The humidity and temperatures variations for Basarabi church (naos).
\\n\\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\\n\\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\\n"}]',published:!0,mainMedia:{caption:"Highly Cited",originalUrl:"/media/original/117"}},components:[{type:"htmlEditorComponent",content:'IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\nThroughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\nReleased this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\nWe wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
\n'}],latestNews:[{slug:"step-in-the-right-direction-intechopen-launches-a-portfolio-of-open-science-journals-20220414",title:"Step in the Right Direction: IntechOpen Launches a Portfolio of Open Science Journals"},{slug:"let-s-meet-at-london-book-fair-5-7-april-2022-olympia-london-20220321",title:"Let’s meet at London Book Fair, 5-7 April 2022, Olympia London"},{slug:"50-books-published-as-part-of-intechopen-and-knowledge-unlatched-ku-collaboration-20220316",title:"50 Books published as part of IntechOpen and Knowledge Unlatched (KU) Collaboration"},{slug:"intechopen-joins-the-united-nations-sustainable-development-goals-publishers-compact-20221702",title:"IntechOpen joins the United Nations Sustainable Development Goals Publishers Compact"},{slug:"intechopen-signs-exclusive-representation-agreement-with-lsr-libros-servicios-y-representaciones-s-a-de-c-v-20211123",title:"IntechOpen Signs Exclusive Representation Agreement with LSR Libros Servicios y Representaciones S.A. de C.V"},{slug:"intechopen-expands-partnership-with-research4life-20211110",title:"IntechOpen Expands Partnership with Research4Life"},{slug:"introducing-intechopen-book-series-a-new-publishing-format-for-oa-books-20210915",title:"Introducing IntechOpen Book Series - A New Publishing Format for OA Books"},{slug:"intechopen-identified-as-one-of-the-most-significant-contributor-to-oa-book-growth-in-doab-20210809",title:"IntechOpen Identified as One of the Most Significant Contributors to OA Book Growth in DOAB"}]},book:{item:{type:"book",id:"470",leadTitle:null,fullTitle:"New Knowledge in a New Era of Globalization",title:"New Knowledge in a New Era of Globalization",subtitle:null,reviewType:"peer-reviewed",abstract:"To better understand the contemporary world, the world of innovation and technology, science should try to synthesize and assimilate social science in the development of our civilization. \nDoes the new era require new knowledge? Does the age of globalization demand new education, new human attitudes? This books tries to clarify these questions. \nThe book New Knowledge in a New Era of Globalization consists of 16 chapters divided into three sections: Globalization and Education; Globalization and Human Being; Globalization and Space. The Authors of respective chapters represent a great diversity of disciplines and methodological approaches as well as a variety of academic culture. This book is a valuable contribution and it will certainly be appreciated by a global community of scholars.",isbn:null,printIsbn:"978-953-307-501-3",pdfIsbn:"978-953-51-5102-9",doi:"10.5772/982",price:139,priceEur:155,priceUsd:179,slug:"new-knowledge-in-a-new-era-of-globalization",numberOfPages:368,isOpenForSubmission:!1,isInWos:1,isInBkci:!1,hash:"08e011d059a55b7a904787039b394b29",bookSignature:"Piotr Pachura",publishedDate:"August 1st 2011",coverURL:"https://cdn.intechopen.com/books/images_new/470.jpg",numberOfDownloads:72433,numberOfWosCitations:12,numberOfCrossrefCitations:12,numberOfCrossrefCitationsByBook:0,numberOfDimensionsCitations:20,numberOfDimensionsCitationsByBook:1,hasAltmetrics:1,numberOfTotalCitations:44,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"October 19th 2010",dateEndSecondStepPublish:"November 16th 2010",dateEndThirdStepPublish:"March 23rd 2011",dateEndFourthStepPublish:"April 22nd 2011",dateEndFifthStepPublish:"June 21st 2011",currentStepOfPublishingProcess:5,indexedIn:"1,2,3,4,5,6",editedByType:"Edited by",kuFlag:!1,featuredMarkup:null,editors:[{id:"33832",title:"Prof.",name:"Piotr",middleName:null,surname:"Pachura",slug:"piotr-pachura",fullName:"Piotr Pachura",profilePictureURL:"https://mts.intechopen.com/storage/users/33832/images/1957_n.jpg",biography:"Dr. Piotr Pachura (assoc. prof. dr. hab.), European academic and scientist, the reader at Częstochowa University of Technology (Poland) and University of Presov (Slovak Rep.). Academic degrees achieved in: social science (MA), economic science (PhD) and geography (dr hab.). Consultant in regional innovation policy and practice. Author of over 80 books and articles, participant in many international research projects, originator of several scientific international journals as e.g. : Springer Journal of Innovation and Entrepreneurship: A Systems View Across Time and Space and Polish Journal of Management Sudies. 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Such materials are being classified not only based on their origin but also on the nature of their processing, properties, functions, and applications. Magnetic materials present the basics of magnetism, magnetic materials, magnetic structures, and their applications in device technologies. Recently, new magnetic materials and hybrid structures have been developed using different synthesis and fabrication techniques. Different phenomena and interesting properties are studied theoretically and experimentally using advanced characterization techniques. Magnetic materials are now the building block of all technological innovation.
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He has worked as a postdoctoral researcher and visiting scientist at several institutions, including National Taiwan University, National Cheng Kung University, Taiwan, and the University of Witwatersrand, South Africa. He has published more than 112 peer-reviewed articles and more than 110 research articles in conference proceedings and meetings. He has also published four books and five book chapters.",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"251855",title:"Prof.",name:"Dipti Ranjan",middleName:null,surname:"Sahu",slug:"dipti-ranjan-sahu",fullName:"Dipti Ranjan Sahu",profilePictureURL:"https://mts.intechopen.com/storage/users/251855/images/system/251855.png",biography:"Dr. Dipti Ranjan Sahu is Associate Professor of Physics, Department of Natural and Applied Sciences, Namibia University of Science and Technology (NUST). 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Facings are inscribed with symbolic designs and different scenes and a large number of inscriptions. Some of these are palaeoslavonic and Cyrillic and some are written in Glagolitic or in Greek, but mostly in an enigmatic writing that could not be decoded so far [2, 3] (Figure 1).
\nThe interior of the churches and crosses, figures incised in the chalk wall.
After the discovery, in 1957, the assembly elements were partially crushed and the rocks have been repositioned in a structure of reinforced concrete and cement mortar. A protective building of concrete has been built for more than half of the site; the rest remained under provisional protection of wood and tar paper. These constructions have not assured proper microclimate, especially in the facing incised [4].
\nThe monument is in an extremely critical situation, taking into account the sensitivity of the chalk rock; it was accelerated and damaged after the assembly discovery. For this reason, it is imperative exceptional measure for protection.
\nSince 1960, construction of a permanent building protection was expected to protect the whole site in front of adverse weather conditions, variations in temperature and humidity and other factors that could compromise the monument.
\nCave monuments are conducted on an area of 2684 sqm. They are protected by a permanent building, on an area of 924 sqm. This construction is made of reinforced concrete with a roof inclined at 30°, applied to the building built between 1971 and 1974. The remaining 1760 square meters were covered with a temporary protection structure made of wood and reed, covered with tar paper. This construction was supposed to protect the monuments of rain, snow, wind and also of changes in temperature and humidity.
\nCurrently, the wooden structure of the building was repaired under provisional protection, and cardboard asphalt was replaced with polycarbonate enclosures in summer 2006 (Figure 2).
\nProvisional protection structure.
The church monuments carved in the Chalk Mountain was strengthened in broken or degraded areas by frost infiltration in reinforced and enamel-coated concrete. Cracks that have been injected with cement and sand mortar have a dark gray appearance on the chalk surface, like a splash.
\nThe original protection plan, of the 1960s, of the monument building was carried out along of the chalk mountain, covering all caves, divided into seven sections corresponding to the monument’s interest areas, respectively to the caves. Unfortunately, this project was interrupted, from a bad administrative conjunction. Since 1989, the project was revived to achieve (Figure 3). In 1994, they started provisional construction works for rehabilitation, with a progress noted especially in steep 2009. Currently, culvert was repaired to prevent rainwater from drain the entire downstream side directly inside the monument site. The roof still shows degraded areas. Since 2010, the monument is only in the scientific researches of specialists and prestigious experts for finding an interdisciplinary rehabilitation solution.
\nThe scheme of the polycarbonate enclosure.
The investigations proposed are:
evaluation of the characteristics of rock samples by laboratory analysis;
determination of compressive strength of fresh and altered rocks;
mineralogical analyses for monitoring the extent of alteration area inside and surrounding of area of interest; and
determination of freeze-thaw durability.
By geo-radar measurements type, a picture of the structure of the subsoil, especially when settling land, has been obtained.
\nThe electrometric method “electric survey vertical” (EVS) and a gravimetric method have been used. The following measurements have been done: the presence of the fluid in saturated or unsaturated rocks, porosity and permeability of rocks, freeze-thaw durability, chemical content of fluids in rocks from the basement, resistivity changes due to different chemical and physical conditions.
\nAlso, the chalk massive structure, changes in the structure and uniformity, the presence of voids, or areas of vulnerability may offer important information.
\nGeophysical work program should have the following objectives: geophysical detail to the foundation of the old and new buildings; geophysical detail of the state geological massif chalk in the archeological monuments; geophysical characterization of chalk massif state; geophysical permanent control of water accumulation condition in career; geophysical investigation to establish the area hydrogeological conditions; and investigations of the geophysical and hydrogeological conditions in the warehouse waste.
\nA total of approximately 150 EVS locations with investigating depths from 30 to 150 m, made with different equidistance, were performed according to the degree of detachment determined by the frost-freeze procedure for chalk pattern for 20 series, which were analyzed by repetitions: dry at 105°C to a uniform mass (M 1) for an hour, submerged 15 min in distilled water, removed from the water, cleaned with a damp canvas, dried up 3 h at 20°C and measured (M 2). After that the samples have been introduced into the freezer for 2 h at −18°C, taken off and immersed in water, thawed, and after that chalk samples are weighted (M 3), [5, 6, 7].
\nDeteriorated chalk measurement was estimated with the formula: % μg = (M 2 – M 3/M 1) × 100, where μg is the freeze factor [8, 9].
\nThe examination of thin petrographic sections, is carried out with a microscope like Leitz polarizer, which is very useful to characterize properties of structure, minerals, cement composition, and the digenetic characteristics of the sample, and then explored with a polarized microscope.
\nThe proposed investigations refer the groundwater conditions’ hydro-geological site near the monument, water accumulation in career and possible leakage of leachate to landfill career. For all these, it has been achieved six boreholes to depths of 15–20m, located outside the site with research role (Figure 4). Except these, the chemical analysis of pre-elevated water from drilling and the analysis of physical properties of the materials present in drilling have been achieved.
\nThe photo of naos.
The obtained results are as follows: porosity—0.5–13.5%; and degree of saturation—ratio between natural humidity (Wn) and the humidity of the same rock but saturated with water (Wsat). In our case, this parameter has the value of 0.3–0.994; density: 2.55 kgf/dm3; apparent density: 1.9–2.8 kg/dm3; and strength = 30 kg/cm2 (Table 1).
\nSensor location | \nRelative humidity | \nTemperature | \n||||
---|---|---|---|---|---|---|
Minimum (%) | \nMedium (%) | \nMaximum (%) | \nMinimum (%) | \nMedium (%) | \nMaximum (%) | \n|
1/inside | \n49.9 | \n68.5 | \n75.8 | \n−1.0 | \n6.5 | \n17.4 | \n
2/inside | \n65.7 | \n77.4 | \n95.9 | \n−1.5 | \n6.8 | \n18.2 | \n
3/inside | \n63.7 | \n83.2 | \n90.9 | \n0 | \n4.8 | \n11.7 | \n
4/inside | \n55.4 | \n77.4 | \n96.2 | \n−2.2 | \n6.8 | \n17.7 | \n
5/inside | \n— | \n— | \n— | \n— | \n— | \n— | \n
6/inside | \n67.3 | \n84.6 | \n100 | \n−1.2 | \n6.0 | \n15.8 | \n
7/inside | \n63.5 | \n82.2 | \n97.9 | \n−2.4 | \n6.9 | \n19.1 | \n
8/inside | \n— | \n— | \n— | \n— | \n— | \n— | \n
9/inside | \n55.4 | \n76.5 | \n87.9 | \n−0.6 | \n6,5 | \n13.9 | \n
The humidity and temperatures variations for Basarabi church (naos).
From the compositional point of view, the piece of chalk is a limestone, which is characterized as a biological clay, containing a multitude of limestone sediments, porous with small granularity and extremely fragile. The chalk sample has an organogenic chemical composition consisting of calcium vaterite and mineral clay, with a chemical formation comprising iron oxides and sediments. The wall is composed of calcium carbonate in a proportion of 90% and silicon dioxide [10]. In some places, there are traces of shells and shells of mollusks and ostracods, foraminifera, radiolar and diatomee, sponges of spongiers and radiolars, as well as crushed animal bones. Analysis of petrographic microscopy confirms that vaterite is generally unstable, except that it becomes stable below 10°C when the framboid is present inside the organic structure in the presence of CO2 [11]. These framboid is in fact a conglomerate of smaller, especially spherical elements, having a dimension size varying between 36 and 150 nm [12, 13] (Table 2).
\nElements | \nInternal (ppm) | \nExternal (ppm) | \n
---|---|---|
Aluminum | \n554 | \n196 | \n
Strontium | \n317 | \n496 | \n
Calcium | \n94,700 | \n96,700 | \n
Barium | \n1.00 | \n16.00 | \n
Manganese | \n169 | \n217 | \n
Iron | \n379 | \n116 | \n
Magnesium | \n132 | \n1304 | \n
Sodium | \n837 | \n1746 | \n
Zinc | \n2.5 | \n82 | \n
Copper | \n0.3 | \n3,5 | \n
Potassium | \n529 | \n127 | \n
The elements’ focus inside and outside the church (minor elements).
When water penetrates through the cracks or breaks of stones or through capillary spaces, it will freeze in winter and the stone will be under great pressure that will cause tearing or splitting, especially if the rock is weak. Chalk stone is considered to be very affected by frost, because it has many empty spaces in its structure, allowing the water to penetrate deep, being a rock with a granular structure with a weak, no frost resistance at all. In combination with these factors, the presence of salt in water, given the generally damp marine environment of the site, easily leads to the disintegration of the rocks [14, 15] by lowering the frost, generating longer periods of thawing, which lead to the creation for longer periods of moisture absorption. This test method has no absolute value but is a variable that provides an indication of frost and thaw resistance, so it does not serve as the only basis for determining the durability of rocks [16, 17]. After the completion of 20 cyclic frozen-thawed series, the weight loss of the samples was determined as shown in Table 3.
\nIdentification of samples | \nInitial weight (g) | \nFinal weight (g) | \nWeight loss | \n
---|---|---|---|
Chalk | \n54 | \n47 | \n7 | \n
Results of mass loss by cooling and thawing.
The viable solution remains with the polycarbonate enclosures, with adequate respiration air flux (Figure 5).
\nThe section through the Chalk Mountain.
One may conclude that our preliminary study of environmental characteristics and control, geological, hydrogeological and geotechnical is very important for research to rehabilitation of Basarabi Chalk Churches by innovative solutions based on nanostructured consolidants for preserving and polymer enclosure for protection with real chances for practical application.
