO3 [13].
Among the reactions for the formation of other types of bonds which were not previously carried in ball milling conditions are C▬P bond by phosphonylation with MnOAc [63], O▬P phosphate nucleoside bond using CDI [64], S▬P bond via Arbuzov reaction [65], C▬B bond by borylation using Ir catalyst [66], and P▬S and P▬Se bond formation by milling of phosphines with S and Se [67].
A recent example of mechanochemical enantioselective reactions is the fluorination of aliphatic cyclic and acyclic β-keto esters using
Enantioselective fluorination of β-keto esters.
The epimerization of (3R,6′R,3′R)-lutein to 3′-epilutein was successfully carried out in a stainless steel jar MET-A (composition 84.5% Fe, 13% Cr) in conjunction with acidic cation-exchange resin [69]. This transformation was accompanied with the formation of anhydrolutein, and the best
Some cycloaddition reactions were carried out in ball mill for the first time. A mechanistic study of Diels-Alder reactions of selected anthracenes by Arrhenius kinetics was reported by Andersen and Mack [70]. The array of 1,3-dipolar cycloaddition reactions is recently extended with nitrones [71] and nitrile oxides [72].
Among the recent examples of oxidation/reduction reactions are Cannizzaro disproportionation of furfural [73] and benzylic oxidation of lignin by oxone and TEMPO [74]. Nitro group was reduced by Ni2B-NaBH4 system [75] and by AuNPs-catalyzed reaction with cyclodextrins as additives [76].
Ionic liquids as novel promoter/additive which could be regenerated were employed for the synthesis of imines [77] and in multicomponent synthesis of 4
Solvent-free mechanochemical conditions were also used in synthesis of reactive species. Synthesis of naphthalenediimide radical ions was achieved by milling of naphthalenediimides with trialkyl and triarylphosphines and Et3N base [79]. The ArSN reaction provides bistrialkyl(aryl)phosphonium naphthalenediimide radical anions which were isolated, and automated ball milling procedure was superior to manual grinding and sonication conditions. The formation of free radicals was also obtained from glucose-based polysaccharides [80].
Several examples of advantageous application of mechanochemistry in supramolecular chemistry are given in recent literature. The encapsulation of fullerene C60 in mechanochemical conditions was extended from γ-cyclodextrin, cucurbit [15], uril and sulfocalix [16], arene hosts to molecular cages [81]. Other molecular guests were encapsulated by ball milling in calixarene (fluorene) [82], cyclodextrins (steroids) [83], as well as daidzein and genistein [84]. Synthesis of metal-organic framework in the presence of guest was used for the entrapment of boron dipyrromethene dyes in MOF. This complex could not be obtained by direct milling of MOF with BODIPY dyes [85]. Furthermore, the size of mechanochemically prepared hemicucurbituril macrocycles was effectively controlled by anion templating [86]. Pseudorotaxanes which were prepared in solution were transformed into diamide rotaxanes [2] by solvent-free reaction of amine and acyl chloride terminus forming amide stoppers [87]. On the other hand, for the synthesis of rotaxanes [2], a one-pot, two-step mechanochemical protocol was used. It involves the preparation of pseudorotaxane and stoppering by 1,3-dipolar alkyne-azide cycloaddition in the second step.
While the photochemical activation of molecules in solution is a well-known phenomenon, its integration with milling mechanochemistry has largely remained unexplored. The first step in this direction was made by MacGillivray who described the photochemical [2+2] dimerization of 4,4′-di(pyridyl)ethylene molecules, pre-assembled in a cocrystal by template-directed solid-state cocrystallization, into a cyclobutane product [88]. The milling, achieved by shaking a glass vial in a vortex machine, was required for the cocrystallization step, while the broadband UV lamp from a laboratory photoreactor was used to affect the dimerization in the solid state. This approach, named “vortex grinding,” requires the vortex shaker to be placed inside the photoreactor chamber and is not compatible with standard milling equipment. Recently, visible light photoredox catalysis has grown into an exciting and very productive research field, but the challenge of combining it with solid-state milling remained. Further investigations by König showed that solvent-free visible light-induced photocatalytic reactions could be realized in thin liquid films by means of a rod mill, consisting of a test tube containing the reaction mixture and a glass rod attached to a stirrer [89] or by a “rotating film reactor” where a glass vial is rotated at 1200 rpm to form a film exposed to blue light [90]. In this way, alcohol oxidations using riboflavin tetraacetate photocatalyst and coupling of aryl halides with pyrroles and phosphites in the presence of rhodamine 6G were accomplished (Figure 16a).
(a) Rod mill and rotating film reactors for solvent-free photocatalysis. (b) MASSPC reactor for simultaneous ball milling and LED irradiation. (c) A multiposition jar adapter for planetary ball milling and the lunar motion of vials in the adapter. (d) Resonant acoustic mixing device and the effect of acceleration on the cocrystallization of carbamazepine and nicotinamide.
In 2017, our group reported on the first successful implementation of mechanochemical ball milling in a commercial shaker mill with visible light photocatalysis, named the “mechanochemically-assisted solid-state photocatalysis” or “MASSPC” [91]. The major obstacle in employing photochemical activation in mechanochemical reactions is the nontransparency of milling jars typically made of stainless steel, tungsten carbide, or Teflon. To overcome this issue, custom-made Duran glass jars completely translucent to visible light were designed. Plastic jars made of polymethylmethacrylate (PMMA), extensively used in real-time in situ monitoring of mechanochemical reactions [92], were found to be inadequate for this purpose due to the insufficient transparency caused by the wear of the plastic material during milling. In parallel, a photochemical reactor that would enable simultaneous high-speed vibrational milling and irradiation of the milled sample was constructed. While the initial experiments with LED strips wrapped around the glass jars showed promise as the simplest solution, prolonged exposure to high-frequency vibrations led to breakage of the strip, and this approach was eventually abandoned. Instead, an LED reactor that would fit around the oscillating glass jar was devised and successfully used in the aerobic thiophenol-promoted photocatalytic oxidation of diphenylacetylene to a diketone benzil (Figure 16b).
The obtained results suggested that singlet oxygen (1O2) was involved in the transformation of an alkyne into the diketone product, while the gas chromatographic analysis allowed reaction quantification and the detection of intermediate isomeric vinyl sulfides as the photoactive species that react with singlet oxygen. The formation of 1O2 under these conditions was also demonstrated by the MASSPC approach by synthesizing anthracene-9,10-
One practical limitation of using conventional ball mills for synthetic purposes is their low throughput, i.e., the inability to process more than a few samples simultaneously. To address this problem, Cravotto and Colacino resorted to modification of a standard jar for planetary ball milling by transforming it to a multiposition jar adapter capable of processing up to 12 samples at the same time [94]. The adapter can be made in different sizes to accommodate 4 vials of 100 mL, 8 vials of 20 mL, or 12 vials of 2 mL volume. In the case of a planetary ball mill equipped with four milling stations, this technical modification enables fast screening and optimization for up to 48 different reaction conditions. Besides high-throughput operation mode and time- and cost-effectiveness, “mechanochemical parallel synthesis” (1)avoids cleaning and cross contamination as the reaction mixtures can be stored or analyzed directly in the vial, (2) it allows reactions on a milligram scale (ca. 10 mg), (3) aluminum adapters serve as heat sinks and prevent reaction mixtures from overheating, and (4) the vials can be periodically loaded/unloaded to enable processing a large number of samples. Vials loaded into a multiposition adapter/jar experience the so-called
The development of mechanochemical parallel synthesis was successfully employed in the synthesis of a library of 3,4-dihydro-2H-benzo[e][1, 3] oxazines by a one-pot three-component reaction between a phenol, a paraformaldehyde, and a primary amine. More than 60 experiments per week were performed, as opposed to expected 6–8 weeks required for the same output using conventional milling. A typical experiment in a 2 mL vial was done on 0.53 mmol scale using 60 stainless steel balls (1 mm diameter), while 20 mL vials were charged with 3.19 mmol of a phenol/amine along with 60 glass beads (3 mm diameter). The reaction mixtures were milled at 550 rpm for 4 h affording yields comparable to solution synthesis.
The traditional paradigm of mechanochemistry is the use of milling balls to introduce mechanical and thermal energy into a system through mechanisms such as impact, shear, or their combination, depending on the milling mode. The number, mass, size, or material the balls are made of, as well as their relation to the volume of a milling jar, are all important variables in determining the outcome of a mechanochemical ball milling reaction. However, in a technique called the “resonant acoustic mixing” or RAM, solid-state reactions can be performed in the absence of milling bodies [95]. Unlike conventional ball milling, where the introduced energy causes physical damage to particles, generates defects, and often leads to aggregation of particulates, compaction, the so-called “snow balling,” or even complete amorphization, RAM is a much softer technique for mixing solids with minimal damage to particles. It is therefore particularly convenient in cases where mixing of impact-sensitive materials such as explosives and propellants is required. In a resonant acoustic mixer device, effective mixing is accomplished by transferring the mechanical energy of a vibrating plate connected to a bed of springs to a sample container placed on top of the plate. The plate and the container are set into an oscillating motion at a fixed resonance frequency, resulting in local zones of intense mixing (Figure 16d). Since the frequency of plate vibration is fixed (ca. 61 Hz), the intensity of mixing is simply adjusted by changing the amplitude of the oscillation; hence the acceleration or the “G-force” exerted on a powder sample in the container can be controlled.
