3.1.4 Polymer-based composites containing magnetic particles composites

A binary or even ternary component consists of two or more types of the fillers provide an effective way to bypass the inherent shortcomings of a single-filler composite. The incorporation of magnetic components will supplement the attenuation properties of a carbon-based EMI shielding material.

Physical blending or deposition of metallic particles within a polymer blend or structure is the most direct way of incorporation a third element, however, such method faces the problem of uniform dispersion and deposition at the bottom layers due to the higher density of metallic particles. Electroless plating of metals on carbon substrates provides a neat way of incorporating metal components uniformly into a system without excessive weight addition. Works by Kim et al. [26] and Yim et al. [27] dispersed nickel coated MWCNT through electroless plating in epoxy and high-density polyethylene, respectively. Figure 5a gives an illustration of

#### Figure 5.

(a) Schematic diagram of the electroless Ni-plating process; (b) SEM images of (1) pristine MWCNTs and (2) Ni-coated MWCNTs, respectively; (c) comparison of the EMI SE of MWCNTs/HDPE and Ni-MWCNTs/ HDPE and (d) the proposed shielding mechanism of Ni-MWCNTs/HDPE [27].

Lightweight Electromagnetic Interference Shielding Materials and Their Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.82270

the nickel coated MWCNTs. It is apparent that the nickel coated MWCNTs appeared rougher comparing to the pristine ones due to the presence of nickel particles as shown Figure 5b. Yim achieved 140% (at 1 GHz, Figure 5c) in enhancement of the EMI SE compared to the pristine MWCNT/polymer composites. The enhancement was attributed to the increased surface conductivity. Figure 5d shows the proposed shielding mechanism of Ni-MWCNTs/HDPE. EM wave was firstly reflected at the composite surfaces upon reaching the surface of the composite. When the penetrated EM wave meets the nickel layer on the MWCNTs, the metallic layer functioned as EM absorbable or reflective fillers. It is evident that the EMI absorbing nature of the metallic layer can be used as an effective additional shielding material despite the small amount present in the systems.

#### 3.2 Foams and aerogels used in EMI shielding

hollow cylinder, that is, single-walled carbon nanotubes (SWCNTs) or of a collection of graphene concentric cylinders, that is, multi-walled carbon nanotubes (MWCNTs) [21, 22]. Graphene sheet (GS), an atomically thick two-dimensional structure, exhibited excellent mechanical, thermal and electrical properties [23]. Both CNTs and graphene offer substantial advantages over conventional carbon fillers and the percolation threshold can be achieved by both at very low content if

In general, carbon fillers with high aspect ratio are generally more effective in imparting electrical conductivities to a polymer matrix, hence it is no surprise to observe the highest SE from fillers with the highest aspect ratio, that is, SWCNTs > MWCNTs > CNFs > CB when the volume fraction of the fillers is the same. The different methods of fillers dispersion and various carbon filler surface modification methods were comprehensively reviewed in the published paper and will not be

A binary or even ternary component consists of two or more types of the fillers

Physical blending or deposition of metallic particles within a polymer blend or structure is the most direct way of incorporation a third element, however, such method faces the problem of uniform dispersion and deposition at the bottom layers due to the higher density of metallic particles. Electroless plating of metals on carbon substrates provides a neat way of incorporating metal components uniformly into a system without excessive weight addition. Works by Kim et al. [26] and Yim et al. [27] dispersed nickel coated MWCNT through electroless plating in epoxy and high-density polyethylene, respectively. Figure 5a gives an illustration of

(a) Schematic diagram of the electroless Ni-plating process; (b) SEM images of (1) pristine MWCNTs and (2) Ni-coated MWCNTs, respectively; (c) comparison of the EMI SE of MWCNTs/HDPE and Ni-MWCNTs/

HDPE and (d) the proposed shielding mechanism of Ni-MWCNTs/HDPE [27].

provide an effective way to bypass the inherent shortcomings of a single-filler composite. The incorporation of magnetic components will supplement the attenu-

discussed in detail here [3, 24]. The EMI shielding performance of the polymer/carbon-fillers composites can also be found in Ref. [3, 7, 24, 25].

3.1.4 Polymer-based composites containing magnetic particles composites

ation properties of a carbon-based EMI shielding material.

properly dispersed.

Electromagnetic Materials and Devices

Figure 5.

220

In view of the rigid index of fuel-economy in the applications of automobile and aerospace, lightweight EMI shielding materials with the combination of reduced density and high EMI SE are much preferred. In this section, we aim to provide a general overview on the preparation of foam and aerogel materials used in EMI shielding and the advantages and challenges faced by each category and possible strategies towards enhancing their EMI shielding performances. The specific EMI SE, defined as the ratio of the EMI SE to the density (SSE) or both density and thickness (SSE/t), is a more appropriate criterion to compare the EMI shielding performance with those of other typical materials for the applications where lightweight is required.

