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Guilherme, S. Freschi de Barros A.C. Tanaka, M.C. Ribeiro Castro and J. Kalil",authors:[{id:"49028",title:"Prof.",name:"Luiza",middleName:null,surname:"Guilherme",fullName:"Luiza Guilherme",slug:"luiza-guilherme"},{id:"59215",title:"Dr.",name:"Samar",middleName:null,surname:"Freschi De Barros",fullName:"Samar Freschi De Barros",slug:"samar-freschi-de-barros"},{id:"59216",title:"Dr.",name:"Ana Cristina",middleName:null,surname:"Tanaka",fullName:"Ana Cristina Tanaka",slug:"ana-cristina-tanaka"},{id:"59217",title:"Dr.",name:"Maria Cristina",middleName:null,surname:"Ribeiro De Castro",fullName:"Maria Cristina Ribeiro De Castro",slug:"maria-cristina-ribeiro-de-castro"},{id:"59218",title:"Prof.",name:"Jorge",middleName:null,surname:"Kalil",fullName:"Jorge Kalil",slug:"jorge-kalil"}]},{id:"22827",title:"Insights from Genomics on Post-Infectious Streptococcal Glomerulonephritis",slug:"insights-from-genomics-on-post-infectious-streptococcal-glomerulonephritis",signatures:"W. Michael McShan and Roya Toloui",authors:[{id:"50422",title:"Prof.",name:"William",middleName:null,surname:"McShan",fullName:"William McShan",slug:"william-mcshan"},{id:"137995",title:"Prof.",name:"Roya",middleName:null,surname:"Toloui",fullName:"Roya Toloui",slug:"roya-toloui"}]},{id:"22828",title:"Atypical Clinical Manifestations of Acute Poststreptococcal Glomerulonephritis",slug:"atypical-clinical-manifestations-of-acute-poststreptococcal-glomerulonephritis",signatures:"Toru Watanabe",authors:[{id:"51276",title:"Dr.",name:"Toru",middleName:null,surname:"Watanabe",fullName:"Toru Watanabe",slug:"toru-watanabe"}]},{id:"22829",title:"Hepatitis C Virus Associated Glomerulonephritis",slug:"hepatitis-c-virus-associated-glomerulonephritis",signatures:"Vincent Ho and Jason Chen",authors:[{id:"45087",title:"Dr.",name:"Vincent",middleName:null,surname:"Ho",fullName:"Vincent Ho",slug:"vincent-ho"},{id:"109733",title:"Dr.",name:"Jason",middleName:null,surname:"Chen",fullName:"Jason Chen",slug:"jason-chen"}]},{id:"22830",title:"Glomerular Pathology in Patients with HIV Infection",slug:"glomerular-pathology-in-patients-with-hiv-infection",signatures:"Enrique Morales, Elena Gutierrez-Solis, Eduardo Gutierrez and Manuel Praga",authors:[{id:"49404",title:"Dr",name:"Enrique",middleName:null,surname:"Morales",fullName:"Enrique Morales",slug:"enrique-morales"},{id:"59326",title:"Dr.",name:"Elena",middleName:null,surname:"Gutierrez",fullName:"Elena Gutierrez",slug:"elena-gutierrez"},{id:"59327",title:"Dr.",name:"Eduardo",middleName:null,surname:"Gutierrez",fullName:"Eduardo Gutierrez",slug:"eduardo-gutierrez"},{id:"59328",title:"Dr.",name:"Manuel",middleName:null,surname:"Praga",fullName:"Manuel Praga",slug:"manuel-praga"}]},{id:"22831",title:"Henoch-Schönlein Purpura Nephritis in Childhood",slug:"henoch-scho-nlein-purpura-nephritis-in-childhood",signatures:"Marco Zaffanello",authors:[{id:"47752",title:"Dr.",name:"Marco",middleName:null,surname:"Zaffanello",fullName:"Marco Zaffanello",slug:"marco-zaffanello"}]},{id:"22832",title:"Lupus Glomerulonephritis",slug:"lupus-glomerulonephritis",signatures:"Chi Chiu Mok",authors:[{id:"61911",title:"Dr.",name:"Chi Chiu",middleName:null,surname:"Mok",fullName:"Chi Chiu Mok",slug:"chi-chiu-mok"}]},{id:"22833",title:"Anti-Glomerular Basement Membrane Disease",slug:"anti-glomerular-basement-membrane-disease",signatures:"Kouichi Hirayama and Kunihiro Yamagata",authors:[{id:"46785",title:"Dr.",name:"Kouichi",middleName:null,surname:"Hirayama",fullName:"Kouichi Hirayama",slug:"kouichi-hirayama"},{id:"47829",title:"Prof.",name:"Kunihiro",middleName:null,surname:"Yamagata",fullName:"Kunihiro Yamagata",slug:"kunihiro-yamagata"}]},{id:"22834",title:"Mixed Hematopoietic Chimerism Allows Cure of Autoimmune Glomerulonephritis: Its Potential and Risks",slug:"mixed-hematopoietic-chimerism-allows-cure-of-autoimmune-glomerulonephritis-its-potential-and-risks",signatures:"Emiko Takeuchi",authors:[{id:"48651",title:"Dr.",name:"Emiko",middleName:null,surname:"Takeuchi",fullName:"Emiko Takeuchi",slug:"emiko-takeuchi"}]},{id:"22835",title:"Differential Diagnosis of the Pulmonary-Renal Syndrome",slug:"differential-diagnosis-of-the-pulmonary-renal-syndrome",signatures:"Martin Kimmel, Niko Braun and Mark Dominik Alscher",authors:[{id:"23846",title:"Prof.",name:"Dominik",middleName:null,surname:"Alscher",fullName:"Dominik Alscher",slug:"dominik-alscher"},{id:"46909",title:"Dr.",name:"Martin",middleName:null,surname:"Kimmel",fullName:"Martin Kimmel",slug:"martin-kimmel"},{id:"53817",title:"Dr.",name:"Niko",middleName:null,surname:"Braun",fullName:"Niko Braun",slug:"niko-braun"}]},{id:"22836",title:"RPGN - Clinical Features, Treatment and Prognosis",slug:"rpgn-clinical-features-treatment-and-prognosis",signatures:"Mitra Naseri",authors:[{id:"54655",title:"Dr.",name:"Mitra",middleName:null,surname:"Naseri",fullName:"Mitra Naseri",slug:"mitra-naseri"}]},{id:"22837",title:"Diabetic Glomerulopathy",slug:"diabetic-glomerulopathy",signatures:"Mahmoud Barazi, Harneet Kaur and Sharma Prabhakar",authors:[{id:"49226",title:"Prof.",name:"Sharma",middleName:null,surname:"Prabhakar",fullName:"Sharma Prabhakar",slug:"sharma-prabhakar"},{id:"119886",title:"Dr.",name:"Mahmoud",middleName:null,surname:"Barazi",fullName:"Mahmoud Barazi",slug:"mahmoud-barazi"},{id:"119887",title:"Dr.",name:"Harneet",middleName:null,surname:"Kaur",fullName:"Harneet Kaur",slug:"harneet-kaur"}]},{id:"22838",title:"Metabolic Syndrome Associated Kidney Damage",slug:"metabolic-syndrome-associated-kidney-damage",signatures:"Hequn Zou, Yuxin Wang, Guimian Zou and Jianxin Wan",authors:[{id:"61378",title:"Prof.",name:"Hequn",middleName:null,surname:"Zou",fullName:"Hequn Zou",slug:"hequn-zou"},{id:"61403",title:"Prof.",name:"Yuxin",middleName:null,surname:"Wang",fullName:"Yuxin Wang",slug:"yuxin-wang"},{id:"61404",title:"Prof.",name:"Guimian",middleName:null,surname:"Zou",fullName:"Guimian Zou",slug:"guimian-zou"},{id:"137996",title:"Dr.",name:"Jianxin",middleName:null,surname:"Wan",fullName:"Jianxin Wan",slug:"jianxin-wan"}]},{id:"22839",title:"Glomerulonephritis and the Cystic Fibrosis Patient",slug:"glomerulonephritis-and-the-cystic-fibrosis-patient",signatures:"Daniel Fischman, Arvin Parvathaneni and Pramil Cheriyath",authors:[{id:"53484",title:"Dr.",name:"Daniel",middleName:null,surname:"Fischman",fullName:"Daniel Fischman",slug:"daniel-fischman"},{id:"58704",title:"Dr.",name:"Pramil",middleName:null,surname:"Cheriyath",fullName:"Pramil Cheriyath",slug:"pramil-cheriyath"},{id:"77506",title:"Dr.",name:"Arvin",middleName:null,surname:"Parvathaneni",fullName:"Arvin Parvathaneni",slug:"arvin-parvathaneni"}]},{id:"22840",title:"Mild Forms of Alport Syndrome: Hereditary Nephropathy in the Absence of Extra-Renal Features",slug:"mild-forms-of-alport-syndrome-hereditary-nephropathy-in-the-absence-of-extra-renal-features",signatures:"Han-Seung Yoon and Michael R. Eccles",authors:[{id:"59735",title:"Prof.",name:"Mike",middleName:null,surname:"Eccles",fullName:"Mike Eccles",slug:"mike-eccles"},{id:"110263",title:"Prof.",name:"Han-Seung",middleName:null,surname:"Yoon",fullName:"Han-Seung Yoon",slug:"han-seung-yoon"}]},{id:"22841",title:"Nephrotic Syndrome in Children – Studies from South Africa",slug:"nephrotic-syndrome-in-children-studies-from-south-africa",signatures:"Gertruida van Biljon",authors:[{id:"50567",title:"Prof.",name:"Gertruida",middleName:null,surname:"Van Biljon",fullName:"Gertruida Van Biljon",slug:"gertruida-van-biljon"}]},{id:"22842",title:"Blood Pressure Control in Patients with Glomerulonephritis",slug:"blood-pressure-control-in-patients-with-glomerulonephritis",signatures:"Toshihiko Ishimitsu",authors:[{id:"52799",title:"Prof.",name:"Toshihiko",middleName:null,surname:"Ishimitsu",fullName:"Toshihiko Ishimitsu",slug:"toshihiko-ishimitsu"}]}]}],publishedBooks:[{type:"book",id:"646",title:"Chronic Kidney Disease",subtitle:null,isOpenForSubmission:!1,hash:"49fc40a7d5b44ec81ee90ab94907dcfa",slug:"chronic-kidney-disease",bookSignature:"Monika Göoz",coverURL:"https://cdn.intechopen.com/books/images_new/646.jpg",editedByType:"Edited by",editors:[{id:"65789",title:"Prof.",name:"Monika",surname:"Göőz",slug:"monika-gooz",fullName:"Monika Göőz"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"7935",title:"Renal Diseases",subtitle:null,isOpenForSubmission:!1,hash:"44715ed141cf23ebdd35ff0d772492df",slug:"renal-diseases",bookSignature:"Edward T. 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Prabhakar",coverURL:"https://cdn.intechopen.com/books/images_new/1299.jpg",editedByType:"Edited by",editors:[{id:"49226",title:"Prof.",name:"Sharma",surname:"Prabhakar",slug:"sharma-prabhakar",fullName:"Sharma Prabhakar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}],publishedBooksByAuthor:[{type:"book",id:"365",title:"An Update on Glomerulopathies",subtitle:"Etiology and Pathogenesis",isOpenForSubmission:!1,hash:"b2089d3d97c524eea28106b44727163d",slug:"an-update-on-glomerulopathies-etiology-and-pathogenesis",bookSignature:"Sharma Prabhakar",coverURL:"https://cdn.intechopen.com/books/images_new/365.jpg",editedByType:"Edited by",editors:[{id:"49226",title:"Prof.",name:"Sharma",surname:"Prabhakar",slug:"sharma-prabhakar",fullName:"Sharma Prabhakar"}],equalEditorOne:null,equalEditorTwo:null,equalEditorThree:null,productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},onlineFirst:{chapter:{type:"chapter",id:"66752",title:"Mechanical Force and Actin Dynamics during Cutaneous Squamous Cell Carcinoma (cSCC) Progression: Opportunities for Novel Treatment Modalities",doi:"10.5772/intechopen.86041",slug:"mechanical-force-and-actin-dynamics-during-cutaneous-squamous-cell-carcinoma-cscc-progression-opport",body:'Cutaneous squamous cell carcinoma (cSCC) most commonly arises in actinically damaged skin and accounts for 25% of cutaneous malignancies diagnosed in the Caucasian population [1]. The incidence of cSCC continues to rise annually, with an estimated 50–200% increase in incidence in the last three decades in USA alone, and is predicted to increase in future years due to an aging global population [2]. Solar ultraviolet radiation is the primary environmental extrinsic cause of cSCC. Intrinsic immunosuppression, the second most common cause, leads to the formation of aggressive cSCC in organ transplant patients, patients on immunomodulatory therapies, and those suffering from recessive dystrophic epidermolysis bullosa, a genetic skin blistering disease [3, 4, 5]. The incidence of cSCC is higher in individuals who are fair-skinned and have a sun-sensitive phenotype; however, the aggressive forms of cSCC are more common in men and the elderly [3]. Despite its prevalence, the relatively low fatality rate of cSCC means that its health and economic burden is often substantially underestimated [3], albeit latest data showing that in addition to significant morbidity cSCC accounts for up to 8000 deaths per year and costs approximately $4.8 billion annually in USA alone [6].