In 2018, Michalchuk and Boldyreva reported the first in situ study of a RAM-induced cocrystallization of nicotinamide (
Since the introduction of real-time in situ techniques for monitoring mechanochemical reactions [92], based on synchrotron PXRD, Raman spectroscopy, and their combination, mechanistic details for a number of organic transformations, metal-organic framework (MOF) systems, and solid-state cocrystallizations have been studied and revealed [96]. These in situ studies also allow for kinetic considerations of solid-state milling reactions under LAG conditions [97], as well as investigations of the effect of milling parameters such as frequency [98], number of milling balls [99], or the ball to reactant ratio on the course of mechanochemical reactions [100]. On a technical side, such investigations go hand in hand with the development of equipment necessary to conduct them. In this respect, accessories such as milling jars for in situ studies deserve special attention. Filinchuk et al. have employed a 3D printer as a low-cost and rapid way to fabricate several types of plastic jars made of PMMA or polylactic acid (PLA) transparent to X-rays and showed how different geometries and material of the jars can reduce background (due to scattering) and minimize absorption, as well as improve the angular resolution during PXRD measurements [101]. In comparison with standard jars used in most experiments (type 0 and its modification type 1), jars with thinner walls (type 2) and added grooves (type 3) or physically separated X-ray probing area in the “two-chamber” jar (type 4) displayed significantly lower background and absorption (Figure 17a). In designs 3 and 4, the size of the groove or the opening between the two chambers is smaller than the ball size, which eliminates the problem of X-ray scattering on milling balls and detection of the corresponding diffraction peaks. The sampling efficiency of 3D-printed jars was tested on the solvent-free mechanochemical PbO polymorph interconversion from β-PbO to α-PbO phase, as a suitable model system. The results showed that the jar design generally affects the rate of β-PbO to α-PbO conversion, with the lowest rate expectedly recorded in the type 4 “two-chamber” jar where the analyzed sample resides in the bottom chamber, while ball milling and intensive mixing take place in the upper chamber. The authors also noted that types 3 and 4 jars are not compatible with liquid-assisted grinding since wet powder materials would probably stick and aggregate in the groove or in the chamber corners.
(a) Different types of 3D-printed plastic jars. (b) Casati’s design of a probing jar and a dual motion ball mill. (c) Twin-screw extruder and its components.
Besides improving the design of milling jars, the development of instrumentation for mechanistic studies is essential, as exemplified by Casati’s design of a new type of in situ ball mill intended for real-time probing of reactions in solids [102]. The new setup, characterized by a dual motion during milling in the form of vertical shaking (up to 50–80 Hz) and continuous slow rotation of the jar, is capable of collecting PXRD data with significantly reduced background and sharper Bragg reflections, which becomes important if high-resolution measurements are desired. Such a design also prevented the aggregation of powder material in the grooves, often encountered in devices where the only motion is shaking insufficient to push the powder out of the groove. In combination with the new design of a two-part milling chamber surrounded by a continuous probing ring where the milling balls cannot enter, it provides opportunities for collecting better resolved PXRD data, reaction monitoring, phase quantification, and line profile analysis (Figure 17b).
An interesting recent contribution to real-time in situ monitoring of organic transformations is the detection of a cocrystal between barbituric acid and vanillin that precedes the formation of C〓C bond in the final Knoevenagel product [103]. The reactant molecules in the cocrystal are positioned to allow nucleophilic attack of the methylene group in barbituric acid to the carbonyl group in vanillin. LAG using ethanol accelerated the reaction, while acetonitrile or nitromethane prolonged the life span of the cocrystal, the structure of which was elucidated from the laboratory PXRD data. Using
Since mechanochemical synthesis in ball mills is inherently associated with thermal effects accompanying the mechanical activation through impact or shear, a complete understanding of milling processes on a microscopic level must also take into consideration the corresponding evolution of heat. The Emmerling group described a combined in situ study of the Knoevenagel reaction between
One of the main drawbacks of mechanochemical synthesis is the lack of ability to perform milling reactions on large scales and in a continuous fashion. Industrial ball mills, which are typically used on these scales, can process tons of materials, whereas for laboratory use, planetary ball mills can deliver products up to several hundred grams. Currently, the most efficient way to increase the product output of mechanochemical reactions is the twin-screw extrusion (TSE), which has been successfully demonstrated in the large-scale solvent-free production of MOFs, cocrystals, and deep eutectic solvents, in space time yields (kg m−3 day−1) three to four times greater than the corresponding solution methods. In a typical TSE design, powdered reactants are fed into the instrument at a certain rate and conveyed by a pair of co- or counter-rotating screws encased in the extruder barrel. As the material moves along the barrel, mixing and kneading elements incorporated into the TSE design exert shearing and compression forces on the reactants, resulting in the product phase which is collected at the exit port (Figure 17c). Besides the screw speed and feed rate, the extruder barrel temperature is another processing parameter that can be modified [106].
James et al. have shown that organic molecules can be synthesized continuously on a large scale using TSE technique under solvent-free conditions. Four condensation reactions (the Knoevenagel reaction, the imine formation, the aldol reaction, and the Michael addition) were optimized by changing the screw speed, feed rate, and temperature, to provide a quantitative conversion to desired products. High-space time yields of >250,000 kg m−3 day−1 for the vanillin-barbituric acid reaction, 14,900 kg m−3 day−1 for the imine product, 35,000 kg m−3 day−1 for the Michael product, and 32,000 kg m−3 day−1 in the case of the aldol product were achieved [106]. TSE was also applied in the large-scale synthesis of 2,2-difluoro-1,3-diphenylpropane-1,3-dione in the presence of Selectfluor as the fluorine source, with the space time yield of 3395 m−3 day−1 vs. only 29 m−3 day−1 obtained in the mixer mill [107]. The three-component solvent-free Biginelli reaction was successfully carried out using TSE, to afford 3,4-dihydropyrimidin-2-(1H)-ones/thiones in optimized yields of 85–91% [108].
A short review of recent literature dealing with organic mechanochemical synthesis is presented.
The authors acknowledge funding by the Croatian Science Foundation grant No. IP-2018-01-3298, cycloaddition strategies towards polycyclic guanidines (CycloGu).
Chronic myeloproliferative disorders are a group of clonal diseases of the stem cell. It is a group of several diseases with some common features. They derive from a multipotential hematopoietic stem cell. A clone of neoplastic cells in all these neoplams is characterized by a lower proliferative activity than that of acute myeloproliferative diseases. In each of these diseases, leukocytosis, thrombocythemia, and polyglobulia may appear at some stage, depending on the diagnosis [1, 2].
The research on interferon has been going on since the 1950s [3]. Then, the attention was paid to its influence on the immune system. It has been noted that it can exert an antiproliferative effect by stimulating cells of the immune system [4]. In 1987, a publication by Ludwig et al. was published, which reported the effectiveness of interferon alpha in the treatment of chronic myeloproliferative disorders [5].
More and more new studies have been showing the effectiveness of interferon alpha in reducing the number of platelets, reducing the need for phlebotomies in patients with polycythemia vera and also in reducing the number of leukocytes. Moreover, interferon reduced the symptoms of myeloproliferative disorders such as redness and itching of the skin. Additionally, it turned out to be effective in reducing the size of the spleen.
Further studies on the assessment of remission using molecular-level response assessments indicate that the interferon action in chronic myeloproliferation diseases targets cells from the mutant clone with no effect on normal bone marrow cells [6].
Over the years, interferon alpha-2a and interferon alpha-2b have been introduced into the treatment of chronic myeloproliferation, followed by their pegylated forms. The introduction of pegylated forms allowed for a reduction in the number of side effects and less frequent administration of the drug to patients. In recent years, monopegylated interferon alpha-2b has been used to further increase the interval between drug administrations while maintaining its antiproliferative efficacy.
The exact mechanism of action of interferon alpha in the treatment of chronic myeloproliferative disease is still not fully understood, but it has an impact on JAK2 (Janus Kinase) signal transducers and activates the STAT signal pathway (Janus Kinase/SignalTransducer and Activator of Transcription).
Interferon alpha binds to IFNAR1 and IFNAR2c, which are type I interferon receptors. Interferon alpha has an impact on JAK2(Janus Kinase) signal transducers and activates the STAT signal pathway. The disturbances in this signaling pathway are observed in chronic myeloproliferative disorders [7].
Interferon inhibits the JAK-STAT signaling pathway by directly inhibiting the action of thrombopoietin in this pathway [8].
So far, three driver mutations have been described in the course of chronic myeloproliferative diseases that affect the functioning of the JAK-STAT pathway.
JAK2 kinase and JAK1, JAK3, and TYK2 kinases belong to the family of non-receptor tyrosine kinases. They are involved in the intracellular signal transduction of the JAK-STAT pathway. It is a system of intracellular proteins used by growth factors and cytokines to express genes that regulate cell activation, proliferation, and differentiation. The mechanism of JAK activation is based on the autophosphorylation of tyrosine residues that occurs after ligand binds to the receptor. JAK2 kinase transmits signals from the hematopoietic cytokine receptors of the myeloid lineage (erythropoietin, granulocyte-colony stimulating factor thrombopoietin, and lymphoid lineage [9].
A somatic G/T point mutation in exon 14 of the JAK2 kinase gene converts valine to phenylalanine at position 617 (V617F) in the JAK2 pseudokinase domain, which allows constitutive, ligand-independent activation of the receptor to trigger a proliferative signal [10].
Mutation of the MPL gene, which encodes the receptor for thrombopoietin, increases the sensitivity of magekaryocytes to the action of thrombopoietin, which stimulates their proliferation [11].
Malfunction of calreticulin as a result of mutation of the CARL gene leads to the activation of the MPL-JAK/STAT signaling pathway, which is independent of the ligand, as calreticulin is responsible, for the proper formation of the MPL receptor. Consequently, there is a clonal proliferation of hematopoietic stem cells [12].
Below, we provide an overview of some clinical studies on the efficacy of interferon in chronic myeloproliferative disorders.
Polycythemia vera (PV) is characterized by an increase in the number of erythrocytes in the peripheral blood.
Polycythemia vera is caused by a clonal mutation in the multipotential hematopoietic stem cell of the bone marrow. The mutation leads to an uncontrolled proliferation of the mutated cell clone, independent of erythropoietin and other regulatory factors. As the mutation takes place at an early stage of hematopoiesis, an increase of the number of erythrocytes as well as of leukocytes and platelets is observed in the peripheral blood. The cause of proliferation in PV independent from external factors is a mutation in the Janus 2 (JAK2) tyrosine kinase gene. The V617F point mutation in the JAK2 gene is responsible for about 96% mutation, and in the remaining cases the mutation arises in exon 12. Both mutations lead to constitutive activation of the JAK-STAT signaling pathway [13].
