**Inflammatory ROS in Fanconi Anemia Hematopoiesis and Leukemogenesis**

Wei Du

*Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio USA*

#### **1. Introduction**

40 Cancer Prevention – From Mechanisms to Translational Benefits

You, H., Jin, J., Shu, H., Yu, B., De Milito, A., Lozupone, F., Deng, Y., Tang, N., Yao, G., Fais,

You, W.K., and McDonald, D.M. (2008). The hepatocyte growth factor/c-Met signaling pathway as a therapeutic target to inhibit angiogenesis. BMB Rep *41*, 833-839. Zatovicova, M., Jelenska, L., Hulikova, A., Csaderova, L., Ditte, Z., Ditte, P., Goliasova, T.,

Zeisberg, M., Strutz, F., and Muller, G.A. (2000). Role of fibroblast activation in inducing

Zhang, F., and Aft, R.L. (2009). Chemosensitizing and cytotoxic effects of 2-deoxy-D-glucose

Zhao, B.C., Wang, Z.J., Mao, W.Z., Ma, H.C., Han, J.G., Zhao, B., and Xu, H.M. (2011).

to catalytic domain. Curr Pharm Des *16*, 3255-3263.

interstitial fibrosis. J Nephrol *13 Suppl 3*, S111-120.

World J Gastroenterol *17*, 2389-2396.

on breast cancer cells. J Cancer Res Ther *5 Suppl 1*, S41-43.

119.

S.*, et al.* (2009). Small interfering RNA targeting the subunit ATP6L of proton pump V-ATPase overcomes chemoresistance of breast cancer cells. Cancer Lett *280*, 110-

Pastorek, J., and Pastorekova, S. (2010). Carbonic anhydrase IX as an anticancer therapy target: preclinical evaluation of internalizing monoclonal antibody directed

CXCR4/SDF-1 axis is involved in lymph node metastasis of gastric carcinoma.

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure (BMF), clonal proliferation of hematopoietic stem cells, and transformation to leukemia and other cancers (Ames *et al.,* 1995; Boglilo *et al.,* 2002; Cohen-Haguenauer *et al.,* 2006; Cumming *et al.,* 2001; Fagerlie *et al.,* 2001; Jonkers *et al.,* 2001; Suematsu *et al.,* 2003). Somatic cell fusion studies show FA is genetically heterogeneous. So far mutations in 15 genes have been identified in FA or FA-like patients (Cohen-Haguenauer *et al.,* 2006; Joenje *et al.,* 1987; Jonkers *et al.,* 2001; Lensch *et al.,* 1999; Stoepker *et al.,* 2011; Yamamoto *et al.,* 2011).  The latter two genes are still thought of as tentative as they do not fall within a defined category biologically and the patients carrying these gene mutations are limited. The majority of mutations are found in *FANCA*, *FANCC* and *FANCC* genes in FA patients (Table 1). Recent studies on the biological function of these FA proteins have demonstrated that eight of the FA proteins (namely, FANCA, B, C, E, F, G, L, and M) form a nuclear multiprotein complex (Collins *et al.,* 2005; D'Andrea *et al.,* 2003; de Winter *et al.,* 2000; Meetei *et al.,* 2003; Smogorzewska *et al.,* 2007; Tischkowitz *et al.,* 2003; Walsh *et al.,* 1994), which functions as a nuclear E3 ubiquitin ligase that monoubiquitinates downstream FANCD2/FANCI dimer in response to DNA damage or DNA replication stress. This FANCD2/FANCI heterodimer then recruits other downstream FA proteins including FANCD1 (which is the breast cancer protein BRCA2), and the recently identified FANCJ, FANCN, FANCO and another breast cancer protein, BRCA1 (D'Andrea *et al.,* 2010), to nuclear loci containing damaged DNA and consequently influence important cellular processes such as DNA replication, cell-cycle control, and DNA damage repair. The core complex also interacts with the FAAP100 and FAPP24 proteins, which are also crucial components in the pathway (Ciccia *et al.,* 2007; Horejsi *et al.,* 2009; Collis *et al.,* 2008, Fig 1). FANCM and its interacting proteins, such as FAAP24 and MHF1, MHF2, also play a role in controlling the processing and stabilization of stalled replication forks (Schwab *et al.,* 2010; Luke-Glaser *et al.,* 2010; Singh *et al.,* 2010).

Inflammatory ROS in Fanconi Anemia Hematopoiesis and Leukemogenesis 43

development of mutant clones, which could be transformed to leukemia (Cumming *et al.,* 1996, 2001; Fagerlie *et al.,* 2001; Haneline *et al.,* 1998, 1999, 2003; Koh *et al.,* 1999; Li X *et al.,* 2004; Li Y *et al.,* 1997; Maciejewski *et al.,* 1995; Nakata *et al.,* 2004; Pang *et al.,* 2001a, 2001b, 2002; Rathbun *et al.,* 1997, 2000; Si *et al.,* 2006; Walsh *et al.,* 1994; Wang *et al.,* 1998; Whitney

Hematological abnormalities are among the most important clinical features of FA. Children with FA often develop pancytopenia during the first few years of life. Complications of BM failure (BMF) are the major causes of morbidity and mortality of FA, and 80% of FA patients die from BMF (Bagby *et al.,* 2003; Buchwald *et al.,* 1998; Fagerlie *et al.,* 2001; Kutler *et al.,* 2003; Lensch *et al.,* 1999; Liu *et al.,* 2000). In addition, patients with FA have high risk of developing myelodysplasia (MDS) or acute myeloblastic leukemia (AML) (Bagby *et al.,* 2003; Buchwald *et al.,* 1998; D'Andrea *et al.,* 2003; Fagerlie *et al.,* 2001; Kennedy *et al.,* 2005; Tischkowitz *et al.,* 2003). During the BMF-MDS-AML progression, FA patients frequently develop clonal chromosomal abnormalities in the BM HSC/P cells. In fact, secondary occurred clonal cytogenetic abnormalities, such as 3q addition, 5q deletion and monosomy 7, are common in in children with FA who have evolved to MDS and AML and non-FA patients with MDS and AML after alkylating agents treatment (Freie *et al.,* 2004; Fridman *et al.,* 2003; Futaki *et al.,* 2002; Giaccia *et al.,* 1998; Lina-Fineman *et al.,* 1995; Rubin *et al.,* West *et*