\nThis study was supported by the grant PN-III-P1-1.2-PCCDI-2017-0476, No. 51 PCCDI/ 2018.
\nNone of the authors have any competing interests in the manuscript.
The authors express many thanks to Ac. Razvan Theodorescu, for scientific consultation in the field of cultural history and arh. PhD Mihai Opreanu, for architectural studies.
\nMeningiomas (MN) are a type of central nervous system (CNS) tumors that arise from the leptomeningeal arachnoid covering the encephalon and the spinal cord, more specifically, from the arachnoid cap cells [1]. In adults, MN accounts for approximately 37.6% of all primary brain tumors, and corresponds to the most common intracranial tumor in adults over 35 years [1, 2]. According to Ostrom et al., incidence of MN in the United States (US) is 8.83 per 100,000 per year [3]. Around 90% of all MN cases are diagnosed intracranially, with the rest arising from the spinal arachnoid [4]. The median age at diagnosis for MN is 65 years [4] with the majority of patients being in the range of 55–74 [4]. Cases in the pediatric population are extremely rare, corresponding only to 0.4–4.6% of all pediatric tumors [2]. There is a female predominance in case proportion, with a female:male ratio of 3:1 for all MN, and 9:1 for spinal cord MNs [2, 5]. MNs are characterized for being slow in growth and often not infiltrative, with an insidious development of symptoms. Clinical presentation of MN might vary from patient to patient, with tumor localization being the main determining factor of clinical features. Signs and symptoms might include headaches because of increased intracranial pressure, focal neurological deficits (mainly cranial nerve focalization), and seizures. In the case of MN developing in the frontal lobe, personality changes, altered mental status and mood disturbances might appear [6].
According to the World Health Organization (WHO), MN is classified in three subtypes: common type or WHO grade I, atypical/intermediate type or WHO grade II and the anaplastic/malignant type or WHO grade III. These high-grade tumors might develop
As high-grade MN continue to be a difficult to treat condition, with high recurrence and low response rates, molecular insights into precision medicine have been investigated in the last two decades. With a better understanding of the cellular and molecular pathways underlying MN pathophysiology, recurrence and malignancy, newer therapies have been considered as possible candidates for the treatment of these conditions. Some agents include newer systemic chemotherapeutic agents like trabectedin, inhibitors of the Epidermal Growth Factor Receptor (EGFR) like erlotinib and gefitinib, inhibitors of the Platelet-Derived Growth Factor Receptor (PDGFR), inhibitors of mTOR, especially from the complex 1 (mTORC1) as well as its upstream and downstream elements (AKT/PI3K and MEK). The biological process of angiogenesis is also under research, with ongoing trials with anti-angiogenic agents from the Tyrosine Kinase Inhibitors (TKIs) targeting the Vascular Endothelial Growth Factor (VEGF) pathway, as well as antibody agents like bevacizumab. As it is expected, immunotherapy with checkpoint inhibitors is also under current investigation, with anti-PD1 and anti-PD-L1 monoclonal antibodies being tested in clinical trials. In this chapter we are going to cover the molecular biology of MNs, especially in the cases of grade II and grade III MN. We will also discuss the current knowledge in systemic treatments as well as therapies in clinical trials and possible candidates that are being tested
Advancements in understanding the pathophysiology and molecular biology of MNs are critical for improving risk evaluation and prognosis. Similarly, to design novel treatments aimed at blocking canonical pathways involved in carcinogenesis and disease evolution. As molecular analyzes of meningiomas continue to evolve, several cytogenetic, genomic, epigenetic, and expression alterations associated with tumor aggressiveness and proclivity for recurrence have been identified as potential biomarkers to enhance risk stratification [12]. Recently, several seminal studies evaluating the genomics of intracranial meningiomas have rapidly changed the understanding of the disease. The importance of NF2 (neurofibromin 2), TRAF7 (tumor necrosis factor [TNF] receptor-associated factor 7), KLF4 (Kruppel-like factor-4), AKT1, SMO (smoothened), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha), and POLR2 (RNA polymerase II subunit A) demonstrates that there are at least six distinct mutational classes of meningiomas. In addition, six methylation classes of meningioma have been appreciated, enabling improved prognosis prediction compared with traditional WHO grades. Genomic studies have shed light on the nature of recurrent meningioma, distinct intracranial locations and mutational patterns, and a potential embryonic cancer stem cell-like origin [13, 14, 15, 16] (Figure 1).
Main cytogenetic and recurrent genetic alterations in recurrent and high-grade meningiomas according to the WHO classification and anatomical location.
A large number of meningiomas possess a normal karyotype, with an overall low incidence of genomic alterations (including somatic copy number alterations—SCNA, rearrangements, and low mutational burden) [17, 18, 19]. However, these disruptions increase following tumor grade, the number of recurrences, and biological aggressiveness. More than half of all identified genomic alterations involve the NF2, which underlies inherited Neurofibromatosis syndrome. Indeed, the most significant SCNA in meningioma is chromosome 22 monosomy, which is present in ~56% of cases and leads to losing the genomic locus containing NF2 (22q12.2) [20, 21]. Among grade I meningiomas, those carrying NF2 alterations are more likely to progress than those with a normal karyotype. In addition, the frequency of NF2 aberrations increases with tumor grade.
Loss of heterozygosity on chromosome 1p is present in 16% of MNs [22]. Characterization of the smallest region of overlapping deletion on this chromosome spans ~3.7 megabases and identified 59 genes, 17 of which have putative tumor-suppressive functions based on gene ontology. The protein methyltransferase and tumor suppressor RIZ1, is located on chromosome 1p, and studies implicate its loss of expression in meningioma progression [23]. Loss of the CDKN2A/CDNK2B locus on chromosome 9q is common in grade II meningiomas that transition to anaplastic lesions [24]. Additionally, a study showed that the levels of p16 and p15, the proteins encoded by CDKN2A and CDKN2B, may hold prognostic significance and/or represent a promising therapeutic target [25]. Recently, Nassiri et al. described four consensus molecular groups of MN by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation, and messenger RNA abundance in a unified analysis [26]. These molecular groups predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of defined molecular groups and uncovered highly abundant and group-specific protein targets [26].
Globally, meningiomas have a low mutation rate (~3.5 mutations per megabase) compared to other cancers [25]. Various efforts to genotype the disease using NGS have identified NF2 mutations as the predominant alteration in spontaneous and Neurofibromatosis syndrome-associated tumors [24], at a frequency of ~40% in low grade and nearly 80% in high-grade tumors [27]. MNs related to alterations in NF2 were more common in the cerebral convexities and posterior skull base than those found in other anatomic locations, and up to 13% were associated with other co-mutations, including single mutations in CREBBP, PIK3CA (R108H), PIK3R1, BRCA1, and SMARCB1 [27]. Unfortunately, within NF2 mutated meningiomas, none of these identified mutations can predict the chance of recurrence, which can vary widely.
TERT promoter mutations have recently been reported in ~6% of all MNs, with ~80% of these also harboring alterations (mutations or deletions) at the NF2 locus [28]. Similar to overall mutational burden, TERT mutations increase with tumor grade. In grade I MN, TERT C228T and C250T mutations are linked with transformation to higher grades [28], prompting many neuro-oncologists to consider standardized testing for TERT promoter mutations. Further studies demonstrate that the presence of C228T and C250T correlates with increased TERT mRNA and functional increases in telomerase activity [29]. In grade II or III tumors, univariate analysis revealed a significant association with decreased PFS (progression-free survival; median 12.5 vs. 26 months,
Non-NF2 mutated meningiomas, which generally have a benign behavior, are usually chromosomally stable, and often located in the anterior, medial, or skull base regions, possess a distinct mutational landscape [27]. Recent high throughput sequencing studies suggest an average of only 1.56 (SD ± 1.07) genomic alterations (GAs) per non-NF2 mutated tumor [31]. The pro-apoptotic E3 ubiquitin ligase, tumor necrosis factor receptor-associated factor 7 (TRAF7) is mutated ~25% of all meningiomas [31]. Such alterations occur in the C-terminal WD40 protein interaction domain, suggesting they may alter protein-protein interactions with MAPK and NF-kB family members [32]. While TRAF7 mutation is mutually exclusive with NF2 mutations, it is almost always correlated with PI3K and activating E17K mutation in AKT1, with the K409Q alteration of KLF4 [33].
AKT1, also referred to as protein kinase B, is a well-known oncogene. AKT activation relies on the PI3K pathway and is recognized as a critical node in the mTOR pathway. The E17 hotspot is the most characterized of AKT1 mutations and leads to constitutive activation of the protein. Mutations in AKT1 have also been shown to confer resistance to allosteric kinase inhibitors in vitro and are oncogenic in many solid tumors. Specifically, the E17K mutation is found in 7–12% of grade I meningiomas [34], is enriched in the meningothelial subtype [17], and is predictive of decreased PFS in olfactory groove tumors [35]. Altering the same signaling pathway PIK3CA mutations are also found in ~7% of non-NF2 tumors and are mutually exclusive with AKT1 mutation [36]. Targeted sequencing of this gene revealed novel non-synonymous mutations, A3140T and A3140G, which are reported as pathogenic, and C112T, which is also predicted to be pathogenic [31]. Indeed, increased PI3K signaling is related to aggressive behavior, especially within high-grade meningiomas [37], suggesting that therapeutics targeted toward this pathway may be a potential option.
Sequencing of 71 meningiomas genes recently identified two novel missense mutations in FGFR3, T932C, and G1376C, both of which were predicted to be pathogenic [31]. Identifying these mutations in patients with skull base low-grade tumors was associated with a good prognosis, given the absence of recurrence and the requirement of IMRT. KLF4 gene encodes a protein that belongs to the Kruppel family of transcription factors. The encoded zinc finger protein is required to control the G1-to-S transition of the cell cycle following DNA damage by mediating the tumor suppressor gene p53. In addition, KLF4 is involved in the differentiation of epithelial cells and may also function in skin, skeletal, and kidney development [38]. In meningiomas, KLF4 is thought to act as a tumor suppressor gene, expressed in low-grade tumors and downregulated in anaplastic tumors. At the genomic level, KLF4 is mutated in ~12% of grade I meningiomas, virtually all of which are of the secretory sub-type and harbor TRAF7 mutations [39]. All identified KLF4 mutations result in a K409Q substitution within the DNA binding domain, which likely alters several protein functions [40].
SMO (Smoothened, Frizzled Class Receptor) gene encoded a G protein-coupled receptor that interacts with the patched protein, a receptor for hedgehog proteins. Mutations in SMO, which result in L412F or W535L substitutions, lead to functional activation of Hedgehog signaling in meningioma [17, 41]. These mutations are present in ~5.5% of grade I meningiomas and are mutually exclusive with TRAF7, KLF4, and AKT1 mutations [27]. Meningiomas with the L412F mutation are more likely to recur (XX) and are enriched at the midline, perhaps due to the role that Hedgehog signaling plays in hemisphere separation during development [36]. Mutations in the Hedgehog family member SUFU are also found at low frequencies in sporadic meningiomas, and their germinal counterpart is also present in familial meningiomatosis [42]. Additional hedgehog family germline mutations occur in SMARCE1 and SMARCB1, though these carry less risk of recurrence than familial NF2 mutations [43, 44].
POLR2A (RNA Polymerase II Subunit A) catalyzes the transcription of DNA into RNA using the four ribonucleoside triphosphates as substrates. In addition, POLR2A is the largest and catalytic component of RNA polymerase II which synthesizes mRNA precursors and many functional non-coding RNAs. POLR2A encodes RPB1 (DNA-directed RNA polymerase II subunit), a gene found altered in about 6% of meningiomas [42]. From another perspective, inactivating somatic and germline mutations or gene deletions in the BAP1 tumor suppressor gene are explicitly found within high-grade rhabdoid meningioma [45]. Also, the loss of BAP1 is correlated with tumor aggressiveness and decreased time to progression. Alterations in the SWI/SNF pathway, specifically mutations in ARID1A, were recently found in 12% of high-grade meningiomas. Other components of this canonical pathway, including SMARCB1, SMARCA4, and PBRM1, are altered in up to 15% of patients with non-NF2-dependent meningiomas [46].
Through whole-genome analysis, global DNA methylation profiling has demonstrated that higher methylation levels are associated with increased tumor aggressiveness and risk of recurrence. DNA methylation is an epigenetic change hypothesized to contribute to genomic instability by silencing genes involved with DNA repair and control of cell cycling. Evidence suggests that methylation status may predict tumor behavior more accurately than the current WHO classification, thus, DNA methylation status has been proposed as an alternative classification system for MNs [47]. The most important genes involved in the DNA methylation of MNs are tissue inhibitors of metalloproteinase 3 (TIMP3), cyclin-dependent kinase inhibitor 2A (CDKN2A), and tumor protein 73 (TP73), which are hypermethylated in at least 10% of cases [48]. TIMP3 hypermethylation results in transcriptional downregulation and inhibits its tumor suppressor properties [49]. In addition, TIMP3 is frequently hypermethylated in higher-grade MNs (40–60%) and is related to a decrease in relapse-free time and increased biological aggressiveness [50]. Notably, TIMP3 is found on chromosome 22q12, and almost all cases with gene hypermethylation had a concurrent allelic loss of 22q. About 60–80% of high-grade meningiomas carry TP73 promoter methylation, a queue event not common in grade I tumors, suggesting its potential use as a marker for high-grade lesions [51].
Recently, several studies highlighted the importance of global methylation profiles in the molecular subclassification of meningiomas [52], Olar et al. demonstrated that unsupervised clustering of DNA methylation data classified meningiomas into two distinct subgroups associated with recurrence-free survival. A statistically significant association between DNA methylation subclasses and tumor recurrence was maintained after adjusting for clinical factors, such as WHO grade and Simpson grade [41]. Similarly, Sahm et al. identified two major groups and six subgroups of meningiomas based on unsupervised clustering of DNA methylation data, with significantly different genomic makeup and clinical behaviors. Interestingly, most non-NF2 meningiomas clustered together into a single benign subgroup [53]. These initial efforts suggest that epigenetic signatures may have solid clinical associations with tumor recurrence, to a more significant extent than can be correlated with mutational genetic analysis and could be used clinically to stratify patients. An additional manifestation of the importance of epigenetic changes in meningioma clinical behavior was recently shown, describing an increased risk of recurrence in tumors that show a loss of histone H3K27 trimethylation [54].
Classically, the identification of meningiomas using immunohistochemistry has been done using the expression of the progesterone receptor (PR) and the epithelial membrane antigen (EMA). However, over the last few years, it has been found that the specificity of RP for the diagnosis of high-grade meningiomas is low, especially when trying to differentiate between clear cell, fibrous, and microcystic subtypes. Likewise, EMA expression correctly identifies ~90% of grade I meningiomas, but only 75% of grade III, with even lower specificity rates for secretory and microcystic subtypes [55]. Due to these markers’ poor performance, the expression of somatostatin receptor 2A (SSTR2A) in combination with EMA was included, a profile that provides a sensitivity of 100% and specificity of 95%, regardless of tumor grade. Likewise, recent work suggests that the absence of Sox10 and STAT6 [56, 57] are superior approaches to distinguishing meningioma from schwannoma, solitary fibrous tumor, and synovial sarcoma.