#### 3.2.1 Polymer-based composite foams

Conductive polymer-based composites foams offer significant reduction in weight, while the pores decrease the real part of the permittivity, accordingly reducing the reflection at the material surface. The porous structure enhances the energy absorption through wave scattering in the walls of the pores. Electrically conductive fillers, including CNFs, CNTs and graphene sheets, are commonly used to form a desirable conducting network within the inherently insulating polymer foam matrix. Yang et al. [28] first reported CNFs reinforced polystyrene (PS) composite foam as a conductive foam for EMI shielding application. The EMI SE of PS/CNFs foam containing 1 wt% CNFs was less than 1 dB, upon increasing CNFs content to 15 wt%, EMI SE increased to 19 dB. Following this work, the authors reported PS/CNTs composite foam with varying CNTs contents from 0 to 7 wt% [4]. The PS/CNTs composite foam achieved a higher EMI SE of above 10 dB compared to 3 dB for the PS/CNFs composite foam at the same filler content of 3 wt%. The difference in the results originated from the remarkable electrical and structural properties of CNTs, such as larger aspect ratio, smaller diameter, higher electrical conductivity and strength, compared to CNFs.

#### 3.2.2 Syntactic foams

Syntactic foam, filling hollow spheres in a matrix, is a kind of lightweight composite materials. The approaches to enhance the EMI SE of syntactic foams include (i) hollow particles made of a conductive material; (ii) coating a conductive layer onto the surface of hollow particles and (iii) adding a second conductive filler in syntactic foam matrix.

Zhang et al. [29] added a second conductive filler, (CNFs, chopped carbon fiber (CCF), and long carbon fiber (LCF)), into syntactic foams containing conductive

transmittance (T) in Figure 6c. The specimens were both reflective and absorptive towards EM radiation at silver content less than 17.8 wt%. The contribution of reflection (0.83) towards EMI SE surpassed that from absorption (0.16) when silver content increased to 28.5%. The dense and thick electrically conductive silver formed due to further increasing the silver content to 30.5 wt% increased the R to

Xu et al. [31] fabricated syntactic foams ("hybridized epoxy composite foams" according to authors) through impregnating expandable epoxy/MWCNT/microsphere blends into a preformed, highly porous, and 3D silver-coated melamine foam (SF) sponge. The highly conductive SF resolved the problem of the foam reduction of high filled epoxy blends and provided channels for rapid electron transport. MWCNTs were used to offset the loss of conductive pathways due to the crystal defects in the silver layer and the insulating epoxy resin. As a result, the EMI SE of 68.1 dB was achieved with only 2 wt% of MWCNTs and 3.7 wt% of silver due

Carbon foam is a class of three-dimensional (3D) architecture consisting of a sponge-like interconnected network of porous carbon. Carbon foams have been wildly used as candidates for realistic EMI shielding applications due to their excellent properties, such as low density, resistance to chemical corrosion, high thermal

carbonization of phthalonitrile (PN)-based polymer foam, as shown in Figure 7a. High EMI SE of 51.2 dB (see Figure 7b, C1000 was labeled as the carbonization of 1000°C) was contributed by the high graphitic carbonaceous species and the intrinsic nitrogen-containing structure. The carbon foams showed the best SSE of

developed by Zhang provides an excellent low-density and high-performance EMI

The EMI SE of carbon foams was closely related to the char yield of polymer precursors and the demanding carbonization conditions. Therefore, a new kind of filler-free lightweight EMI shielding material, is in demand, which can be prepared without the stringent processing conditions. In view of the lightweight requirement, assembling one dimensional (1D) CNTs and two-dimensional (2D) graphene sheets into three dimensional (3D) macroscopic porous structures (e.g., sponges,

(a) Schematic representation of the preparation of PN-based carbon foams and (b) EMI SE of carbon foams [32].

shielding material for use in areas where mechanical integrity is desired.

/g so far when mechanical property was considered. The carbon foam

) carbon foam by direct

and electrical conductivity, and high temperature resistance. Zhang et al. [32] prepared a novel ultralight (0.15 g/cm3

foams and aerogels) emerged as an efficient approach.

0.97 and resultant in reflection as the dominant shielding mechanism.

Lightweight Electromagnetic Interference Shielding Materials and Their Mechanisms

to the synergy of the MWCNT and SF.

DOI: http://dx.doi.org/10.5772/intechopen.82270

3.2.3 Carbon foams

341.1 dB cm3

Figure 7.

223

3.2.4 CNTs/graphene foams

Table 2.

Comparison of the EMI SE (dB) of CNF, CCF, and LCF reinforced syntactic foam.

hollow carbon microspheres (HCMs). The EMI SE values of used syntactic foams at the same filler content were compared, as shown as Table 2. The results showed that CNFs is more effective in providing EMI shielding compared to CCF and LCF due to the larger aspect ratio of CNFs.