Excessive apoptosis and subsequent failure of the HSC compartment led to progressive BMF in FA patients have been documented from *in vitro* and *in vivo* studies. However, the molecular etiology of BMF and leukemia in FA remains to be elucidated. Compelling evidence suggest that altered expression of certain growth factors and cytokines, such as reduced expression of interleukin-6 (IL-6) and granulocyte-macrophage colony stimulating

in part be responsible for hematopoietic disease progression in FA (de Cremoux *et al.,* 1996; Dufour *et al.,* 2003; Rosselli *et al.,* 1992; 1994; Schultz *et al.,* 1993; Stark *et al.,* 1993). It is conceivable that these alterations may change the BM microenvironment (for instance, leading to factor deprivation or constant exposure to mitogenic inhibitors) and cause deregulation of cellular homeostasis. It has also been shown that FA BM cells are

Koh *et al.,* 1999; Li X *et al.,* 2004; Li Y *et al.,* 2004; Nakata *et al.,* 2004; Pang *et al.,* 2001a, 2001b, 2002; Rathbun *et al.,* 1997, 2000; Reid *et al.,* 2006; Rosselli *et al.,* 1992; Schultz *et al.,* 1993; Si *et al.,* 2006; Wang *et al.,* 1998; Whitney *et al.,* 1996), which may subsequently lead to cell apoptosis. Indeed, studies of FA patients have demonstrated that BM from FA patients has decreased number of colony-forming progenitors, as well as a reduction in colony size (Doneshbod–Skibba *et al.,* 1980; Gluckman *et al.,* 1989). These data demonstrate defective

In contrast to FA patients, mouse models deficient for several FA genes, including *Fanca*, *Fancc*, *Fancd2* and *Fancg*, do not show no spontaneous hematological defects or leukemia development (Cheng *et al.,* 2000; Whitney *et al.,* 1996; Wong & Buchwald, 2002; Yang *et al.,* 2001). Studies in the Fanca and Fancc mouse models show that while blood count and the

(Dufour *et al.,* 2003; Fagerlie *et al.,* 2001; Haneline *et al.,* 1998;

in patient BM cells, may

 (IFN-) and

factor (GM-CSF) but increased secretion of mitotic inhibitor TNF-

hypersensitive to a variety of extracellular cytokines, including interferon-

hematopoiesis in FA (Bagby *et al.,* 2003; Fagerlie *et al.,* 2001; Tischkowitz *et al.,* 2003).

*et al.,* 1996).

*al.,* 2000).

tumor necrosis factor

(TNF-

**2. FA hematopoiesis**

Table 1. Complementation groups and interaction proteins of Fanconi Anemia.

Fig. 1. Function of the FA pathway. Eight FA proteins form a nuclear core complex, which acts as ubiquitin ligase. FANCM interacts with FAAP24, FAAP100 as well as MHF1 and MFH2, resulting in complex chromatin loading and controlling the processing and stabilization of stalled forks, respectively. In response to DNA damage or replication stress, nuclear core complex monoubiquitinates two other FA proteins, FANCD2 and FANCI, which then recruit other downstream FA proteins FANCD1, FANCJ, and FANCN to damaged DNA and involved in DNA repair, cell-cycle control to repair ICL (interstrand crosslink) lesions and to maintain genome stability.

Many studies indicate that FA proteins might play specific roles in hematopoiesis by governing the responses of hematopoietic cells to both genotoxic and cytotoxic stresses. Loss of FA functions causes excessive apoptosis of HSC and progenitor cells (HSC/P) cells leading to BMF in the early stage of FA. As the disease progresses, apoptosis as well as genomic instability impose a selective pressure on FA HSC/P cells and promote the development of mutant clones, which could be transformed to leukemia (Cumming *et al.,* 1996, 2001; Fagerlie *et al.,* 2001; Haneline *et al.,* 1998, 1999, 2003; Koh *et al.,* 1999; Li X *et al.,* 2004; Li Y *et al.,* 1997; Maciejewski *et al.,* 1995; Nakata *et al.,* 2004; Pang *et al.,* 2001a, 2001b, 2002; Rathbun *et al.,* 1997, 2000; Si *et al.,* 2006; Walsh *et al.,* 1994; Wang *et al.,* 1998; Whitney *et al.,* 1996).


**2. Aim**

This study aimed to evaluate the progress of knowledge and learning outcomes of a group of Thai EPs before and after 3LC simulation exercise in seven documented and essential areas (CSCATTT): Command and control, Safety, Communication, Triage, Treatment, and Transport, which according to MIMMS concept are essential elements to lead and manage a MID [18].