As a result of the uncontrolled proliferation, blood viscosity increases, which generates symptoms such as headaches and dizziness, visual disturbances, or erythromelalgia. As the number of all hematopoietic cells, including the granulocytes ones, increases, the difficult to control symptoms of their hyperdegranulation may appear, among which gastric ulcer or skin itching is often observed. During the disease progression, the spleen and liver become enlarged.
The most common complication of the disease is episodes of thrombosis, especially arterial one. During the course of the disease, it can also evolve into myelofibrosis or acute myeloid leukemia.
The treatment of PV is aimed at preventing thromboembolic complications, relieving the general symptoms, the appearance of hepatosplenomegaly as well as preventing its progression.
Each patient should receive an antiplatelet drug chronically, and usually acetylsalicylic acid is the choice. Most often, the treatment is started with phlebotomy in order to rapidly lower the hematocrit level. If cytoreductive therapy is necessary, the drugs of first choice are hydroxycarbamide and interferon [2].
However, the research on the mechanism of the action of interferons is still ongoing. In vitro studies with CD34+ cells from peripheral blood of patients diagnosed with polycythemia vera showed that interferon inhibits clonal changed cells selectively. It was found that interferon alpha-2b and pegylated interferon alpha-2a reduce the percentage of cells with JAK2 V617F mutation by about 40%. Pegylated interferon alpha-2a works by activating mitogen-activated protein kinase P38. It affects CD34+ cells of patients with polycythemia vera by increasing the rate of their apoptosis [6].
A case of a patient with PV with a confirmed chromosomal translocation t(6;8) treated with interferon alpha-2b, which resulted in a reduction of the clone with translocation by 50% from the baseline value, was also described [14].
In 2019, the results of a phase II multicenter study were published, which aimed at assessing the effectiveness of recombinant pegylated interferon alpha-2a in cases of refractory to previously hydroxycarbamide therapy. The study included 65 patients with essential thrombocythemia (ET) and 50 patients with polycythemia vera. All patients had previously been treated with hydroxycarbamide and showed resistance to this drug or its intolerance.
The assessment of the response was performed after 12 months of treatment. Overall response rate to interferon was higher in patients diagnosed with ET than in patients with polycythemia vera. In essential thrombocythemia, the percentage of achieved complete remissions was 43 and 26% of partial remissions. The remission rate in ET patients was higher if calreticulin CALR gene mutation was present. Patients with polycythemia vera achieved complete remission in 22% of cases and partial remission in 38% of cases.
Treatment-related side effects that follow to discontinuation of treatment were reported in almost 14% of patients [15].
The duration of response to treatment with pegylated interferon alpha-2a and the assessment of its safety in long-term use in patients with chronic myeloproliferative disorders was the goal of a phase II of the single-center study. Forty-three adult patients with polycythemia vera and 40 patients with essential thrombocythemia were enrolled in the study. The complete hematological response was defined as a decrease in hemoglobin concentration below 15.0 g/l, without phlebotomies, a resolution of splenomegaly, and no thrombotic episodes in the case of PV, and for essential thrombocythemia—a decrease platelet count below 440,000/μl and two other conditions as above. The assessment of the hematological response was performed every 3–6 months. The median follow-up was 83 months.
The hematological response was obtained in 80% of cases for the entire group. In patients with polycythemia vera, 77% of patients achieved a complete response (CR) while 7% a partial response (PR). The duration of response averaged 65 months for CR and 35 months for PR. In the group of patients diagnosed with essential thrombocythemia, CR was achieved in 73% and PR in 3%. The durance of CR was 58 months and PR was 25 months.
The molecular response for the entire group was achieved in 63% of cases.
The overall analysis showed that the duration of hematological remission and its achievement with pegylated interferon alpha-2a treatment is not affected neither by baseline disease characteristics nor JAK2 allele burden and disease molecular status. There was also no effect on age, sex, or the presence of splenomegaly.
During the course of the study, 22% of patients discontinued the treatment, because of toxicity. Toxicity was the greatest at the beginning of treatment. The starting dose was 450 μg per week and was gradually tapered off.
Thus, on the basis of the above observations, the researchers established that pegylated interferon alpha-2a may give long-term hematological and molecular remissions [16].
The assessment of pegylated interferon alpha-2a in group of patients diagnosed with polycythemia vera only was performed. The evaluation was carried out on a group of 27 patients. Interferon decreased the JAK2 V617F allele burden in 89% of cases. In three patients who were JAK2 homozygous at baseline, after the interferon alpha-2a treatment wild-type of JAK2 reappeared. The reduction of the JAK2 allele burden was estimated from 49% to an average 27%, and additional in one patient the mutant JAK2 allele was not detectable after treatment. It can therefore be postulated that the action of pegylated interferon alpha-2a is directed to cells of the polycythemia vera clone [17].
In 2005, the results of treatment by pegylated interferon alpha-2b of 21 patients diagnosed with polycythemia vera and 21 patients diagnosed with essential thrombocythemia were published. In the case of polycythemia vera in 14 patients, PRV-1 gene mutation was initially detected. In 36% of cases, PRV-1 expression normalized after treatment with pegylated interferon alpha-2b. For the entire group of 42 patients, the remission assessment showed that complete remission was achieved in 69% cases after 6 months of treatment. However, only in 19 patients remission was still maintained 2 years after the start of the study. Pegylated interferon alpha-2b was equally effective in patients with PV and ET. The use and the type of prior therapy did not affect the achievement of remission [18].
Another study with enrolled only PV patients included 136 patients. They were divided into two arms. One group received interferon alpha-2b and the other group received hydroxycarbamide. Interferon dosage was administered in 3 million units three times a week for 2 years and then 5 million units two times a week. Hydroxycarbamide was administered at a dose between 15 and 20 mg/kg/day.
In the group of patients treated with interferon, a significantly lower percentage of patients developed erythromelalgia (9.4%) and distal parasthesia (14%) compared with the group treated with hydroxycarbamide, for whom these percentages were respectively: 29 and 37.5%. Interferon alpha-2b was found to be more effective in inducing a molecular response, which was achieved in 54.7% of cases, in comparison with hydroxycarbamide—19.4% of cases, despite the fact that the percentage of achieved general hematological responses did not differ between the groups and amounted about 70%. The 5-year progression free period in the interferon group was achieved in a higher percentage (66%) than in the hydroxycarbamide group (46.7%) [19].
The most recent form of interferon approved by the
Thanks to these changes to the structure of the molecule, it was possible to achieve a significant increase in its half-life. Ropeginterferon can be administered subcutaneously to patients every 14 days. The clinical trials conducted so far have assessed the ropeginterferon dose from 50 micrograms to a maximum dose of 500 microgams administered as standard every 2 weeks. The possible dose change in case of side effects includes not only the reduction of the drug dose itself, but also the extension of the interval between doses. The extension of the dosing interval up to 4 weeks was assessed.
Ropeginterforn was approved in 2019 by the EMA for the use in patients diagnosed with polycythemia vera without splenomegaly, as monotherapy.
Ropeginterferon, like the previous forms of interferons used in treatment, is contraindicated in patients with severe mental disorders, such as severe depression. It is also a contraindication in patients with noncompensatory standard treatment of disorders of the thyroid gland as well as severe forms of autoimmune diseases. The safety profile of ropeginterferon is similar to that of other forms of alpha interferons. The most common side effects are flu-like symptoms [20].
Ropeginterferon has been shown to exhibit in vitro activity against JAK2-mutant cells. The activity of ropeginterferon against JAK2-positive cells is similar to that of other forms of interferons used actually for standard therapy. Ropeginterferon has an inhibitory effect on erythroid progenitor cells with a mutant JAK2 gene. At the same time, it has almost no effect on progenitor cells without the mutated allele (JAK2-wile-type) and normal CD34+ cells. A gradual decrease of JAK2-positive cells was observed in patients with PV during ropeginterferon treatment. The examination was performed after 6 and 12 months of treatment. In comparison, the reduction in the percentage of JAK2 positive cells in patients treated with hydroxycarbamide was significantly lower.
These results may suggest that ropeginterferon may cause elimination of the mutant clone, but further prospective clinical trials are needed to confirm this theory. The evaluation was performed on a group of patients enrolled in the PROUD-PV study who were treated in France [21].
In 2017, a multicenter study was opened in Italy. The study was of the second phase. In total, 127 patients with polycythemia vera were included in the study. All patients enrolled on the study had low-risk PV. The clinical trial consisted of two arms. Patients received phlebotomies and low-dose aspirin in one arm and ropeginterferon in the other arm. The aim of the study was to achieve a hematocrit of 45% or lower without any evidence of disease progression. Ropeginterferon was administered every 2 weeks at a constant dose of 100 μg.
The response to the treatment was assessed after 12 months. The reduction of hematocrit to the assumed level was achieved in significantly higher percentage of patients in the ropeginterferon group than of patients who received only phlebotomies and aspirin. In addition, none of the patients treated with ropeginterferon experienced disease progression during the course of the study, while among those treated with phlebotomies, 8% of patients progressed.
Grade 4 or 5 adverse events were not observed in patients treated with ropeginterferon, and the incidence of remaining adverse event (AE) was small and comparable in both arms. The most common side effects in the ropeginterferon group were flu-like symptoms and neutropenia; however, the third-grade neutropenia was the most common (8% of cases) [22].
One of the most important clinical studies on the use of ropeginterferon was the PROUD-PV study and its continuation: the CONTINUATION-PV study. These were three-phase, multicenter studies. The aim of the study was to compare the effectiveness of ropeginterferon in relation to hydroxycarbamide. The study included adult patients diagnosed with polycythemia vera treated with hydroxycarbamide for less than 3 years and no cytoreductive treatment at all. In total, 257 patients received this treatment. The patients were divided into two groups: those receiving ropeginterferon or the other being given hydroxycarbamide.