Zhang et al. [30] also demonstrated the effect of functionalization of HCMs on the EMI SE of the epoxy-HCMs syntactic foam. HCMs were coated with polydopamine (PDA) via the self-polymerization of dopamine. The PDA coating promotes dispersion and served as a reducing agent to deposit silver (Ag) particles on the surface of HCMs as illustrated in Figure 6a. The average EMI SE of the epoxy-HCMs syntactic foam containing Ag-PDA-HCMs with 28.5 and 30.5 wt% of silver in the X-band achieved 49.5 and 60.2 dB, respectively as shown in Figure 6b. The SSE reached up to 46.3 dB cm3 /g, demonstrating the prospect of epoxy/Ag-PDA-HCMs syntactic foam as a lightweight high-performance EMI shielding material. The corresponding EMI shielding mechanism of this syntactic foam was analyzed by comparing the values of reflectance (R), absorptance (A), and

#### Figure 6.

(a) Schematic illustration of the procedure for preparation of PDA-HCMs and Ag-PDA-HCMs; (b) EMI SE in the frequency range from 8 to 12 GHz for syntactic foam containing pristine HCMs and Ag-PDA-HCMs with different silver contents; and (c) reflectance (R), absorbance (A), and transmittance (T) of EM radiation over syntactic foams containing Ag-PDA-HCMs with different silver content at 10 GHz [30].

### Lightweight Electromagnetic Interference Shielding Materials and Their Mechanisms DOI: http://dx.doi.org/10.5772/intechopen.82270

transmittance (T) in Figure 6c. The specimens were both reflective and absorptive towards EM radiation at silver content less than 17.8 wt%. The contribution of reflection (0.83) towards EMI SE surpassed that from absorption (0.16) when silver content increased to 28.5%. The dense and thick electrically conductive silver formed due to further increasing the silver content to 30.5 wt% increased the R to 0.97 and resultant in reflection as the dominant shielding mechanism.

Xu et al. [31] fabricated syntactic foams ("hybridized epoxy composite foams" according to authors) through impregnating expandable epoxy/MWCNT/microsphere blends into a preformed, highly porous, and 3D silver-coated melamine foam (SF) sponge. The highly conductive SF resolved the problem of the foam reduction of high filled epoxy blends and provided channels for rapid electron transport. MWCNTs were used to offset the loss of conductive pathways due to the crystal defects in the silver layer and the insulating epoxy resin. As a result, the EMI SE of 68.1 dB was achieved with only 2 wt% of MWCNTs and 3.7 wt% of silver due to the synergy of the MWCNT and SF.


3. Giant magnetostrictive actuator experiment

The experiments mainly include the giant magnetostrictive actuator, NI host controller, capture cards and displays, LabVIEW software, FN15150 power amplifier, MEL laser displacement sensor, and CHINT current transformer. NI equipment and software are used to capture and display the current and displacement signal, the amplifier amplifies NI weak signals to drive actuators, and the laser displacement sensor is used to accurately measure the actuator displacement. The GMA experiment setup is shown in Figure 3. This experiment studies the hysteresis nonlinear model displacement responses to the preload and the bias magnetic field intensity, as shown in Figures 4 and 5. By optimising the actuator preload and bias magnetic field, the GMA can eliminate the doubling phenomenon and work perfectly within a linear range, which can enhance the actuator output linearity.

#### Figure 3.

current) and bias magnetic field Hb, λs is the saturation magnetostrictive coefficient, σ~ ¼ σ0 þ σ is the external stress (σ0 is the preload), μ0 is the vacuum permeability, Ms is the saturation magnetisation, λ is the axial magnetostriction strain, a is the shape factor of non-hysteresis magnetisation, k is the irreversible loss coeffi-

ible factor, the parameter δ � þ1 when dH >0 and parameter δ � �1 when dH < 0, Man is the non-hysteresis magnetisation, Mirr is the irreversible magnetisation, Mrev is reversible magnetisation, and M is the total magnetisation. C, ρ, L, A, and SH are, respectively, the damping, density, length and cross-sectional area, and axial compliance coefficient of the magnetostrictive rod; m1 ¼ ρLA=3, c1 ¼ cA=L, and k1 ¼ A=SHL are, respectively, the equivalent mass, damping, and stiffness coefficient of the magnetostrictive rod; m2, c2, and k2 are, respectively, the equivalent mass, damping, and stiffness coefficient of the end load; and s is the Laplace

s is the integrated magnetic domain coefficient, c is the revers-

cient, α is the molecular field parameter of interacting magnetic torque,

Noise and Vibration Control - From Theory to Practice

2.2 Magnetostrictive actuator model for wide frequency range

dM dt ¼ ∂M ∂H dH dt þ

Eqs. (2)–(5), the differential susceptibility can be expressed as such:

magnetisation intensity M can be expressed as follows:

∂M

change rate can be determined by Eq. (11):

magnetisation change rate can be obtained:

dt ¼ ð Þ 1 � c

SHσ

þ

dM

4

∂H ¼ ð Þ 1 � c

∂M ∂σ ¼ SHσ

When the driving frequency is low, temperature and eddy current can be ignored on the actuator linearity. However, to fully describe the actuator dynamic characteristics on a wide frequency range, it is necessary to consider the hysteresis

where magnetisation change rate is made up of differential susceptibility ∂M=∂H, the magnetic field change rate ∂H=∂t, magnetisation stress change rate ∂M=∂σ, and stress change rate ∂σ=∂t. The key is to solve for ∂M=∂H and ∂σ~=∂t. By