**4. Recommendation**

For a future arrangement of sustainable cities, the new urban agenda, adopted in Quito (Ecuador) on October 17, 2016, complements the 17 sustainable development goals assumed by world leaders at the end of 2015 through Agenda 2030 for Sustainable Development. The Strategic Vision of Sustainable Urbanization, negotiated for more than 3 years and presented at the Conference on Housing and Sustainable Urban Development (Habitat III), provides for a comprehensive approach to urbanization for the next 20 years. Thus, the sustainable urban development agenda proposed by UNDP is focused on concrete actions and sets global standards for sustainable urban development. It also includes a series of recommendations centered on rethinking how people will build, manage and live in cities by 2036 [5]. The economic and environmental footprint of urban centers is very high, despite the fact that they only cover a small part of the globe (0.51% of total land area globally). In terms of percentages, cities accounted for over 80% of world GDP in 2014, producing more than 70% of global greenhouse gas emissions and 80% overall energy consumption. At the same time, experts estimate that in 20–30 years the development of urban centers will be significant, tripling in size and reaching about 1.2 million square kilometers in 2030. Consequently, authorities are encouraged to use renewable energy sources (by 2040, the global energy system should meet the demand of 9 billion people), improve public transport, eliminate pollution and sustainably manage natural resources. According to the 11th sustainable development objective, focusing on the sustainability of cities and urban communities, two-thirds of mankind (around 6.5 billion people) will live in urban areas by 2050. That is why the way we build and manage our urban spaces becomes essential for our sustainable development policy. If 26 years ago mankind numbered 10 megalopolis, with more than 10 million inhabitants, in 2014 the number of these urban centers reached 28, totaling 453 million inhabitants. Thus, UNDP's goal in the next 20 years is to create safe and sustainable urban centers, which also aim to tackle challenges such as eradicating poverty, social inequalities and reducing climate change. The new urban agenda also addresses current issues such as urban poverty, unemployment, climate change, pollution, exclusion of marginalization of vulnerable groups (migrants and refugees), reduction of natural disasters and gender disparities. Even if the new agenda for urban development remains just a recommendation, UNDP recognizes that it needs to support national governments and local communities to meet the proposed objectives, the only ones that would favor the creation of more resilient and secure urban centers for citizens [5].

need to park in the city centers is reduced. In this connection, attractive walking and cycling paths should be established, which connect the city center with its inner periphery. If people can go and cycle between houses, work, institutions and leisure facilities on beautiful and safe trails, more people will want to choose an excellent transport to the short distances. The edges of the city can be of great importance to health. One would think it was the most natural thing in the world to run or cycle the trip in green surroundings, at least for those living in a smaller city. But much of the land surrounding the cities is used for agriculture or other business purposes. When planning new housing quarters, it is essential from the start to think of

Introductory Chapter: Overview of Sustainable Cities, Theory and Practices

http://dx.doi.org/10.5772/intechopen.82632

13

healthy and recreational path systems into plans for the benefit of the entire city.

**4.2. Applying for sustainable model theories in planning and design city processes**

take into account local conditions and needs based on the principles of subsidiarity.

funds that are always insufficient can be used more efficiently.

existing situation;

of the city and the surrounding area;

and environmental future of each area.

of the city;

This requires an active application of the "Integrated Approach" idea into urban development processes, where integrated urban development policy is a simultaneous and fair consideration of all issues and concerns relevant to urban development. Integrated urban development policy is a process that coordinates critical spatial, sectoral and temporal matters. The involvement of economic factors, stakeholders and public opinion is essential. Integrated urban development policy is a vital status for implementing the UN's Sustainable Development Strategy. Its implementation of a requirement of a holistic world dimension, however, must

Establishing a balance between the various interests of urban actors, supported by integrated urban development policy, is a viable basis for a consensus between the state, regions, cities, citizens and economic actors. Putting together knowledge and financial resources, public

Integrated Urban Development Policy involves actors outside the administration and enables citizens to play an active role in shaping their living environment. At the same time, these measures can provide more certainty regarding planning and investment. We recommend cities from all over the world to develop integrated urban development programs for cities as a whole. These implementation-oriented planning tools must have the following roles:

• describe the qualities and defects of cities and neighborhoods, based on an analysis of the

• define realistic development objectives for the urban area and develop a coherent vision

• to coordinate technical and sectoral plans and policies related to the various regions of the city and to ensure that planned investments will help to promote a balanced development

• be organized at the local and regional level and involve citizens and other partners who can make a substantial contribution to the qualitative modeling of the economic, social, cultural

• to coordinate and to focus from space the use of funds by public and private sector;

#### **4.1. Back to the human scale interpretations**

Quite large streets intersect many cities. It was considered 30–40 years ago to be the best answer to the challenge of rising car traffic. The roads lead, among other things, to large parking spaces in the city centers, which were built to ensure that people still wanted to shop on the city's main street when compared to pedestrian streets. Therefore, higher density is a significant challenge for many cities. Where city centers in the big cities are often characterized by high frequency, high versatility and a complicated life, many medium-sized cities have hollowed urban corridors that are quite desolate and insecure for much of the time. Paradoxically, the center in many cities is often the characteristics that characterize the periphery of the big city. These problems can be solved in many places by building closer. In some places, underground parking facilities or parking garages can be built. This gives new opportunities to looped parking spaces. Here, it is essential to mix housing, non-polluting professions, institutions, new activities and recreational green areas. This also creates a "green density" and stimulates health. Elsewhere, it may be better to think of public transport, so the need to park in the city centers is reduced. In this connection, attractive walking and cycling paths should be established, which connect the city center with its inner periphery. If people can go and cycle between houses, work, institutions and leisure facilities on beautiful and safe trails, more people will want to choose an excellent transport to the short distances. The edges of the city can be of great importance to health. One would think it was the most natural thing in the world to run or cycle the trip in green surroundings, at least for those living in a smaller city. But much of the land surrounding the cities is used for agriculture or other business purposes. When planning new housing quarters, it is essential from the start to think of healthy and recreational path systems into plans for the benefit of the entire city.