cSCC generally presents as a scaly, red or bleeding abnormal lesion on sun-exposed areas, and is associated with relatively benign outcomes and a low risk of metastasis. However, cSCC can demonstrate dramatic histopathological heterogeneity, resulting in a wide range of clinical outcomes [7]. Histopathologic subtypes of cSCC are broadly divided into low-grade SCC (Figure 1A) that are well-differentiated but have low metastatic potential (keratoacanthomas, SCC
Representative histopathological features of low-grade and high-grade cSCC. (A) Low-grade cSCC in situ with prominent dyskeratosis and aberrant mitosis at all levels of the epidermis, with marked parakeratosis and intact basement membrane. (B) High-grade poorly-differentiated cSCC lesions showing prominent keratinization and the formation of “pearl like” structures where dermal nests of keratinocytes attempt to mature. Adapted from Yanofsky et al. [
With increasingly longer life expectancy, the health and economic burden of cSCC is likely to continue to increase significantly. Hence, a better understanding of factors contributing to cSCC progression and metastasis is necessary to aid development of novel therapies, aimed at combatting cSCC in the community. Despite recent advances in gene expression screening technologies that have begun to identify candidate genes commonly mutated in patients with cSCC (including TP53, CDKN2A, Ras and NOTCH1), which may be responsible for regulating motility and invasion in cSCC, a comprehensive understanding of the factors contributing to cSCC invasion including mechanical tension and actin dynamics is still emerging [8]. One thing that is clear is that patient outcome directly correlates with the degree of local and regional invasion, and coordinated regulation of the actin cytoskeleton is critical to cell motility, invasion and metastasis [9]. Consequently, the signaling pathways involved in mediating chemotactic cues from the extracellular environment that regulate the actin cytoskeleton and mechanical forces, guiding cancer cell invasion and metastasis, have been and continue to be an area of intense study.
Recent studies have revealed a number of proteins and molecules that are aberrantly expressed in cSCC. These proteins link cell migratory signals to the actin cytoskeleton, thereby playing an instrumental role in the ability of cancer cells to resist chemotherapy and/or metastasize [10]. In this chapter we will describe the actin dynamics and mechanical force governing tumor cell migration, invasion and metastasis. We will outline the main signaling pathways governing the formation of invasive protrusions by cancer cells with regard to the function of key regulatory proteins involved in actin cytoskeleton remodeling in cSCC.
The metastatic spread of aggressive cancers, including cSCC, is a highly selective process involving a series of sequential and orchestrated steps in the so-called “metastatic cascade”: detachment from the primary tumor site, cell migration and invasion of the surrounding extracellular matrix (ECM), intravasation into vasculature, extravasation at a secondary site, and interaction with the extracellular environment to form metastatic tumors [11]. Each of these steps offers the potential for design of different therapeutic approaches to combat aggressive cSCC. Indeed, a number of recent studies have identified novel therapeutic approaches including both adjuvant and neoadjuvant treatments, with clinical trials utilizing epidermal growth factor receptor inhibitors and immune checkpoint blockers (nivolumab, pembrolizumab, and ipilimumab) showing promising early results as potential treatments of cSCC [12]. Recent trials using cytotoxic chemotherapy have, however, shown limited advances for the treatment of cSCC, and trials investigating combined immune checkpoint inhibitor and radiation therapies, which may have synergistic effects in treatment of cSCC, are still pending [13]. This highlights the need for increased research to close the gaps in our knowledge of cSCC biology, including better understanding of the factors that lead to aggressive cSCC, the role of microbiomes and HPV infection, the role that mechanical force and actin dynamics plays in this process, prediction of clinical response to therapies including immune checkpoint blockade, and how to tailor better prevention and treatment strategies to individual risk factors and needs [6]. Emerging evidence on the crosstalk between different components of the cytoskeleton in metastatic progression combined with clinical data illustrating strong relationships between cytoskeletal alterations and metastasis in various cancers pinpoints important opportunities for potential therapeutic targets [11]. Later in this chapter we will describe current research that has attempted to identify the steps of the metastatic cascade suitable and most amenable for therapeutic intervention, with a focus on harnessing our knowledge of actin cytoskeleton remodeling and mechanical forces to postulate therapeutic strategies targeting cytoskeletal and cytoskeletal-associated proteins critical in cSCC.
The skin is exposed to and responds to a wide range of mechanical signals throughout homeostasis and through to malignancy. Mechanical forces have been shown to regulate these normal cellular processes including stem cell renewal, lineage differentiation and proliferation, wound healing, as well as transformation through changes in the actin cytoskeleton—the ability to protrude, adhere to the ECM, migrate through tissue and invade into the underlying basement membrane.
The types of mechanical forces exerted upon the skin can vary depending on the context. In homeostasis, tensile/stretch forces and compressive forces arise as a result of muscle and joint movements, and physical location—skin stretched over bone is under significantly more stress than when over fat or muscle [14]. Tensile forces cause cells to elongate and expand, and therefore are generated at sites of wounding as epithelial cells migrate in and contract to close the wound. This can generate scarring and fibrosis, which can lead to skin cancer including cSCC [15]. Compressive forces generate different biomechanics in skin cells compared to tensile force [16]. Compressive forces are able to activate Rho-ROCK signaling (described below) in the skin, which has been shown to play a role in tumor progression [17]. In melanoma, it was found that stress-bearing areas of the foot were more conducive to cancer development due to increased mechanical compressive stress [18]. Changes in substrate stiffness underlie these mechanical signals (Figure 2), and it has been shown that stiff stroma can lead to an activation of integrin signaling and subsequent cSCC development [19].
Mechanical forces acting upon skin cells. The major types of mechanical forces experienced by skin cells are compressive (inward pushing) and tensile (stretching) forces, which in cSCC progression are generated by an increase in extracellular matrix stiffening. These are sensed by the cell, which then is able to respond accordingly.
Cells have the ability to sense these changes in their environment (process referred to as “mechanosensing”). The mechanical signal is then converted to a biochemical signal in a process called mechanotransduction, and the biochemical signals initiate a cascade of changes within the cell at the transcriptional, translational and post-translational levels that result in a cell that can appropriately and reciprocally respond to the extracellular signals (process referred to as “mechanoreciprocity”) [20]. In disease states including cSCC, the heightened and/or constitutive extracellular signals generate a detrimental loop of ever-increasing mechanoreciprocal signaling, hence leading to enhanced tumor progression, invasion and eventually metastasis [20].
Triggered by the changes in the cell microenvironment, the actin cytoskeleton undergoes a number of changes that allows a cell to become more motile and/or invasive. The ability of a cell to undergo directed migration is essential to its ability to metastasize, and is characterized by an ordered process (Figure 3) of membrane protrusion at the leading edge (filopodia and lamellipodia) and sides (invadopodia) of the cell, contact and adhesion between the protrusion and the matrix, movement of the main cell body, and retraction of the trailing edge [21, 22]. Lamellipodia are flat membrane protrusions containing dendritic arrays of actin filaments that branch out like a sheet from the leading edge of a cell. This particular form of protrusion is thought to have a major role in cell migration as their morphology allows the cell to make multiple contacts with the underlying substrate and pull the cell forward. Filopodia are narrow protrusions made up of bundled and cross-linked actin filaments that also stretch out from the leading edge. Invadopodia, unlike lamelli- and filopodia, are protrusions branching out from the sides of a cell, which have increased membrane remodeling and matrix degradation proteins [21]. These particular membrane protrusions are often seen in cancer cells including during cSCC progression [23].
Cell motility as controlled by the actin cytoskeleton. Upon sensing of extracellular cues, intracellular signaling cascades generate cytoskeletal protrusions (lamellipodia and filopodia) at the leading edge containing actin filaments, as well as invasive protrusions (invadopodia) at the sides of the cell, necessary for cSCC invasion. The cell adheres to the matrix, forming integrin-mediated focal adhesions. The nucleus and cell body are then pushed forward as the trailing edge contracts, via stress fibers. The rear of the cell then detaches, allowing the cell to migrate forward.
Adhesions between the cancer cells and matrix are necessary for invasion and are largely mediated by integrins (discussed in detail below) [22]. During cSCC progression, there is an increase in cellular attachment to the ECM and, concurrently, a decrease in attachment to neighboring epithelial cells signified by a reduction in levels of E-cadherin expression. Following matrix adhesion, the trailing edge of the cell contracts, allowing the cell to move forward. Myosin II is required for this actin filament contraction, and is largely regulated by signaling through the small G-protein Rho. Once the cell contracts, its tail detaches as focal adhesion complex components are cleaved [22]. Actin remodeling proteins are essential in these processes, and often regulate cell-cell and cell-stroma attachment and turnover of focal adhesions, allowing cell traction and movement to take place. The coordination of actin polymerization and contraction allows the cSCC cell the ability to migrate through dense, stiff ECM and stroma to metastasize to lymph node or surrounding organs.