> Man � Mirr δk � α~ð Þ Man � Mirr

According to magneto-mechanical coupling model [16], the magnetisation stress

ξ ð Þþ Man � M c

where ξ is the energy coupling parameters of per unit volume and other param-

Man � Mirr δk � α~ð Þ Man � Mirr

dσ~

In summary, Eqs. (1)–(12) constitute the hysteresis nonlinear model of the giant magnetostrictive actuator, which can describe the displacement and force

dH

∂Man ∂σ

eters are the same as above. Substituting Eqs. (10) and (11) into Eq. (9), the

ξ ð Þþ Man � M c

þ c

∂Man

þ c

dt

∂Man ∂H

∂Man

∂M ∂σ dσ~

dt (9)

∂H (10)

∂σ (11)

dt

(12)

loss, eddy current losses, additional loss, and stress changes. In this case,

α~ ¼ α þ 9λsσ0=2μ0M2

transform operator.

The giant magnetostrictive actuator experiment.

Figure 4. Curves of displacement changes with the preload.

M1x€ þ C1ð Þþ x\_ � y\_ K1ð Þ¼ x � y p � f

Nonlinear Giant Magnetostrictive Actuator and Its Application in Active Control

Y ¼ y as system output. Thus, the state space can be obtained using Eq. (14):

B1w. Eq. (14) can be further expressed as follows:

surface, assuming the system switching function as Eq. (4) [29, 30].

, B ¼ B~1 B~2 " #

X\_ ðÞ¼ t AXð Þþ t Buð Þþ t B1wð Þt

Based on full state feedback, the sliding mode can make the system reach the sliding mode surface and achieve sliding mode movement in a jump way. Therefore, it is essential for dynamic characteristics to rationally design the sliding mode

where S is the switching function, Θ is 1 � 4 dimension switching matrix, and X ¼ x; y; x\_; y\_ � �T are the state variables. The non-singular state transition matrix

Γ∈R4�4 is taken to regulate Eq. (16), and the coordinate transformation is the following:

Eq. (17) into Eqs. (15) and (16), it gets the system canonical form and the switching

Z\_ðÞ¼ t AZð Þþ t BUð Þt

S tðÞ¼ ΘZ

T h iT

, B ¼ 0 B~2

Θ2

, and A22 ∈R1�1

" #T

, B~1 ∈R3�1

, and Θ ¼ ΘΓ�1

, where Z1ð Þt ∈R3�1

¼ AXð Þþ t BUð Þt

YðÞ¼ t CXð Þt

(

3 7 7

�

DOI: http://dx.doi.org/10.5772/intechopen.86463

3 7 7 5, B1 ¼

4.2 Sliding mode control design

where Γ ¼ I3 �B~1B~2

surface as Eq. (18):

where A ¼ ΓAΓ�1

A21 A22 " #, and Θ ¼ Θ1

, A21 ∈R1�3

A ¼ A11 A12

A12 ∈R3�1

7

0 I1

" #

where A ¼

0 0 �1=M1 1=M2

B ¼

U ¼ u þ B�1

M2y€ þ C2y\_ þ K2y þ C1 y\_ � x\_ � � þ K1 y � x � � ¼ f

Take X ¼ x; y; x\_; y\_ � �T as state variables and the middle platform displacement

X\_ ðÞ¼ t AXð Þþ t Buð Þþ t B1wð Þt

0010 0001 �K1=M1 K1=M1 �C1=M1 C1=M1 K1=M2 �ð Þ K1 þ K2 =M2 C1=M2 �ð Þ C1 þ C2 =M2

5, C ¼ ½ � 0100 , u ¼ ½ � f , w ¼ ½ � p , and Y ¼ ½ � y . Let

S tðÞ¼ ΘX (16)

ZðÞ¼ t ΓXð Þt (17)

, and B~2 ∈R1�1

; let ZðÞ¼ t

, Z2ð Þt ∈ R1�1

; then Eq. (18) can be decomposed as Eq. (19):

; substituting

Z1ð Þt Z2ð Þt � �,

, A11 ∈R3�3

(18)

,

(13)

(14)

(15)

Figure 5. Curves of displacement changes with the bias magnetic field intensity.

Figure 4 shows that the actuator displacement increases with the preload, but when the preload is greater than 7 MPa, experimental curves began to appear asymmetrical, so the preload cannot be greater than 7 MPa. Figure 5 shows that without the paranoid magnetic field, actuator output is butterfly-shaped with a strong nonlinearity, but when the paranoid magnetic field increases, the output linearity also gradually increases. Finally, σ0 ¼ 6:7MPa and Hb ¼ 14kA=mare selected in the study which can give the actuators better linearity.