#### **4.2. Applying for sustainable model theories in planning and design city processes**

by world leaders at the end of 2015 through Agenda 2030 for Sustainable Development. The Strategic Vision of Sustainable Urbanization, negotiated for more than 3 years and presented at the Conference on Housing and Sustainable Urban Development (Habitat III), provides for a comprehensive approach to urbanization for the next 20 years. Thus, the sustainable urban development agenda proposed by UNDP is focused on concrete actions and sets global standards for sustainable urban development. It also includes a series of recommendations centered on rethinking how people will build, manage and live in cities by 2036 [5]. The economic and environmental footprint of urban centers is very high, despite the fact that they only cover a small part of the globe (0.51% of total land area globally). In terms of percentages, cities accounted for over 80% of world GDP in 2014, producing more than 70% of global greenhouse gas emissions and 80% overall energy consumption. At the same time, experts estimate that in 20–30 years the development of urban centers will be significant, tripling in size and reaching about 1.2 million square kilometers in 2030. Consequently, authorities are encouraged to use renewable energy sources (by 2040, the global energy system should meet the demand of 9 billion people), improve public transport, eliminate pollution and sustainably manage natural resources. According to the 11th sustainable development objective, focusing on the sustainability of cities and urban communities, two-thirds of mankind (around 6.5 billion people) will live in urban areas by 2050. That is why the way we build and manage our urban spaces becomes essential for our sustainable development policy. If 26 years ago mankind numbered 10 megalopolis, with more than 10 million inhabitants, in 2014 the number of these urban centers reached 28, totaling 453 million inhabitants. Thus, UNDP's goal in the next 20 years is to create safe and sustainable urban centers, which also aim to tackle challenges such as eradicating poverty, social inequalities and reducing climate change. The new urban agenda also addresses current issues such as urban poverty, unemployment, climate change, pollution, exclusion of marginalization of vulnerable groups (migrants and refugees), reduction of natural disasters and gender disparities. Even if the new agenda for urban development remains just a recommendation, UNDP recognizes that it needs to support national governments and local communities to meet the proposed objectives, the only ones that would favor

the creation of more resilient and secure urban centers for citizens [5].

Quite large streets intersect many cities. It was considered 30–40 years ago to be the best answer to the challenge of rising car traffic. The roads lead, among other things, to large parking spaces in the city centers, which were built to ensure that people still wanted to shop on the city's main street when compared to pedestrian streets. Therefore, higher density is a significant challenge for many cities. Where city centers in the big cities are often characterized by high frequency, high versatility and a complicated life, many medium-sized cities have hollowed urban corridors that are quite desolate and insecure for much of the time. Paradoxically, the center in many cities is often the characteristics that characterize the periphery of the big city. These problems can be solved in many places by building closer. In some places, underground parking facilities or parking garages can be built. This gives new opportunities to looped parking spaces. Here, it is essential to mix housing, non-polluting professions, institutions, new activities and recreational green areas. This also creates a "green density" and stimulates health. Elsewhere, it may be better to think of public transport, so the

**4.1. Back to the human scale interpretations**

12 Sustainable Cities - Authenticity, Ambition and Dream

This requires an active application of the "Integrated Approach" idea into urban development processes, where integrated urban development policy is a simultaneous and fair consideration of all issues and concerns relevant to urban development. Integrated urban development policy is a process that coordinates critical spatial, sectoral and temporal matters. The involvement of economic factors, stakeholders and public opinion is essential. Integrated urban development policy is a vital status for implementing the UN's Sustainable Development Strategy. Its implementation of a requirement of a holistic world dimension, however, must take into account local conditions and needs based on the principles of subsidiarity.

Establishing a balance between the various interests of urban actors, supported by integrated urban development policy, is a viable basis for a consensus between the state, regions, cities, citizens and economic actors. Putting together knowledge and financial resources, public funds that are always insufficient can be used more efficiently.

Integrated Urban Development Policy involves actors outside the administration and enables citizens to play an active role in shaping their living environment. At the same time, these measures can provide more certainty regarding planning and investment. We recommend cities from all over the world to develop integrated urban development programs for cities as a whole. These implementation-oriented planning tools must have the following roles:

Coordination between local and regional levels needs to be strengthened [13]. The aim is to establish at a regional and metropolitan level a balanced partnership between cities and rural areas as well as between small, medium and large cities. Urban policy issues and decisions can no longer be viewed in isolation at the level of each city. Our cities must be focal points for the development of the regions and take responsibility for territorial cohesion. That is why it would be useful if our cities were to work more closely in the network globally. Integrated Urban Development Policy provides a set of tools that have already proven their worth in many cities, which it can offer an efficient and cooperative management structures. These are indispensable for increasing the competitiveness of cities from the devolved countries. They facilitate early and timely coordination between economic, infrastructure, real estate and service development, taking into account, among other things, the impact of existing social trends on seasonal and population aging trends and energy policy conditions. To achieve the planned objectives and policy, it is important to consider that the following action strategies to be of crucial importance for improving the competitiveness of devoted world cities.

controversial. A prominent area is the public institutions where schools, kindergartens and jobs are found. The quality of public spaces, urban anthropic landscapes, architecture and urban development play an important role in the living conditions of city citizens. These local characteristics are important for attracting businesses in the knowledge industry, a creative

Introductory Chapter: Overview of Sustainable Cities, Theory and Practices

http://dx.doi.org/10.5772/intechopen.82632

15

Trees and green areas have many advantages; they relax the stressed eyes. Trees and plants not only purify the air but also lower temperatures in the big cities in the summer months. Plants help to drain rainwater, thus reducing the need for other and perhaps more expensive solutions. Therefore, it does not play just a role in the urban transformation that should have a green dimension. Also, the existing city can be developed to make it greener and greener—for example, thinking of green roofs and green facades. Contrarily, changes in business structures create a natural need to transform past, often centrally located industrial areas into new types of jobs, for private and public services or for housing [14]. At the same time, there is also the need for a useful framework for the companies that remain in the city. When the major cities are transformed, it is essential to think about both the green and the health and to adapt the solutions to modern people. When laying parks and green fields on former industrial areas, it is essential that they are designed in such a way that the city's users and residents can quickly get a run or organize a ball game.