During the PROUD-study, drug doses were increased until the hematocrit was achieved below 45% without the use of phlebotomies, and the normalization of the number of leukocytes and platelets was reached.
The PROUD-PV study lasted 12 months. After this time, the patients continued the treatment under the CONTINUATION-PV study for further 36 months. After the final analysis performed in the 12th month at the end of PROUD study, it was found that the hematological response rates did not differ between the ropeginterferon and hydroxycarbamide treatment groups. These were consecutively 43% in the ropeginterferon arm and 46% in the control arm.
However, after analyzing the CONTINUATION- PV study, it turned out that after 36 months of treatment, the rates of hematological responses begin to prevail in the group of patients receiving ropeginterferon, 53% versus 38% in the control group. Thus, from the above data, it can be seen that the response rate to ropeginterferon increases with the duration of treatment [23].
Another analysis of patients participating in the PROUD and CONTINUATION studies was based on the assessment of treatment results after 24 months, dividing patients into two groups according to age (under and over 60 years).
The initial comparison of both groups of patients showed that older patients had a more aggressive course of the disease. Patients over 60 years of age had a higher percentage of cells with a mutant JAK2 allele. They experienced both general symptoms and some complications, such as thrombosis, more frequently. Both patients under 60 years of age and over 60 years of age in the ropeginterferon arm had a higher rate of molecular response, namely 77.1 and 58.7% compared with the HU remission: 33.3 and 36.1%, respectively. Significantly higher reductions in the JAK2 allele were observed in both groups of patients after ropeginterferon treatment: it was 54.8% for younger patients and 35.1% for elderly patients. For comparison, this difference in the group of patients treated with HU was 4.5 and 18.4%, respectively.
What is more, the age did not affect the frequency of ropeginterferon side effects. In addition, the incidence of adverse ropeginterferon disorders was similar to that observed in the hydroxycarbamide group [24].
Essential thrombocythemia is a clonal growth of multipotential stem cells in the bone marrow. The consequence of this is increased proliferation of megakaryocytes in the bone marrow and an increase in the number of platelets in the peripheral blood. The level of platelets above 450,000/μl is considered a diagnostic criterion.
Essential thrombocythemia may progress over time to a more aggressive form of myeloproliferation, i.e., myelofibrosis. The disease can also evolve into acute myeloid leukemia or myelodysplastic syndrome, both with very poor prognosis. Thromboembolic complications are serious, and they concern over 20% of patients. Thrombosis occurs in the artery and venous area. Moreover, in patients with a very high platelet count, above 1,000,000/μl, bleeding may occur as a result of secondary von Willebrand syndrome [1, 2].
The treatment of ET is primarily aimed to prevent thrombotic complications.
In low-risk patients, only acetylsalicylic acid is used. In cases of high-risk patients, hydroxycarbamide is the first-line drug for most patients. Anagrelide and interferon are commonly used as second-line drugs.
Due to the possible effects of hydroxycarbamide of cytogenetic changes in the bone marrow cells after long-lasting usage, some experts recommend the use of interferon in younger patients in the first line. Interferon is also used as the drug of choice in patients planning a pregnancy [25].
The efficacy of pegylated interferon alpha-2a was assessed on the basis of the group of 39 patients with essential thrombocythemia and 40 patients with polycythemia vera.
Of the overall group, 81% of patients were previously treated prior to the study entry. The patients received pegylated interferon alpha-2a in a dose of 90 μg once a week. The dose of 450 μg was associated with a high percentage of intolerance.
In patients with essential thrombocythemia, the complete remission was achieved in 76%, while the overall hematological response rate brought 81%. Moreover, the molecular remission was achieved in 38%, in 14% of cases, JAK2 transcript became not detectable.
Patients diagnosed with polycythemia vera achieved 70% complete hematological remission and 80% general hematological response to treatment. JAK2 transcript was undetectable in 6% of patients. Molecular remission was achieved in 54% of cases.
Pegylated interferon alpha-2a at the dose of 90 μg per week was very well tolerated. In total, 20% of patients experienced a grade of 3 or 4 of adverse reaction, which was neutropenia. In addition, an increase in liver function tests was observed. Grade 4 of AE was not observed among patients who started the treatment with 90 μg/week while grade 3 neutropenia was an adverse event in only 7% of cases [26].
The effect of interferon alpha-2b treatment in patients with ET and PV was investigated. The study was prospective. Some of the results concerning the group of patients with polycythemia vera are presented in the subsection on polycythemia vera. In total, 123 patients with diagnosed essential thrombocythemia participated in the study. All of them received interferon alpha-2b. The patients were divided into two groups depending on the presence of the JAK2 V617F mutation. The enrolled patients were between 18 and 65 years of age. The treatment they received was, sequentially, interferon alpha-2b in the dose of 3 million units three times a week for the first 2 years, after which time the dose was changed into a maintenance dose, which amounted to 5 million units two times a week.
The analysis showed that the patients with the JAK2 V617F mutation present in a higher percentage achieved an overall hematological response as well as a complete hematological response. The overall hematological response was achieved in 83% of patients with JAK2 mutation, and the complete hematological remission was achieved in 23 cases. In the group of ET patients without the JAK2 V617F mutation, overall hematological response was achieved in 61.4%, while the complete hematological remission was achieved in 12 patients. The 5-year progression-free survival was obtained in 75.9% in the JAKV617F group and only in 47.6% without the mutation.
A significant proportion of patients experienced mild side effects. Grade 3 and 4 of adverse events were severe, most of them being a fever. The isolated cases of elevated liver tests and nausea have also been reported [19].
Pegylated interferon alpha-2b in patients with essential thrombocythemia who were previously treated with hydroxycarbamide, anagrelide, and other forms of interferon alpha, however, due to the lack of efficacy or toxicity, the patients required a change of treatment, was assessed. Pegylated interferon alpha-2b turned out to be effective in these cases. It led to the complete hematological remission in 91% of patients after 2 months of therapy, and in 100% of patients after 4 months. However, merely 11 patients participated in the study. Also only two patients required treatment discontinuation due to the side effects such as depression and general fatigue grade 3 [27].
In case of pregnant patients, interferon is currently considered the only safe cytoreductive drug. Over the years, several analyses of the results of interferon treatment during pregnancy have been carried out.
The assessment of 34 pregnancies in 23 women diagnosed with ET was performed retrospectively. All the pregnancies included in the analysis were of high risk. This high risk was associated with a high platelet count above 1,500,000/μl, a history of thrombotic episode, severe microcirculation disorders, or a history of major hemorrhage.
It turned out that the use of interferon allowed the birth of an alive child in 73.5% of cases. There was no difference in efficacy between the basic and pegylated forms of interferon alpha. In pregnancies without interferon treatment, the percentage of live births was only 60%. Moreover, it was not found if the presence of the JAK2 V617F mutation had any influence on the course of pregnancy [28].
An analysis of the course of pregnancy in patients with ET was assessed in Italy. Data from 17 centers were taken into account. Data from 122 pregnancies were collected from 92 women. In patients diagnosed with essential thrombocythemia, the risk of the spontaneous loss of pregnancy is about 2.5 times higher than among the general population. In the contrary to the study quoted above, it was found that the presence of the JAK2 mutation increases the risk of pregnancy loss. The proportion of live births in patients exposed to interferon during pregnancy was 95%, compared with 71.6% in the group of patients not treated with interferon.
The multivariate analysis also showed that the use of acetylsalicylic acid during pregnancy had no effect on the live birth rate of patients with ET [29].
Whatever its form, interferon is the drug of first choice in pregnancy. Hydroxycarbamide and anagrelide should be withdrawn for about 6 months, and at least for 3 months, before the planned conception. Experts recommend the use of interferon in high-risk pregnancies [30]. A Japanese analysis of 10 consecutive pregnancies in ET patients showed 100% live births in patients who received interferon [31].
In myelofibrosis (MF), monoclonal megakaryocytes produce cytokines that stimulate the proliferation of normal, non-neoplastic fibroblasts and stimulate angiogenesis. The consequence of this is the gradual fibrosis of the bone marrow, impaired hematopoiesis in the bone marrow, and the formation of extramedullary location mainly in the sites of fetal hematopoiesis, i.e., in the spleen and the liver.
The production of various cytokines by neoplastic megakaryocytes leads to the proliferation of normal, noncancerous fibroblasts as well as to increased angiogenesis.
Progressive bone marrow fibrosis leads to worsening anemia and thrombocytopenia. On the other hand, the production of proinflammatory cytokines by megakaryoblasts leads to the general symptoms such as weight loss, fever, joint pain, night sweats, and consequently, progressive worsening of general condition.
The prognosis for myelofibrosis is poor. In about 20% of patients, myelofibrosis evolves into acute myeloid leukemia with poor prognosis.
Currently, the only effective method of treatment that gives a chance to prolong the life is allogeneic bone marrow transplantation. However, this method is only available to younger patients.
The goal of treatment of patients who have not been qualified for allotranspalntation is to reduce the symptoms and to improve the patient’s quality of life. In case of leukocytosis cytoreducing drugs, such as hydroxycarbamide, melphalan, or cladribine can be used. They cause a reduction in the number of leukocytes and may, to some extent, inhibit splenomegaly. Interferon alpha has been used successfully for the treatment of myelofibrosis for many years. The results of its effectiveness will be presented below [2].
Currently, the JAK2 inhibitor ruxolitinib is approved for the treatment of myelofibrosis with enlarged spleen in intermediate and high-risk patients. Ruxolitinib reduces the size of the spleen, reduces general symptoms, and improves the quality of life; however, it does not prolong the overall survival of patients [32].
In 2015, the results of a retrospective study were published to compare the histological parameters of the bone marrow before and after interferon treatment. Twelve patients diagnosed with primary myelofibrosis as well as post-PV MF and post-ET MF were enrolled in the study. Patients were treated with pegylated recombinant interferon alpha-2a or recombinant interferon alpha-2b in standard doses. The time of treatment was from 1 to 10 years. Some patients had previously been treated with hydroxycarbamide or anagrelide. In all cases, karyotype was normal. The prognostic factor of Dynamic International Prognostic Scoring System (DIPSS) was assessed at the beginning as well as during the treatment.