*Article* **Compact Wideband Four-Port MIMO Antenna for Sub-6 GHz and Internet of Things Applications**

**Nathirulla Sheriff 1,\* , Sharul Kamal 1, Hassan Tariq Chattha 2 , Tan Kim Geok 3 and Bilal A. Khawaja 4**

**Abstract:** A compact four-port multi-input, multi-output (MIMO) antenna with good isolation is proposed for sub-6 GHz and Internet of Things (IoT) applications. Four similar L-shaped antennae are placed orthogonally at 7.6 mm distance from the corner of the FR4 substrate. The wideband characteristics and the required frequency band are achieved through the L-shaped structure and with proper placement of the slots on the substrate. To obtain good isolation between the ports, rectangular slots are etched in the bottom layer and are interconnected. The proposed antenna has total dimensions of 40 mm × 40 mm × 1.6 mm. The interconnected ground plane provides good isolation of less than −17 dB between the ports, and the impedance bandwidth obtained by the proposed four-port antenna is about 54% between the frequency range of 3.2 GHz to 5.6 GHz, thus providing a wideband antenna characteristic covering sub-6 GHz 5G bands (from 3.4 to 3.6 GHz and 4.8 to 5 GHz) and the WLAN band (5.2 GHz). The proposed design antenna is fabricated and tested. Good experimental results are achieved when compared with the simulation results. As the proposed design is compact and low profile, this antenna could be a suitable candidate for 5G and IoT devices.

**Keywords:** 5G; MIMO; IoT devices; Wi-Fi; four-ports; sub-6 GHz


*6.3.1 Functions of the Bureau*

#### *6.3.2 Advantage of corruption*

Corruption is believed to be destructive by nature [3]. It affects the growth of every nation negatively [1]. As bad as corruption may be, studies have proven that it also has its advantages [1, 4, 11]. Their argument is situated within the context of "*grease-the-wheel"* theory. According to these studies, corruption especially in the area of bribery could enhance the performance of an economy based on the theory. Buttressing this argument, [3], using panel data of 54 developing nations examined the impact of corruption on the growth of these nations. The study revealed that, in countries with weak institutions, corruption plays a vital role in the growth of such nations. As such, corruption can be seen to be advantageous to such nations. Given a nation that is faced with political instability, inefficient government, and weak institutions that hinder growth, corruption especially bribery greases the wheels of growth through the creation of funds, which is termed as "speed money." This "speed money" lubricates the economy and enhances growth.

In another view, giving a religious coloration, the holy book states in the book of Proverbs 18:16 that, "*our gift will make room for us,"* and in another version*, "your gift will make room for you, to be happy, healthy and prosperous."* In this context, gift offers at any level could be positively infectious. This buttresses the grease-the-wheel theory or rubs the palm hypothesis that corruption helps things to go smoothly.

Nonetheless, the positive possible influence that corruption may have on other economies, it could be safe to conclude that corruption has affected the growth of the Nigerian economy overtime. Since Nigeria is a developing nation with weak institutions, and high rate of bribery, it therefore means that the existence of speed money has contributed to the growth that Nigeria has experienced over the years. Nonetheless, there could be to examine the economic gains and pains of corruption.


**3.3. RTK-mediated immune suppression**

involved in glycolysis, angiogenesis, invasion and epithelial-mesenchymal transition (EMT), which are critical for tumor growth and progression, and likely cooperate and activate other aberrant RTK signaling pathways [36, 37]. We and other reports showed that, in response to hypoxia condition, significantly increased activity of EGFR, as well as its mutant protein EGFRvIII, which further promoted activation of convergent downstream signaling pathways including Ras/MAPK, PI3K/Akt, JAK2/STAT3, and NF-κB signaling, and enhanced malignant

behaviors in GBM cells in vitro, and most likely to act in the same way in vivo [1, 38].

**3.2. RTK and ECM/integrin signaling**

36 Glioma - Contemporary Diagnostic and Therapeutic Approaches

level is greatly correlated with poor clinical prognosis [51, 52].

In addition to VEGF, supplementary proangiogenic factors including FGF, PDGF, placentalike growth factor (PLGF), integrins, HGF/scatter factor, ephrins, angiopoietins (ANGPT), and interleukin-8 (IL-8), matrix-metalloproteinase (MMP)-2, MMP-9, collagen type I α1 (COLIA1), endothelial markers CD34, Tenascin-C, neuron-glial antigen 2 (NG-2) on pericytes, insulin-like growth factor (IGF), and EGF present in GBM [39–42]. Interestingly, many of these factors are RTK ligands and may bind to respective RTK on vascular endothelial cells or GBM cells, act in autocrine or paracrine manner to stimulate the events of neo-angiogenesis. Activation of these proangiogenic factors interacts with a number of signaling pathways include activation of Ras/ Raf/MAPK [41, 42], PTEN/PI3K/AKT [40], PLC-γ/protein kinase C (PKC) [40], nitric oxide (NO) [43], PDGFB [44], and Notch1 [45]. GBMs are diagnosed at the advanced stages when they show hypoxia and leaky vasculatures [35]. The critical role that VEGF and these pro-angiogenic factors play in angiogenesis has rendered them appealing targets to exploit in cancer therapeutics [43].