Growing mountains of waste and eutrophication of the garden are two of the environmental problems that life in metropolitan areas can cause if politicians and civil servants do not work deliberately to end the cycle in the city. Working to make all residents easily sort their waste and leave it at places near the home is an important part of the material cycle. Well-functioning water treatment plants that take care of and clean the water from different chemicals and nutrients before it flows into the sea are also important. The sludge from the purification plants can partly be used in the production of biogas, and if it is sufficiently clean from poison,

**4.5. Modernizing infrastructure networks and increasing energy efficiency**

An essential contribution to improving living conditions, environmental quality and the creation of favorable factors for commercial locations can be ensured through sustainable, accessible and affordable urban transport with coordinated links to urban and regional transport networks [14]. Particular attention should be paid to traffic management and interconnection of modes of transport, including cyclists and pedestrians. Urban transport needs to

and skilled workforce and for tourism.

*4.4.1. Objectives of using recycling materials model*

it is possible to return to farmland as manure. These tasks require special attention in cities:

• Water and drainage

• Energy

• Transport and communications

**4.4. Applying for green and healthy urban transformations**

#### *4.2.1. Greater sustainability requires both cultural and technical conversion*

It is necessary to continue to safeguard the conservative buildings and cultural environments in the cities and promote new beautiful architecture. We must also create urban spaces that are strange and exciting to live in. Here, climate change can help us. More rainfall and warmer rainfall mean that more massive amounts of rainwater will be wasted when the large, fortified areas characteristic of the towns prevent rainwater from slipping into the soil [13]. Rain can be collected in artificial lakes or ponds that can prevent flooding. The reduction can be increased with more green areas, plantings and coatings that allow rainwater to sip down to groundwater. In this way, we can mitigate the effects of climate change while strengthening both the blue and the green flair of the cities. The city's buildings can also be used in the fight against climate change. It is technically possible to build houses, with sound building materials and houses that do not use energy but produce it. This is primarily about spreading knowledge about the type of construction.

#### *4.2.2. Integrity and innovation in planning*

Applying positive criteria of sustainability means creating sustainable cities is about reconciling and balancing many interests. The municipal reform has meant larger municipalities with many different urban communities. It can contribute to the fact that the cities increasingly have different roles, can complement each other instead of neighboring two former municipalities to compete and should be able to do the same. It requires holistic orientation, innovation and attitude changes.

#### **4.3. Creating and securing respectable quality of public spaces**

It is all the places in the community where there is access and where people are allowed to move freely outside the four walls of the home. There may be streets and alleys, educational institutions or meetings that may be more or less public. However, it is also the rooms that are carried by media of all kinds, which contain public debate and other expressions and where there is public access. Here, people may more or less be involved, and so it can be controversial. A prominent area is the public institutions where schools, kindergartens and jobs are found. The quality of public spaces, urban anthropic landscapes, architecture and urban development play an important role in the living conditions of city citizens. These local characteristics are important for attracting businesses in the knowledge industry, a creative and skilled workforce and for tourism.

#### **4.4. Applying for green and healthy urban transformations**

Trees and green areas have many advantages; they relax the stressed eyes. Trees and plants not only purify the air but also lower temperatures in the big cities in the summer months. Plants help to drain rainwater, thus reducing the need for other and perhaps more expensive solutions. Therefore, it does not play just a role in the urban transformation that should have a green dimension. Also, the existing city can be developed to make it greener and greener—for example, thinking of green roofs and green facades. Contrarily, changes in business structures create a natural need to transform past, often centrally located industrial areas into new types of jobs, for private and public services or for housing [14]. At the same time, there is also the need for a useful framework for the companies that remain in the city. When the major cities are transformed, it is essential to think about both the green and the health and to adapt the solutions to modern people. When laying parks and green fields on former industrial areas, it is essential that they are designed in such a way that the city's users and residents can quickly get a run or organize a ball game.

#### *4.4.1. Objectives of using recycling materials model*

Growing mountains of waste and eutrophication of the garden are two of the environmental problems that life in metropolitan areas can cause if politicians and civil servants do not work deliberately to end the cycle in the city. Working to make all residents easily sort their waste and leave it at places near the home is an important part of the material cycle. Well-functioning water treatment plants that take care of and clean the water from different chemicals and nutrients before it flows into the sea are also important. The sludge from the purification plants can partly be used in the production of biogas, and if it is sufficiently clean from poison, it is possible to return to farmland as manure.

These tasks require special attention in cities:

Coordination between local and regional levels needs to be strengthened [13]. The aim is to establish at a regional and metropolitan level a balanced partnership between cities and rural areas as well as between small, medium and large cities. Urban policy issues and decisions can no longer be viewed in isolation at the level of each city. Our cities must be focal points for the development of the regions and take responsibility for territorial cohesion. That is why it would be useful if our cities were to work more closely in the network globally. Integrated Urban Development Policy provides a set of tools that have already proven their worth in many cities, which it can offer an efficient and cooperative management structures. These are indispensable for increasing the competitiveness of cities from the devolved countries. They facilitate early and timely coordination between economic, infrastructure, real estate and service development, taking into account, among other things, the impact of existing social trends on seasonal and population aging trends and energy policy conditions. To achieve the planned objectives and policy, it is important to consider that the following action strategies

to be of crucial importance for improving the competitiveness of devoted world cities.