In addition, marking for lymphocyte infiltration can contribute to the grading of meningiomas and the prediction of response to some interventions. Most low-grade meningiomas possess a high percentage of CD-3+ T-lymphocytes but relatively few CD20+ B cells; however, across tumor grades, these populations are greatly enriched compared to those seen in peripheral blood mononuclear cells (PBMC) [58]. Flow cytometry analysis reveals evidence of class switching in B cells, an increased percentage of CD8+ cells compared to CD4+ T cells, and a prevalence of CD45RO+/CD45RA− effector cells compared to naive T cells [59]. This information allows predicting that tumor-infiltrating immune cells have had exposure to various tumor antigens despite low BMR. Among high-grade meningiomas and particularly anaplastic tumors, there is a reduction in the count of CD4+, CD8+, and PD-1+ T cells, and an increase in the number of FoxP3+ T-regulatory cells (Tregs) [60]. This immune cell phenotype, also observed in other tumor types, is associated with tumor-mediated evasion of the immune system.
Du et al. report high levels of PD-L1 mRNA, which correlated to protein expression levels, in ~40% of grade I, 60% of grade II, and 77–88% of grade III meningiomas [59]. Nevertheless, Everson et al. only identified PD-L1 expression in 25% of grade III cases, with no expression detected in grade I or II cases [25]. The controversy has been amplified since PD-L1 does not predict outcomes. However, in the future, the expression of TIM-3 and LAG-3 could be helpful to consider the use of agonist monoclonal antibodies [58]. Another potential biomarkers that could predict the response to targeted therapies are EGFR expression, which is present in up to 90% of meningiomas [25]. Furthermore, the expression of TOP2A (35% of the samples) is associated with a higher tumor grade and could be useful to assess the usefulness of anthracyclines or trabectedin. Likewise, TOP1 over-expression is observed in 29% of meningiomas and correlates with sensitivity to irinotecan and topotecan, while elevated levels of PDGFR and c-MET are observed in more than 20% of cases [25] (Figure 2).
Signaling pathways and potential targets implicated in high-grade meningiomas.
The classical first-line treatment for all MNs is surgery. However, high grade meningiomas have a high recurrence rate; up to 60% of tumors may recur after 15 years of complete resection [12, 61]. Unfortunately, at the moment there are no standard effective treatments determined because of lack of existent evidence [12]. The use of systemic treatments as standard care remains experimental and is reserved for cases of recurrent/progressive disease not suitable for surgery or radiotherapy [62]. Hereafter we are going to present some of the systemic strategies currently in used and under study. A summary of the main therapies that have shown some benefit in MN treatment can be seen in Table 1, and a summary of current active clinical trials is shown in Table 2.
Type of agent | Medication | Mechanism of action |
---|---|---|
Chemotherapy | Temozolomide | Alkylating agent |
Irinotecan | Topoisomerase 1 inhibitor | |
Hydroxyurea | Ribonucleotide reductase inhibitor | |
Trabectedin | Mechanism unclear | |
Plant-derived agents | AKBA | Induction of apoptosis and antiinflammatory |
Curcumin | Interaction with multiple cell signaling proteins | |
EGFR antagonists | Gefitinib | EGFR antagonist |
Erlotinib | EGFR antagonist | |
Monoclonal antibodies | Humanized antibodies to EGFR | |
PDGFR antagonists | Imatinib | PDGFR antagonist |
Satinib | PDGFR inhibitors | |
Nilotinib | PDGFR inhibitors | |
mTOR inhibitors | Temsirolimus | mTOR inhibitor |
Vistusertib | mTOR inhibitor | |
Everolimus | mTOR inhibitor | |
VEGFR antagonists | Bevacizumab | Humanized monoclonal antibody to VEGFR |
Cediranib | VEGFR antagonist | |
Combination antagonists | Sorafenib | VEGFR and PDGFR antagonist |
Sunitinib | VEGFR and PDGFR antagonist | |
Vatalanib | VEGFR and PDGFR antagonist | |
Hormonal agents | Megestrol Mifepristone | Progesterone receptor partial agonist Progesterone receptor competitive antagonist |
Tamoxifen | Estrogen receptor antagonist | |
Octreotide Pasireotide | Somatostatin mimetic Somatostatin mimetic | |
Pegvisomant | Growth hormone receptor antagonist | |
Lutathera | Somatostatin receptor afinity and radiation β- emission | |
Fenretinide | Synthetic retinoid induces apoptosis | |
Immunomodulators | IFNα 2B | Antiproliferative and antiangiogenic |
Nivolumab Pembrolizumab Aveoumab Sintilimab | PD-1 receptor and ligand inhibitors | |
Trametinib | Inhibits MEK1 and MEK2 | |
Alpelisib | PI3K inhibitor | |
Ipililumab | CTLA-4 blockade | |
Oncolytic virus | Adenovirus | Antineoplastic effect against the malignant meningioma and significant tumor regression |
Herpes virus | Replication of adenovirus and oncolysis at high dose and at a lower dose meningioma cells killing | |
Farnesyl transferase inhibitors | Tipifarnib | Farnesyl transferase inhibitor |
Possible adjunctive agents | Calcium channel blockers | Reduction of intracellular calcium concentrations |
Statins | MAPK pathway inhibition | |
Antiretrovirals | Protein downregulation | |
RNAi | Antisense abrogation of mRNA strands |
A summary of different agents with promising evidence in the treatment of high-grade meningioma.
ClinicalTrials.gov Identifier | Status | Intervention | Arms | Outcomes |
---|---|---|---|---|
NCT03071874 | Active, not recruiting | AZD2014 a dual mTORC1/mTORC2 inhibitor | Experimental: AZD2014 | PFS OS Radiographic response rate Duration of radiographic response Frequency of adverse events |
NCT02648997 | Recruiting | Nivolumab 240 mg every 2 weeks Nivolumab 480 mg once every 4 weeks | Experimental: Cohort 1 (original cohort): Nivolumab Monotherapy | PFS Median PFS Median OS Objective radiologic response rate Adverse events |
Ipilimumab 1 mg/kg every 3 weeks Nivolumab 480 mg once every 4 weeks Nivolumab 3 mg/kg every 3 weeks External Beam RT | Experimental: Cohort 2: Nivolumab in Combination with Ipilimumab | PFS Median PFS Median OS Objective radiologic response rate Adverse events | ||
NCT03279692 | Active, not recruiting | Pembrolizumab | Experimental: Pembrolizumab | PFS OS Toxicity Intracraneal response |
NCT04997317 | Recruiting | 177Lu-DOTA-JR11 (Phase 0); Cycle 1 and Cycle 2 (cross-over) 177Lu-DOTATOC (Phase 0); Cycle 1 and Cycle 2 (cross-over), Cycle 3 and 4 | Active Comparator: Phase 0: Group A | Change in Tumor-to-dose limiting organ dose ratio T-to-bone marrow Change in Tumor-to-dose limiting organ dose ratio T-to-kidney Assessment of treatment safety (phase I/II) by number of AEs graded according to CTCAE v5.0 |
177Lu-DOTA-JR11 (Phase 0); Cycle 1 and Cycle 2 (cross-over) 177Lu-DOTATOC (Phase 0); Cycle 1 and Cycle 2 (cross-over), Cycle 3 and 4 | Active Comparator: Phase 0: Group B | |||
177Lu-DOTA-JR11 (Phase I/II) | Active Comparator: Phase I/II | |||
NCT03971461 | Recruiting | Lutathera | Experimental: Lutathera | PFS at 6 months Objective response rate OS at 12 months PFS OS |
NCT04082520 | Recruiting | Gallium Ga 68-DOTATATE Lutetium Lu 177 Dotatate Magnetic Resonance Imaging Positron Emission Tomography Quality-of-Life Assessment Questionnaire Administration | Treatment (gallium Ga 68-DOTATATE PET/MRI, Lutathera) | PFS at 6 months OS PFS Adverse events incidence Change in quality of life Local control Duration of local control Objective response to treatment Response rate by volumetric analysis |
NCT03016091 | Recruiting | Pembrolizumab | Experimental: Arm 1 IV Pembrolizumab | PFS at 6 months PFS at 12 months OS |
NCT03604978 | Recruiting | Ipilimumab Nivolumab Stereotactic Radiosurgery | Patients receive nivolumab | Maximum tolerated combination of radiosurgery and nivolumab plus or minus ipilimumab Incidence of adverse event profile Objective response rate Objective radiological response PFS OS Changes of peripheral T-cells |
NCT02333565 | Unknown | Everolimus Octreotide | Experimental: Combinaison everolimus and octreotide | PFS rate |
NCT04501705 | Recruiting | Apatinib mesylate | Experimental: test group | PFS-6% ORR OS |
NCT03267836 | Recruiting | Avelumab Proton surgery | Experimental: Avelumab + proton therapy | Immunogenicity Safety of therapy Pathologic response PFS OS |
NCT04728568 | Recruiting | Sintilimab | Experimental: Sintilimab | PFS at 6 months OS |
NCT03631953 | Recruiting | Trametinib Alpelisib | Experimental: Alpelisib in combination with Trametinib administered | Dose Limiting Toxicity (DLT) rate of combination Alpelisib and Trametinib |
NCT00904735 | Unknown | Hydroxyurea Imatinib mesylate | Experimental: Arm I Patients receive hydroxyurea and imatinib | PFS Survival Response rate according to MacDonald criteria Toxicity as assessed by NCI CTCAE v. 3.0 |
Hydroxyurea | Experimental: Arm II Patients receive hydroxyurea |
A summary of currently ongoing clinical trials that assess the effectiveness and safety of different systemic therapies in high-grade meningiomas.
It is known that chemotherapy is poorly effective as adjuvant treatment after surgery and radiotherapy. Some clinical trials and case series have shown a minimal or no impact in patients’ outcomes. However, some agents are being tested in several clinical trials [63].
Hydroxyurea is a ribonucleotide reductase inhibitor that was initially developed to treat myeloproliferative disorders and chronic myelogenous leukemia [64]. It induces apoptosis in meningioma cells, arresting meningioma cells in the S-phase of the cell cycle [63]. In pre-clinical trials from Schrell et al., they demonstrated that hydroxyurea prevent recurrence for 24 months in patients who had complete resection [65, 66]. However, clinical trials, failed to provide similar results showing that 50% of the patients achieve stable disease, a median PFS of 44–176 weeks and acceptable toxicity [63, 65, 66, 67, 68, 69, 70, 71]. Other retrospective studies with small sample sizes, have shown a median PFS of 10–80 weeks [64]. Weston et al. also found that hydroxyurea may prevent progression, but does not reduce tumor size and causes significant side effects [72]. It is important to emphasize that in these trials many patients did not received radiotherapy or that radiotherapy was administered concurrently, making data interpretation difficult [73]. In addition, a retrospective study of 60 patients from Chamberlain et al. reported a disease progression in 65% of the patients and a median PFS of 4 months in patients treated with hydroxyurea after recurrence (Chamberlain and Johnston, 2011). Finally, some studies suggest hydroxyurea may have outcomes equivalent to those when radiation therapy was used [74].
Additionally, some studies reported reduction of hydroxyurea efficacy when other concomitant therapies are administrated [64]. In a study by Reardon et al., hydroxyurea and imatinib were used to treat patients with recurrent refractory meningiomas, a good tolerance was reported; however, the combination did not affect survival [75]. Other authors suggest that chemotherapy should be based on expression of drug resistance genes, in patients whose mRNA analysis predicted sensitivity to chemotherapy. In these cases, a concomitant treatment with mitoxantrone and hydroxyurea reported long-term efficacy [61]. Currently, some investigators are looking for the role of hydroxyurea as an adjunct to other therapies, such as calcium channel blockers, as calcium channel antagonists have an inhibitory effect on meningioma growth in culture [76]. For this matter, Ragel et al. reported that calcium channel antagonists can block stimulatory effects of growth factors on meningioma cell cultures and increase hydroxyurea effectiveness [77]. Evidence of hydroxyurea treatment in patients with high grade meningioma varies widely across patients. Demonstrating that this treatment is generally well-tolerated but evidence in tumor control is not conclusive to establish a standard treatment in high-grade MNs.
Trabectedin it is an alkylating agent used in soft tissue sarcomas. It inhibits transcription, its mechanism is not completely understood but some studies reported decreased cell proliferation, induction of apoptosis and inhibition of transcription factor binding by binding to the minor groove of the DNA helix [78]. In the randomized phase II clinical trial NCT02234050 by EORTC Brain Tumor Group (EORTC-1320-BTG), treatment with trabectidin in grade II/III meningiomas did not improve PFS or OS and it was associated with significantly higher toxicity as compared to local standard care. A median PFS of 4.17 months was reported in the local standard care arm and of 2.43 months in the trabectedin arm (hazard ratio [HR] for progression, 1.42; 80% CI, 1.00–2.03;
Temozolomide another alkylating agent, used as standard care in management of glioma. It does not prolong PFS in clinical trials of recurrent meningioma [80]. It is believed that the no effect on meningioma could be due to intact activity of the DNA repair enzyme O6-methylguanine DNA methyltransferase (MGMT) [63, 81, 82].
Chamberlain et al. reported a median time tumor progression of 4.6 years and median OS of 5.3 years in patients treated with cyclophosphamide, doxorubicin, and vincristine. They also reported high toxicity and very low response. However, without a control group the results are difficult to interpret [83]. Some small case series also reported results by administrating cyclophosphamide, adriamycin, vincristine, isofosfamide/mesna or adriamycin/dacarbazine, but the evidence is limited [84]. In some in vitro an in vivo animal studies, was reported that irinotecan has an anti-meningioma effect. However, it did not show benefits in phase II clinical trials [81, 82, 85].
Finally, some preclinical studies evaluated the response of Plant-Derived Chemotherapeutic Agents. Curic et al. described an antitumorigenic properties from curcumin (from the spice plant
Unlike other solid tumors, MN presents with a low mutation rate of approximately 3.5 mutations per megabase [25]. However, the case of high-grade MNs has been evaluated recently. Bi et al. analyzed 39 samples of high-grade MN and found an average of 23 (range 1–223) nonsynonymous coding alterations. This number of alterations is similar to that of craniopharyngioma and thyroid cancer, but considerably lower than other aggressive tumors like head and neck carcinoma, colorectal carcinoma and melanoma [34]. Because of its relatively low mutational burden, very few potential molecular targets have been identified. Interestingly, Bi et al. found that non-NF2 driver mutations in high-grade MN was considerably lower than in low grade MN, which reduces the number of possible targets than can be addressed. In the other hand, NF2 is usually altered in high-grade MN (80% of cases) more frequently than in low grade MN (40%). Most of genetic and regulatory alterations that have been described in high grade MN occur downstream to a disrupted NF2 protein. Some of the pathways altered might involve Rac1/Cdc42, Ras/JNK and the master regulator AP-1 [89]. Furthermore, one of the main pathways associated with NF2 is the mTOR signaling cascade. NF2 naturally acts as a repressor of the mTORC1 and mTORC2, and when it is mutated, unregulated activation of this pathway occurs. Based on this, mTOR and some of its upstream/downstream effectors (Akt/PI3K) have been identified as potential targets. Other pathways regulated by receptor tyrosine kinases (RTKs) like EGFR, PDGFR and VEGFR (angiogenesis) are also being studied.