Bone marrow cellularity decreased in cases with increased bone marrow cellularity before the treatment. After the interferon treatment, a reduction in the degree of bone marrow fibrosis was found. The parameters, such as the density of naked nuclei and the density of megakaryocytes in the bone marrow, also improved.
It proves that if the JAK2 V617F mutation had been present, DIPSS was decreased after interferon treatment. This relationship was not observed in patients without the JAK2 V617F mutation. The improvement in peripheral blood morphological parameters and the overall clinical improvement correlated with the improvement in the assessed histological parameters of the bone marrow.
Before the initiation of interferon, seven patients had splenomegaly. During the treatment with interferon, the complete resolution of splenomegaly was achieved in 17% of patients (two cases), and its size decreased in 25% (three cases). A good clinical response was achieved in 83% during interferon therapy. There was no significant difference in response between the two types of interferon used [33].
A prospective study was also conducted in patients with low and intermediate-1 risk group myelofibrosis. Seventeen patients were enrolled. Patients received interferon alpha-2b (0.5–3 milion units/three times a week) or pegylated interferon alpha-2a (45–90 μg/week). The duration of therapy was on average 3.3 years.
Most of the patients responded to the treatment. Partial remission was found in seven patients and complete remission in two patients. Moreover, in four cases, the disease was stabilized and in one case the clinical improvement was achieved. Three patients did not respond to treatment at all and progressed to myelofibrosis. Additionally, the assessment in reducing spleen size was performed. At baseline, 15 patients have splenomegaly, nine of them achieved the compete regression of spleen size [34].
However, the efficacy of interferon in the treatment of myelofibrosis appears to be limited only to a less advanced form, when the bone marrow still has an adequate percentage of normal hemopoiesis and the marrow stroma is not significantly fibrotic. In more advanced stages, interferon was not shown to have any significant effect on the regression of the fibrosis process [35].
In 2020, the results of the COMBI study were published. That was a two-phase, multicenter, single-arm study that investigated the efficacy and safety of the combination of ruxolitinib and pegylated interferon alpha. Thirty-two patients with PV and 18 patients with primary and secondary myelofibrosis participated in the study. The patients were at age 18 and older. Remission was achieved in 44% of myelofibrosis cases, including 28% (5 patients) of complete remission. In patients with PV, the results were slightly worse: 31% of remissions, including 9% of complete remissions. Patients received pegylated interferon alpha-2a (45 μg/week) or pegylated interferon alpha-2b (35 μg/week) in low doses and ruxolitinib in doses of 5–20 mg twice a day.
For the entire group of patients (with PV and MF), the initial JAK2 allele burden was 47% at baseline, and after 2 years of treatment with interferon and ruxolitinib, it decreased to 12%.
The treatment toxicity was low. The highest incidence of side effects occurred at initiation of therapy. It was mostly anemia and thrombocytopenia.
The observations from the COMBI study show that, for the combination of interferon in lower doses with ruxolitinib, it may be effective and well tolerated even in the group of patients who had intolerance to interferon used as the only drug in higher doses. The combined treatment improved the bone marrow in terms of fibrosis and its cellularity. It also allowed to improve the value of peripheral blood counts [36].
It is currently known that some of the additional mutations are associated with a worse prognosis in patients with myelorpoliferation, including patients with myelofibrosis. Some of these mutations have been identified as high-risk molecular mutations. These are ASXL1, EZH2, IDH1/2, or SRSF2. Earlier studies have shown their association with a more aggressive course of the disease, worse prognosis, and shorter survival of patients, as well as a poorer response to treatment. Due to their importance, they have been included in the diagnostic criteria of myelofibrosis [37].
It is also known that the presence of driver mutations, i.e., JAK2, CALR, and MPL or triple negativity, may affect the course of myeloproliferation, including the incidence of thromboembolic complications.
The assessment of the influence of driver mutations and a panel of selected additional mutations on the effectiveness of interferon treatment in patients with myelofibrosis was performed on a group of 30 patients. Only the patients with low- and intermediate-1-risk were enrolled in the study. The treatment with pegylated interferon alpha-2a or interferon alpha-2b resulted in a complete remission in two patients and partial remission in nine patients. The disease progressed in three cases. One patient relapsed and four died. The remaining patients achieved a clinical improvement or disease stabilization. In the studied group, it was not found if the effectiveness of interferon treatment was influenced by the lack of driver mutations. Among the group of four patients with additional mutations, two died and one had disease progression. It was a mutation of ASXL1 and SRSF2. The treatment with interferon in patients without additional molecular mutations in the early stages of the disease may prevent further progression of the disease [38].
The side effects of interferon in the group of patients with myelofibrosis are similar to those occurring after the treatment of other chronic myeloproliferative diseases. The most frequently described are hematological toxicity- anemia and thrombocytopenia, less often is the appearance of leukopenia. Hematological toxicity usually resolves with dose reduction or extension of the dose interval. The most frequently nonhematological toxicity was fatigue, muscle pain, weakness, and depression symptoms. All symptoms are usually mild and do not exceed grade 2 [38].
However, the use of interferon in the treatment of myelofibrosis has not been recommended as a standard therapy. Interferon is still being evaluated in clinical trials, or it is used in selected patients as a nonstandard therapy in this diagnosis.
Mastocytosis is characterized by an excessive proliferation of abnormal mast cells and their accumulation in various organs.
The basis for the development of mastocytosis is ligand-independent activation of the KIT receptor, resulting from mutations in the KIT proto-oncogene. The KIT receptor is a trans membrane receptor with tyrosine kinase’s activity. Its activation stimulates the proliferation of mast cells. That excessive numbers of mast cells infiltrate tissues and organs and release mediators such as histamine, interleukine-6, tryptase, heparin, and others, which are responsible for the appearance of symptoms typical of mastocytosis. In addition, the infiltration of tissues for mast cells itself causes damage to the affected organs.
The prognosis of mastocytosis depends on the type of the disease. In the case of cutaneous mastocytosis (CM), in the majority of cases prognosis is good and the disease does not shorten the patient’s life, but in aggressive systemic mastocytosis (ASM), the average follow-up is about 40 months. Mast cell leukemia has a poor prognosis with a median follow-up of approximately 1 year.
Systemic mastocytosis usually requires the implementation of cytoreductive therapy. The first line of therapy is interferon alone or its combination with corticosteroids. In aggressive systemic mastocytosis, the first line in addition to interferon 2-CdA can be used. An effective drug turned out to be midostaurin in the case of the present KIT mutation. In patients without the KIT D816V mutation, treatment with imatinib may be effective. In the case of mast cell leukemia, multidrug chemotherapy is most often required, as in acute leukemias, followed by bone marrow transplantation [39].
Systemic mastocytosis requiring treatment is a rare disease, this is why the studies available in the literature evaluating various therapies concern mostly small groups of patients.
In 2002, the French authors presented their experiences on the use of interferon in patients with systemic mastocytosis. They included 20 patients. The patients received interferon alpha-2b in gradually increased doses.
The patients were assessed after 6 months. In cases in which bone marrow was infiltrated for mast cells at baseline, it still remained infiltrated after 6 months of treatment.
However, the responses were obtained in terms of symptoms related to mast cell degranulation. Partial remission was achieved in 35% of patients and minor remission in 30%. It concerns mainly skin lesions and vascular congestion. Moreover, the assessment of the histamine level in the plasma revealed a decrease of it in patients who previously presented symptoms related to the degranulation of mast cells, such as gastrointestinal disorders and flushing.
A high percentage of side effects were found during treatment. They concerned 35% of patients. Depression and cytopenia were most frequent ones [40].
Another analysis was a report of five patients with systemic mastocytosis treated with interferon and prednisolone. All patients received interferon alpha-2b in a dose of 3 million units three times a week and four patients additionally received prednisolone. Four patients responded to interferon treatment at varying degrees. One patient, who at baseline had bone marrow involvement by mast cells in above 10%, progressed to mast cell leukemia. In two patients, the symptoms C resolved completely and in one of them they partially disappeared. In one case, stabilizing disease was achieved [41].
In 2009, a retrospective analysis of patients treated with cytoreductive therapy due to mastocytosis was published. The authors collected data from 108 patients treated at the Mayo Clinic. This analysis allowed for the comparison of the efficacy of four drugs used in systemic mastocytosis. There were interferon alpha alone or in the combination with prednisone—among 40 patients, hydroxycarbamide—among 26 ones, imatinib—among 22 persons, and 2-chlorodeoxyadenosine (2-CdA)—among 22 patients.
After dividing the patients into three additional groups on the basis of the type of mastocytosis—indolent systemic mastocytosis, aggressive systemic mastocytosis, and systemic mastocytosis associated with another clonal hematological nonmast cell lineage disease (SM-AHNMD)—the effectiveness of each of type of therapy was assessed.
The highest response rates in indolent and aggressive mastocytosis were achieved with interferon treatment. They were 60% of the responses in both groups, and in the SM-AHNMD group of patients, the percentage was also one of the highest and amounted to 45%. The second most effective drug was 2-CdA. The response rates were 56% for indolent MS, 50% for aggressive MS, and 55% for SM-AHNMD. The patients treated with imatinib achieved response in 14, 50, and 9% by following groups, respectively. In contrast, patients with indolent and aggressive systemic mastocytosis did not respond to hydroxycarbamide treatment at all. The response rate in both groups was 0%. However, patients with MS associated with another clonal hematological nonmast cell lineage disease achieved 21% response to hydroxycarbamide. Additionally, it was found that only interferon relieved symptoms caused by the release of inflammatory mediators by mast cells.
The additional analysis showed no influence of the TET 2 mutation on the response to treatment [42].