It is necessary to continue to safeguard the conservative buildings and cultural environments in the cities and promote new beautiful architecture. We must also create urban spaces that are strange and exciting to live in. Here, climate change can help us. More rainfall and warmer rainfall mean that more massive amounts of rainwater will be wasted when the large, fortified areas characteristic of the towns prevent rainwater from slipping into the soil [13]. Rain can be collected in artificial lakes or ponds that can prevent flooding. The reduction can be increased with more green areas, plantings and coatings that allow rainwater to sip down to groundwater. In this way, we can mitigate the effects of climate change while strengthening both the blue and the green flair of the cities. The city's buildings can also be used in the fight against climate change. It is technically possible to build houses, with sound building materials and houses that do not use energy but produce it. This is primarily about spreading knowledge

Applying positive criteria of sustainability means creating sustainable cities is about reconciling and balancing many interests. The municipal reform has meant larger municipalities with many different urban communities. It can contribute to the fact that the cities increasingly have different roles, can complement each other instead of neighboring two former municipalities to compete and should be able to do the same. It requires holistic orientation,

It is all the places in the community where there is access and where people are allowed to move freely outside the four walls of the home. There may be streets and alleys, educational institutions or meetings that may be more or less public. However, it is also the rooms that are carried by media of all kinds, which contain public debate and other expressions and where there is public access. Here, people may more or less be involved, and so it can be

*4.2.1. Greater sustainability requires both cultural and technical conversion*

about the type of construction.

innovation and attitude changes.

**4.3. Creating and securing respectable quality of public spaces**

*4.2.2. Integrity and innovation in planning*

14 Sustainable Cities - Authenticity, Ambition and Dream

#### **4.5. Modernizing infrastructure networks and increasing energy efficiency**

An essential contribution to improving living conditions, environmental quality and the creation of favorable factors for commercial locations can be ensured through sustainable, accessible and affordable urban transport with coordinated links to urban and regional transport networks [14]. Particular attention should be paid to traffic management and interconnection of modes of transport, including cyclists and pedestrians. Urban transport needs to be adapted to different housing, work, environment and public space requirements. Technical infrastructure, especially water supply, sewerage network and other urban networks, needs to be improved and adapted to changing needs in order to meet future demands and ensure quality in urban living. The key requirements for the sustainability of public utilities are energy efficiency, rational use of natural resources and economic efficiency in operation.

Watch Institute, is by far the only fossil fuel remaining in 2050. The energy scenarios do not determine whether they are compatible with sustainable development or not [16]. In general, the vision of a multifaceted architecture shows that it is necessary to design and work cooperatively with an architectural theory to transform the lateral conceptual viewer of the

Introductory Chapter: Overview of Sustainable Cities, Theory and Practices

http://dx.doi.org/10.5772/intechopen.82632

17

Local energy systems can be used in many places. Energy system means the recovery and storage of energy in the form of heat from the ground. The design of the building may be controlled by any local energy system. For faced the future energy shortage, it is required to recognize all survived opportunities. In this context, it is necessary to consider all existent

Geothermal energy is the heat energy stored in the Earth's crust and flows out to the ground. The heat comes mainly from radioactive decomposition. The geothermal gradient varies from place to place. In Nordic countries, such as Sweden or Denmark, the sedimentary bedrock has the best conditions, and heat can be recovered using deep drilled wells

Soil heat utilizes heat energy from the sun and rain stored passively in the ground. The heat is absorbed through plastic hoses laid down at 1–2 m depth in which a freeze-dried liquid circulates. The heat is then recycled using a heat pump. To heat a small house, a surface area

soils that hold the moisture are well suited. Silt should be avoided due to the risk of fire. If the hoses are laid under the groundwater, water is important, so that coarse grains are

Cities are places where knowledge is created and shared. Exploiting the full potential of knowledge in a city depends on the quality of day care and school education, the transfer of opportunities offered by education and training systems, social and cultural networks, opportunities for lifelong training, the excellence of university education and research institutes and the existing transfer network between industry, the business sector and the scientific community. Integrated urban development policy can help improve these factors, for example, bringing together all stakeholders, supporting networks and optimizing infrastructure. Integrated urban development promotes social and intercultural dialog [18]. Integrated urban development strategies, participatory urban management and good governance can help to make effective use of the potential of European cities, particularly in terms of competitiveness and growth, and to reduce disparities between and within neighborhoods. These integrated urban development strategies bring citizens the opportunity of social and

is required. If the hoses are laid above the groundwater surface, fine-grained

multilateral design process [17].

possibilities [15, 16].

[15, 16].

of 400–600 m<sup>2</sup>

preferable [15].

democratic participation.

*4.5.3. Efficient use of local energy systems*

*4.5.4. Efficient uses of geothermal energy*

**4.6. Proactive innovation and educational policies**

Analysis of possibilities for 2020 indicates that the developed countries can reduce their energy use by about 50%, while the developing countries with largely unchanged energy consumption per capita could reach a tangible standard equivalent to the one we had in Western Europe in the 1970s. The condition is that energy efficient technologies must be used in both developed and developing countries [15].

#### *4.5.1. Energy efficiency in combater of climate change*

The energy efficiency of buildings needs to be improved. This concerns both existing and new buildings. Renovating existing dwellings can have a significant impact on energy efficiency and on the quality of life of residents. Increased attention should be paid to prefabricated buildings, old buildings or lower quality buildings. Optimized and efficient infrastructure networks and energy-efficient buildings will reduce costs for both businesses and citizens. A basis for the efficient and sustainable use of resources is a compact structure of human settlements. This can be achieved through territorial and urban planning that prevents uncontrolled urban expansion through strong land supply and speculative development. Urban planning strategy to achieve a functional mix between housing, jobs, education and recreational use of urban areas has proven to be sustainable. Cities need to help ensure and improve the quality of life of their inhabitants and business attractiveness by providing sophisticated information and communication technologies in the fields of education, employment, social services, health and safety. Technical infrastructure, especially water supply, sewerage network and other urban networks, needs to be improved and adapted to changing needs in order to meet future demands and ensure quality urban living. The key requirements for the sustainability of public utilities are energy efficiency, rational use of natural resources and economic efficiency in operation.