The EGFR pathway has been demonstrated to play a role in the tumorigenesis of a great proportion of meningioma cases. Torp et al. demonstrated that EGFR expression is not detectable in healthy and injured adult human meninges, but is expressed in cases of meningioma [90]. Arnli et al. also showed that EGFR was absent in healthy meninges but present in MN [91]. Narla et al. analyzed 79 samples of MN using immunohistochemistry, to detect EGFR expression. They found that EGFR was expressed in all different grades of MN, but its expression was considerably higher in grade I MN (82.93%), than grade II MN (35.71%) and grade III MN (20%) (
Similar results were published by Wernicke et al. who found in a cohort of 89 MN samples that EGFR expression was more common in grade I MN than in other grades. They also showed that the staining percentage (SP) of immunoreactive cells was associated with histopathologic subtypes (
In 2010, results from a phase II trial of erlotinib and gefitinib for the treatment of MN were published. Erlotinib is an orally available, reversible TKI directed against EGFR. Its use has been approved in different neoplastic disorders including non-small cell lung cancer (NSCLC) and pancreatic cancer [98]. Gefitinib is a first-generation EGFR-TKI also approved for the treatment of locally advanced and advanced NSCLC [99]. In 2010, a clinical trial enrolled patients with recurrent histologically confirmed MN that were treated with no more than 2 chemotherapy regimens.
The study evaluated 25 patients with a median age of 57 years. From this cohort, 16 patients received gefitinib and 9 received erlotinib. Nine patients had atypical MN and 8 had anaplastic MN. PFS and OS were assessed at 6 and 12 months. For patients with low-grade histology, PFS-6 was 25%, PFS12 was 13%, OS-6 was 63% and OS12 50%. In the other hand, high-grade meningiomas seemed to respond a little better with a PFS6 of 29%, PFS-12 18%, OS6 71% and OS-12 65%. When statistical analysis was done no significant difference between low-grade and high-grade MN was seen [100]. Survival outcomes were not significantly better than that of standard treatment.
In 2020 Ferluga et al. found that STAT1 is overexpressed and present a constitutive phosphorylation in MN. They also found that this overactivation was not associated with the JAK-STAT pathway but instead it was induced by the constitutive phosphorylation of EGFR. They even demonstrated that STAT1 knockdown models presented a significant reduction of cellular proliferation as well as a deactivation of AKT and ERK1/2. The most interesting finding of this study was that the researchers used BM-1 cells and exposed them to three different EGFR inhibitors, two from second generation (canertinib and afatinib) and one first generation (erlotinib). After exposure to canertinib and afatinib, a decrease in about 60% of STAT1 expression was seen as well as an almost complete elimination of phosphorylated forms of STAT1, this effect was not seen after exposure to erlotinib.
Lapatinib is a dual EGFR/ErbB2 inhibitor currently approved for the treatment of advanced breast cancer with ErbB2 (HER2) expression [101]. There is preclinical evidence of lapatinib efficacy in decreasing tumoral growth in NF2-related Schwannomas. Ammoun et al. demonstrated that when NF2 is mutated or lost, there is an upregulation of different RTKs in Schwannoma, with EGFR and HER2 being two of the highest expressed [102]. Similar results have been seen in NF2-related MN. When the researchers added lapatinib at 5 and 10 μM concentrations to cultures of Schwannoma cells derived from patients’ samples, they found that lapatinib successfully induced inhibition of the intracellular pathways downstream HER2, including ERK 1/2 and Akt. They also showed that after 24 h of exposure to lapatinib, cell viability decreased in a dose-dependent manner, with statistically significant differences between both concentrations of lapatinib to baseline, and from lapatinib 5 μM to lapatinib 10 μM [102].
The same group of researchers also tested lapatinib during a phase II clinical trial, with good results in terms of volumetric response, progression-free survival and safety profile [103]. Six years after this trial, the authors did a retrospective analysis of patients presenting with NF2-related meningiomas from the same cohort of patients with Schwannoma. Eight patients fulfilled criteria for analysis. After two months under treatment with lapatinib, the best volumetric response achieved was 26.1%. It is important to mention that in the group that was receiving lapatinib, two tumors increased in volume by more than 20%. Results from this analysis were confusing, with no clear benefit of lapatinib, however, the sample was extremely small, and the analysis was retrospective. This study might influence the development of future, prospective, larger clinical trials specifically for patients with MN [104].
In 2001, Crombet et al. published their results on the efficacy of a mouse anti-human neutralizing monoclonal antibody against EGFR (ior egf/r3). They performed a phase I clinical trial using this antibody in 9 patients with high-grade brain tumors that persisted or relapased after surgery. Only one of the patients had MN (hemangiopericytic). The patient had 48 years old and a Karnofsky Performance Score of 90. She received four doses of 160 mg of antibody. At the end of the study, no objective response was seen in any of the patients, however the remained with stable disease until 6 months after the last antibody dose [105]. Even though EGFR inhibition has revolutionized cancer care in neoplasms with high incidence like NSCLC and colorectal cancer, these effects have not been seen in brain tumors, even when EGFR upregulation has been proved. Further studies must be performed with newer and more effective EGFR inhibitors, including monoclonal antibodies.
PDGFR is another RTK whose expression is critical during development, as well as in the growth and differentiation of certain cell lineages. Its role in multiple chronic diseases have been studied, and it is considered a possible target in conditions like cancer, fibrosis, neurological disorders and atherosclerosis. The PDGF/PDGFR axis promotes cell proliferation, survival and migration primarily in cells of mesenchymal origin [106]. The ligands for PDGFR are four different polypeptide chains (PDGF-A, PDGF-B, PDGF-C and PDGF-D) which can be organized in an array of dimers that behave as functional growth factors (PDGF-AA, PDGF-BB, PDGF-AB, PDGF-CC and PDGF-DD [107]. These ligands have two different receptors, PDGFRα and PDGFRβ. The different ligands bind to the receptors with a differential specificity. PDGF-A, -B and -C will bind strongly to PDGFRα while the others will bind to PDGFRβ [106].
It has been demonstrated that MN expresses different forms of PDGF ligands, namely PDGF-AA and PDGF-BB, and expresses considerable levels of PDGFRβ. It has been shown that the PDGF/PDGFR axis might play a key role in the tumorigenesis of MN. Black et al. proved that PDGFRβ in MN cells derived from patients are susceptible to the stimulation with PDGF-BB ligands, with a shown increased in the activation of MAPK [21] and c-fos, a critical part of the master regulator AP-1, and a recognized proto-oncogene [108, 109]. Unlike EGFR expression, PDGFR levels appear to be higher in atypical and anaplastic MN than in grade I MN. In those MN that express PDGFR and the aforementioned PDGF ligands, there is an autocrine loop that supports maintenance and cell growth [109]. Todo et al. demonstrated that there is a considerable decrease in meningioma cells proliferation when these cells are given a neutralizing antibody against PDGF-BB. They saw a similar but less potent behavior when an anti-PDGF-AA antibody, also suggesting that the PDGF-BB pathway is the most important for meningioma maintenance [110].
Imatinib, a potent PDGF inhibitor currently used in different conditions (mainly chronic myeloid leukemia), has also been proven in MN patients. Imatinib possess a very low IC50 of 0.1 μM, this is especially important in MN as the blood-brain-barrier might decrease the flux of imatinib and other drug particles into the brain. In the NABTC 01–08 study, 23 patients with MN were enrolled, with 13 patients bearing low grade tumors, five with atypical MN and five with anaplastic MN. Response was only evaluated in 19 patients from whom 10 patients experienced disease progression. The rest of the patients remained disease stable. Median PFS was only 2 months, with a PFS6 of 29.4%. When analyzed separately, PFS for grade I MN was 3 months and PFS6 was as high as 45%. In the case of high-grade MN, PFS was 2 months but PFS6 was 0%.
The current landscape of PDGF inhibition is somewhat promising. Other agents like sunitnib, MLN518, dasatinib, AMN 107, pazopanib, sorafenib, CP673451 and CHIR 265 have been studied [111]. Furthermore, combination therapies using imatinib and other different agents like hydroxyurea [112], which has showed some benefit in the treatment of glioblastoma in a Phase I/II trial [113].
The mTORC1 (mammalian target of rapamycin complex 1) pathway has been reported to interact with merlin as a negative regulator of cell growth control [114]. mTOR is a serine/threonine kinase involved in cell signaling controlling transcription, actin cytoskeleton organization, translational activation, and metabolism in response to environmental cues [9]. The protein exists in two distinct multiprotein complexes. The rapamycin-sensitive complex mTORC1 regulates cell growth and proliferation in response to growth factors and metabolic conditions, whereas the rapamycin-insensitive mTORC2 regulates locally restricted growth processes within a cell and is involved in cell migration. Merlin was shown to enhance the kinase activity of mTORC2 [115].
Previously, Pachou et al. [116] found that mTORC1 is activated in the majority of MNs (7–10%) and that systemic mTORC1 inhibition can impair meningioma tumor formation in vivo. In addition, Akt is well known to be an upstream element of mTORC1 and to be activated in meningioma cells by platelet-derived growth factor [117]. PDGF also induces phosphorylation of p70S6K, the expression of which was reported to be increased in malignant MNs [118].
Several groups analyzed the biological effects of everolimus and temsirolimus on meningioma cell viability. They could clearly show that both inhibitors were effective in reducing meningioma cell viability and proliferation [114]. Moreover, evidence was found that the NF2 gene status may affect the response to both inhibitors but differentially activated mTOR pathways could not explain this result in isogenic meningioma cell lines with and without merlin expression [119]. Further, octreotide was shown to augment the inhibitory effect on the mTOR pathway in meningioma cell lines because mTOR inhibition increases the hyperphosphorylation of AKT which thereby increases cell proliferation [120].
In 2020, Graillon et al. reported the results of the CEVOREM trial, a phase II open label study that evaluated the combination of everolimus and octreotide in 20 high-grade MNs patients. Furthermore, four patients harbored NF2 germline mutation [121]. The overall PFS6 was 55% (95% CI 31.3–73.5%), and 6- and 12-month OS rates were 90% (95% CI 65.6–97.4%) and 75% (95% CI 50.0–88.7%), respectively. A decrease >50% was observed in the growth rate at 3 months in 78% of tumors. In addition, the median tumor growth rate decreased from 16.6%/3 months before inclusion to 0.02%/3 months at 3 months (
In a small trial, everolimus has also been studied in conjunction with bevacizumab without finding any objective tumor response but showing a slight increase in PFS for those with high-grade MNs (NCT00972335) [122]. In this study, 88% of the 18 patients showed SD for a median duration of 10 months (2–29 months). Nevertheless, overall median PFS was 22 months (95% CI 4.5–26.8), higher for patients with WHO grade II and III than grade I tumors (22.0 months vs. 17.5 months). Four patients discontinued treatment due to toxicity (proteinuria, 2; colitis, 1, thrombocytopenia, 1), but another grade 3 toxicity was uncommon, and no patient had grade 4 toxicity. The interesting improvement in higher histological grade MNs could be due to their increased vasculature and the increased dependence on the mTOR pathway of these lesions [122].
There is currently a phase 0, single group assignment, trial for everolimus in NF2 mutant MNs and vestibular schwannomas (NCT01880749). There are two single group assignment phase II trials of another mTOR inhibitor, AZD2014; NCT03071874 for recurrent grade II/III MNs and NCT02831257 for NF2 patients with MNs. These trials will help determine the efficacy of mTOR inhibition in patients with these challenging lesions. Besides, a case report of a female patient with metastatic meningotheliomatous meningioma involving the brain and the lung was treated with the pan-AKT inhibitor, AZD5363 for AKT1E17K mutation, showed a favorable and durable response [123]. Ex vivo cultured meningioma cells revealed sensitivity to the drug as shown by pan-AKT accumulation on immunoblots. The patient has been treated for more than a year with a response which warrants further research [123].
Angiogenesis depends on the balance between angiogenic and anti-angiogenic regulators [124]. Among the former, VEGF has been demonstrated to play an essential role in stimulating angiogenesis by promoting the migration, proliferation, and tube formation of endothelial cells. VEGF upregulation has been shown in MNs, suggesting its role as a pro-angiogenic factor responsible for edema formation in these tumors [125, 126, 127].
Neoangiogenesis in MNs is regulated by the balance between concentrations of both VEGF and semaphorin 3A (SEMA3A) in the tumor’s microenvironment rather than by VEGF alone [125]. Accordingly, neo-angiogenesis would be blocked or stimulated depending on the prevalence of VEGF or SEMA3A with a high ratio between VEGF and SEMA3A as a negative predictor of recurrences [125]. Additionally, VEGF expression in MNs seems to be enhanced by hypoxia-inducible factor 1-alpha [128] and EGF [129], and reduced by dexamethasone.
Caveolin-1 (cav-1), which is a 20-KDa protein mainly expressed by fibroblasts, endothelial cells, myocytes, and adipocytes, seems to be involved in the oncogenesis and progression of several neoplasms, including MNs [130]. Similar to what has been reported in several solid tumors, a significant correlation has been shown between tumor-cell-derived cav-1 and microvascular density (MVD) in MNs [131], suggesting that this protein behaves as a pro-angiogenic factor. Consistent with this hypothesis, cav-1 has been shown to regulate endothelial cell growth and differentiation and to stimulate capillary tubule formation in vitro [132]. Moreover, VEGF-mediated pathological angiogenesis is strikingly reduced in cav-1 knock-out mice [133]. On the other hand, the association between cav-1 expression and MVD may also be related to factors regulating both the MNs neo-angiogenesis and cav-1 expression. Indeed, cav-1 may function as a pro-tumorigenic factor that can stimulate cell proliferation, following its tyrosine-14 phosphorylation by Src kinase [134].
Endothelin-1 (ET-1) has been demonstrated to play a role in the mechanism of meningioma tumorigenesis via the ETA receptor [135]. ET-1 expression/upregulation may contribute to meningioma growth by inducing the formation of new blood vessels. Indeed, a significant correlation has been shown between the expression of ET-1 and that of VEGF or MVD in MNs, in agreement with its proangiogenic action in these tumors.
Following these biological considerations, several angiogenesis inhibitors, such as bevacizumab, sunitinib, and vatalanib, have been evaluated in phase II trials with promising results [136]. The efficacy and safety of bevacizumab were evaluated in grades II and III MNs, finding a PFS6 of 43.8%. In addition, a review of 22 additional case reports for a total of 92 patients revealed a PFS of 16.8 months with 6 months PFS of 73% in those exposed to bevacizumab [137]. A phase II trial designed for all grades recurrent MNs that included 15 patients (15, 22, and 13 grade I, II, and III, respectively) showed stability of the disease in 100% of benign tumors and 82–85% among those with high-grade injuries. In addition, the PFS6, the median PFS, and OS, were 87%, 22.5 months, and 35.6 months for patients with grade I tumors, while this distribution was 77%, 15.3 months, and not reached for grade II, and 46%, 3.7 months, and 12.4 months for grade III, respectively [138]. There is an ongoing phase II trial evaluating bevacizumab in recurrent and progressive MNs (NCT01125046).