A number of different pathways are activated downstream of mechanical signals, causing changes in the actin cytoskeleton. Signaling pathways involved in cytoskeletal dynamics during cSCC progression are also activated as a result of constitutive or heightened growth factor signaling [24]. Together, the combination of mechanical and biochemical signals can trigger a multitude of intracellular signaling cascades that ultimately affect cell morphology. In this section, we will discuss the broad families of proteins regulating actin dynamics and mechanical forces in cSCC, an overview of which is illustrated in Figure 4. The overview provided in this chapter will not cover all the pathways or actin remodeling proteins involved but focus on those most relevant to cSCC progression, invasion and metastasis.
Major pathways regulating cytoskeletal dynamics downstream of mechanical signals in cSCC. Graphical representation of signaling pathways which respond to mechanical force and govern downstream actin remodeling during cSCC progression.
Integrins are well-characterized as the first point of contact for mechanical signal transduction. Inactive heterodimers on the cell surface, they are partially activated by intracellular proteins (“inside-out” signaling) before full activation upon binding to extracellular ligands (“outside-in” signaling) [25]. Binding to the extracellular ligand results in full activation of the integrin receptor and leads to the formation of either an intracellular focal adhesion complex to link the ECM to the actin cytoskeleton, or hemidesmosomes, linking the ECM to intermediate filaments. The integrin that is activated is context-dependent in regards to the particular focal adhesion complexes that are formed, broadly encompassing a range of adaptor proteins including: talin, vinculin, paxillin, Flightless I (Flii), focal adhesion kinase (FAK) and integrin-linked kinase (ILK). FAK is rapidly recruited to focal adhesions upon integrin activation and is auto-phosphorylated, driving downstream signaling. FAK phosphorylation, stimulated by integrin activation, allows binding of Src-family kinases that are then able to trans-phosphorylate FAK. This leads to activation of ERK/MAPK signaling, and this complex is therefore able to control cell shape and regulate focal adhesions [26]. In cSCC, a step-wise increase in activation of FAK from unaffected margin skin to hyperproliferative skin and invasive cSCC [27] results in elevated integrin-FAK-Src signaling that stimulates keratinocyte migration [28] and drives progression of benign papillomas to aggressive cSCC [29, 30]. In cSCC, it has been demonstrated that FAK function is required for cancer stem cell maintenance, regulating cSCC initiation, growth, regression, and progression [31]. Actin remodeling protein Flii, which will be discussed in detail in Section 2.4, has been shown not to directly bind integrin receptors but form focal adhesion complexes with adaptor proteins and regulate integrin activation, downstream Src/paxillin signaling and focal adhesion turnover in a Rac1 dependent manner [25, 32]. Additionally, latest research has shown that actin remodeling proteins Flii and gelsolin, which have always been thought to be intracellular, have also both been shown to be secreted where they function to sequester extracellular actin post tissue injury, modulate inflammation and affect collagen VII anchoring fibril formation. Flii is able to modulate inflammation via toll-like receptor 4 (TLR-4) signaling, as Flii leucine-rich repeat (LRR) domains have 50% similarity to LRR domains of TLR-4, by which the immune system is able to detect infection or injury. The binding of LRRs to PAMP and DAMP molecules activates intracellular TLR signaling and ultimately results in the release of proinflammatory cytokine secretion [33]. The extracellular roles of Flii and gelsolin in respect to mechanosensing and cSCC progression are still to be examined. Nevertheless, it is clear that the coordinated activation of integrin receptors, focal adhesion complex formation and downstream signaling stimulation is essential for cytoskeletal changes that are necessary for cell migratory and invasive capability during cSCC progression.
Downstream of integrin activation are the Rho small GTPases, which are part of the Ras superfamily and key regulators of cell cytoskeletal dynamics through both actin polymerization and organization, hence driving cancer cell motility [34]. Of this subfamily, RhoA, Rac1 and Cdc42 are the best-characterized.
RhoA is involved in actomyosin contractility, formation of actin stress fibers and assembly of focal adhesion complexes. The main regulator of cytoskeletal dynamics leading to formation of stress fibers is myosin II, and its regulatory subunit myosin regulatory light chain-2 (MLC2) can be activated by RhoA signaling leading to contraction of actin fibers. Rho-associated kinases ROCK1 and ROCK2 are serine/threonine kinases that contain a Rho-binding domain and are activated by RhoA in its active GTP-bound form, directly activate MLC2 via phosphorylation. Due to its roles in cell contractility and movement, Rho-ROCK signaling has been implicated as a driver for invasiveness during cSCC progression but also plays a positive role in physiological normal wound healing processes [35]. In human cSCCs, ROCK is not only highly expressed but also activated in the hyperproliferative skin and invasive regions of the tumor, as shown by phosphorylation of the ROCK substrate myosin phosphatase (MYPT1) [27]. In the skin, this ROCK-mediated actomyosin contractility is required for proliferation of the epidermis, as ROCK activation stabilizes β-catenin through phosphoinositide 3-kinase (PI3K), Akt, and inhibition of its phosphorylating kinase GSK3β [36]. During cancer progression from normal skin through to hyperproliferative and invasive cSCC, nuclear localization of active β-catenin and inactivation of GSK3β is increased, accompanied also by a progressive increase in FAK activation [27, 36]. It has further been demonstrated that a negative regulator of ROCK signaling, 14-3-3ζ, is significantly down-regulated in human cSCCs. As genetic deletion of 14-3-3ζ results in significantly larger papillomas in the two-stage chemical carcinogenesis (DMBA-TPA) mouse model of SCC, this suggests that uncontrolled ROCK signaling can drive cSCC tumor growth [35].
Cdc42 is involved in formation of F-actin microspikes and filopodia in both normal and cSCC cells, by via actin polymerization at the leading edge and at the sides of the cells, contributing to cSCC invasion. Traf6 has been demonstrated to regulate Cdc42 to induce these F-actin microspikes in SCC cells [37]. When Cdc42 is absent in keratinocytes, cells are no longer able to properly process and deposit ECM components or integrin receptors, hence halting cellular migration [38]. Taken together, these studies demonstrate roles for Cdc42 in both skin cell migration and invasion, necessary cellular processes for progression of cSCC. Cdc42 is necessary for proper cellular polarity in normal and migratory cells [34], and this in turn activates G-proteins of the Rac subfamily of Rho small GTPases [39].
Rac1 is hyperactivated in cSCC via integrins including α3β1, and is important for keratinocyte cell proliferation [40, 41]. Rac1 stimulates polymerization of actin via multiple kinase signaling cascades including that of MAP kinase (elevating the transcription factors AP-1, NFκB and CRE). This therefore allows the cell to form a branched actin network, necessary for leading-edge lamellipodia formation and membrane ruffling [42]. Indeed, actin remodeling protein, Flightless I (Flii), has been shown to regulate focal adhesion by inhibition of paxillin phosphorylation via a Rac1 dependent pathway [32]. Rac1 can be activated by Tiam1, and it was shown in the two-stage chemical carcinogenesis cSCC model that genetic deletion of Tiam1 significantly reduced tumor incidence, burden and growth. However, SCC tumors that did arise in Tiam-null mice were significantly more invasive and malignant, potentially due to a loss of cell-matrix adhesion [43]. This highlights the dual homeostatic and tumor-promoting roles that actomyosin regulatory pathways can play during cSCC progression.
Rho-associated kinase ROCK can also phosphorylate and activate LIM kinases 1 and 2, which are then able to phosphorylate and inactivate cofilin, an F-actin severing protein, resulting in F-actin filament stabilization [44]. Accordingly, it has been shown that LIMK1 levels are increased in cSCC tumor tissue compared to normal skin, and that LIMK1 silencing can suppress cell growth and invasion in cSCC cell lines [45]. In addition, it has been suggested that LIMK is required in the microenvironment in leading fibroblasts, to allow for efficient remodeling of the ECM and subsequent cSCC invasion [46]. It has been demonstrated that cofilin phosphorylation can be abolished by treating cSCC cells with LIMK inhibitors. This reduces β-catenin accumulation and epidermal proliferation via reversing actomyosin contractility [36], however clinical trials using these inhibitors are still pending. The involvement of Rho GTPases in cellular migration and invasion in cSCC due to cytoskeletal rearrangement implicates this family of proteins as drivers of cancer initiation, progression and metastasis. Hence, targeting Rho pathway signaling, in particular that of RhoA-ROCK signaling, is an attractive therapeutic option that will be explored later in this chapter.
Actin nucleation promoting molecules are activated downstream of Rho GTPases and growth factor receptors. Wiskott-Aldrich syndrome protein (WASP) family members, via Erk, paxillin, and Src signaling together with cortactin, act to stimulate the actin-related protein (Arp) 2/3 complex which in turn mediates actin polymerization [47].
The WASP family consists of WASP proteins and WASP-family verprolin-homologous (WAVE) proteins. WASP proteins interact with Rho GTPases in order to form cellular protrusions and allow the cell to migrate, for example, N-WASP is involved in formation of filopodia and invadopodia upon its activation by Cdc42. WASP proteins bind to G-actin and Arp2/3 resulting in their activation and hence triggering actin filament production. WASP and WAVE proteins also bind profilin, which transports actin monomers onto the growing ends of actin filaments, and is therefore also an important factor in cell motility [47]. As a loss of N-WASP in keratinocytes causes epidermal hyperplasia and a reduction in epithelial cell tight junctions [48], this highlights the need for proper control of these processes. The formation of cellular protrusions also relies on the Src protein cortactin, which binds to and activates the Arp2/3 complex independently of WASP, thereby regulating actin filament nucleation. Cortactin binds to F-actin, stabilizing actin filaments and allowing it to properly activate Arp2/3 [49, 50]. In head and neck SCC, overexpression of cortactin increases cancer cell proliferation and increases cell survival in anchorage-independent conditions [51], while in oral SCC, silencing of cortactin was shown to significantly impair invasiveness and downregulate the levels of epithelial markers, indicating an epithelial to mesenchymal transition (EMT) [52], a process by which epithelial cells lose their adhesion to one another and acquire a migratory and invasive mesenchymal phenotype (discussed in further detail below). Indeed, Arp2/3 complex proteins are required for cell proliferation and migration in other forms of SCC [53, 54], and based on the Arp2/3 role in actin filament polymerization, it is clear that Arp2/3 is also critical for actin cytoskeletal remodeling leading to cancer cell motility and invasion.