In the literature, there are also single cases of mastocytosis presenting trials of nonstandard treatment. That is description of a patient with systemic mastocytosis with mast cell bone marrow involvement. Mutation of c-kit Asp816Val was present. Patient progressed despite treatment with dasatinib and 2-chlorodeoxyadenosine. The patient developed symptoms related to the degranulation of mast cells and increased ascites.
The patient was treated with pranlukast, which is an anti-leukotriene receptor antagonist due to an asthma episode. The rate of ascites growth decreased significantly after one administration. The patient required paracentesis every 10 days and not every 3 days, as before starting to take the drug. After 15 days of treatment with pranlukast, the patient received interferon alpha, which resulted in complete regression of ascites, resolution of pancytopenia, and complete disappearance of the c-kit mutation clone. The infiltration of mast cells in the bone marrow significantly decreased [43].
Interferon alpha was also effective in a patient with systemic mastocytosis associated with myelodysplastic syndrome with the c-kit D816V mutation, which was refractory to imatinib treatment [44].
Interferon alpha also proved to be effective in the treatment of osteoporotic lesions appearing in the course of mastocytosis.
The series of 10 cases with resolved mastocytosis and osteoporosis-related fractures was presented in 2011. The patients received interferon alpha in a dose of 1.5 million units three times a week as well as pamindronic acid. The patients were treated for an average of 60 months. For the first 2 years, pamindronate was given at a dose of 1 mg/kg every month, and then every 3 months.
During the course of the study, no patient had a new-bone fracture. The level of alkaline phosphatase decreased by 25% in relation to the value before treatment and tryptase by 34%. Bone density increased during treated with interferon and pamindronate. The increase was on average 12% in the spine bones and 1.9% in the hip bones. At the same time, there was no increase in the density of the hip bone and a minimal increase in the density of the spine in patients treated with pamindronate alone.
The results of this observation suggest that it is beneficial to add low doses of interferon alpha to pamindronate treatment in terms of bone density increase [45].
That experiences show that interferon used in systemic mastocytosis significantly improves the quality of life of patients by inhibiting the symptoms caused by degranulation of mast cells. They prevent bone fractures and, in some patients, they cause remission of bone marrow infiltration by mast cells.
Chronic neutrophilic leukemia (CNL) is a very rare disease. It is characterized by the clonal proliferation of mature neutrophils.
The diagnostic criteria proposed by the World Health Organization (WHO) comprise leukocyte counts above 25,000/μl (including more than 80% of rod and segmented
Physical examination often shows enlargement of the liver and spleen, moreover, patients complain on weight loss and weakness [1].
The prognosis varies. The average survival time for patients with CNL is less than 2 years.
Only few descriptions of chronic neutrophilic leukemia are available in the literature, and these are mostly single case reports.
Because it is an extremely rare disease, there are no established and generally accepted treatment standards. In most cases, patients are given hydroxycarbamide or interferon. Patients who are eligible for a bone marrow transplant may benefit from this treatment. Bone marrow allotransplantation remains the only method that gives a chance for a significant extension of life.
The German authors presented a series of 14 cases of chronic neutrophilic leukemia. The group of patients consisted of eight women and six men. The average age was 64.7 years. From the entire group of patients, longer survival was achieved only in three cases. One of these patients was treated with interferon alpha and achieved hematological remission, the other underwent bone marrow allotransplantation from a family donor, and the third one was treated with hydroxycarbamide and transfusions as needed. The follow-up period of the patient after allogeneic matched related donor transplantation (allo-MRD) was 73 months, and for the patient after interferon treatment it was 41 months.
The remaining patients died within 2 years of diagnosis. Six patients, the largest group, died due to intracranial bleeding, three patients died because of leukemia cell tissue infiltration, one patient because of the disease transformation into leukemia, and one patient because of pneumonia [46].
It can be seen from these experiences that treatment with interferon alpha can significantly extend the survival time of patients.
The case of a 40-year-old woman diagnosed with chronic neutrophilic leukemia is presented by Yassin and coauthors. Initially, the patient had almost 41,000 leukocytes in the peripheral blood. In a physical examination, splenomegaly and hepatomegaly were not present. Patient received pegylated interferon alpha-2a. The initially dose was 50 μg once a week for the first 2 weeks, then the dose was increased to 135 μg weekly for 6 weeks, and then the dose interval was extended to another 2 weeks. As a result of the treatment, the general condition of the patient improved and the parameters of peripheral blood counts were normalized [47].
Another case report presented in the literature describes a 41-year-old woman diagnosed with CNL accompanied by focal segmental glomerulosclerosis (FSGS). The patient had increasing leukocytosis for several months. On the admission to the hospital, leukocytosis was 94,000/μl. Moreover, the number of platelets in the morphology exceeded 1,000,000/μl. More than a year earlier, the patient had splenectomy due to splenomegaly and spleen infraction.
Additionally, JAK2 V617F mutation was found. Some authors suggest that the presence of JAK2 mutation may be associated with longer survival in CNL.
The patient received hydroxycarbamide for 3 months and reduction in the number of leukocytes was achieved. After this time, interferon alpha-2b was added to hydroxycarbamide. As a result, focal segmental glomerulosclerosis disappeared and the renal tests improved [48].
Another case of chronic neutrophilic leukemia with a JAK2 gene mutation concerns a 53-year-old man. The patient’s baseline leukocytosis was 33,500/μl, including the neutrophil count of 29,700/μl. The patient also had splenomegaly.
The treatment with interferon alpha-2b at a dose of 3 million units every other day was started. After a month of treatment, the number of leukocytes was reduced to less than 10,000/μl. Then the patient was treated chronically with interferon alpha-2b in doses of 3 million units every 2 weeks. As a result of the therapy, the number of leukocytes remains between 8 and 10,000/μl. The patient remains in general good condition [49].
A series of two CNL cases are also shown. The first patient was a 70-year-old woman with stable leukocytosis of about 35,000/μl and the remaining morphology parameters in normal range. The patient was only observed for 5 years until hepasplenomegaly progressed rapidly. Then, interferon alpha-2b was included. Due to the treatment, the rapid regression of hepatosplenomegaly was achieved.
The second case is a 68-year-old woman with baseline leukocytosis of almost 14,000/μl. In this case, the treatment with hydroxycarbamide was started immediately. However, no improvement was achieved. After 6 weeks of HU treatment, interferon alpha-2b 3 million units 3 times a week was implemented and leukocytosis decreased. Due to the interferon treatment, the disease stabilized for a long time. Because the patient experienced an adverse reaction, a severe flu-like syndrome, interferon was discontinued. After interferon withdrawal, the disease progressed gradually and the treatment attempts by busulfan and 6-mercaptopurine were unsuccessful. Therefore, interferon was readministered and the disease went into remission. Interferon treatment was continued at a reduced dose. The disease regression was achieved again.
Additionally, the patient showed an improvement in the function of granulocytes in terms of phagocytosis and an improvement in neutral killer (NK) cell function after treatment with interferon [50].
The above examples show that interferon alpha is effective in the treatment of chronic neutrophilic leukemia. The side effects are rare and can be managed with dose reductions. Moreover, in these cases, interferon is also effective in a reduced dose. Disease remission or regression can be achieved without typical of CNL complications, such as intracranial bleeding.
Interferon has been used in the past to treat chronic myeloid leukemia. The treatment with tyrosine kinase inhibitors is now a standard practice. However, in a small number of patients, they are ineffective or exhibit unmanageable toxicity. Therefore, the attempts are underway to use interferon in combination with TKI in lower doses, which is to ensure the enhancement of the antiproliferative effect while reducing the toxicity.
There are ongoing attempts to use ropeginterferon in patients diagnosed with chronic myeloid leukemia, in whom treatment with imatinib alone has not led to deep molecular response (DMR). The first phase study was conducted in a small group of patients with chronic myeloid leukemia. The patients in first chronic phase treated with imatinib who did not achieve DMR, but in complete hematologic remission and complete cytogenetic remission, were included in the study. Patients have been treated with imatinib for at least 18 months. Twelve patients were enrolled in the study, and they completed the study according to the protocol. These patients received additional ropeginterferon to imatinib and four achieved DMR. Low toxicity was observed during the treatment. Among the hematological toxicities, neutropenia was the most common. There was no nonhematological toxicity with a degree higher than 1/2 during the treatment. Moreover, it has been found that better effects and fewer side effects are obtained when ropeginterferon is administered for a longer time, but in lower doses. The comparison of the effectiveness of interferon in chronic myeloproliferative disorders based on selected articles is presented in Table 1 [51].
Source | Type of trial | Interferon | Diagnosis | No. | Prior treatment status | Response rate |
---|---|---|---|---|---|---|
Yacoubet al. [15] | Phase II, multicenter | Pegylated IFN alfa-2a | PV | 50 | Resistance to HU or HU intolerance | CR:22% PR:38% |
ET | 65 | CR:43% PR:26% | ||||
Masarova et al. [16] | Phase II, single-center | Pegylated IFN alfa-2a | PV | 43 | Untreated or previously treated with cytoreductive therapy | CR:77% PR:7% |
ET | 40 | CR:73% PR:3% | ||||
Samuelsson et al. [18] | Phase II | Pegylated IFN alfa-2b | PV | 21 | Untreated or previously treated with cytoreductive therapy | CR: 69% for the entire group |
ET | 21 | |||||
Huang BT et al. [19] | Open label, multicenter | IFN alfa-2b | PV | 136 | Untreated or previously treated with cytoreductive therapy | OHR:70% Molecular response:54.7% |
ET | 123 | OHR (JAK2+ patients):83% CHR:23 cases OHR (JAK2-patients): 61.4% CHR:12 cases | ||||
Gisslinger et al. [23] | phase III, multicenter | Ropeginterferon | PV | 257 | Previously treated | OHR:53% |
Quintás-Cardama et al. [26] | phase II | Pegylated IFN alfa-2a | PV | 40 | Untreated or previously treated with cytoreductive therapy | OHR:80% CR:70% Molecular remission:54% |
ET | 39 | OHR:81% CR:76% Molecular remission:38% | ||||
Sørensen et al. [36] | Phase III, multicenter, COMBI | Pegylated IFN alfa-2a with ruxolitinib or Pegylated IFN alfa-2b with ruxolitinib | PV | 32 | Untreated or previously treated with cytoreductive therapy | OHR:44% CR:28% |
MF | 18 | OHR:31% CR:9% | ||||
Casassus et al. [40] | Open label, multicenter | IFN alpha-2b | Mastocytosis | 20 | Untreated and previously treated | PR:35% Minor remission: 30% |
Comparison of the effectiveness of interferon in chronic myeloproliferative disorders.