Kaley et al. reported a prospective, multicenter single-arm phase 2 trial that investigated the efficacy of sunitinib, a tyrosine kinase inhibitor that inhibits VEGF and PDGF receptors, which are over-expressed in MNs [139]. Thirty-six patients with grade II and III recurrent or progressive MNs were enrolled. They were heavily pre-treated (median five recurrences) and received sunitinib at 50 mg per day for days 1–28 of a 42-day cycle. The PFS6 was 42%, the median PFS was 5.2 months (95% CI 2.8–8.3), and the median overall survival was 24.6 months (16.5–38.4). Adverse events included four (8%) intratumoral hemorrhages, of which one was fatal, one (2%) grade 4 thrombotic microangiopathy, and one (2%) grade 3 gastrointestinal perforation. MRI perfusion in the exploratory group indicated that sunitinib is an active agent, and expression of VEGFR2 predicted PFS with a median of 1.4 months in VEGFR2-negative patients versus 6.4 months in VEGFR2- positive patients (
Evidence suggests that meningioma growth could be hormone dependent because of the female predominance specially after puberty and reproductive years. Additionally, that 30% of the meningiomas are estrogen receptor positive and 70% are progesterone receptor positive [76]. It is also known, that high grade meningiomas express more estrogen receptors whereas benign meningiomas express more progesterone receptors [141]. It is also important to add, that approximately 90% of meningiomas express somatostatin receptors [142]. Therefore, hormonal therapies have been utilized in high grade meningioma treatment.
Due to estrogen receptors low expression, treatment with tamoxifen (estrogen receptor antagonist) has not shown effective results. Additionally, there is not any reports of androgen receptor antagonists in meningiomas [143]. In 1993 Goodwin et al. in a retrospective case series of 21 patients with meningioma treated with tamoxifen, they reported response in only 1 patient and disease progression in 10 patients [144]. Additionally, in a case study from Markwalder et al. a small group of patients with inoperable meningiomas that received tamoxifen were studied and only two patients show radiographical partial response [145].
Currently, due to the lack of evidence of anti-estrogenic agents’ effect on meningioma no recommendation is available. Mifepristone is a progesterone receptor inhibitor. In a study published in 1991 by Wolfsberger et al., they used mifepristone as treatment of unresectable meningioma patients, they reported that five patients showed reduction of tumor size on neuroimaging and visual field improvement; in addition, three patients experienced headache relief and improvement in extraocular muscle function. No toxicities were reported [141]. Other study by Lamberts et al. reported stable disease in three patients, tumor size reduction in other three patients and no toxicities were reported [146]. These studies were limited because of the small sample size and tumor stage wasn’t described in any of them. Therefore, more studies are needed to conclude the effect of mifeprisotne in high grade meningiomas. Other trial by Ji et al. reported a median PFS of 10 months and a median OS of 31 months in the mifepristone arm of patients with recurrent meningioma [147]. Additionally, in 2006 Grunberg et al. reported a reduction of less than 10% of the tumor area without clinical improvement in eight patients with unresectable meningioma who received mifepristone [148].
Megestrol acetate is an oral progesterone agonist that was used in a small trial. However no response was observed in high grade meningiomas [76]. So far there is no evidence that supports the use of progesterone receptor inhibitors in high grade meningiomas.
Somatostatin is important in regulation and proliferation of normal cells and tumor cells. It is known that meningiomas report the highest frequency of somatostatin receptor expression in brain tumors, especially the sst2A subtype. It is also reported that somatostatin inhibits meningioma growth in vitro in most studies, but increases meningioma proliferation in some [76].
Chamberlan et al. reported that 31% of patients demonstrated a partial radiographic response and 44% achieved PFS at 6 months with minimal toxicity in patients treated with octreotide (a somatostatin agonist). Furthermore, one-third of patients showed stable disease after treatment [149]. Therefore, somatostatin analogs are recommended for systemic treatment of unresectable or radiorefractory relapsed meningiomas [150]. The phase II CEVOREM trial explored the efficacy of the combination of everolimus (an mTOR inhibitor) and octreotide in high grade meningiomas treatment. The trial reported that the 6-month progression-free survival rate was 55% and the 6-month overall survival was 90% and 12-month survival rate was 90%. Additionally, a decrease of more than 50% was observed in the growth rate at 3 months in 78% of the tumors. That happens because, octreotide suppressed AKT activation during everolimus treatment and synergistically reduced expression of downstream proteins [121]. The previous results suggest that the combination of everolimus and octreotide could be a very good option to treat high grade meningiomas, however more studies are needed. In other phase II trial by Johnson et al. only 2 of 12 high grade cases experience long progression-free intervals, but at the end all patients experienced disease progression with median time of 17 weeks; a median survival 2.7 years was reported and octreotide was well-tolerated [151]. Additionally, an in- vitro study by Graillon et al. reported a significant anti-proliferative effects octreotide, but no apoptotic response [152].
Parasoreotide (SOM230C) is an intramuscularly long-acting somatostatin analogue. In the phase II trial by Norden et al., they reported that pasireotide has limited activity in recurrent meningiomas, a PFS-6 of 17% and median PFS of 15 weeks were reported. Furthermore, expression of somatostatin receptor was predictive of favorable response. However the findings in this trial require further investigation [153]. These findings are promising, nevertheless, larger randomized studies should be conducted to make a solid conclusion.
Growth hormone is secreted by the pituitary gland, and it induces production of insulin-like growth factor-I (IGF-I-), these hormones influence normal growth and metabolism [73]. There is existent evidence that reports abuntant growth hormone receptors expression in meningioma cells. There is also reported that inhibition of these receptors represents a decreased meningioma cell proliferation [154]. McCutcheon et al. reported that administration of pegvisomant reduces meningioma growth and in some cases causes tumor regression. Pegvisomant blocks growth hormone receptors and induces downregulation of the GH/IGF-I axis [155]. In other study, Puduvalli et al. reported that fenretinide, a synthetic retinoid, induced apoptosis in meningioma primary cells tested, it also increases levels of the death receptor DR5 and causes mitochondrial membrane depolarization. They also reported eradication of IGF-I proliferation in the meningioma cells [156].
Finally, insulin-like growth factor-II acts like IGF-I. In multiple studies have reported that the invasiveness of meningiomas is correlated to levels of IGF-II expression [157]. However, several studies are needed to establish IGF-II blockade could be an option to treat patients with meningiomas. These results provide preliminary evidence, but further studies are needed to explore these options as treatment against meningioma.
Existent evidence, shows that recombinant interferon-α (INF-α) is a biologic agent able to inhibit DNA synthesis, it binds to the interferon-a/b receptor and is involved in cell resistance to viral infection [64]. In 1991 in vitro studies also reported that interferon-alpha inhibits tumor cells growth [158].
In 1997 Kaba et al., reported a minor reduction of tumor size in one patient and a stable disease that lasted up to 14 months in four of six patients with recurrent unresectable meningioma who received INF-α 2b [159]. Other study in 2001, reported a stable disease that lasted up to eight years in nine of twelve patients treated with INF-α [160]. In 2008 Chamberlain and Glantz, reported in a phase II study that 26 of 35 patients that received treatment with INF-α demonstrated stable disease after the first 3 cycles and that 9 patients developed progressive disease. Additionally, a PFS rate was 54% at 6 months and 31% at 12 months were reported, median time to tumor progression was 7 months and median survival was 8 months. Furthermore, no patient demonstrated neuroradiographic complete or partial response, fatigue, anemia and leukopenia were the most common toxicities but overall, the drug was safe. A limitation form this study is that it was conducted only in patients with refractory grade I meningiomas [161]. Currently, these options are used as therapy for recurrent meningiomas or progression following surgery and radiation. It is also used for meningiomas that no respond to standard treatment options. Nevertheless, evidence that supports the use of interferons for meningiomas is poor.
Oncolytic viruses are biologic anti-tumor agents that selectively kill tumor cells leaving non tumoral cells intact [63]. A lot of oncolytic viruses have been investigated in different clinical trials, however no clinical trials have been conducted in meningiomas [162].
There are a few preclinical trials conducted in meningioma models. In 2005 Grill et al. evaluated the efficacy of conditionally replicating adenovirus (Ad) for oncolysis of meningiomas of 12 patients. Four different Ads were constructed and tested on meningioma cells and spheroids: Ad with an E1ACR2 deletion (Ad.d24), Ad with complete E1 region (Ad.E1+), Ad encoding the luciferase marker gene (Ad.Luc) and Ad encoding the luciferase gene in the E3 region (Ad.E1Luc). They demonstrated replication of adenovirus and oncolysis in primary cell cultures of meningioma cells at high dose (greater than 50 plaque-forming units per cell). Additionally, they also reported that at a lower dose (5 plaque-forming units per cell), Ad.d24 kills meningioma cells more efficiently than Ad.E1+ in benign, atypical, and malignant meningiomas [163].
Herpes virus it has a large dsDNA with more than 30 kb making the virus encoding for nonessential genes, this feature allows for genetic manipulation. Additionally, herpesviruses have a good safety profile, because they replicate in the nucleus without causing insertional mutagenesis [164].
In 1992, Market et al. added thymidine kinase-negative herpes simplex-I mutant virus, d/sptk, to meningioma cell cultures. They reported an antineoplastic effect against the malignant meningioma and significant tumor regressions [165]. In the study from Yazaki et al., reported that mutant herpes simplex virus (termed G207) can replicate and kill cells from human malignant meningiomas in cell culture. They also reported tumor growth reduction in nude mice harboring human malignant meningioma [166]. Additionally, it is reported that efficacy of oncolytic herpes simplex viruses (HSV) as single agent is unsatisfactory; so in 2006 Liu et al. demonstrated that oncolytic HSV encoding dnFGFR enhances antitumor efficacy [167]. In 2016 Nigim et al., reported that G47∆, an oncolytic HSV derived from G207, was able to replicate and kill several human primary meningioma cultures in vitro. They also reported that this treatment prolonged survival, with 20% of mice surviving more than160 days. Furthermore, a lack of signs of encephalitic associated with G47∆ treatment was reported [168]. In 2018, they also reported that the mechanism of action of oHSV enables killing NF2 intact and mutant meningiomas and meningiomas that harbor other mutations [63].
Several studies have demonstrated the ability of oncolytic viruses to recruit T cells and induce immune responses against virus and tumor. Furthermore, some studies have demonstrated that oncolytic viruses combined with other cancer therapies, create synergistic effects in brain cancer treatment. Although many questions remain to be answered to fully exploit the therapeutic potential of oncolytic viruses against meningiomas [169].
Several studies have aimed to characterize the interactions between MNs and the immune system. Specifically, studies of the immune microenvironment in MNs have revealed that NY-ESO-1, PD-L1, PD-L2, B7-H3, and CTLA-4 are expressed in MNs and may be at least partly responsible for the suppression of the anti-tumor immune response [170, 171]. PD-L1 is expressed in MNs, and expression levels are higher for higher-grade tumors [172]. The expression of these proteins has been associated with tumor progression, recurrence, and poor survival outcomes. Fang et al. extensively characterized the immune infiltrate in MNs and found that the immune cells infiltrating MNs are mainly antigen-experienced T cells and B cells [58]. In their study, B cells were activated and underwent immunoglobulin class switching, somatic hypermutation, and clonal expansion. T-cells demonstrated evidence of antigen exposure and increased expression of PD-1 and TIM-3, which can be a sign of an exhausted phenotype. Tumor-infiltrating lymphocytes in MNs are mainly T-cells. Interestingly in anaplastic MNs, the number of CD4 and CD8 T-cells is low. At the same time, the proportion of Tregs is increased [59]. These data support the notion that an immunosuppressive microenvironment in MNs may contribute to tumor progression.
In a mouse model of meningioma, infusion of anti-PD1 antibody avelumab plus highly-active NK cells (HaNK) led to increased survival, showing the importance of innate NK cell activity [173]. Currently there are two case reports on PD-L1 checkpoint inhibition for recurrent MNs [174, 175]. The cases report disease-free recurrence for >2 years in one patient and > 6 months in another patient, with both having reductions in tumor volume, cerebral edema, and patient-reported symptoms following nivolumab treatment. Based on the existing evidence on PD-L1 expression in recurrent MNs, five clinical trials are enrolling patients with to receive anti-PD1 antibodies nivolumab, avelumab, or pembrolizumab. An ongoing phase II trial is designed to compare nivolumab alone to combination therapy with the anti-CTLA-4 antibody ipilimumab (NCT02648997). A phase Ib trial will investigate the preoperative use of avelumab in combination with hypo-fractionated proton radiotherapy for 3 months to evaluate its effect on the size of unresected MNs (NCT03267836). The other trials are recruiting patients with recurrent MNs to receive adjuvant immunotherapy as PD1 blockade.
Chimeric Antigen Receptor (CAR) T cell therapies are a novel therapeutic approach to cancer. The standard treatment consists in the leukapheresis of autologous peripheral blood mononuclear cells from the patient bearing the tumor. After successful leukapheresis, T cell isolation is performed. T cells are then grown in culture and are further transduced with a lentiviral vector carrying an integrative plasmid that encodes the CAR, which is essentially a fusion protein containing a single-chain variable fragment derived from a full antibody, plus a transmembrane domain and different array of intracellular co-receptor and co-stimulatory domains that will trigger the intracellular signaling necessary for T cell activation [176].
CAR-T cell therapies were initially approved in 2017 (axi-cel and tisa-cel) for the treatment of relapsed/refractory diffuse large B cell lymphoma and relapsed/refractory B-cell acute lymphoblastic leukemia [177]. Unfortunately, the landscape of CAR-T cell therapies in solid tumors has not been promising, mainly due to different resistance from typical features of the tumor microenvironment like high acidity, immune effector exhaustion induction and the extracellular matrix. Different workaround strategies have been explored to address these problems and currently, highly engineered cells and very complex therapies (CAR-Ts in combination with checkpoint inhibition, or small molecules, or chemotherapy, or immunomodulators) are under study in different clinical trials [178].
Brain tumors have not been an exception in CAR-T development, with glioblastoma being the most attacked condition. Tang et al. reported a case of a patient with an anaplastic MN that underwent three surgical resections and had an Ommaya device implanted. IHC from her tumor sample showed a high expression of B7-H3, also known as CD276 ([179], p. 3). The researchers prepared CAR-Ts from autologous PBMCs, and during CAR-T development patient recur and CAR-Ts were administered in three doses via the Ommaya device. A fourth surgical treatment was performed as patient was progressing quickly, and unfortunately the patient died one day after surgery. Post-mortem analysis of the tumor sample showed that CAR-T indeed penetrated the tumor and successfully targeted some cells expressing B7-H3, however, as not all the tumor was expressing this molecule, antigen loss and selection of other cells with a different transcriptome occurred [180]. Even though results were not as expected, this case marks an important step toward the development of cell therapies of different natures, to treat brain tumors, especially those of high recurrency and aggressiveness.
Treatment in MN has remained similar since some decades ago. Major improvements in survival are achieved mainly by surgery and radiation therapy. Most cases of MN will respond to these conventional therapies, however, transformation of low-grade MN to high-grade MN, or de novo high-grade MN are highly recurrent and impose a very low survivability. For these tumors, surgery and radiation therapy are less than enough. With the era of genomic analysis and a better understanding of the genetic basis of cancer, different molecular targets and new therapeutic approaches have been studied for high-grade MN treatment. In this review we went through the main critical advancements in evidence that suggests that molecular targeting might be the future of high-grade MN treatment. To the date, all these molecular approaches are still under study, a conventional management is still the mainstay, but we hope in the following years, new evidence of the clinical relevance of these therapies is available and introduction of them into the therapeutic arsenal could be a true.