The actin cytoskeleton is composed of three distinct elements including microfilaments, microtubules and intermediate filaments. Tight regulation of cytoskeletal elements must be coordinated, and latest research has shown that interplay between actin and microtubules is bidirectional [55]. Actin-based motility is also dependent on the balanced activity of number of specific actin remodeling proteins. In this section we will highlight main actin remodeling proteins that have been shown to have specific functions in cSCC progression, including members of the tropomyosin family of actin-associated proteins, the gelsolin family of actin remodeling proteins, and Podoplanin, a simple glycoprotein with important roles in cSCC progression.
Members of the tropomyosin family of actin remodeling proteins display a tissue- and time-specific expression, while their association with actin filaments impairs isoform-specific regulation of actin filament dynamics [56]. Tropomyosin proteins assemble as polymers in the major groove of the polymerized actin filament and their association drives actin filament turnover, hence playing an important part in a number of cellular functions including motility and metastasis [57]. There are over 40 different isoforms of tropomyosin and few have been described as having an important role in cSCC progression. High expression of Tm5NM1, a specific cytoskeletal tropomyosin isoform, has been shown to inhibit cell migration and invasion as well as impair normal wound healing via its effects on Src activation, focal adhesion stabilization, increased actin filament tension, and paxillin phosphorylation [58]. Current research is examining the effect of Tm5NM1 inhibitor TR100 on cSCC progression (see Section 3). On the other hand, downregulation of tropomyosin-1 and complete loss of β-tropomyosin has been identified in human esophageal SCC, while α-tropomyosin has been shown to be preferentially expressed in keratinocytes of the multistage model of murine cSCC, collectively suggesting isoform specific functions [59, 60, 61].
The dynamic remodeling of the actin cytoskeleton is also tightly regulated by the gelsolin family of actin remodeling proteins, which includes: gelsolin, villin, adseverin, capG, advillin, supervillin, and Flightless I (Flii) [62]. These actin binding proteins function in the cytoplasm of the cells where they control actin organization by severing pre-existing filaments, capping the fast growing filament ends and bundling filaments, enabling filament reassembly into new cytoskeletal structures that are required for cell motility, invasion and metastasis [63]. Studies have shown that downregulation of gelsolin proteins counteracts cancer cell invasion
The expression of Podoplanin, a small mucin-like protein, has also been linked to remodeling of the actin cytoskeleton in cSCC. Podoplanin is upregulated in the invasive front of a number of human carcinomas including cSCC and has been shown to induce collective cell migration by filopodia formation, via downregulating the function of Rho small GTPases [73, 74]. Podoplanin has also been linked to an increase in the migration of cancer-associated fibroblasts as well as endothelial network formation [75]. Collectively these findings suggest that Podoplanin is able to induce an alternative pathway of tumor cell invasion in the absence of traditional epithelial-mesenchymal transition.
Taken together, these studies highlight the important role of actin remodeling in cSCC progression and outline the importance of bidirectional stimulation of actin remodeling by both intrinsic factors and the microenvironment, critical to tumor invasion/metastasis. These findings provide a rationale for development of novel therapeutic strategies that target tumor invasion and metastasis.
Changes in the actin cytoskeletal structure result in changes to cell morphology, creating a cell more conducive to invasion. One of the commonly recognized requirements of metastasis is a cellular transition from epithelial to mesenchymal phenotype (EMT). This transition is characterized by upregulation of genes including vimentin, SNAI1 (snail), SNAI2 (slug) and Zeb1, and a downregulation of epithelial genes including cadherins, as well as concurrent loss of cell-cell junctions [76]. For example, in head and neck SCC an increase in matrix stiffness and hence increased mechanical signaling caused an increase in EMT markers in tumor-initiating cells [71]. Cells undergoing EMT develop an elongated spindle-like morphology, due to the enhanced membrane protrusion formation [77]. It has been shown in A431 cells, a human epidermal SCC cell line, that loss of T-cadherin induces elongation of cells and formation of lamellipodia and multiple leading edges via changes in EGF-stimulated motility and invasion, as T-cadherin influences EGFR localization and responsiveness [78]. Of note, RhoA activation was also increased upon the loss of T-cadherin [79]. Likewise, Podoplanin is also capable of transforming cells to an invasive state without having to undergo EMT, due to rearrangements of the actin cytoskeleton [74].
The remodeling of the actin cytoskeleton also creates intracellular reciprocal forces that balance out the forces received by the cell from the extracellular microenvironment. Actin polymerization extends the filament network, and as filaments in the leading edge are compressed between transient associations with the cell membrane and the bulk of the actin cytoskeletal network behind them, intracellular force is generated. As protrusions are extended and retracted, actin filaments experience tension from transient bonds with the membrane, becoming bent or compressed [80]. Activation of the mechanotransduction pathways described above, downstream of ECM stiffness in cSCC, can also increase the propensity for augmented interactions with the stroma, and generate a tumor-promoting environment that enhances mechanoreciprocal signaling [20, 36].
Metastasis is a complex process requiring significant reorganization of the actin cytoskeleton and coordinated involvement of number of key proteins. These proteins interact directly and indirectly with both actin and microtubule networks, hence significantly influencing migratory and metastatic cell phenotypes. Strong clinical relationships between actin cytoskeletal alterations and cutaneous cancer metastasis have been previously described [11], offering potential opportunities for therapeutic intervention. For example, up-regulation of cortactin, an actin-binding adaptor protein in melanoma, has been directly linked to increased distal metastasis and reduced disease-free survival, while up-regulation of Ras mRNA has been directly linked to Stage III and Stage IV disease in head and neck SCC [81, 82]. The complex nature of cellular migration and invasion presents challenges in developing therapeutic approaches, as compensatory pathways may overcome the effects of specific inhibitors. This highlights the need for development of combinational and adjuvant therapies targeting multiple pathways that are involved in actin dynamics to treat aggressive cSCC. Pharmacological inhibitors of actin have failed clinical development due to non-specific effects on normal actin function in tissue, resulting in high levels of cardiotoxicity. Hence, research efforts have centered on therapeutic approaches that can modify signaling pathways regulating the actomyosin cytoskeleton and/or target cytoskeletal and cytoskeletal-associated proteins [11].
Increasingly it has been recognized that microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are involved in regulating cytoskeletal dynamics through regulation of gene expression. lncRNAs have been shown to regulate lamellipodia formation by downregulating integrin expression in cSCC [83]. A number of miRNAs have also been shown to play a role in regulating cell cytoskeletal dynamics and interactions with stroma in cSCC, including: miR-340 [84], miR-20a [45], miR-31 [85] and miR-125b [86]. These miRNAs act via inhibiting RhoA, LIMK1, WAVE3 and matrix metalloproteinase (MMP)-13 respectively. The use of miRNAs in the clinic has clear potential, however clinical trials are yet to be undertaken.
One of the signaling pathways participating in regulation of cancer cell motility, invasion and metastasis is the ROCK signaling pathway, described in detail above. Hyperactivation of this pathway promotes cancer cell invasion in many solid tumors and studies have shown that Rho signaling through ROCK promotes the rounded bleb-associated mode of amoeboid motility, thereby promoting tumor cell metastasis [87]. Earlier reports have shown that treatment with the selective ROCK inhibitor Y-27632 increases SCC cell adhesion, upregulates expression of E-cadherin, and decreases the phosphorylation of cofilin (thereby activating it), resulting in altered actin cytoskeleton rearrangement [88]. In the two-stage chemical carcinogenesis model, Y27632 treatment resulted in significantly smaller and fewer papillomas, with a reduced rate of cSCC conversion. This was associated with reduced collagen deposition in the ECM, which would indicate a decrease in mechanical signaling due to ECM stiffness [36]. This illustrates that inhibition of ROCK is a potential strategy for treatment of solid cancers including cSCC.
A potential upstream regulator of ROCK-mediated cell migration is gamma-actin. Modulation of gamma-actin changes the directional cell migration via effects on microtubule dynamics and cell polarity, hence highlighting the crosstalk between actin cytoskeleton and microtubule signaling as a potential modality for targeting specific components of the network [89]. More recent studies, using newer generations of ROCK inhibitors and pharmacological small molecule inhibitors of the downstream effectors of ROCK that have micro-tubule stabilizing effects, are also showing some promise in regulating tumor metastasis, however no compounds are yet clinically approved [90]. Another potential therapeutic strategy is harnessing the ability of 14-3-3ζ, a negative regulator of ROCK signaling, to moderate mechanoreciprocity in cSCC [35]. These approaches are particularly enticing due to the negative effects that clinical targeting of ROCK itself can potentially have [91].
Interestingly, studies investigating the interactions between SCC cells and cancer-associated fibroblasts have shown that ROCK activity is also an important requirement for adjacent stromal fibroblasts. ROCK activity positively influences the JAK1-STAT3 signaling pathway resulting in increased actomyosin contractility and proinflammatory cytokine secretion, favoring cSCC cancer cell invasion [92]. Consequently, these studies suggest that approaches aimed at inhibiting ROCK signaling have the potential to interrupt both intrinsic and microenvironment-derived signals during cSCC progression.
Actin remodeling proteins have long been implicated in cSCC, as a dysregulated actin cytoskeleton and an aberrant tumor microenvironment is a hallmark of aggressive cSCC [11, 93]. One particular actin remodeling protein, Flightless I (Flii), has been identified as a tumor promoter with transcriptional activity in colorectal, breast and hepatocellular carcinoma cell lines [66]. However, recent studies have also shown that Flii is significantly increased in human and mouse cSCC tissue samples, while secreted Flii is elevated in the sera of patients with cSCC and is increased in different cSCC cell lines established from human primary, recurring and metastatic cSCC as well as immortalized keratinocytes [23]. Human cSCC samples show positive staining for Flii in invading keratinocytes, surrounding tumor stroma and the outer hyperkeratotic layer of cSCC nodules present in the deep dermis [23]. Together, these data suggest that Flii is not only an important regulator of the actin cytoskeleton involved in cSCC progression but also a potential therapeutic target and diagnostic marker of cSCC severity. Indeed, overexpression of Flii resulted in severe cSCC development via evasion of apoptosis, while reducing Flii expression using intradermal injections of FnAb during cSCC initiation and progression significantly reduced Flii expression in both the tumor microenvironment and in the serum, and led to significantly smaller tumor size (Figure 5) and decreased cellular sphere formation and invasion
Reducing Flii expression prior to initiation and development of cSCC using FnAb results in decreased cSCC progression. As Flii is increased in human SCC samples, the effect of preventative FnAb treatment prior to SCC induction was investigated in FliiTg/Tg mice. Mice were treated with FnAb 2 weeks prior to cSCC induction and every second week throughout the trial and SCC development. (A and B) Reducing Flii levels in mice skin using preventative FnAb treatment prior to cSCC induction and during development resulted in decreased tumor progression and size relative to IgG control mice that have significantly larger and more developed necrotic and ulcerated tumors. (
Remodeling and polymerization of actin filaments is critical during cSCC invasion and formation of invadopodia. Increased Flii levels have shown to weaken cell-stroma and cell-cell adhesions via alteration of GTPase and Src/paxillin signaling pathway activity [32] and augmented integrin-facilitated cell migration [25]. This promotes tumor progression and facilitates invadopodia formation and subsequent tumor invasion into surrounding tissue [23]. Indeed, Flii is significantly increased in invading cSCC and has been demonstrated to associate with cortactin at leading edges of invadopodia and to regulate the invasive properties of cSCC keratinocytes [23]. Systemic and topical therapeutic approaches using FnAb are currently in development with FnAb as a therapy for wound healing now entering the final pre-clinical validation stage [68, 94]. Flii has been shown to colocalize with structural (Claudin-1, -4 and -6) and adaptor (ZO-1 and -2) tight junction proteins and its overexpression in keratinocytes results in an altered F-actin/G-actin ratio, which can be restored using FnAb [72]. Therefore, taken together, these studies suggest that therapies targeting Flii may be a potential strategy for reducing the severity of cSCC in the community, however clinical trials using FnAb are still pending.