PV: polycythemia vera; ET: essential thrombocythemia; MF: myelofibrosis; HU: hydroxycarbamide/hydroxyurea; CR: complete remission; PR: partial remission; and OHR: overall hematological response.
Interferon alpha appears to be an effective and safe drug in the most type of chronic myeloproliferative disorders. Nowadays, all forms of its using have similar effectiveness. Interferon alpha can be effective even in cases of resistance for first-line treatment. Trial research is currently underway to combine it with some new drugs, such as ruxolitinib, and to add it to the already well-established therapy, it is a promising option for patients with refractory disease.
From time to time, new forms of interferon, such as ropeginterferon, are introduced, which gives hope for better effectiveness, better safety profile, and greater comfort in its use for patients who have to be treated for many years. In the case of the use of interferons alpha in the treatment of chronic myeloproliferative diseases, there are still opportunities to extend its use and to study its combination with newly introduced drugs.
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\\n\\nSara Uhac, COO
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\\n\\nAdrian Assad De Marco
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\\n"}]'},components:[{type:"htmlEditorComponent",content:"Our business values are based on those any scientist applies to their research. We have created a culture of respect and collaboration within a relaxed, friendly and progressive atmosphere, while maintaining academic rigour.
\n\nCo-founded by Alex Lazinica and Vedran Kordic: “We are passionate about the advancement of science. As Ph.D. researchers in Vienna, we found it difficult to access the scholarly research we needed. We created IntechOpen with the specific aim of putting the academic needs of the global research community before the business interests of publishers. Our Team is now a global one and includes highly-renowned scientists and publishers, as well as experts in disseminating your research.”
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\n\nSara Uhac, COO
\n\nSara Uhac was appointed Managing Director of IntechOpen at the beginning of 2014. She directs and controls the company’s operations. Sara joined IntechOpen in 2010 as Head of Journal Publishing, a new strategically underdeveloped department at that time. After obtaining a Master's degree in Media Management, she completed her Ph.D. at the University of Lugano, Switzerland. She holds a BA in Financial Market Management from the Bocconi University in Milan, Italy, where she started her career in the American publishing house Condé Nast and further collaborated with the UK-based publishing company Time Out. Sara was awarded a professional degree in Publishing from Yale University (2012). She is a member of the professional branch association of "Publishers, Designers and Graphic Artists" at the Croatian Chamber of Commerce.
\n\nAdrian Assad De Marco
\n\nAdrian Assad De Marco joined the company as a Director in 2017. With his extensive experience in management, acquired while working for regional and global leaders, he took over direction and control of all the company's publishing processes. Adrian holds a degree in Economy and Management from the University of Zagreb, School of Economics, Croatia. A former sportsman, he continually strives to develop his skills through professional courses and specializations such as NLP (Neuro-linguistic programming).
\n\nDr Alex Lazinica
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After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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Urban tunnels are often made in soils with very low values of overburden. Risks of collapse and large deformations at the surface are high; thus negative impact on old buildings are likely to occur if appropriate measures are not taken in advance, when designing and constructing the tunnel. For deep tunnels with high overburden and low rock mass properties, squeezing conditions and excessive loads around the excavation can jeopardize the stability of the tunnel, leading to extensive collapse. The aim of the chapter is to give details on advance computational modelling and analytical methodologies, which can be used in order to design shallow and deep tunnels and to present real case studies from around the world, from very shallow tunnels in India with only 4.5 m overburden to a deep tunnel in Venezuela with extreme squeezing conditions under 1300 m overburden.",book:{id:"7690",slug:"tunnel-engineering-selected-topics",title:"Tunnel Engineering",fullTitle:"Tunnel Engineering - Selected Topics"},signatures:"Spiros Massinas",authors:[{id:"295762",title:"Dr.",name:"Spiros",middleName:null,surname:"Massinas",slug:"spiros-massinas",fullName:"Spiros Massinas"}]},{id:"68157",title:"Introductory Chapter: Textile Manufacturing Processes",slug:"introductory-chapter-textile-manufacturing-processes",totalDownloads:4484,totalCrossrefCites:16,totalDimensionsCites:26,abstract:null,book:{id:"8892",slug:"textile-manufacturing-processes",title:"Textile Manufacturing Processes",fullTitle:"Textile Manufacturing Processes"},signatures:"Faheem Uddin",authors:[{id:"228107",title:"Prof.",name:"Faheem",middleName:null,surname:"Uddin",slug:"faheem-uddin",fullName:"Faheem Uddin"}]},{id:"66828",title:"Breathing Monitoring and Pattern Recognition with Wearable Sensors",slug:"breathing-monitoring-and-pattern-recognition-with-wearable-sensors",totalDownloads:3113,totalCrossrefCites:12,totalDimensionsCites:16,abstract:"This chapter introduces the anatomy and physiology of the respiratory system, and the reasons for measuring breathing events, particularly, using wearable sensors. Respiratory monitoring is vital including detection of sleep apnea and measurement of respiratory rate. The automatic detection of breathing patterns is equally important in other respiratory rehabilitation therapies, for example, magnetic resonance exams for respiratory triggered imaging, and synchronized functional electrical stimulation. In this context, the goal of many research groups is to create wearable devices able to monitor breathing activity continuously, under natural physiological conditions in different environments. Therefore, wearable sensors that have been used recently as well as the main signal processing methods for breathing analysis are discussed. The following sensor technologies are presented: acoustic, resistive, inductive, humidity, acceleration, pressure, electromyography, impedance, and infrared. New technologies open the door to future methods of noninvasive breathing analysis using wearable sensors associated with machine learning techniques for pattern detection.",book:{id:"7654",slug:"wearable-devices-the-big-wave-of-innovation",title:"Wearable Devices",fullTitle:"Wearable Devices - the Big Wave of Innovation"},signatures:"Taisa Daiana da Costa, Maria de Fatima Fernandes Vara, Camila Santos Cristino, Tyene Zoraski Zanella, Guilherme Nunes Nogueira Neto and Percy Nohama",authors:[{id:"192464",title:"Ph.D.",name:"Percy",middleName:null,surname:"Nohama",slug:"percy-nohama",fullName:"Percy Nohama"},{id:"285706",title:"MSc.",name:"Taísa Daiana",middleName:null,surname:"Da Costa",slug:"taisa-daiana-da-costa",fullName:"Taísa Daiana Da Costa"},{id:"285707",title:"MSc.",name:"Maria de Fatima Fernandes",middleName:null,surname:"Vara",slug:"maria-de-fatima-fernandes-vara",fullName:"Maria de Fatima Fernandes Vara"},{id:"285708",title:"BSc.",name:"Camila Santos",middleName:null,surname:"Cristino",slug:"camila-santos-cristino",fullName:"Camila Santos Cristino"},{id:"285709",title:"Prof.",name:"Guilherme Nunes",middleName:null,surname:"Nogueira Neto",slug:"guilherme-nunes-nogueira-neto",fullName:"Guilherme Nunes Nogueira Neto"},{id:"293109",title:"BSc.",name:"Tyene",middleName:null,surname:"Zoraski Zanella",slug:"tyene-zoraski-zanella",fullName:"Tyene Zoraski Zanella"}]},{id:"41411",title:"Textile Dyes: Dyeing Process and Environmental Impact",slug:"textile-dyes-dyeing-process-and-environmental-impact",totalDownloads:20676,totalCrossrefCites:101,totalDimensionsCites:320,abstract:null,book:{id:"3137",slug:"eco-friendly-textile-dyeing-and-finishing",title:"Eco-Friendly Textile Dyeing and Finishing",fullTitle:"Eco-Friendly Textile Dyeing and Finishing"},signatures:"Farah Maria Drumond Chequer, Gisele Augusto Rodrigues de Oliveira, Elisa Raquel Anastácio Ferraz, Juliano Carvalho Cardoso, Maria Valnice Boldrin Zanoni and Danielle Palma de Oliveira",authors:[{id:"49040",title:"Prof.",name:"Danielle",middleName:null,surname:"Palma De Oliveira",slug:"danielle-palma-de-oliveira",fullName:"Danielle Palma De Oliveira"},{id:"149074",title:"Prof.",name:"Maria Valnice",middleName:null,surname:"Zanoni",slug:"maria-valnice-zanoni",fullName:"Maria Valnice Zanoni"},{id:"153502",title:"Ph.D.",name:"Farah",middleName:null,surname:"Chequer",slug:"farah-chequer",fullName:"Farah Chequer"},{id:"153504",title:"MSc.",name:"Gisele",middleName:null,surname:"Oliveira",slug:"gisele-oliveira",fullName:"Gisele Oliveira"},{id:"163377",title:"Dr.",name:"Juliano",middleName:null,surname:"Cardoso",slug:"juliano-cardoso",fullName:"Juliano Cardoso"},{id:"163393",title:"Dr.",name:"Elisa",middleName:null,surname:"Ferraz",slug:"elisa-ferraz",fullName:"Elisa Ferraz"}]},{id:"70242",title:"Advancements in the Fenton Process for Wastewater Treatment",slug:"advancements-in-the-fenton-process-for-wastewater-treatment",totalDownloads:1985,totalCrossrefCites:13,totalDimensionsCites:26,abstract:"Fenton is considered to be one of the most effective advanced treatment processes in the removal of many hazardous organic pollutants from refractory/toxic wastewater. It has many advantages, but drawbacks are significant such as a strong acid environment, the cost of reagents consumption, and the large production of ferric sludge, which limits Fenton’s further application. The development of Fenton applications is mainly achieved by improving oxidation efficiency and reducing sludge production. This chapter presents a review on fundamentals and applications of conventional Fenton, leading advanced technologies in the Fenton process, and reuse methods of iron containing sludge to synthetic and real wastewaters are discussed. Finally, future trends and some guidelines for Fenton processes are given.",book:{id:"9415",slug:"advanced-oxidation-processes-applications-trends-and-prospects",title:"Advanced