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Data are collected from Turkish CPAs’ survey responses, which are based on a seven-point Likert scale, and analyzed using explanatory factor analysis. 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By means of these studies, it becomes easier to understand accounting as a social and political activity within itself and thus to be able to understand the economic, institutional, political and social environment of the turnover of the practices. In this regard, the main aim of this study is to explain the development of the public accounting system in Turkey with the help of institutional theory. Thus, it is aimed to explain all the dynamics that provide the institutionalization of state account in the national sense, together with the economic, political and social processes of the period in question. It is revealed that the regulatory arrangements directly contribute to the institutionalization of a field, and as a result, how the public organizations directly contribute to the institutionalization process.",book:{id:"6000",slug:"accounting-and-corporate-reporting-today-and-tomorrow",title:"Accounting and Corporate Reporting",fullTitle:"Accounting and Corporate Reporting - Today and Tomorrow"},signatures:"Ceray Aldemir and Tuğba Uçma Uysal",authors:[{id:"204342",title:"Dr.",name:"Ceray",middleName:null,surname:"Aldemir",slug:"ceray-aldemir",fullName:"Ceray Aldemir"},{id:"204348",title:"Dr.",name:"Tugba",middleName:null,surname:"Ucma Uysal",slug:"tugba-ucma-uysal",fullName:"Tugba Ucma Uysal"}]}],mostDownloadedChaptersLast30Days:[{id:"78825",title:"Accounting Quality and Its Challenges in 21st Century",slug:"accounting-quality-and-its-challenges-in-21st-century",totalDownloads:256,totalCrossrefCites:0,totalDimensionsCites:0,abstract:"This paper describes current research to drive future research challenges in accounting quality. The definition of accounting quality is mainly varying depending on the objective that the study pointed. Previous research revealed that many proxies describe the accounting quality but most of them from the financial perspective. Furthermore, this paper tries to expose this research issue in the behavioural approach and drive future research in the mixed method. It concludes that the behavioural issues can be a research model, triggering future research challenges in accounting quality. The authors support these triggers from the perspectives of political hegemony, bureaucracy ratcheting, cognitive distortion, and international accounting standard. Finally, we infer and simultaneously predict that accounting quality would broaden its concepts and lasting impression in the 21st century.",book:{id:"10818",slug:"accounting-and-finance-innovations",title:"Accounting and Finance Innovations",fullTitle:"Accounting and Finance Innovations"},signatures:"Sumiyana Sumiyana, Hendrian Hendrian, Ruslan Effendi, Krisnhoe Fitrijati and Sriwidharmanely Sriwidharmanely",authors:[{id:"328451",title:"Prof.",name:"Sumiyana",middleName:null,surname:"Sumiyana",slug:"sumiyana-sumiyana",fullName:"Sumiyana Sumiyana"},{id:"328452",title:"Dr.",name:"Sriwidharmanely",middleName:null,surname:"Sriwidharmanely",slug:"sriwidharmanely-sriwidharmanely",fullName:"Sriwidharmanely Sriwidharmanely"},{id:"350499",title:"Dr.",name:"Hendrian",middleName:null,surname:"Hendrian",slug:"hendrian-hendrian",fullName:"Hendrian Hendrian"},{id:"350500",title:"Dr.",name:"Ruslan",middleName:null,surname:"Effendi",slug:"ruslan-effendi",fullName:"Ruslan Effendi"},{id:"350501",title:"Dr.",name:"Krisnhoe",middleName:null,surname:"Fitrijati",slug:"krisnhoe-fitrijati",fullName:"Krisnhoe Fitrijati"}]},{id:"61095",title:"Ethical Awareness, Ethical Decision Making, and Transparency: A Study on Turkish CPAs in Istanbul",slug:"ethical-awareness-ethical-decision-making-and-transparency-a-study-on-turkish-cpas-in-istanbul",totalDownloads:1619,totalCrossrefCites:3,totalDimensionsCites:3,abstract:"This research aims to reveal the connections among ethical awareness, ethical decision making, and transparency from the perspective of certified public accountants (CPAs) in Istanbul. Data are collected from Turkish CPAs’ survey responses, which are based on a seven-point Likert scale, and analyzed using explanatory factor analysis. Hypotheses were tested using ordinary least squares regression, and the results show that, based on the participants’ average responses, CPAs are affected mainly by the level of their ethical awareness in decision making about an ethical issue or transparency of financial reports, which indicates that the three concepts are strongly connected to each other.",book:{id:"6660",slug:"accounting-from-a-cross-cultural-perspective",title:"Accounting from a Cross-Cultural Perspective",fullTitle:"Accounting from a Cross-Cultural Perspective"},signatures:"Nida Türegün",authors:[{id:"238085",title:"Ph.D.",name:"Nida",middleName:null,surname:"Türegün",slug:"nida-turegun",fullName:"Nida Türegün"}]},{id:"78745",title:"Analysis of Return and Risk of Cryptocurrency Bitcoin Asset as Investment Instrument",slug:"analysis-of-return-and-risk-of-cryptocurrency-bitcoin-asset-as-investment-instrument",totalDownloads:421,totalCrossrefCites:1,totalDimensionsCites:0,abstract:"This study aims to explore the potential use of the cryptocurrency bitcoin as an investment instrument in Indonesia. The return obtained from bitcoin cryptocurrency is compared to other investment instruments, namely stock returns, gold and the rupiah exchange rate. The research period was carried out based on research data from 2011 to 2020. This study employee compares means test (t test) and analysis of variance (F test) on rate of return of bitcoin investment. The bitcoin return compare to the rate of return form the others investments instruments namely exchange rate, gold and stock. The study collected 120 data of each investments instruments: bitcoin, exchange rate, gold and stock from various of sources during 2011–2020. Then, we calculate the return and risk of individual investment instruments. The results showed that the bitcoin currency had the highest rate of return 18% with a standard deviation of 61% compared to exchange rate, gold and stock returns. While the rate of return for the others investment instruments showed less than 0.5% with standard deviation less than 5%. The rate of return bitcoin has significance difference compare to the rate of return of exchange rate, gold and stock. The study contribute for the investors who would like to invest on bitcoin. The investors should understand the characteristic of bitcoin in term of rate of returns and also the risk. This study also contributes to government of Indonesia on crypto currency development. The Indonesia government should adopt and regulate on crypto currency in the future to secure the investor and economic growth.",book:{id:"10818",slug:"accounting-and-finance-innovations",title:"Accounting and Finance Innovations",fullTitle:"Accounting and Finance Innovations"},signatures:"Sunita Dasman",authors:[{id:"348739",title:"Dr.",name:"Sunita",middleName:null,surname:"Dasman",slug:"sunita-dasman",fullName:"Sunita Dasman"}]},{id:"55587",title:"Historical Development of Government Accounting",slug:"historical-development-of-government-accounting",totalDownloads:2774,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Government accounting aims at preventing waste in government services and establishing a balance between optimal expenditure and services by managing government assets and government sources in the most efficient way. This balance can be established only by obtaining complete and accurate information from government accounting system on time. Since the users have a low level of knowledge needs in government accounting system, it has been recorded for long years in a cash basis manner. However, as the government’s area of operation expanded and the needs increased, it became obvious that cash basis system had lacking parts. So it started to focus on recording financial transactions and financial reporting. These lacking parts in the accounting system tried to be overcome through a new regulation by focusing on the areas where cash basis accounting system was insufficient; and a change was experienced with regard to applying the accrual basis in the areas of government accounting and financial reporting. This study aims to explain the historical development of government accounting by applications in countries and especially by detailed expressions for Turkey. As a result of the literature review and the examination of countries’ government accounting practices, it has been determined that the government accounting practice has made the correct transition from cash basis to accrual basis.",book:{id:"6000",slug:"accounting-and-corporate-reporting-today-and-tomorrow",title:"Accounting and Corporate Reporting",fullTitle:"Accounting and Corporate Reporting - Today and Tomorrow"},signatures:"Mihriban Coşkun Arslan",authors:[{id:"203724",title:"Dr.",name:"Mihriban",middleName:null,surname:"Coşkun Arslan",slug:"mihriban-coskun-arslan",fullName:"Mihriban Coşkun Arslan"}]},{id:"55289",title:"Behavioral Accounting and its Interactions",slug:"behavioral-accounting-and-its-interactions",totalDownloads:4019,totalCrossrefCites:1,totalDimensionsCites:1,abstract:"Behavioral accounting is a branch of accounting that is related to behavior besides the accounting knowledge. It deals with the attitude and behavior of people when they are encountered with an accounting phenomenon which determines the behavior that they will show in decision‐making. This special area of accounting addresses such aspects as human information‐processing behavior, judgment quality, accounting problems that are created by users and providers of accounting information, and accounting information users’ and producers’ decision‐making skills. Behavioral research tries to find out how individuals make decisions and interact and influence other individuals, organizations, markets, and society. Behavioral accounting concept is examined under the topics of the influence of accounting information on behavior, managerial control (budget participation, nonfinancial measures, leadership, and balanced scorecard), auditing (auditor‐client negotiations, auditor’s judgment, and decision‐making), and ethics (ethical decision‐making, ethical orientation, and rationalizations on unethical behavior) in this chapter.",book:{id:"6000",slug:"accounting-and-corporate-reporting-today-and-tomorrow",title:"Accounting and Corporate Reporting",fullTitle:"Accounting and Corporate Reporting - Today and Tomorrow"},signatures:"Filiz Angay Kutluk",authors:[{id:"203083",title:"Associate Prof.",name:"Filiz",middleName:null,surname:"Angay Kutluk",slug:"filiz-angay-kutluk",fullName:"Filiz Angay Kutluk"}]}],onlineFirstChaptersFilter:{topicId:"62",limit:6,offset:0},onlineFirstChaptersCollection:[],onlineFirstChaptersTotal:0},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:8,numberOfPublishedChapters:87,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:98,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:27,numberOfPublishedChapters:286,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:139,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:0,numberOfUpcomingTopics:2,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!1},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:9,numberOfPublishedChapters:101,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:0,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!1},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:9,numberOfOpenTopics:4,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}},{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. 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He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. 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Completed the Course Medical Mycology, the Centraalbureau voor Schimmelcultures (CBS), Fungal Biodiversity Centre, Netherlands (2006). International Union of Microbiological Societies (IUMS) Fellow, and International Emerging Infectious Diseases (IEID) Fellow, Centers for Diseases Control and Prevention (CDC), Atlanta, USA. Diploma of Dermatological Scientist, Japanese Society for Investigative Dermatology. Ph.D. of Juntendo University, Japan. Bachelor’s and Master’s degree, Medicine, West China University of Medical Sciences. Chair of Sichuan Medical Association Dermatology Committee. General Secretary of The 19th Annual Meeting of Chinese Society of Dermatology and the Asia Pacific Society for Medical Mycology (2013). In charge of the Annual Medical Mycology Course over 20-years authorized by National Continue Medical Education Committee of China. Member of the board of directors of the Asia-Pacific Society for Medical Mycology (APSMM). Associate editor of Mycopathologia. Vice-chief of the editorial board of Chinses Journal of Mycology, China. Board Member and Chair of Mycology Group of Chinese Society of Dermatology.",institutionString:null,institution:{name:"Sichuan University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"5",title:"Parasitic Infectious Diseases",coverUrl:"https://cdn.intechopen.com/series_topics/covers/5.jpg",isOpenForSubmission:!0,editor:{id:"67907",title:"Dr.",name:"Amidou",middleName:null,surname:"Samie",slug:"amidou-samie",fullName:"Amidou Samie",profilePictureURL:"https://mts.intechopen.com/storage/users/67907/images/system/67907.jpg",biography:"Dr. Amidou Samie is an Associate Professor of Microbiology at the University of Venda, in South Africa, where he graduated for his PhD in May 2008. He joined the Department of Microbiology the same year and has been giving lectures on topics covering parasitology, immunology, molecular biology and industrial microbiology. He is currently a rated researcher by the National Research Foundation of South Africa at category C2. He has published widely in the field of infectious diseases and has overseen several MSc’s and PhDs. His research activities mostly cover topics on infectious diseases from epidemiology to control. His particular interest lies in the study of intestinal protozoan parasites and opportunistic infections among HIV patients as well as the potential impact of childhood diarrhoea on growth and child development. He also conducts research on water-borne diseases and water quality and is involved in the evaluation of point-of-use water treatment technologies using silver and copper nanoparticles in collaboration with the University of Virginia, USA. 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His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. 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He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:null,institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}},editorTwo:null,editorThree:null}]},overviewPageOFChapters:{paginationCount:2,paginationItems:[{id:"81644",title:"Perspective Chapter: Ethics of Using Placebo Controlled Trials for Covid-19 Vaccine Development in Vulnerable Populations",doi:"10.5772/intechopen.104776",signatures:"Lesley Burgess, Jurie Jordaan and Matthew Wilson",slug:"perspective-chapter-ethics-of-using-placebo-controlled-trials-for-covid-19-vaccine-development-in-vu",totalDownloads:4,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"SARS-CoV-2 Variants - Two Years After",coverURL:"https://cdn.intechopen.com/books/images_new/11573.jpg",subseries:{id:"6",title:"Viral Infectious Diseases"}}},{id:"80546",title:"Streptococcal Skin and Skin-Structure Infections",doi:"10.5772/intechopen.102894",signatures:"Alwyn Rapose",slug:"streptococcal-skin-and-skin-structure-infections",totalDownloads:48,totalCrossrefCites:0,totalDimensionsCites:0,authors:null,book:{title:"Streptococcal Infections",coverURL:"https://cdn.intechopen.com/books/images_new/10828.jpg",subseries:{id:"3",title:"Bacterial Infectious Diseases"}}}]},overviewPagePublishedBooks:{paginationCount:13,paginationItems:[{type:"book",id:"6667",title:"Influenza",subtitle:"Therapeutics and Challenges",coverURL:"https://cdn.intechopen.com/books/images_new/6667.jpg",slug:"influenza-therapeutics-and-challenges",publishedDate:"September 19th 2018",editedByType:"Edited by",bookSignature:"Shailendra K. 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He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:null,institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7064",title:"Current Perspectives in Human Papillomavirus",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7064.jpg",slug:"current-perspectives-in-human-papillomavirus",publishedDate:"May 2nd 2019",editedByType:"Edited by",bookSignature:"Shailendra K. Saxena",hash:"d92a4085627bab25ddc7942fbf44cf05",volumeInSeries:2,fullTitle:"Current Perspectives in Human Papillomavirus",editors:[{id:"158026",title:"Prof.",name:"Shailendra K.",middleName:null,surname:"Saxena",slug:"shailendra-k.