Pharmacological inhibition of actin-associated proteins aimed at compromising the survival and invasion of tumor cells may also have clinical benefit. One example of this strategy is harnessing TR100 inhibition of the tropomyosin isoform Tm5NM1. Tm5NM1 belongs to a family of actin-associated proteins that regulate the activity of several effectors of actin filament dynamics [95], as described above. The TR100 inhibitor has been shown to preferentially disrupt the actin cytoskeleton of tumor cells, impairing tumor cell motility and viability, and reducing melanoma growth both
Microtubule targeting agents of both synthetic and natural design, and microtubule stabilizing and destabilizing agents, have been the focus of anti-cancer therapy in the last decade and remain one of the most successful group of agents in the clinic [97, 98]. Their ability to regulate the tubulin-microtubule equilibrium disrupts the mitotic spindle, halting the cell cycle and resulting in cell death. They have been shown to be effective in combination with anti-angiogenic and anti-vascular properties and in some cases have demonstrated the ability to overcome multi-drug resistance, supporting their utilization as a chemotherapy [99]. Epothilones are a new class of anti-microtubule agents currently in clinical trials. Epothilones have shown activity in cSCC cell lines and in melanoma clinically, however clinical trials on cSCC patients are still pending [100, 101]. Other examples of microtubule-targeting agents, which have shown clinical promise in different subtypes of SCC including metastatic and recurrent disease, include semisynthetic compounds docetaxel and eribulin and a natural compound called rhizoxin [102, 103, 104]. While microtubule-targeting compounds are widely used as chemotherapeutic agents, they do have variability in different cancers, cancer cells frequently develop resistance to them, and they can be toxic to normal tissue, highlighting the need for better research and refinement of these compounds as well as a need to further understand their interactions with microtubule-associated proteins [105]. It is possible that microtubule-targeting agents also exert broader effects on tumor cell migration, invasion and metastasis and future studies should explore their effects on cSCC in combination with actin pathway inhibitors. Gaining a better understanding on the interplay of regulatory proteins governing the mechanotransduction and actin cytoskeletal remodeling involved in tumor cell migration, invasion and metastasis will lead to increased efforts to exploit therapeutic avenues targeting the actin cytoskeleton to treat aggressive cSCC.
The contribution of actin cytoskeletal remodeling and actomyosin signaling during SCC progression is significant and cannot be undervalued in the search for new treatment modalities. Recent research has identified a number of potential novel therapeutic targets within regulatory actin and microtubule signaling pathways that should be explored as potential therapeutic adjuvants to immunomodulatory therapies currently in clinical trials. A comprehensive understanding of the regulatory network of cutaneous mechanotransduction, mechanical forces and actin dynamics in cSCC, as discussed in this chapter, will facilitate the development of novel approaches to curb the incidence and progression of aggressive cSCC in the community, generating new inroads toward development of novel, individually personalized and efficient therapeutic approaches.
Dr. Zlatko Kopecki is supported by a Future Industries Institute Foundation Fellowship from University of South Australia. Dr. Sarah Boyle is supported by a Royal Adelaide Hospital Research Fund Early Career Fellowship.
The authors declare no conflict of interest.
Akt | protein kinase B—serine/threonine-specific protein kinase |
AP-1 | activator protein 1—transcription factor that regulates various cellular processes downstream of stimuli |
Arp2/3 | actin-related proteins 2/3 complex—protein complex regulating the actin cytoskeleton |
Cdc42 | cell division control protein 42—protein involved in regulation of cell cycle |
CDKN2A | cyclin-dependent kinase inhibitor 2A |
CRE | cAMP-response element |
cSCC | cutaneous squamous cell carcinoma |
DAMPs | damage-associated molecular pattern molecules |
DMBA | 7,12-dimethylbenz[a]-anthracene—polycyclic aromatic hydrocarbon that acts as a carcinogen |
ECM | extracellular matrix |
EGF | epidermal growth factor |
EGFR | epidermal growth factor receptor |
EMT | epithelial to mesenchymal transition |
Erk | extracellular signal-regulated kinase—kinase involved in regulation of cellular processes such as meiosis and mitosis |
FAK | focal adhesion kinase—a focal adhesion-associated protein kinase involved in cellular adhesion |
Flii | Flightless I |
FnAb | Flii neutralizing antibody |
GSK3β | glycogen synthase kinase 3-beta—serine/threonine protein kinase |
GTPase | enzyme that binds and hydrolyzes guanosine-5′-triphosphate |
H&E | hematoxylin and eosin |
HPV | human papillomavirus |
ILK | integrin-linked kinase |
JAK | janus kinase |
LIMK | LIM-domain kinase |
lncRNA | long non-coding RNA |
MAPK | mitogen-activated protein kinase |
miRNA | microRNA |
MLC2 | myosin regulatory light chain-2—subunit of myosin, which regulates cell contractility |
MMP | matrix metalloproteinase—endopeptidases that degrade various ECM proteins |
MYPT1 | myosin phosphatase target subunit 1—subunit of myosin phosphatase, which dephosphorylates MLC and thereby opposes contractility |
NFκB | nuclear factor kappa-light-chain enhancer of activated B cells—protein complex that regulates transcription and other cellular processes |
PAMPs | pathogen-associated molecular pattern molecules |
PI3K | phosphoinositide 3-kinase—intracellular signal transducer enzymes ROCK: Rho-associated coiled-coil containing kinases |
SNAI1 | snail—transcription factor promoting repression of E-cadherin |
SNAI2 | slug—transcription factor promoting repression of E-cadherin |
STAT | signal transducer and activator of transcription proteins—intracellular transcription factor |
Tiam1 | T-lymphoma invasion and metastasis-inducing protein 1—regulates Rho-like proteins and transduces extracellular signals |
TP53 | tumor protein p53 |
TPA | 12-o-tetradecanoylphorbol-13-acetate—tumor promoting phorbol ester |
TLR-4 | toll-like receptor 4—transmembrane receptor that activates NFκB signaling |
Tm5NM1 | tropomyosin isoform 5NM1 |
Traf6 | tumor necrosis factor (TNF) receptor associated factor 6 |
WASP | Wiskott-Aldrich syndrome protein |
WAVE | WASP-family verprolin-homologous |
Zeb1 | zinc-finger E-box-binding homeobox 1—transcription factor that induces EMT by repression of E-cadherin and other genes |
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After positions as a lecturer at the University of Port Elizabeth, he accepted a position as Associate Professor at the University of Pretoria, South Africa.\r\n\r\nIn 1992, he motivates the concept of 'television and computer-based education” as means to reach large student numbers with only the best of teaching expertise and publishes an article on the concept in the SA Journal of Higher Education of 1993 (and later in 2003). The University of Pretoria subsequently approved a series of test projects on the concept with outreach to Mamelodi and Eerste Rust in 1993. In 1994, the University established a 'Unit for Telematic Education ' as a support section for multiple faculties at the University of Pretoria. In subsequent years, the concept of 'telematic education” subsequently becomes well established in academic circles in South Africa, grew in popularity, and is adopted by many universities and colleges throughout South Africa as a medium of enhancing education and training, as a method to reaching out to far out communities, and as a means to enhance study from the home environment.\r\n\r\nProfessor Snyman in subsequent years pursued research in semiconductor physics, semiconductor devices, microelectronics, and optoelectronics.\r\n\r\nIn 2000 he joined the TUT as a full professor. Here served for a period as head of the Department of Electronic Engineering. Here he makes contributions to solar energy development, microwave and optoelectronic device development, silicon photonics, as well as contributions to new mobile telecommunication systems and network planning in SA.\r\n\r\nCurrently, he teaches electronics and telecommunications at the TUT to audiences ranging from first-year students to Ph.D. level.\r\n\r\nFor his research in the field of 'Silicon Photonics” since 1990, he has published (as author and co-author) about thirty internationally reviewed articles in scientific journals, contributed to more than forty international conferences, about 25 South African provisional patents (as inventor and co-inventor), 8 PCT international patent applications until now. Of these, two USA patents applications, two European Patents, two Korean patents, and ten SA patents have been granted. A further 4 USA patents, 5 European patents, 3 Korean patents, 3 Chinese patents, and 3 Japanese patents are currently under consideration.\r\n\r\nRecently he has also published an extensive scholarly chapter in an internet open access book on 'Integrating Microphotonic Systems and MOEMS into standard Silicon CMOS Integrated circuitry”.\r\n\r\nFurthermore, Professor Snyman recently steered a new initiative at the TUT by introducing a 'Laboratory for Innovative Electronic Systems ' at the Department of Electrical Engineering. The model of this laboratory or center is to primarily combine outputs as achieved by high-level research with lower-level system development and entrepreneurship in a technical university environment. Students are allocated to projects at different levels with PhDs and Master students allocated to the generation of new knowledge and new technologies, while students at the diploma and Baccalaureus level are allocated to electronic systems development with a direct and a near application for application in industry or the commercial and public sectors in South Africa.