#### *4.5.2. Efficient use of renewable energy systems*

The utilization of bioenergy, water and wind power can increase significantly. In the case of biofuels, it may be difficult to make the land sufficient for increased energy supplies, while the production of food and industrial raw materials must also increase and reach for about 10 billion people. Solar cells in desert areas could be an opportunity to produce electricity. Major and urgent efforts are needed to develop the technology needed for renewable energy laws. Various global scenarios for energy supply in 2050 have been made by, among others, the World Energy Council (WEC), the World Watch Institute and the Intergovernmental Panel on Climate Change (IPCC). In all scenarios, fossil and renewable fuels are used. Most of the scenarios still have nuclear power in the energy balance of 50 years, but the share of nuclear power of total energy supply is less than today. Much of fossil fuels will still be used. The natural gas dominates coal and oil in all future images and, according to the World Watch Institute, is by far the only fossil fuel remaining in 2050. The energy scenarios do not determine whether they are compatible with sustainable development or not [16]. In general, the vision of a multifaceted architecture shows that it is necessary to design and work cooperatively with an architectural theory to transform the lateral conceptual viewer of the multilateral design process [17].

#### *4.5.3. Efficient use of local energy systems*

be adapted to different housing, work, environment and public space requirements. Technical infrastructure, especially water supply, sewerage network and other urban networks, needs to be improved and adapted to changing needs in order to meet future demands and ensure quality in urban living. The key requirements for the sustainability of public utilities are energy efficiency, rational use of natural resources and economic efficiency in operation.

Analysis of possibilities for 2020 indicates that the developed countries can reduce their energy use by about 50%, while the developing countries with largely unchanged energy consumption per capita could reach a tangible standard equivalent to the one we had in Western Europe in the 1970s. The condition is that energy efficient technologies must be used in both

The energy efficiency of buildings needs to be improved. This concerns both existing and new buildings. Renovating existing dwellings can have a significant impact on energy efficiency and on the quality of life of residents. Increased attention should be paid to prefabricated buildings, old buildings or lower quality buildings. Optimized and efficient infrastructure networks and energy-efficient buildings will reduce costs for both businesses and citizens. A basis for the efficient and sustainable use of resources is a compact structure of human settlements. This can be achieved through territorial and urban planning that prevents uncontrolled urban expansion through strong land supply and speculative development. Urban planning strategy to achieve a functional mix between housing, jobs, education and recreational use of urban areas has proven to be sustainable. Cities need to help ensure and improve the quality of life of their inhabitants and business attractiveness by providing sophisticated information and communication technologies in the fields of education, employment, social services, health and safety. Technical infrastructure, especially water supply, sewerage network and other urban networks, needs to be improved and adapted to changing needs in order to meet future demands and ensure quality urban living. The key requirements for the sustainability of public utilities are energy efficiency, rational use of natural resources and economic

The utilization of bioenergy, water and wind power can increase significantly. In the case of biofuels, it may be difficult to make the land sufficient for increased energy supplies, while the production of food and industrial raw materials must also increase and reach for about 10 billion people. Solar cells in desert areas could be an opportunity to produce electricity. Major and urgent efforts are needed to develop the technology needed for renewable energy laws. Various global scenarios for energy supply in 2050 have been made by, among others, the World Energy Council (WEC), the World Watch Institute and the Intergovernmental Panel on Climate Change (IPCC). In all scenarios, fossil and renewable fuels are used. Most of the scenarios still have nuclear power in the energy balance of 50 years, but the share of nuclear power of total energy supply is less than today. Much of fossil fuels will still be used. The natural gas dominates coal and oil in all future images and, according to the World

developed and developing countries [15].

16 Sustainable Cities - Authenticity, Ambition and Dream

efficiency in operation.

*4.5.2. Efficient use of renewable energy systems*

*4.5.1. Energy efficiency in combater of climate change*

Local energy systems can be used in many places. Energy system means the recovery and storage of energy in the form of heat from the ground. The design of the building may be controlled by any local energy system. For faced the future energy shortage, it is required to recognize all survived opportunities. In this context, it is necessary to consider all existent possibilities [15, 16].

#### *4.5.4. Efficient uses of geothermal energy*

Geothermal energy is the heat energy stored in the Earth's crust and flows out to the ground. The heat comes mainly from radioactive decomposition. The geothermal gradient varies from place to place. In Nordic countries, such as Sweden or Denmark, the sedimentary bedrock has the best conditions, and heat can be recovered using deep drilled wells [15, 16].

Soil heat utilizes heat energy from the sun and rain stored passively in the ground. The heat is absorbed through plastic hoses laid down at 1–2 m depth in which a freeze-dried liquid circulates. The heat is then recycled using a heat pump. To heat a small house, a surface area of 400–600 m<sup>2</sup> is required. If the hoses are laid above the groundwater surface, fine-grained soils that hold the moisture are well suited. Silt should be avoided due to the risk of fire. If the hoses are laid under the groundwater, water is important, so that coarse grains are preferable [15].

#### **4.6. Proactive innovation and educational policies**

Cities are places where knowledge is created and shared. Exploiting the full potential of knowledge in a city depends on the quality of day care and school education, the transfer of opportunities offered by education and training systems, social and cultural networks, opportunities for lifelong training, the excellence of university education and research institutes and the existing transfer network between industry, the business sector and the scientific community. Integrated urban development policy can help improve these factors, for example, bringing together all stakeholders, supporting networks and optimizing infrastructure. Integrated urban development promotes social and intercultural dialog [18]. Integrated urban development strategies, participatory urban management and good governance can help to make effective use of the potential of European cities, particularly in terms of competitiveness and growth, and to reduce disparities between and within neighborhoods. These integrated urban development strategies bring citizens the opportunity of social and democratic participation.