-saxena",fullName:"Shailendra K. Saxena",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRET3QAO/Profile_Picture_2022-05-10T10:10:26.jpeg",biography:"Professor Dr. Shailendra K. Saxena is a vice dean and professor at King George's Medical University, Lucknow, India. His research interests involve understanding the molecular mechanisms of host defense during human viral infections and developing new predictive, preventive, and therapeutic strategies for them using Japanese encephalitis virus (JEV), HIV, and emerging viruses as a model via stem cell and cell culture technologies. His research work has been published in various high-impact factor journals (Science, PNAS, Nature Medicine) with a high number of citations. He has received many awards and honors in India and abroad including various Young Scientist Awards, BBSRC India Partnering Award, and Dr. JC Bose National Award of Department of Biotechnology, Min. of Science and Technology, Govt. of India. Dr. Saxena is a fellow of various international societies/academies including the Royal College of Pathologists, United Kingdom; Royal Society of Medicine, London; Royal Society of Biology, United Kingdom; Royal Society of Chemistry, London; and Academy of Translational Medicine Professionals, Austria. He was named a Global Leader in Science by The Scientist. He is also an international opinion leader/expert in vaccination for Japanese encephalitis by IPIC (UK).",institutionString:null,institution:{name:"King George's Medical University",institutionURL:null,country:{name:"India"}}}]},{type:"book",id:"7123",title:"Current Topics in Neglected Tropical Diseases",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7123.jpg",slug:"current-topics-in-neglected-tropical-diseases",publishedDate:"December 4th 2019",editedByType:"Edited by",bookSignature:"Alfonso J. Rodriguez-Morales",hash:"61c627da05b2ace83056d11357bdf361",volumeInSeries:3,fullTitle:"Current Topics in Neglected Tropical Diseases",editors:[{id:"131400",title:"Prof.",name:"Alfonso J.",middleName:null,surname:"Rodriguez-Morales",slug:"alfonso-j.-rodriguez-morales",fullName:"Alfonso J. Rodriguez-Morales",profilePictureURL:"https://mts.intechopen.com/storage/users/131400/images/system/131400.png",biography:"Dr. Rodriguez-Morales is an expert in tropical and emerging diseases, particularly zoonotic and vector-borne diseases (especially arboviral diseases). He is the president of the Travel Medicine Committee of the Pan-American Infectious Diseases Association (API), as well as the president of the Colombian Association of Infectious Diseases (ACIN). He is a member of the Committee on Tropical Medicine, Zoonoses, and Travel Medicine of ACIN. He is a vice-president of the Latin American Society for Travel Medicine (SLAMVI) and a Member of the Council of the International Society for Infectious Diseases (ISID). Since 2014, he has been recognized as a Senior Researcher, at the Ministry of Science of Colombia. He is a professor at the Faculty of Medicine of the Fundacion Universitaria Autonoma de las Americas, in Pereira, Risaralda, Colombia. He is an External Professor, Master in Research on Tropical Medicine and International Health, Universitat de Barcelona, Spain. He is also a professor at the Master in Clinical Epidemiology and Biostatistics, Universidad Científica del Sur, Lima, Peru. In 2021 he has been awarded the “Raul Isturiz Award” Medal of the API. Also, in 2021, he was awarded with the “Jose Felix Patiño” Asclepius Staff Medal of the Colombian Medical College, due to his scientific contributions to COVID-19 during the pandemic. He is currently the Editor in Chief of the journal Travel Medicine and Infectious Diseases. His Scopus H index is 47 (Google Scholar H index, 68).",institutionString:"Institución Universitaria Visión de las Américas, Colombia",institution:null}]},{type:"book",id:"7839",title:"Malaria",subtitle:null,coverURL:"https://cdn.intechopen.com/books/images_new/7839.jpg",slug:"malaria",publishedDate:"December 11th 2019",editedByType:"Edited by",bookSignature:"Fyson H. Kasenga",hash:"91cde4582ead884cb0f355a19b67cd56",volumeInSeries:4,fullTitle:"Malaria",editors:[{id:"86725",title:"Dr.",name:"Fyson",middleName:"Hanania",surname:"Kasenga",slug:"fyson-kasenga",fullName:"Fyson Kasenga",profilePictureURL:"https://mts.intechopen.com/storage/users/86725/images/system/86725.jpg",biography:"Dr. Kasenga is a graduate of Tumaini University, Kilimanjaro Christian Medical College, Moshi, Tanzania and Umeå University, Sweden. He obtained a Master’s degree in Public Health and PhD in Public Health and Epidemiology. He has a background in Clinical Medicine and has taken courses at higher diploma levels in public health from University of Transkei, Republic of South Africa, and African Medical and Research Foundation (AMREF) in Nairobi, Kenya. Dr. Kasenga worked in different places in and outside Malawi, and has held various positions, such as Licensed Medical Officer, HIV/AIDS Programme Officer, HIV/AIDS resource person in the International Department of Diakonhjemet College, Oslo, Norway. He also managed an Integrated HIV/AIDS Prevention programme for over 5 years. He is currently working as a Director for the Health Ministries Department of Malawi Union of the Seventh Day Adventist Church. Dr. Kasenga has published over 5 articles on HIV/AIDS issues focusing on Prevention of Mother to Child Transmission of HIV (PMTCT), including a book chapter on HIV testing counseling (currently in press). 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His research interest focuses on computational chemistry and molecular modeling of diverse systems of pharmacological, food, and alternative energy interests by resorting to DFT and Conceptual DFT. He has authored a coauthored more than 255 peer-reviewed papers, 32 book chapters, and 2 edited books. He has delivered speeches at many international and domestic conferences. He serves as a reviewer for more than eighty international journals, books, and research proposals as well as an editor for special issues of renowned scientific journals.",institutionString:"Centro de Investigación en Materiales Avanzados",institution:{name:"Centro de Investigación en Materiales Avanzados",country:{name:"Mexico"}}},{id:"76477",title:"Prof.",name:"Mirza",middleName:null,surname:"Hasanuzzaman",slug:"mirza-hasanuzzaman",fullName:"Mirza Hasanuzzaman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/76477/images/system/76477.png",biography:"Dr. Mirza Hasanuzzaman is a Professor of Agronomy at Sher-e-Bangla Agricultural University, Bangladesh. He received his Ph.D. in Plant Stress Physiology and Antioxidant Metabolism from Ehime University, Japan, with a scholarship from the Japanese Government (MEXT). Later, he completed his postdoctoral research at the Center of Molecular Biosciences, University of the Ryukyus, Japan, as a recipient of the Japan Society for the Promotion of Science (JSPS) postdoctoral fellowship. He was also the recipient of the Australian Government Endeavour Research Fellowship for postdoctoral research as an adjunct senior researcher at the University of Tasmania, Australia. Dr. Hasanuzzaman’s current work is focused on the physiological and molecular mechanisms of environmental stress tolerance. Dr. Hasanuzzaman has published more than 150 articles in peer-reviewed journals. He has edited ten books and written more than forty book chapters on important aspects of plant physiology, plant stress tolerance, and crop production. According to Scopus, Dr. Hasanuzzaman’s publications have received more than 10,500 citations with an h-index of 53. He has been named a Highly Cited Researcher by Clarivate. He is an editor and reviewer for more than fifty peer-reviewed international journals and was a recipient of the “Publons Peer Review Award” in 2017, 2018, and 2019. He has been honored by different authorities for his outstanding performance in various fields like research and education, and he has received the World Academy of Science Young Scientist Award (2014) and the University Grants Commission (UGC) Award 2018. He is a fellow of the Bangladesh Academy of Sciences (BAS) and the Royal Society of Biology.",institutionString:"Sher-e-Bangla Agricultural University",institution:{name:"Sher-e-Bangla Agricultural University",country:{name:"Bangladesh"}}},{id:"187859",title:"Prof.",name:"Kusal",middleName:"K.",surname:"Das",slug:"kusal-das",fullName:"Kusal Das",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSBDeQAO/Profile_Picture_1623411145568",biography:"Kusal K. Das is a Distinguished Chair Professor of Physiology, Shri B. M. Patil Medical College and Director, Centre for Advanced Medical Research (CAMR), BLDE (Deemed to be University), Vijayapur, Karnataka, India. Dr. Das did his M.S. and Ph.D. in Human Physiology from the University of Calcutta, Kolkata. His area of research is focused on understanding of molecular mechanisms of heavy metal activated low oxygen sensing pathways in vascular pathophysiology. He has invented a new method of estimation of serum vitamin E. His expertise in critical experimental protocols on vascular functions in experimental animals was well documented by his quality of publications. He was a Visiting Professor of Medicine at University of Leeds, United Kingdom (2014-2016) and Tulane University, New Orleans, USA (2017). For his immense contribution in medical research Ministry of Science and Technology, Government of India conferred him 'G.P. Chatterjee Memorial Research Prize-2019” and he is also the recipient of 'Dr.Raja Ramanna State Scientist Award 2015” by Government of Karnataka. He is a Fellow of the Royal Society of Biology (FRSB), London and Honorary Fellow of Karnataka Science and Technology Academy, Department of Science and Technology, Government of Karnataka.",institutionString:"BLDE (Deemed to be University), India",institution:null},{id:"243660",title:"Dr.",name:"Mallanagouda Shivanagouda",middleName:null,surname:"Biradar",slug:"mallanagouda-shivanagouda-biradar",fullName:"Mallanagouda Shivanagouda Biradar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243660/images/system/243660.jpeg",biography:"M. S. Biradar is Vice Chancellor and Professor of Medicine of\nBLDE (Deemed to be University), Vijayapura, Karnataka, India.\nHe obtained his MD with a gold medal in General Medicine and\nhas devoted himself to medical teaching, research, and administrations. He has also immensely contributed to medical research\non vascular medicine, which is reflected by his numerous publications including books and book chapters. Professor Biradar was\nalso Visiting Professor at Tulane University School of Medicine, New Orleans, USA.",institutionString:"BLDE (Deemed to be University)",institution:{name:"BLDE University",country:{name:"India"}}},{id:"289796",title:"Dr.",name:"Swastika",middleName:null,surname:"Das",slug:"swastika-das",fullName:"Swastika Das",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/289796/images/system/289796.jpeg",biography:"Swastika N. Das is Professor of Chemistry at the V. P. Dr. P. G.\nHalakatti College of Engineering and Technology, BLDE (Deemed\nto be University), Vijayapura, Karnataka, India. She obtained an\nMSc, MPhil, and PhD in Chemistry from Sambalpur University,\nOdisha, India. Her areas of research interest are medicinal chemistry, chemical kinetics, and free radical chemistry. She is a member\nof the investigators who invented a new modified method of estimation of serum vitamin E. She has authored numerous publications including book\nchapters and is a mentor of doctoral curriculum at her university.",institutionString:"BLDEA’s V.P.Dr.P.G.Halakatti College of Engineering & Technology",institution:{name:"BLDE University",country:{name:"India"}}},{id:"248459",title:"Dr.",name:"Akikazu",middleName:null,surname:"Takada",slug:"akikazu-takada",fullName:"Akikazu Takada",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248459/images/system/248459.png",biography:"Akikazu Takada was born in Japan, 1935. After graduation from\nKeio University School of Medicine and finishing his post-graduate studies, he worked at Roswell Park Memorial Institute NY,\nUSA. He then took a professorship at Hamamatsu University\nSchool of Medicine. In thrombosis studies, he found the SK\npotentiator that enhances plasminogen activation by streptokinase. He is very much interested in simultaneous measurements\nof fatty acids, amino acids, and tryptophan degradation products. By using fatty\nacid analyses, he indicated that plasma levels of trans-fatty acids of old men were\nfar higher in the US than Japanese men. . He also showed that eicosapentaenoic acid\n(EPA) and docosahexaenoic acid (DHA) levels are higher, and arachidonic acid\nlevels are lower in Japanese than US people. By using simultaneous LC/MS analyses\nof plasma levels of tryptophan metabolites, he recently found that plasma levels of\nserotonin, kynurenine, or 5-HIAA were higher in patients of mono- and bipolar\ndepression, which are significantly different from observations reported before. In\nview of recent reports that plasma tryptophan metabolites are mainly produced by\nmicrobiota. He is now working on the relationships between microbiota and depression or autism.",institutionString:"Hamamatsu University School of Medicine",institution:{name:"Hamamatsu University School of Medicine",country:{name:"Japan"}}},{id:"137240",title:"Prof.",name:"Mohammed",middleName:null,surname:"Khalid",slug:"mohammed-khalid",fullName:"Mohammed Khalid",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/137240/images/system/137240.png",biography:"Mohammed Khalid received his B.S. degree in chemistry in 2000 and Ph.D. degree in physical chemistry in 2007 from the University of Khartoum, Sudan. He moved to School of Chemistry, Faculty of Science, University of Sydney, Australia in 2009 and joined Dr. Ron Clarke as a postdoctoral fellow where he worked on the interaction of ATP with the phosphoenzyme of the Na+/K+-ATPase and dual mechanisms of allosteric acceleration of the Na+/K+-ATPase by ATP; then he went back to Department of Chemistry, University of Khartoum as an assistant professor, and in 2014 he was promoted as an associate professor. In 2011, he joined the staff of Department of Chemistry at Taif University, Saudi Arabia, where he is currently an assistant professor. His research interests include the following: P-Type ATPase enzyme kinetics and mechanisms, kinetics and mechanisms of redox reactions, autocatalytic reactions, computational enzyme kinetics, allosteric acceleration of P-type ATPases by ATP, exploring of allosteric sites of ATPases, and interaction of ATP with ATPases located in cell membranes.",institutionString:"Taif University",institution:{name:"Taif University",country:{name:"Saudi Arabia"}}},{id:"63810",title:"Prof.",name:"Jorge",middleName:null,surname:"Morales-Montor",slug:"jorge-morales-montor",fullName:"Jorge Morales-Montor",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/63810/images/system/63810.png",biography:"Dr. Jorge Morales-Montor was recognized with the Lola and Igo Flisser PUIS Award for best graduate thesis at the national level in the field of parasitology. He received a fellowship from the Fogarty Foundation to perform postdoctoral research stay at the University of Georgia. He has 153 journal articles to his credit. He has also edited several books and published more than fifty-five book chapters. He is a member of the Mexican Academy of Sciences, Latin American Academy of Sciences, and the National Academy of Medicine. He has received more than thirty-five awards and has supervised numerous bachelor’s, master’s, and Ph.D. students. Dr. Morales-Montor is the past president of the Mexican Society of Parasitology.",institutionString:"National Autonomous University of Mexico",institution:{name:"National Autonomous University of Mexico",country:{name:"Mexico"}}},{id:"217215",title:"Dr.",name:"Palash",middleName:null,surname:"Mandal",slug:"palash-mandal",fullName:"Palash Mandal",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217215/images/system/217215.jpeg",biography:null,institutionString:"Charusat University",institution:null},{id:"49739",title:"Dr.",name:"Leszek",middleName:null,surname:"Szablewski",slug:"leszek-szablewski",fullName:"Leszek Szablewski",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49739/images/system/49739.jpg",biography:"Leszek Szablewski is a professor of medical sciences. He received his M.S. in the Faculty of Biology from the University of Warsaw and his PhD degree from the Institute of Experimental Biology Polish Academy of Sciences. He habilitated in the Medical University of Warsaw, and he obtained his degree of Professor from the President of Poland. Professor Szablewski is the Head of Chair and Department of General Biology and Parasitology, Medical University of Warsaw. Professor Szablewski has published over 80 peer-reviewed papers in journals such as Journal of Alzheimer’s Disease, Biochim. Biophys. Acta Reviews of Cancer, Biol. Chem., J. Biomed. Sci., and Diabetes/Metabol. Res. Rev, Endocrine. He is the author of two books and four book chapters. He has edited four books, written 15 