\r\n\r\nProfessor Snyman received the WIRSAM Award of 1983 and the WIRSAM Award in 1985 in South Africa for best research papers by a young scientist at two international conferences on electron microscopy in South Africa. He subsequently received the SA Microelectronics Award for the best dissertation emanating from studies executed at a South African university in the field of Physics and Microelectronics in South Africa in 1987. In October of 2011, Professor Snyman received the prestigious Institutional Award for 'Innovator of the Year” for 2010 at the Tshwane University of Technology, South Africa. This award was based on the number of patents recognized and granted by local and international institutions as well as for his contributions concerning innovation at the TUT.",institutionString:null,institution:{name:"University of South Africa",country:{name:"South Africa"}}},{id:"317279",title:"Mr.",name:"Ali",middleName:"Usama",surname:"Syed",slug:"ali-syed",fullName:"Ali Syed",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/317279/images/16024_n.png",biography:"A creative, talented, and innovative young professional who is dedicated, well organized, and capable research fellow with two years of experience in graduate-level research, published in engineering journals and book, with related expertise in Bio-robotics, equally passionate about the aesthetics of the mechanical and electronic system, obtained expertise in the use of MS Office, MATLAB, SolidWorks, LabVIEW, Proteus, Fusion 360, having a grasp on python, C++ and assembly language, possess proven ability in acquiring research grants, previous appointments with social and educational societies with experience in administration, current affiliations with IEEE and Web of Science, a confident presenter at conferences and teacher in classrooms, able to explain complex information to audiences of all levels.",institutionString:null,institution:{name:"Air University",country:{name:"Pakistan"}}},{id:"75526",title:"Ph.D.",name:"Zihni Onur",middleName:null,surname:"Uygun",slug:"zihni-onur-uygun",fullName:"Zihni Onur Uygun",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/75526/images/12_n.jpg",biography:"My undergraduate education and my Master of Science educations at Ege University and at Çanakkale Onsekiz Mart University have given me a firm foundation in Biochemistry, Analytical Chemistry, Biosensors, Bioelectronics, Physical Chemistry and Medicine. After obtaining my degree as a MSc in analytical chemistry, I started working as a research assistant in Ege University Medical Faculty in 2014. In parallel, I enrolled to the MSc program at the Department of Medical Biochemistry at Ege University to gain deeper knowledge on medical and biochemical sciences as well as clinical chemistry in 2014. In my PhD I deeply researched on biosensors and bioelectronics and finished in 2020. Now I have eleven SCI-Expanded Index published papers, 6 international book chapters, referee assignments for different SCIE journals, one international patent pending, several international awards, projects and bursaries. In parallel to my research assistant position at Ege University Medical Faculty, Department of Medical Biochemistry, in April 2016, I also founded a Start-Up Company (Denosens Biotechnology LTD) by the support of The Scientific and Technological Research Council of Turkey. Currently, I am also working as a CEO in Denosens Biotechnology. The main purposes of the company, which carries out R&D as a research center, are to develop new generation biosensors and sensors for both point-of-care diagnostics; such as glucose, lactate, cholesterol and cancer biomarker detections. My specific experimental and instrumental skills are Biochemistry, Biosensor, Analytical Chemistry, Electrochemistry, Mobile phone based point-of-care diagnostic device, POCTs and Patient interface designs, HPLC, Tandem Mass Spectrometry, Spectrophotometry, ELISA.",institutionString:null,institution:{name:"Ege University",country:{name:"Turkey"}}},{id:"246502",title:"Dr.",name:"Jaya T.",middleName:"T",surname:"Varkey",slug:"jaya-t.-varkey",fullName:"Jaya T. Varkey",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/246502/images/11160_n.jpg",biography:"Jaya T. Varkey, PhD, graduated with a degree in Chemistry from Cochin University of Science and Technology, Kerala, India. She obtained a PhD in Chemistry from the School of Chemical Sciences, Mahatma Gandhi University, Kerala, India, and completed a post-doctoral fellowship at the University of Minnesota, USA. She is a research guide at Mahatma Gandhi University and Associate Professor in Chemistry, St. Teresa’s College, Kochi, Kerala, India.\nDr. Varkey received a National Young Scientist award from the Indian Science Congress (1995), a UGC Research award (2016–2018), an Indian National Science Academy (INSA) Visiting Scientist award (2018–2019), and a Best Innovative Faculty award from the All India Association for Christian Higher Education (AIACHE) (2019). She Hashas received the Sr. Mary Cecil prize for best research paper three times. She was also awarded a start-up to develop a tea bag water filter. \nDr. Varkey has published two international books and twenty-seven international journal publications. She is an editorial board member for five international journals.",institutionString:"St. Teresa’s College",institution:null},{id:"250668",title:"Dr.",name:"Ali",middleName:null,surname:"Nabipour Chakoli",slug:"ali-nabipour-chakoli",fullName:"Ali Nabipour Chakoli",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/250668/images/system/250668.jpg",biography:"Academic Qualification:\r\n•\tPhD in Materials Physics and Chemistry, From: Sep. 2006, to: Sep. 2010, School of Materials Science and Engineering, Harbin Institute of Technology, Thesis: Structure and Shape Memory Effect of Functionalized MWCNTs/poly (L-lactide-co-ε-caprolactone) Nanocomposites. Supervisor: Prof. Wei Cai,\r\n•\tM.Sc in Applied Physics, From: 1996, to: 1998, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Determination of Boron in Micro alloy Steels with solid state nuclear track detectors by neutron induced auto radiography, Supervisors: Dr. M. Hosseini Ashrafi and Dr. A. Hosseini.\r\n•\tB.Sc. in Applied Physics, From: 1991, to: 1996, Faculty of Physics & Nuclear Science, Amirkabir Uni. of Technology, Tehran, Iran, Thesis: Design of shielding for Am-Be neutron sources for In Vivo neutron activation analysis, Supervisor: Dr. M. Hosseini Ashrafi.\r\n\r\nResearch Experiences:\r\n1.\tNanomaterials, Carbon Nanotubes, Graphene: Synthesis, Functionalization and Characterization,\r\n2.\tMWCNTs/Polymer Composites: Fabrication and Characterization, \r\n3.\tShape Memory Polymers, Biodegradable Polymers, ORC, Collagen,\r\n4.\tMaterials Analysis and Characterizations: TEM, SEM, XPS, FT-IR, Raman, DSC, DMA, TGA, XRD, GPC, Fluoroscopy, \r\n5.\tInteraction of Radiation with Mater, Nuclear Safety and Security, NDT(RT),\r\n6.\tRadiation Detectors, Calibration (SSDL),\r\n7.\tCompleted IAEA e-learning Courses:\r\nNuclear Security (15 Modules),\r\nNuclear Safety:\r\nTSA 2: Regulatory Protection in Occupational Exposure,\r\nTips & Tricks: Radiation Protection in Radiography,\r\nSafety and Quality in Radiotherapy,\r\nCourse on Sealed Radioactive Sources,\r\nCourse on Fundamentals of Environmental Remediation,\r\nCourse on Planning for Environmental Remediation,\r\nKnowledge Management Orientation Course,\r\nFood Irradiation - Technology, Applications and Good Practices,\r\nEmployment:\r\nFrom 2010 to now: Academic staff, Nuclear Science and Technology Research Institute, Kargar Shomali, Tehran, Iran, P.O. Box: 14395-836.\r\nFrom 1997 to 2006: Expert of Materials Analysis and Characterization. Research Center of Agriculture and Medicine. Rajaeeshahr, Karaj, Iran, P. O. Box: 31585-498.",institutionString:"Atomic Energy Organization of Iran",institution:{name:"Atomic Energy Organization of Iran",country:{name:"Iran"}}},{id:"248279",title:"Dr.",name:"Monika",middleName:"Elzbieta",surname:"Machoy",slug:"monika-machoy",fullName:"Monika Machoy",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/248279/images/system/248279.jpeg",biography:"Monika Elżbieta Machoy, MD, graduated with distinction from the Faculty of Medicine and Dentistry at the Pomeranian Medical University in 2009, defended her PhD thesis with summa cum laude in 2016 and is currently employed as a researcher at the Department of Orthodontics of the Pomeranian Medical University. She expanded her professional knowledge during a one-year scholarship program at the Ernst Moritz Arndt University in Greifswald, Germany and during a three-year internship at the Technical University in Dresden, Germany. She has been a speaker at numerous orthodontic conferences, among others, American Association of Orthodontics, European Orthodontic Symposium and numerous conferences of the Polish Orthodontic Society. She conducts research focusing on the effect of orthodontic treatment on dental and periodontal tissues and the causes of pain in orthodontic patients.",institutionString:"Pomeranian Medical University",institution:{name:"Pomeranian Medical University",country:{name:"Poland"}}},{id:"252743",title:"Prof.",name:"Aswini",middleName:"Kumar",surname:"Kar",slug:"aswini-kar",fullName:"Aswini Kar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/252743/images/10381_n.jpg",biography:"uploaded in cv",institutionString:null,institution:{name:"KIIT University",country:{name:"India"}}},{id:"204256",title:"Dr.",name:"Anil",middleName:"Kumar",surname:"Kumar Sahu",slug:"anil-kumar-sahu",fullName:"Anil Kumar Sahu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/204256/images/14201_n.jpg",biography:"I have nearly 11 years of research and teaching experience. I have done my master degree from University Institute of Pharmacy, Pt. Ravi Shankar Shukla University, Raipur, Chhattisgarh India. I have published 16 review and research articles in international and national journals and published 4 chapters in IntechOpen, the world’s leading publisher of Open access books. I have presented many papers at national and international conferences. I have received research award from Indian Drug Manufacturers Association in year 2015. My research interest extends from novel lymphatic drug delivery systems, oral delivery system for herbal bioactive to formulation optimization.",institutionString:null,institution:{name:"Chhattisgarh Swami Vivekanand Technical University",country:{name:"India"}}},{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. Scientific interests: computer analysis and processing of images, biomedical images, databases and programming languages. He is an author and co-author of scientific publications covering analysis and processing of biomedical images and development of database systems.",institutionString:"University of Silesia",institution:null},{id:"212432",title:"Prof.",name:"Hadi",middleName:null,surname:"Mohammadi",slug:"hadi-mohammadi",fullName:"Hadi Mohammadi",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/212432/images/system/212432.jpeg",biography:"Dr. Hadi Mohammadi is a biomedical engineer with hands-on experience in the design and development of many engineering structures and medical devices through various projects that he has been involved in over the past twenty years. Dr. Mohammadi received his BSc. and MSc. degrees in Mechanical Engineering from Sharif University of Technology, Tehran, Iran, and his PhD. degree in Biomedical Engineering (biomaterials) from the University of Western Ontario. He was a postdoctoral trainee for almost four years at University of Calgary and Harvard Medical School. He is an industry innovator having created the technology to produce lifelike synthetic platforms that can be used for the simulation of almost all cardiovascular reconstructive surgeries. He’s been heavily involved in the design and development of cardiovascular devices and technology for the past 10 years. He is currently an Assistant Professor with the University of British Colombia, Canada.",institutionString:"University of British Columbia",institution:{name:"University of British Columbia",country:{name:"Canada"}}},{id:"254463",title:"Prof.",name:"Haisheng",middleName:null,surname:"Yang",slug:"haisheng-yang",fullName:"Haisheng Yang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/254463/images/system/254463.jpeg",biography:"Haisheng Yang, Ph.D., Professor and Director of the Department of Biomedical Engineering, College of Life Science and Bioengineering, Beijing University of Technology. He received his Ph.D. degree in Mechanics/Biomechanics from Harbin Institute of Technology (jointly with University of California, Berkeley). Afterwards, he worked as a Postdoctoral Research Associate in the Purdue Musculoskeletal Biology and Mechanics Lab at the Department of Basic Medical Sciences, Purdue University, USA. He also conducted research in the Research Centre of Shriners Hospitals for Children-Canada at McGill University, Canada. Dr. Yang has over 10 years research experience in orthopaedic biomechanics and mechanobiology of bone adaptation and regeneration. He earned an award from Beijing Overseas Talents Aggregation program in 2017 and serves as Beijing Distinguished Professor.",institutionString:"Beijing University of Technology",institution:null},{id:"255757",title:"Dr.",name:"Igor",middleName:"Victorovich",surname:"Lakhno",slug:"igor-lakhno",fullName:"Igor Lakhno",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255757/images/system/255757.jpg",biography:"Lakhno Igor Victorovich was born in 1971 in Kharkiv (Ukraine). \nMD – 1994, Kharkiv National Medical Univesity.