Oxidation Processes",fullTitle:"Advanced Oxidation Processes - Applications, Trends, and Prospects"},signatures:"Min Xu, Changyong Wu and Yuexi Zhou",authors:[{id:"307479",title:"Dr.",name:"Changyong",middleName:null,surname:"Wu",slug:"changyong-wu",fullName:"Changyong Wu"},{id:"307546",title:"Prof.",name:"Yuexi",middleName:null,surname:"Zhou",slug:"yuexi-zhou",fullName:"Yuexi Zhou"},{id:"311139",title:"Dr.",name:"Min",middleName:null,surname:"Xu",slug:"min-xu",fullName:"Min Xu"}]}],onlineFirstChaptersFilter:{topicId:"24",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"82676",title:"Electrospinning of Fiber Matrices from Polyhydroxybutyrate for the Controlled Release Drug Delivery Systems",slug:"electrospinning-of-fiber-matrices-from-polyhydroxybutyrate-for-the-controlled-release-drug-delivery-",totalDownloads:13,totalDimensionsCites:0,doi:"10.5772/intechopen.105786",abstract:"The submission provides an overview of current state of the problem and authors’ experimental data on manufacturing nonwoven fibrous matrices for the controlled release drug delivery systems (CRDDS). The choice of ultrathin fibers as effective carriers is determined by their characteristics and functional behavior, for example, such as a high specific surface area, anisotropy of some physicochemical characteristics, spatial limitations of segmental mobility that are inherent in nanosized objects, controlled biodegradation, and controlled diffusion transport. The structural-dynamic approach to the study of the morphology and diffusion properties of biopolymer fibers based on polyhydroxybutyrate (PHB) is considered from several angles. In the submission, the electrospinning (ES) application to reach specific characteristics of materials for controlled release drug delivery is discussed.",book:{id:"11127",title:"Electrospinning - Material Technology of the Future",coverURL:"https://cdn.intechopen.com/books/images_new/11127.jpg"},signatures:"Anatoly A. Olkhov, Svetlana G. Karpova, Anna V. Bychkova, Alexandre A. Vetcher and Alexey L. Iordanskii"},{id:"82600",title:"Impact of the Spreading of Sludge from Wastewater Treatment Plants on the Transfer and Bio-Availability of Trace Metal Elements in the Soil-Plant System",slug:"impact-of-the-spreading-of-sludge-from-wastewater-treatment-plants-on-the-transfer-and-bio-availabil",totalDownloads:12,totalDimensionsCites:0,doi:"10.5772/intechopen.103745",abstract:"The spreading of sludge from sewage treatment plants increased the production of durum wheat and rapeseed. Their richness in nitrogen, phosphorus, and potassium gives them a beneficial effect on crops. However, the application of the sludge can induce increases in the concentration of metals in plant tissues. This increase can generate disturbances at the level of the cell and organelles, such as mitochondria and chloroplasts, which can be altered. Repeated applications of the sludge on the same site tend to increase the accumulation of heavy metals in the soil, so that an cause toxicities for soil microorganisms, animals, and humans, via the food chain. However, it is important to specify that these nuisances mainly concerned industrial sludge, but the use of this sludge is strictly prohibited. In addition, the high doses used in our field experiments are significantly higher than those authorized in agricultural practice. Finally, the risk assessment by calculating both the level of consumer exposure and the number of years for soil saturation shows that the use of urban sludge is safe, especially in the short and medium-term. Nevertheless, the quality of the sludge to be spread must be constantly monitored.",book:{id:"11173",title:"Wastewater Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/11173.jpg"},signatures:"Najla Lassoued and Bilal Essaid"},{id:"81249",title:"Electrospun Polymeric Substrates for Tissue Engineering: Viewpoints on Fabrication, Application, and Challenges",slug:"electrospun-polymeric-substrates-for-tissue-engineering-viewpoints-on-fabrication-application-and-ch",totalDownloads:8,totalDimensionsCites:0,doi:"10.5772/intechopen.102596",abstract:"Electrospinning is the technique for producing nonwoven fibrous structures, to mimic the fabrication and function of the native extracellular matrix (ECM) in tissue. Prepared fibrous with this method can act as potential polymeric substrates for proliferation and differentiation of stem cells (with the cellular growth pattern similar to damaged tissue cells) and facilitation of artificial tissue remodeling. Moreover, such substrates can improve biological functions, and lead to a decrease in organ transplantation. In this chapter, we focus on the fundamental parameters and principles of the electrospinning technique to generate natural ECM-like substrates, in terms of structural and functional complexity. In the following, the application of these substrates in regenerating various tissues and the role of polymers (synthetic/natural) in the formation of such substrates is evaluated. Finally, challenges of this technique (such as cellular infiltration and inadequate mechanical strength) and solutions to overcome these limitations are studied.",book:{id:"11127",title:"Electrospinning - Material Technology of the Future",coverURL:"https://cdn.intechopen.com/books/images_new/11127.jpg"},signatures:"Azadeh Izadyari Aghmiuni, Arezoo Ghadi, Elmira Azmoun, Niloufar Kalantari, Iman Mohammadi and Hossein Hemati Kordmahaleh"},{id:"82145",title:"Slope Casting Process: A Review",slug:"slope-casting-process-a-review",totalDownloads:9,totalDimensionsCites:0,doi:"10.5772/intechopen.102742",abstract:"Semi solid processing is a near net shape casting process and one of the promising techniques to obtain dendritic free structure of metals. Semi solid casting gives numerous advantages than solid processing and liquid processing. Semi solid casting process gives, Laminar flow filling of die without turbulence, Lower metal temperature, Less shrinkage, Less porosity, Higher mechanical properties. Semi solid casting process is industrially successful, producing a variety of products with good quality. Slope Casting process is a simple technique to produce semi solid feed-stoke with globular microstructure and dendrite free structure castings. Slope casting process depends on different process parameters like slope length, slope angle, pouring temperature etc. The present study mainly focuses on review of various explorations made by researchers with different process parameters of the Slope casting process and explain the mechanisms that lead to microstructural changes which leads to good mechanical properties.",book:{id:"11119",title:"Casting Processes",coverURL:"https://cdn.intechopen.com/books/images_new/11119.jpg"},signatures:"Mukkollu Sambasiva Rao and Amitesh Kumar"},{id:"81861",title:"Emerging Human Coronaviruses (SARS-CoV-2) in the Environment Associated with Outbreaks Viral Pandemics",slug:"emerging-human-coronaviruses-sars-cov-2-in-the-environment-associated-with-outbreaks-viral-pandemics",totalDownloads:25,totalDimensionsCites:0,doi:"10.5772/intechopen.103886",abstract:"In December 2019, there was a cluster of pneumonia cases in Wuhan, a city of about 11 million people in Hubei Province. The World Health Organization (WHO), qualified CoVid-19 as an emerging infectious disease on March 11, 2020, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which spreads around the world. Coronaviruses are also included in the list of viruses likely to be found in raw sewage, as are other viruses belonging to the Picornaviridae family. SRAS-CoV-2 has been detected in wastewater worldwide such as the USA, France, Netherlands, Australia, and Italy according to the National Research Institute for Public Health and the Environment. In addition, the SARS-CoV-2 could infect many animals since it has been noticed in pigs, domestic and wild birds, bats, rodents, dogs, cats, tigers, cattle. Therefore, the SARS-CoV-2 molecular characterization in the environment, particularly in wastewater and animals, appeared to be a novel approach to monitor the outbreaks of viral pandemics. This review will be focused on the description of some virological characteristics of these emerging viruses, the different human and zoonotic coronaviruses, the sources of contamination of wastewater by coronaviruses and their potential procedures of disinfection from wastewater.",book:{id:"11173",title:"Wastewater Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/11173.jpg"},signatures:"Chourouk Ibrahim, Salah Hammami, Eya Ghanmi and Abdennaceur Hassen"},{id:"81797",title:"Study of Change Surface Aerator to Submerged Nonporous Aerator in Biological Pond in an Industrial Wastewater Treatment in Daura Refinery",slug:"study-of-change-surface-aerator-to-submerged-nonporous-aerator-in-biological-pond-in-an-industrial-w",totalDownloads:11,totalDimensionsCites:0,doi:"10.5772/intechopen.104860",abstract:"Daura refinery, with a capacity of 140,000 barrel per stream day as a refining capacity, wastewater discharged from refining and treatment processing units, polluted water as foul water, drainages, oil spills, blowdown of boilers and cooling towers, and many other polluted water sources, aims to remove pollutants and reject clean water to the river; wastewater treatment system takes place in this treatment process. Wastewater treatment system suffers from many problems and specifically biological stage; at this stage, activated sludge with bacteria, should be supplied with oxygen, aeration system done by surface aerators with four surface fans; these fans suffer from high vibration, loss support, and in consequence, lack in oxygen supply to aerobic bacteria less than 4 ppm. The nonporous aerator is suggested as an oxygen source for the biological pool. The pilot plant builds the aim to study the ability to apply the new aeration system at the biological pool, pilot plant build with 1 cubic meter capacity tank and continuous overflow of wastewater of 10 liters.min−1, air injected with the pressure of (0.5–0.75) bar(g), and airflow of (7.6–9.7) liter.min−1 respectively. Oxygen concentration was recorded as (3.4–6.0) ppm; in terms of consumption power, changing the aeration system reduces it to less than 20%.",book:{id:"11173",title:"Wastewater Treatment",coverURL:"https://cdn.intechopen.com/books/images_new/11173.jpg"},signatures:"Omar M. 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