scripts for students, is the ad hoc reviewer of over 30 peer-reviewed journals, and editorial member of peer-reviewed journals. Prof. Szablewski’s research focuses on cell physiology, genetics, and pathophysiology. He works on the damage caused by lack of glucose homeostasis and changes in the expression and/or function of glucose transporters due to various diseases. He has given lectures, seminars, and exercises for students at the Medical University.",institutionString:"Medical University of Warsaw",institution:{name:"Medical University of Warsaw",country:{name:"Poland"}}},{id:"173123",title:"Dr.",name:"Maitham",middleName:null,surname:"Khajah",slug:"maitham-khajah",fullName:"Maitham Khajah",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/173123/images/system/173123.jpeg",biography:"Dr. Maitham A. Khajah received his degree in Pharmacy from Faculty of Pharmacy, Kuwait University, in 2003 and obtained his PhD degree in December 2009 from the University of Calgary, Canada (Gastrointestinal Science and Immunology). Since January 2010 he has been assistant professor in Kuwait University, Faculty of Pharmacy, Department of Pharmacology and Therapeutics. His research interest are molecular targets for the treatment of inflammatory bowel disease (IBD) and the mechanisms responsible for immune cell chemotaxis. He cosupervised many students for the MSc Molecular Biology Program, College of Graduate Studies, Kuwait University. Ever since joining Kuwait University in 2010, he got various grants as PI and Co-I. He was awarded the Best Young Researcher Award by Kuwait University, Research Sector, for the Year 2013–2014. He was a member in the organizing committee for three conferences organized by Kuwait University, Faculty of Pharmacy, as cochair and a member in the scientific committee (the 3rd, 4th, and 5th Kuwait International Pharmacy Conference).",institutionString:"Kuwait University",institution:{name:"Kuwait University",country:{name:"Kuwait"}}},{id:"195136",title:"Dr.",name:"Aya",middleName:null,surname:"Adel",slug:"aya-adel",fullName:"Aya Adel",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/195136/images/system/195136.jpg",biography:"Dr. Adel works as an Assistant Lecturer in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. Dr. Adel is especially interested in joint attention and its impairment in autism spectrum disorder",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"94911",title:"Dr.",name:"Boulenouar",middleName:null,surname:"Mesraoua",slug:"boulenouar-mesraoua",fullName:"Boulenouar Mesraoua",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/94911/images/system/94911.png",biography:"Dr Boulenouar Mesraoua is the Associate Professor of Clinical Neurology at Weill Cornell Medical College-Qatar and a Consultant Neurologist at Hamad Medical Corporation at the Neuroscience Department; He graduated as a Medical Doctor from the University of Oran, Algeria; he then moved to Belgium, the City of Liege, for a Residency in Internal Medicine and Neurology at Liege University; after getting the Belgian Board of Neurology (with high marks), he went to the National Hospital for Nervous Diseases, Queen Square, London, United Kingdom for a fellowship in Clinical Neurophysiology, under Pr Willison ; Dr Mesraoua had also further training in Epilepsy and Continuous EEG Monitoring for two years (from 2001-2003) in the Neurophysiology department of Zurich University, Switzerland, under late Pr Hans Gregor Wieser ,an internationally known epileptologist expert. \n\nDr B. Mesraoua is the Director of the Neurology Fellowship Program at the Neurology Section and an active member of the newly created Comprehensive Epilepsy Program at Hamad General Hospital, Doha, Qatar; he is also Assistant Director of the Residency Program at the Qatar Medical School. \nDr B. Mesraoua's main interests are Epilepsy, Multiple Sclerosis, and Clinical Neurology; He is the Chairman and the Organizer of the well known Qatar Epilepsy Symposium, he is running yearly for the past 14 years and which is considered a landmark in the Gulf region; He has also started last year , together with other epileptologists from Qatar, the region and elsewhere, a yearly International Epilepsy School Course, which was attended by many neurologists from the Area.\n\nInternationally, Dr Mesraoua is an active and elected member of the Commission on Eastern Mediterranean Region (EMR ) , a regional branch of the International League Against Epilepsy (ILAE), where he represents the Middle East and North Africa(MENA ) and where he holds the position of chief of the Epilepsy Epidemiology Section; Dr Mesraoua is a member of the American Academy of Neurology, the Europeen Academy of Neurology and the American Epilepsy Society.\n\nDr Mesraoua's main objectives are to encourage frequent gathering of the epileptologists/neurologists from the MENA region and the rest of the world, promote Epilepsy Teaching in the MENA Region, and encourage multicenter studies involving neurologists and epileptologists in the MENA region, particularly epilepsy epidemiological studies. \n\nDr. Mesraoua is the recipient of two research Grants, as the Lead Principal Investigator (750.000 USD and 250.000 USD) from the Qatar National Research Fund (QNRF) and the Hamad Hospital Internal Research Grant (IRGC), on the following topics : “Continuous EEG Monitoring in the ICU “ and on “Alpha-lactoalbumin , proof of concept in the treatment of epilepsy” .Dr Mesraoua is a reviewer for the journal \"seizures\" (Europeen Epilepsy Journal ) as well as dove journals ; Dr Mesraoua is the author and co-author of many peer reviewed publications and four book chapters in the field of Epilepsy and Clinical Neurology",institutionString:"Weill Cornell Medical College in Qatar",institution:{name:"Weill Cornell Medical College in Qatar",country:{name:"Qatar"}}},{id:"282429",title:"Prof.",name:"Covanis",middleName:null,surname:"Athanasios",slug:"covanis-athanasios",fullName:"Covanis Athanasios",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/282429/images/system/282429.jpg",biography:null,institutionString:"Neurology-Neurophysiology Department of the Children Hospital Agia Sophia",institution:null},{id:"190980",title:"Prof.",name:"Marwa",middleName:null,surname:"Mahmoud Saleh",slug:"marwa-mahmoud-saleh",fullName:"Marwa Mahmoud Saleh",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/190980/images/system/190980.jpg",biography:"Professor Marwa Mahmoud Saleh is a doctor of medicine and currently works in the unit of Phoniatrics, Department of Otolaryngology, Ain Shams University in Cairo, Egypt. She got her doctoral degree in 1991 and her doctoral thesis was accomplished in the University of Iowa, United States. Her publications covered a multitude of topics as videokymography, cochlear implants, stuttering, and dysphagia. She has lectured Egyptian phonology for many years. Her recent research interest is joint attention in autism.",institutionString:"Ain Shams University",institution:{name:"Ain Shams University",country:{name:"Egypt"}}},{id:"259190",title:"Dr.",name:"Syed Ali Raza",middleName:null,surname:"Naqvi",slug:"syed-ali-raza-naqvi",fullName:"Syed Ali Raza Naqvi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259190/images/system/259190.png",biography:"Dr. Naqvi is a radioanalytical chemist and is working as an associate professor of analytical chemistry in the Department of Chemistry, Government College University, Faisalabad, Pakistan. Advance separation techniques, nuclear analytical techniques and radiopharmaceutical analysis are the main courses that he is teaching to graduate and post-graduate students. In the research area, he is focusing on the development of organic- and biomolecule-based radiopharmaceuticals for diagnosis and therapy of infectious and cancerous diseases. Under the supervision of Dr. Naqvi, three students have completed their Ph.D. degrees and 41 students have completed their MS degrees. He has completed three research projects and is currently working on 2 projects entitled “Radiolabeling of fluoroquinolone derivatives for the diagnosis of deep-seated bacterial infections” and “Radiolabeled minigastrin peptides for diagnosis and therapy of NETs”. He has published about 100 research articles in international reputed journals and 7 book chapters. Pakistan Institute of Nuclear Science & Technology (PINSTECH) Islamabad, Punjab Institute of Nuclear Medicine (PINM), Faisalabad and Institute of Nuclear Medicine and Radiology (INOR) Abbottabad are the main collaborating institutes.",institutionString:"Government College University",institution:{name:"Government College University, Faisalabad",country:{name:"Pakistan"}}},{id:"58390",title:"Dr.",name:"Gyula",middleName:null,surname:"Mozsik",slug:"gyula-mozsik",fullName:"Gyula Mozsik",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/58390/images/system/58390.png",biography:"Gyula Mózsik MD, Ph.D., ScD (med), is an emeritus professor of Medicine at the First Department of Medicine, Univesity of Pécs, Hungary. He was head of this department from 1993 to 2003. His specializations are medicine, gastroenterology, clinical pharmacology, clinical nutrition, and dietetics. His research fields are biochemical pharmacological examinations in the human gastrointestinal (GI) mucosa, mechanisms of retinoids, drugs, capsaicin-sensitive afferent nerves, and innovative pharmacological, pharmaceutical, and nutritional (dietary) research in humans. He has published about 360 peer-reviewed papers, 197 book chapters, 692 abstracts, 19 monographs, and has edited 37 books. He has given about 1120 regular and review lectures. He has organized thirty-eight national and international congresses and symposia. He is the founder of the International Conference on Ulcer Research (ICUR); International Union of Pharmacology, Gastrointestinal Section (IUPHAR-GI); Brain-Gut Society symposiums, and gastrointestinal cytoprotective symposiums. He received the Andre Robert Award from IUPHAR-GI in 2014. Fifteen of his students have been appointed as full professors in Egypt, Cuba, and Hungary.",institutionString:"University of Pécs",institution:{name:"University of Pecs",country:{name:"Hungary"}}},{id:"277367",title:"M.Sc.",name:"Daniel",middleName:"Martin",surname:"Márquez López",slug:"daniel-marquez-lopez",fullName:"Daniel Márquez López",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/277367/images/7909_n.jpg",biography:"Msc Daniel Martin Márquez López has a bachelor degree in Industrial Chemical Engineering, a Master of science degree in the same área and he is a PhD candidate for the Instituto Politécnico Nacional. His Works are realted to the Green chemistry field, biolubricants, biodiesel, transesterification reactions for biodiesel production and the manipulation of oils for therapeutic purposes.",institutionString:null,institution:{name:"Instituto Politécnico Nacional",country:{name:"Mexico"}}},{id:"196544",title:"Prof.",name:"Angel",middleName:null,surname:"Catala",slug:"angel-catala",fullName:"Angel Catala",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/196544/images/system/196544.jpg",biography:"Angel Catalá studied chemistry at Universidad Nacional de La Plata, Argentina, where he received a Ph.D. in Chemistry (Biological Branch) in 1965. From 1964 to 1974, he worked as an Assistant in Biochemistry at the School of Medicine at the same university. From 1974 to 1976, he was a fellow of the National Institutes of Health (NIH) at the University of Connecticut, Health Center, USA. From 1985 to 2004, he served as a Full Professor of Biochemistry at the Universidad Nacional de La Plata. He is a member of the National Research Council (CONICET), Argentina, and the Argentine Society for Biochemistry and Molecular Biology (SAIB). His laboratory has been interested for many years in the lipid peroxidation of biological membranes from various tissues and different species. Dr. Catalá has directed twelve doctoral theses, published more than 100 papers in peer-reviewed journals, several chapters in books, and edited twelve books. He received awards at the 40th International Conference Biochemistry of Lipids 1999 in Dijon, France. He is the winner of the Bimbo Pan-American Nutrition, Food Science and Technology Award 2006 and 2012, South America, Human Nutrition, Professional Category. In 2006, he won the Bernardo Houssay award in pharmacology, in recognition of his meritorious works of research. Dr. Catalá belongs to the editorial board of several journals including Journal of Lipids; International Review of Biophysical Chemistry; Frontiers in Membrane Physiology and Biophysics; World Journal of Experimental Medicine and Biochemistry Research International; World Journal of Biological Chemistry, Diabetes, and the Pancreas; International Journal of Chronic Diseases & Therapy; and International Journal of Nutrition. He is the co-editor of The Open Biology Journal and associate editor for Oxidative Medicine and Cellular Longevity.",institutionString:"Universidad Nacional de La Plata",institution:{name:"National University of La Plata",country:{name:"Argentina"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",biography:"Francisco Javier Martín-Romero (Javier) is a Professor of Biochemistry and Molecular Biology at the University of Extremadura, Spain. He is also a group leader at the Biomarkers Institute of Molecular Pathology. Javier received his Ph.D. in 1998 in Biochemistry and Biophysics. At the National Cancer Institute (National Institute of Health, Bethesda, MD) he worked as a research associate on the molecular biology of selenium and its role in health and disease. After postdoctoral collaborations with Carlos Gutierrez-Merino (University of Extremadura, Spain) and Dario Alessi (University of Dundee, UK), he established his own laboratory in 2008. The interest of Javier's lab is the study of cell signaling with a special focus on Ca2+ signaling, and how Ca2+ transport modulates the cytoskeleton, migration, differentiation, cell death, etc. He is especially interested in the study of Ca2+ channels, and the role of STIM1 in the initiation of pathological events.",institutionString:null,institution:{name:"University of Extremadura",country:{name:"Spain"}}},{id:"217323",title:"Prof.",name:"Guang-Jer",middleName:null,surname:"Wu",slug:"guang-jer-wu",fullName:"Guang-Jer Wu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217323/images/8027_n.jpg",biography:null,institutionString:null,institution:null},{id:"148546",title:"Dr.",name:"Norma Francenia",middleName:null,surname:"Santos-Sánchez",slug:"norma-francenia-santos-sanchez",fullName:"Norma Francenia Santos-Sánchez",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/148546/images/4640_n.jpg",biography:null,institutionString:null,institution:null},{id:"272889",title:"Dr.",name:"Narendra",middleName:null,surname:"Maddu",slug:"narendra-maddu",fullName:"Narendra Maddu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/272889/images/10758_n.jpg",biography:null,institutionString:null,institution:null},{id:"242491",title:"Prof.",name:"Angelica",middleName:null,surname:"Rueda",slug:"angelica-rueda",fullName:"Angelica Rueda",position:"Investigador Cinvestav 3B",profilePictureURL:"https://mts.intechopen.com/storage/users/242491/images/6765_n.jpg",biography:null,institutionString:null,institution:null},{id:"88631",title:"Dr.",name:"Ivan",middleName:null,surname:"Petyaev",slug:"ivan-petyaev",fullName:"Ivan Petyaev",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Lycotec (United Kingdom)",country:{name:"United Kingdom"}}},{id:"423869",title:"Ms.",name:"Smita",middleName:null,surname:"Rai",slug:"smita-rai",fullName:"Smita Rai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424024",title:"Prof.",name:"Swati",middleName:null,surname:"Sharma",slug:"swati-sharma",fullName:"Swati Sharma",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"439112",title:"MSc.",name:"Touseef",middleName:null,surname:"Fatima",slug:"touseef-fatima",fullName:"Touseef Fatima",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"Integral University",country:{name:"India"}}},{id:"424836",title:"Dr.",name:"Orsolya",middleName:null,surname:"Borsai",slug:"orsolya-borsai",fullName:"Orsolya Borsai",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Agricultural Sciences and Veterinary Medicine of Cluj-Napoca",country:{name:"Romania"}}},{id:"422262",title:"Ph.D.",name:"Paola Andrea",middleName:null,surname:"Palmeros-Suárez",slug:"paola-andrea-palmeros-suarez",fullName:"Paola Andrea Palmeros-Suárez",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Guadalajara",country:{name:"Mexico"}}}]}},subseries:{item:{id:"26",type:"subseries",title:"Machine Learning and Data Mining",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence",scope:"The scope of machine learning and data mining is immense and is growing every day. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. 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Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. 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