ECM/ integrins are key components mediating the dialog between cells and the microenvironment.  These receptors play a role in the regulation of cell adhesion to ECM proteins or cell surface proteins [47]. Binding of ECM to integrins result in cell adhesion and activation of focal adhesion (FA)-associated signaling pathways [48] and thereafter cascades of intensive activation of downstream signaling that involved in cell proliferation and invasion [49]. Within FA complexes, further auto-phosphorylation of focal adhesion kinase (FAK) leads to its binding to SRC kinase and formation of activated FAK-SRC complexes. Consequently, FAK-SRC complexes activate cascades of downstream pathways including the Ras/Raf/MAPK, RAF/JNK, Rho/Rac/PAK and PI3K/Akt/mTOR [50]. Notably, FAK protein is overexpressed in many tumors including GBM, and its expression

ECM dysregulation is essential for establishing and maintaining a functional tumor microenvironment. ECM in GBM is stiffer and more cross-linked than that in the normal brain tissue, inducing abnormal cell behaviors such as aggressive cell invasion [35]. Dysfunction of ECM and its cognate receptor integrin may lead to aberrant signaling transduction pathways including Ras/Raf/MAPK, Raf/JNK, Rho/Rac/PAK and PI3K/Akt/mTOR, shaping a tumor microenvironment to promote tumor survival, angiogenesis, and invasion [31]. Importantly, many of these cellular signaling pathways are convergent with downstream signaling pathways of RTKs, implicating interaction and cross-talk of RTK- and ECM/integrin-mediated function in GBM GBM patients show marked intratumoral and systemic immunosuppression. The tumor microenvironment contains multiple immunosuppressive factors including TGFβ2, prostaglandin-E2, IL-10; and receptor molecules B7-H1, Fas-ligand, etc. [63]. The tumor is heavily infiltrated by microglia/macrophages, which can represent up to 30% of viable cells in the tumor mass, but lymphocytes infiltration is not common [64]. These monocytes/macrophages in the tumor environment interact with GBM cells and develop immunosuppressive myeloidderived suppressor cells (MDSCs). Systemic immunosuppression in GBM patients shows that total T-cell counts are greatly decreased, especially CD4+ T cell counts [65]. Furthermore, T-cell function is markedly abnormal [66]. Besides other factors that may underlie T-cell dysfunction, increases in circulating cell populations such as regulatory T cells (Tregs) and MDSCs may be more important [67, 68].

Because of immunosuppressive features of GBM, in recent years, new therapies such as tumor vaccines and peptides are tested in preclinical and clinical studies [63]. The mutant protein EGFRvIII is a cancer specific antigen bearing a targetable epitope that is almost exclusively present in GBM [69]. Rindopepimut is composed of an EGFRvIII-specific peptide conjugated with an adjuvant protein KLH (keyhole limpet hemocyanin). The vaccination produced active anti-tumor response with significant survival benefit in GBM patients. Furthermore, the underlying immune response is not only effective regarding specific removal of EGFRvIII-positive GBM cells, but also the increase in the titer of anti-EGFRvIII sera in beneficial patients [70]. More importantly, phase II clinical trial with the vaccine confirmed these results [71], and the randomized phase III clinical study is ongoing [63]. EGFRvIII lacks the ligand binding domain and is persistently activated, promoting tumor formation by activating aberrant signaling pathways, epigenetic mechanisms, and metabolic networks, and thus, is a promising cancer target [72]. Further with rindopepimut efficacy, chimeric antigen receptor (CAR) T cells transduced with humanized scFv against EGFRvIII were produced, and the studies are ongoing [73]. Other immunotherapy approaches that are tested or ongoing in GBM clinical studies include the administration of dendritic cells-based therapies; application of check-point inhibitor drugs, and adoptive cell therapy (ACT), etc.

Cancer development, progression, and response to treatment are greatly influenced by cancer cells' intracellular metabolism and the exogenous tumor environment [93]. The metabolic reprograming that cancer cells adapted to take up and utilize nutrients to drive tumor growth rigorously often relies on signaling and epigenetic/transcriptional networks induced by activated oncogenes (e.g., EGFR, RAS, MYC) and deactivated tumor suppressor proteins (e.g., TP53) [94, 95]. In primary GBM, the frequent genetic changes of key components of RTK/PI3K/Akt pathways, one of the three core signaling pathways that significantly altered in GBM [96], may result in constitutive activation of mechanistic target of rapamycin (mTOR) signaling [96, 97]. Recent studies showed cooperation between EGFRvIII signaling and c-Myc, the transcription factor and one of the master regulators of cancer metabolism [96], to reprogram cellular metabolism and promote tumor proliferation via activation of mTOR signaling, resulting in changes in intracellular nutrients levels [98–100]. Moreover, RTK- and Myc-dependent metabolic reprogramming maybe also involved in IDH1-mutant glioma malignant progression [101, 102]. Therefore, targeted therapies against Myc-dependent metabolism may be an effective therapy for patients with high-grade gliomas. Recent data indicated that extracellular nutrients such as glucose or acetate were required to maintain EGFRvIII signaling via activating mTORC2 [96], leading to GBM resistance to molecularly targeted therapies [103]. Nonetheless, the intricate interactions between the oncogenic signaling and cancer metabolism have only been recently revealed, and metabolism in primary GBM is dominantly regulated hypoxia and RTK-dependent c-Myc upregulation to modify cancer metabolome and cause resistance to therapies [93]. Future studies are needed to govern regulations on genetic and epigenetic alterations, oncogenic signaling and cancer metabolic reprograming, and

Receptor Tyrosine Kinase Interaction with the Tumor Microenvironment in Malignant…

http://dx.doi.org/10.5772/intechopen.76873

39

translate these insights into more effective treatments for GBM patients.

gable targets, including EGFR and EGFRvIII, VEGFR and PDGFR family.