\nOb&Gyn; – 1997, master courses in Kharkiv Medical Academy of Postgraduate Education.\nPhD – 1999, Kharkiv National Medical Univesity.\nDSc – 2019, PL Shupik National Academy of Postgraduate Education \nLakhno Igor has been graduated from an international training courses on reproductive medicine and family planning held in Debrecen University (Hungary) in 1997. Since 1998 Lakhno Igor has worked as an associate professor of the department of obstetrics and gynecology of VN Karazin National University and an associate professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education. Since June 2019 he’s a professor of the department of obstetrics and gynecology of VN Karazin National University and a professor of the perinatology, obstetrics and gynecology department of Kharkiv Medical Academy of Postgraduate Education . He’s an author of about 200 printed works and there are 17 of them in Scopus or Web of Science databases. Lakhno Igor is a rewiever of Journal of Obstetrics and Gynaecology (Taylor and Francis), Informatics in Medicine Unlocked (Elsevier), The Journal of Obstetrics and Gynecology Research (Wiley), Endocrine, Metabolic & Immune Disorders-Drug Targets (Bentham Open), The Open Biomedical Engineering Journal (Bentham Open), etc. He’s defended a dissertation for DSc degree \\'Pre-eclampsia: prediction, prevention and treatment”. Lakhno Igor has participated as a speaker in several international conferences and congresses (International Conference on Biological Oscillations April 10th-14th 2016, Lancaster, UK, The 9th conference of the European Study Group on Cardiovascular Oscillations). His main scientific interests: obstetrics, women’s health, fetal medicine, cardiovascular medicine.",institutionString:"V.N. Karazin Kharkiv National University",institution:{name:"Kharkiv Medical Academy of Postgraduate Education",country:{name:"Ukraine"}}},{id:"89721",title:"Dr.",name:"Mehmet",middleName:"Cuneyt",surname:"Ozmen",slug:"mehmet-ozmen",fullName:"Mehmet Ozmen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/89721/images/7289_n.jpg",biography:null,institutionString:null,institution:{name:"Gazi University",country:{name:"Turkey"}}},{id:"243698",title:"M.D.",name:"Xiaogang",middleName:null,surname:"Wang",slug:"xiaogang-wang",fullName:"Xiaogang Wang",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243698/images/system/243698.png",biography:"Dr. Xiaogang Wang, a faculty member of Shanxi Eye Hospital specializing in the treatment of cataract and retinal disease and a tutor for postgraduate students of Shanxi Medical University, worked in the COOL Lab as an international visiting scholar under the supervision of Dr. David Huang and Yali Jia from October 2012 through November 2013. Dr. Wang earned an MD from Shanxi Medical University and a Ph.D. from Shanghai Jiao Tong University. Dr. Wang was awarded two research project grants focused on multimodal optical coherence tomography imaging and deep learning in cataract and retinal disease, from the National Natural Science Foundation of China. He has published around 30 peer-reviewed journal papers and four book chapters and co-edited one book.",institutionString:"Shanxi Eye Hospital",institution:{name:"Shanxi Eye Hospital",country:{name:"China"}}},{id:"242893",title:"Ph.D. Student",name:"Joaquim",middleName:null,surname:"De Moura",slug:"joaquim-de-moura",fullName:"Joaquim De Moura",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/242893/images/7133_n.jpg",biography:"Joaquim de Moura received his degree in Computer Engineering in 2014 from the University of A Coruña (Spain). In 2016, he received his M.Sc degree in Computer Engineering from the same university. He is currently pursuing his Ph.D degree in Computer Science in a collaborative project between ophthalmology centers in Galicia and the University of A Coruña. His research interests include computer vision, machine learning algorithms and analysis and medical imaging processing of various kinds.",institutionString:null,institution:{name:"University of A Coruña",country:{name:"Spain"}}},{id:"267434",title:"Dr.",name:"Rohit",middleName:null,surname:"Raja",slug:"rohit-raja",fullName:"Rohit Raja",position:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRZkkQAG/Profile_Picture_2022-05-09T12:55:18.jpg",biography:null,institutionString:null,institution:null},{id:"294334",title:"B.Sc.",name:"Marc",middleName:null,surname:"Bruggeman",slug:"marc-bruggeman",fullName:"Marc Bruggeman",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/294334/images/8242_n.jpg",biography:"Chemical engineer graduate, with a passion for material science and specific interest in polymers - their near infinite applications intrigue me. \n\nI plan to continue my scientific career in the field of polymeric biomaterials as I am fascinated by intelligent, bioactive and biomimetic materials for use in both consumer and medical applications.",institutionString:null,institution:null},{id:"244950",title:"Dr.",name:"Salvatore",middleName:null,surname:"Di Lauro",slug:"salvatore-di-lauro",fullName:"Salvatore Di Lauro",position:null,profilePictureURL:"https://intech-files.s3.amazonaws.com/0030O00002bSF1HQAW/ProfilePicture%202021-12-20%2014%3A54%3A14.482",biography:"Name:\n\tSALVATORE DI LAURO\nAddress:\n\tHospital Clínico Universitario Valladolid\nAvda Ramón y Cajal 3\n47005, Valladolid\nSpain\nPhone number: \nFax\nE-mail:\n\t+34 983420000 ext 292\n+34 983420084\nsadilauro@live.it\nDate and place of Birth:\nID Number\nMedical Licence \nLanguages\t09-05-1985. Villaricca (Italy)\n\nY1281863H\n474707061\nItalian (native language)\nSpanish (read, written, spoken)\nEnglish (read, written, spoken)\nPortuguese (read, spoken)\nFrench (read)\n\t\t\nCurrent position (title and company)\tDate (Year)\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. Private practise.\t2017-today\n\n2019-today\n\t\n\t\nEducation (High school, university and postgraduate training > 3 months)\tDate (Year)\nDegree in Medicine and Surgery. University of Neaples 'Federico II”\nResident in Opthalmology. Hospital Clinico Universitario Valladolid\nMaster in Vitreo-Retina. IOBA. University of Valladolid\nFellow of the European Board of Ophthalmology. Paris\nMaster in Research in Ophthalmology. University of Valladolid\t2003-2009\n2012-2016\n2016-2017\n2016\n2012-2013\n\t\nEmployments (company and positions)\tDate (Year)\nResident in Ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl.\nFellow in Vitreo-Retina. IOBA. University of Valladolid\nVitreo-Retinal consultant in ophthalmology. Hospital Clinico Universitario Valladolid. Sacyl. National Health System.\nVitreo-Retinal consultant in ophthalmology. Instituto Oftalmologico Recoletas. Red Hospitalaria Recoletas. \n\t2012-2016\n2016-2017\n2017-today\n\n2019-Today\n\n\n\t\nClinical Research Experience (tasks and role)\tDate (Year)\nAssociated investigator\n\n' FIS PI20/00740: DESARROLLO DE UNA CALCULADORA DE RIESGO DE\nAPARICION DE RETINOPATIA DIABETICA BASADA EN TECNICAS DE IMAGEN MULTIMODAL EN PACIENTES DIABETICOS TIPO 1. Grant by: Ministerio de Ciencia e Innovacion \n\n' (BIO/VA23/14) Estudio clínico multicéntrico y prospectivo para validar dos\nbiomarcadores ubicados en los genes p53 y MDM2 en la predicción de los resultados funcionales de la cirugía del desprendimiento de retina regmatógeno. Grant by: Gerencia Regional de Salud de la Junta de Castilla y León.\n' Estudio multicéntrico, aleatorizado, con enmascaramiento doble, en 2 grupos\nparalelos y de 52 semanas de duración para comparar la eficacia, seguridad e inmunogenicidad de SOK583A1 respecto a Eylea® en pacientes con degeneración macular neovascular asociada a la edad' (CSOK583A12301; N.EUDRA: 2019-004838-41; FASE III). Grant by Hexal AG\n\n' Estudio de fase III, aleatorizado, doble ciego, con grupos paralelos, multicéntrico para comparar la eficacia y la seguridad de QL1205 frente a Lucentis® en pacientes con degeneración macular neovascular asociada a la edad. (EUDRACT: 2018-004486-13). Grant by Qilu Pharmaceutical Co\n\n' Estudio NEUTON: Ensayo clinico en fase IV para evaluar la eficacia de aflibercept en pacientes Naive con Edema MacUlar secundario a Oclusion de Vena CenTral de la Retina (OVCR) en regimen de tratamientO iNdividualizado Treat and Extend (TAE)”, (2014-000975-21). Grant by Fundacion Retinaplus\n\n' Evaluación de la seguridad y bioactividad de anillos de tensión capsular en conejo. Proyecto Procusens. Grant by AJL, S.A.\n\n'Estudio epidemiológico, prospectivo, multicéntrico y abierto\\npara valorar la frecuencia de la conjuntivitis adenovírica diagnosticada mediante el test AdenoPlus®\\nTest en pacientes enfermos de conjuntivitis aguda”\\n. National, multicenter study. Grant by: NICOX.