Since the phase III trials of Temozolomide in 2005, there have been few successes regarding treatment for patients with malignant glioma [82]. RTKs, which are the most commonly amplified and mutated genes in cancers, are the key targets in cancer research including malignant glioma. Up to date, three RTKs and their family members present the major drug-

Small molecular weight kinase inhibitors include gefitinib (EGFR) and erlotinib (EGFR and EGFRvIII), and these two irreversible inhibitors, unfortunately, have achieved limited success either as a single agent or as combination therapies in numerous Phase I and II trials in patients with newly diagnosed or recurrent GBM [104–107]. The resistance may be driven by a subset of EGFR mutations, activation of alternate signaling pathways and suppression of EGFRvIII on extrachromosomal DNA, etc. [72]. Besides, irreversible inhibitors currently in clinical trials including lapatinib (EGFR, ErbB-2), AEE788 (EGFR, VEGFR), and dacomitinib

**4. Lessons from RTK-targeted therapies**

**4.1. Experience with RTK-targeted therapies in GBM**

*4.1.1. EGFR family and EGFRvIII*

EGFR also plays a protruding role in GBM cell invasion and aggressiveness [74]. It was previously showed that microglia cells stimulate GBM invasion via the EGFR signaling [75]. Coniglio et al. [76] demonstrated in vitro that microglia secreted EGF, which may activate EGFR and signaling pathways in GBM cells [77]. For example, EGFR or EGFRvIII may activate the STAT3 pathway [38], which is induced in various immune populations, and mediate immunosuppression potentiated by the GSCs [78]. Moreover, recent data implicated VEGF as a potent mediator of immunosuppression, again via GSC-associated mechanisms [79, 80]. A VEGF inhibitor, aflibercept, was applied in combination with an antitumor vaccine. Delayed tumor progression and survival extension were observed, which confirmed the efficacy of combining antiangiogenic and immunotherapy approaches, as well as the value of delineating tumor microenvironment [81]. Antiangiogenic therapy added to immunotherapeutic approaches toward glioma may show clinical benefits, among which the endogenous microenvironment or vaccineinduced inflammatory responses is importantly subsidiary to its effectiveness [82].

### **3.4. RTK, GSC and tumor metabolism**

GSCs or glioma initiating cells (GICs) are preferentially located in perivascular and around necro/hypoxic zones where they closely react with the microenvironment and, thus, escape from apoptotic stimuli and preserve the capacity of self-renewal [83]. These interactions with microenvironment components, such as stromal cells or extracellular matrix (ECM) etc., seem important for GSC maintenance, possibly via metabolic and/or epigenetic modifications [83, 84]. Besides, GSCs may be protected from external factors via specific survival signals that they receive from the niche [85]. For instance, hypoxia induces VEGF expression, which promotes angiogenesis and supports the GSC tumor-initiating capacity [86, 87].

Besides VEGF/VERGFR signaling, HGF/Met signaling involves in regulating cell growth, motility and has a role in embryogenesis, degenerative disease and wound healing [88]. This RTK-mediated signaling also promotes the acquisition of stem-cell like properties in glioma cells and the formation and malignant progression of GBM [89, 90]; overexpressing of Met in vitro in glioma cells was highly clonogenic [88]. Met expression seems to be associated with genetic features with EGFR and the tumor suppressor PTEN inactivation, indicating cooperation among these RTK-mediated signaling in keeping GSC phenotype in glioma [91, 92]. A recent mouse study showed that EGFR inhibition induces increased c-Met expression and associated proliferation of GSCs expressing pluripotency TFs and displaying multi-lineage potential [89]. There is now the debate as to the long-term safety of anti-EGFR treatments, which may possibly induce MET-driven GSC populations [88, 89]. On the other hand, however, it implies the combination of targeting EGFRvIII and GSC as a new therapeutic approach.

Cancer development, progression, and response to treatment are greatly influenced by cancer cells' intracellular metabolism and the exogenous tumor environment [93]. The metabolic reprograming that cancer cells adapted to take up and utilize nutrients to drive tumor growth rigorously often relies on signaling and epigenetic/transcriptional networks induced by activated oncogenes (e.g., EGFR, RAS, MYC) and deactivated tumor suppressor proteins (e.g., TP53) [94, 95]. In primary GBM, the frequent genetic changes of key components of RTK/PI3K/Akt pathways, one of the three core signaling pathways that significantly altered in GBM [96], may result in constitutive activation of mechanistic target of rapamycin (mTOR) signaling [96, 97].