\n\nEuropean multicentric trial: 'Evaluation of clinical outcomes following the use of Systane Hydration in patients with dry eye”. Study Phase 4. Grant by: Alcon Labs'\n\nVLPs Injection and Activation in a Rabbit Model of Uveal Melanoma. Grant by Aura Bioscience\n\nUpdating and characterization of a rabbit model of uveal melanoma. Grant by Aura Bioscience\n\nEnsayo clínico en fase IV para evaluar las variantes genéticas de la vía del VEGF como biomarcadores de eficacia del tratamiento con aflibercept en pacientes con degeneración macular asociada a la edad (DMAE) neovascular. Estudio BIOIMAGE. IMO-AFLI-2013-01\n\nEstudio In-Eye:Ensayo clínico en fase IV, abierto, aleatorizado, de 2 brazos,\nmulticçentrico y de 12 meses de duración, para evaluar la eficacia y seguridad de un régimen de PRN flexible individualizado de 'esperar y extender' versus un régimen PRN según criterios de estabilización mediante evaluaciones mensuales de inyecciones intravítreas de ranibizumab 0,5 mg en pacientes naive con neovascularización coriodea secunaria a la degeneración macular relacionada con la edad. CP: CRFB002AES03T\n\nTREND: Estudio Fase IIIb multicéntrico, randomizado, de 12 meses de\nseguimiento con evaluador de la agudeza visual enmascarado, para evaluar la eficacia y la seguridad de ranibizumab 0.5mg en un régimen de tratar y extender comparado con un régimen mensual, en pacientes con degeneración macular neovascular asociada a la edad. CP: CRFB002A2411 Código Eudra CT:\n2013-002626-23\n\n\n\nPublications\t\n\n2021\n\n\n\n\n2015\n\n\n\n\n2021\n\n\n\n\n\n2021\n\n\n\n\n2015\n\n\n\n\n2015\n\n\n2014\n\n\n\n\n2015-16\n\n\n\n2015\n\n\n2014\n\n\n2014\n\n\n\n\n2014\n\n\n\n\n\n\n\n2014\n\nJose Carlos Pastor; Jimena Rojas; Salvador Pastor-Idoate; Salvatore Di Lauro; Lucia Gonzalez-Buendia; Santiago Delgado-Tirado. Proliferative vitreoretinopathy: A new concept of disease pathogenesis and practical\nconsequences. Progress in Retinal and Eye Research. 51, pp. 125 - 155. 03/2016. DOI: 10.1016/j.preteyeres.2015.07.005\n\n\nLabrador-Velandia S; Alonso-Alonso ML; Di Lauro S; García-Gutierrez MT; Srivastava GK; Pastor JC; Fernandez-Bueno I. Mesenchymal stem cells provide paracrine neuroprotective resources that delay degeneration of co-cultured organotypic neuroretinal cultures.Experimental Eye Research. 185, 17/05/2019. DOI: 10.1016/j.exer.2019.05.011\n\nSalvatore Di Lauro; Maria Teresa Garcia Gutierrez; Ivan Fernandez Bueno. Quantification of pigment epithelium-derived factor (PEDF) in an ex vivo coculture of retinal pigment epithelium cells and neuroretina.\nJournal of Allbiosolution. 2019. ISSN 2605-3535\n\nSonia Labrador Velandia; Salvatore Di Lauro; Alonso-Alonso ML; Tabera Bartolomé S; Srivastava GK; Pastor JC; Fernandez-Bueno I. Biocompatibility of intravitreal injection of human mesenchymal stem cells in immunocompetent rabbits. Graefe's archive for clinical and experimental ophthalmology. 256 - 1, pp. 125 - 134. 01/2018. DOI: 10.1007/s00417-017-3842-3\n\n\nSalvatore Di Lauro, David Rodriguez-Crespo, Manuel J Gayoso, Maria T Garcia-Gutierrez, J Carlos Pastor, Girish K Srivastava, Ivan Fernandez-Bueno. A novel coculture model of porcine central neuroretina explants and retinal pigment epithelium cells. Molecular Vision. 2016 - 22, pp. 243 - 253. 01/2016.\n\nSalvatore Di Lauro. Classifications for Proliferative Vitreoretinopathy ({PVR}): An Analysis of Their Use in Publications over the Last 15 Years. Journal of Ophthalmology. 2016, pp. 1 - 6. 01/2016. DOI: 10.1155/2016/7807596\n\nSalvatore Di Lauro; Rosa Maria Coco; Rosa Maria Sanabria; Enrique Rodriguez de la Rua; Jose Carlos Pastor. Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study. Journal of Ophthalmology. 2015:821864, 2015. DOI: 10.1155/2015/821864\n\nIvan Fernandez-Bueno; Salvatore Di Lauro; Ivan Alvarez; Jose Carlos Lopez; Maria Teresa Garcia-Gutierrez; Itziar Fernandez; Eva Larra; Jose Carlos Pastor. Safety and Biocompatibility of a New High-Density Polyethylene-Based\nSpherical Integrated Porous Orbital Implant: An Experimental Study in Rabbits. Journal of Ophthalmology. 2015:904096, 2015. DOI: 10.1155/2015/904096\n\nPastor JC; Pastor-Idoate S; Rodríguez-Hernandez I; Rojas J; Fernandez I; Gonzalez-Buendia L; Di Lauro S; Gonzalez-Sarmiento R. Genetics of PVR and RD. Ophthalmologica. 232 - Suppl 1, pp. 28 - 29. 2014\n\nRodriguez-Crespo D; Di Lauro S; Singh AK; Garcia-Gutierrez MT; Garrosa M; Pastor JC; Fernandez-Bueno I; Srivastava GK. Triple-layered mixed co-culture model of RPE cells with neuroretina for evaluating the neuroprotective effects of adipose-MSCs. Cell Tissue Res. 358 - 3, pp. 705 - 716. 2014.\nDOI: 10.1007/s00441-014-1987-5\n\nCarlo De Werra; Salvatore Condurro; Salvatore Tramontano; Mario Perone; Ivana Donzelli; Salvatore Di Lauro; Massimo Di Giuseppe; Rosa Di Micco; Annalisa Pascariello; Antonio Pastore; Giorgio Diamantis; Giuseppe Galloro. Hydatid disease of the liver: thirty years of surgical experience.Chirurgia italiana. 59 - 5, pp. 611 - 636.\n(Italia): 2007. ISSN 0009-4773\n\nChapters in books\n\t\n' Salvador Pastor Idoate; Salvatore Di Lauro; Jose Carlos Pastor Jimeno. PVR: Pathogenesis, Histopathology and Classification. Proliferative Vitreoretinopathy with Small Gauge Vitrectomy. Springer, 2018. ISBN 978-3-319-78445-8\nDOI: 10.1007/978-3-319-78446-5_2. \n\n' Salvatore Di Lauro; Maria Isabel Lopez Galvez. Quistes vítreos en una mujer joven. Problemas diagnósticos en patología retinocoroidea. Sociedad Española de Retina-Vitreo. 2018.\n\n' Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor Jimeno. iOCT in PVR management. OCT Applications in Opthalmology. pp. 1 - 8. INTECH, 2018. DOI: 10.5772/intechopen.78774.\n\n' Rosa Coco Martin; Salvatore Di Lauro; Salvador Pastor Idoate; Jose Carlos Pastor. amponadores, manipuladores y tinciones en la cirugía del traumatismo ocular.Trauma Ocular. Ponencia de la SEO 2018..\n\n' LOPEZ GALVEZ; DI LAURO; CRESPO. OCT angiografia y complicaciones retinianas de la diabetes. PONENCIA SEO 2021, CAPITULO 20. (España): 2021.\n\n' Múltiples desprendimientos neurosensoriales bilaterales en paciente joven. Enfermedades Degenerativas De Retina Y Coroides. SERV 04/2016. \n' González-Buendía L; Di Lauro S; Pastor-Idoate S; Pastor Jimeno JC. Vitreorretinopatía proliferante (VRP) e inflamación: LA INFLAMACIÓN in «INMUNOMODULADORES Y ANTIINFLAMATORIOS: MÁS ALLÁ DE LOS CORTICOIDES. 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This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. 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Novel computational algorithms for image analysis, scene understanding, biometrics, deep learning and their software or hardware implementations for natural and medical images, robotics, VR/AR, applications are some research directions relevant to this topic.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/24.jpg",keywords:"Image Analysis, Scene Understanding, Biometrics, Deep Learning, Software Implementation, Hardware Implementation, Natural Images, Medical Images, Robotics, VR/AR"},{id:"25",title:"Evolutionary Computation",scope:"Evolutionary computing is a paradigm that has grown dramatically in recent years. This group of bio-inspired metaheuristics solves multiple optimization problems by applying the metaphor of natural selection. It so far has solved problems such as resource allocation, routing, schedule planning, and engineering design. Moreover, in the field of machine learning, evolutionary computation has carved out a significant niche both in the generation of learning models and in the automatic design and optimization of hyperparameters in deep learning models. This collection aims to include quality volumes on various topics related to evolutionary algorithms and, alternatively, other metaheuristics of interest inspired by nature. 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It has become a massive part of our daily lives, making predictions based on experience, making this a fascinating area that solves problems that otherwise would not be possible or easy to solve. This topic aims to encompass algorithms that learn from experience (supervised and unsupervised), improve their performance over time and enable machines to make data-driven decisions. It is not limited to any particular applications, but contributions are encouraged from all disciplines.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/26.jpg",keywords:"Intelligent Systems, Machine Learning, Data Science, Data Mining, Artificial Intelligence"},{id:"27",title:"Multi-Agent Systems",scope:"Multi-agent systems are recognised as a state of the art field in Artificial Intelligence studies, which is popular due to the usefulness in facilitation capabilities to handle real-world problem-solving in a distributed fashion. 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We welcome chapters presenting research on the many applications of multi-agent studies including, but not limited to, the following key areas: machine learning for multi-agent systems; modeling swarms robots and flocks of UAVs with multi-agent systems; decision science and multi-agent systems; software engineering for and with multi-agent systems; tools and technologies of multi-agent systems.",coverUrl:"https://cdn.intechopen.com/series_topics/covers/27.jpg",keywords:"Collaborative Intelligence, Learning, Distributed Control System, Swarm Robotics, Decision Science, Software Engineering"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"25",title:"Environmental Sciences",doi:"10.5772/intechopen.100362",issn:"2754-6713",scope:"
\r\n\tScientists have long researched to understand the environment and man’s place in it. The search for this knowledge grows in importance as rapid increases in population and economic development intensify humans’ stresses on ecosystems. Fortunately, rapid increases in multiple scientific areas are advancing our understanding of environmental sciences. Breakthroughs in computing, molecular biology, ecology, and sustainability science are enhancing our ability to utilize environmental sciences to address real-world problems.
\r\n\tThe four topics of this book series - Pollution; Environmental Resilience and Management; Ecosystems and Biodiversity; and Water Science - will address important areas of advancement in the environmental sciences. They will represent an excellent initial grouping of published works on these critical topics.
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
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",annualVolume:11967,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/39.jpg",editor:{id:"137040",title:"Prof.",name:"Jose",middleName:null,surname:"Navarro-Pedreño",fullName:"Jose Navarro-Pedreño",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRAXrQAO/Profile_Picture_2022-03-09T15:50:19.jpg",institutionString:"Miguel Hernández University of Elche, Spain",institution:null},editorTwo:null,editorThree:null,editorialBoard:[{id:"177015",title:"Prof.",name:"Elke Jurandy",middleName:null,surname:"Bran Nogueira Cardoso",fullName:"Elke Jurandy Bran Nogueira Cardoso",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRGxzQAG/Profile_Picture_2022-03-25T08:32:33.jpg",institutionString:"Universidade de São Paulo, Brazil",institution:null},{id:"211260",title:"Dr.",name:"Sandra",middleName:null,surname:"Ricart",fullName:"Sandra Ricart",profilePictureURL:"https://mts.intechopen.com/storage/users/211260/images/system/211260.jpeg",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}}]},{id:"40",title:"Ecosystems and Biodiversity",keywords:"Ecosystems, Biodiversity, Fauna, Taxonomy, Invasive species, Destruction of habitats, Overexploitation of natural resources, Pollution, Global warming, Conservation of natural spaces, Bioremediation",scope:"