Recent studies showed cooperation between EGFRvIII signaling and c-Myc, the transcription factor and one of the master regulators of cancer metabolism [96], to reprogram cellular metabolism and promote tumor proliferation via activation of mTOR signaling, resulting in changes in intracellular nutrients levels [98–100]. Moreover, RTK- and Myc-dependent metabolic reprogramming maybe also involved in IDH1-mutant glioma malignant progression [101, 102]. Therefore, targeted therapies against Myc-dependent metabolism may be an effective therapy for patients with high-grade gliomas. Recent data indicated that extracellular nutrients such as glucose or acetate were required to maintain EGFRvIII signaling via activating mTORC2 [96], leading to GBM resistance to molecularly targeted therapies [103]. Nonetheless, the intricate interactions between the oncogenic signaling and cancer metabolism have only been recently revealed, and metabolism in primary GBM is dominantly regulated hypoxia and RTK-dependent c-Myc upregulation to modify cancer metabolome and cause resistance to therapies [93]. Future studies are needed to govern regulations on genetic and epigenetic alterations, oncogenic signaling and cancer metabolic reprograming, and translate these insights into more effective treatments for GBM patients.


**5. Acknowledgements**

The authors wish to acknowledge financial support received from the UNU/INRA and the TWOWS. They also wish to thank Mrs B. Asante (University of Ghana Legon) and Mrs P, Maartens (University of Kwa-Zulu Natal) for technical assistance.


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Preface

Chapter 7 **Challenges and Opportunities for Reducing Losses to Fast-**

Ghazala Naeem, Abdullah Usman and Jamila Nawaz

**Pakistan 135**

**VI** Contents

**Arriving Tsunamis in Remote Villages Along the Coast of**

In the recent years, the world has experienced few mega-tsunamis which have caused exten‐ sive loss of life and property. The most destructive ones were in December 2004 in Sumatra, causing more than 290,000 deaths and in March 2011 in Japan, creating a nuclear accident. Because of these events, the recent advances in tsunami study have led the scientists to bet‐ ter understanding of the cause of tsunami, its propagation and most importantly, the system of warning ahead of tsunami arrival to the vulnerable coastal area. In continuation, the me‐ teorological effects, meteo-tsunami and underwater volcanic eruption as other tsunamigenic sources are also being better documented and investigated. At last, let's also mention that onshore earthquake close to coast or located at the onshore part of the subduction zone has triggered the creation of mud-volcano island offshore and onshore, for example large earth‐ quake of onshore Iran 2013 event. It is also important to mention as a pivotal point, the event of 2004 which has triggered many global initiatives such as a new tsunami detection system, more detailed coastal modeling, tsunami-compatible coastal developments and inte‐ grated approach for regional early warning system and public educations, awareness and preparedness. In these advances the environmental damage of urban communities (coastal) and ecosystems and consequently regional economic impact have been largely unattended to date, yet they may have very long-lasting effects both on environmental quality and on regional economy.

The book is divided into four sections. Section 1 covers the introduction to the topic. Section 2 which consists of two chapters provides information on tsunami propagation from the open sea to the coast and talks about coastal tsunami warning using deployed HF radar sys‐ tems in many different parts of North America and Japan. The tsunami propagation, pre‐ liminary methods for evaluating the suitability of radar sites for tsunami detection using simulated tsunami velocities and factors affecting tsunami detectability are discussed and methods for reducing the false alarms are described.

Section 3 consists of two parts covering multi-scale meteorological systems resulted in me‐ teo-tsunami (meteorological tsunami is a kind of ocean long wave with the tsunami frequen‐ cy band from several minutes to 2 hours driven by atmospheric forcing at the sea interface). The second chapter of this section provides some details and scientific information, includ‐ ing some very important case studies on tsunami generation due to a landslide or a submar‐ ine volcanic eruption.

In Section 4, occurrence and characteristics of tsunami in Sweden, using paleo-tsunami events from different parts of Scandinavia are discussed in Chapter 6. Chapter 7 discusses challenges and opportunities for reducing losses to fast-arriving tsunamis in remote villages along the coast of Pakistan coast.

As a concluding remark, one important aspect concerning the local tsunamis is the role of the earthquake effect before tsunami waves are being generated and propagated toward the coast, and also an integrated worldwide tsunami early warning system needs to be fully ac‐ counted for in the future scientific discussion.

This book is based on expert writing with the objective of providing a collection of different aspects of tsunami events from generation by different sources including non-seismic, to propagation, detection, and warning dissemination. It is strongly believed that all the infor‐ mation provided here should play an important role in tsunami risk reduction and mitiga‐ tion. The presented chapters have been peer reviewed and accepted for publication. We would like to express our gratitude to the contributing authors who have been the key factor in this achievement. Finally, we would like to specially thank the InTech publisher who ini‐ tiated this book and guided and helped the Editor for its completion.