#### **4.7. Applying for new business for new opportunities**

Business development in the last two to three decades has been of major importance for urban development. Retail trade is an important factor in urban life. Wherever shops are placed, they dramatically affect traffic and trade patterns. Large sections of the industry have moved or disappeared, more may follow in the coming years. The abandoned industrial areas at the ports, in the city center or in their periphery open up opportunities for building closer and greener for the benefit of both city life and sustainability. Shipping and fishing have also changed; therefore, in many port cities, it is necessary to consider how the areas can be recycled. Even though many jobs have been closed, even population of people has increased. It is typical in industries that do not pollute or disrupt. There are industries that can be more easily mixed with, for example, housing, and can contribute to a good urban environment. This makes it necessary to consider whether existing rules and planning traditions to regulate coexistence between businesses and housing are still appropriate [19]. There are also professions that necessarily have to be in the cities and in the ports. Many of these companies are venture companies that cannot be instantly integrated with homes and other common urban activities. It is essential to ensure that these companies can continue to function and develop, and it must be ensured that there are sufficient safety distances around these companies—for the sake of both the companies themselves and their neighbors. It also means that the ports should not only be emptied for business and converted into, for example residential areas [20]. There is still a need for ports and shipping.

environment between the different areas of the city. In addition, social inequalities and differences in levels of economic development of the areas continue to increase, which contributes to the imbalance. A policy of social integration that contributes to reducing inequalities and preventing social exclusion will be the best guarantee for maintaining security in our cities. In order to achieve the objectives of social cohesion and integration within cities and urban areas, a good conception of housing policies is needed [22]. It is better to heed early warning signals and to take immediate and effective measures to remedy the situation as this approach saves resources. If an area has begun decaying, the cost and difficulties of returning that area to the waterline may often be higher. The government must provide the general framework and rehabilitation incentives for the inhabitants of the affected areas. Active involvement from residents and a better dialog between politicians, residents and economic actors are essential to finding the best solution for each disadvantaged urban area. It is believed that the following action strategies, included in an integrated urban development policy, are crucial

Introductory Chapter: Overview of Sustainable Cities, Theory and Practices

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19

**4.10. Remarkable attention on sustainable solution of "Transport in the city"**

The world's largest cities have very bad air quality. Traffic jams are common in cities worldwide, including the majority of the in some countries. In big cities, it is common that people travel several hours daily in order to access the workplace. The level of motoring has in many places reached a point where the problems are no longer possible to accept. Today, there are hundreds of millions of motor vehicles in the world, and many hundred thousands of people are killed on the roads each year [23]. In some countries, the goal is for every household to get a car. The trend in many countries is that the number of cars increases as income increases, households are divided and cities are expanding. Another problem is the poor connectivity between human settlements due to the poor quality of road infrastructure. Agenda 2030 addresses these issues by upgrading the transport system so that it can better connect cities and settlements and make it affordable, including financially and durable, to ensure that all world citizens benefit from the urbanization process. The focus is also on increasing access to green and public spaces, reducing the negative impact of cities on the environment per capita and reducing direct economic losses caused

The oldest suburbs were based on modes such as trams, city busses and trains. The newer suburbs are often based on the car as the dominant mode of transport. The vehicle is a minimal sustainable mode of transportation—especially if it only has the driver on board. The most of the crowds on the landing roads and in the big cities come from the suburbs. The suburb of the future must also be based on modes other than the car. Suburbs can be connected to the city center with light railways or modern trams that can transport a lot of passengers with a modest width. In other places, frequent and fast buses can reduce the need for driving. Attractive bicycle parking at stations and stops can encourage more to use bus

for deprived urban areas.

by disasters.

or train.

*4.10.1. Suburbans have to connect with the cities objectively*

#### **4.8. Paying attention to underground construction concept**

In many countries such as Japan, Malaysia and China, planning to take advantage of surfaces of the inner parts more effectively have begun in these countries. A solution for creating a sustainable future for the Earth's growing population is building on several floors, that is, to use surfaces above and below ground level. The compact city is seen as a model for future low-energy society. Japan, for instance, are looking at building whole cities down the mountain. The most important subject which required a clear answer is a way to cope with the transport problems in the largest cities. In order to accommodate all the facilities needed in the metropolitan areas, underground construction is being increasingly used for warehouses, business centers, shelters and facilities for work, leisure and cultural activities [21]. There are obvious environmental benefits. When an underground project is to be evaluated in an environmental impact assessment way, the aforementioned option should also be evaluated environmentally.

#### **4.9. Paying particular attention to "negative areas" in the context of the city as a whole**

Cities face major challenges, particularly in connection with changes in economic and social structures and globalization. Specific issues, among others, are a high unemployment rate and social exclusion phenomena. Within a city, there may be considerable differences not only in terms of economic and social opportunities but also in terms of the quality of the environment between the different areas of the city. In addition, social inequalities and differences in levels of economic development of the areas continue to increase, which contributes to the imbalance. A policy of social integration that contributes to reducing inequalities and preventing social exclusion will be the best guarantee for maintaining security in our cities. In order to achieve the objectives of social cohesion and integration within cities and urban areas, a good conception of housing policies is needed [22]. It is better to heed early warning signals and to take immediate and effective measures to remedy the situation as this approach saves resources. If an area has begun decaying, the cost and difficulties of returning that area to the waterline may often be higher. The government must provide the general framework and rehabilitation incentives for the inhabitants of the affected areas. Active involvement from residents and a better dialog between politicians, residents and economic actors are essential to finding the best solution for each disadvantaged urban area. It is believed that the following action strategies, included in an integrated urban development policy, are crucial for deprived urban areas.

#### **4.10. Remarkable attention on sustainable solution of "Transport in the city"**

The world's largest cities have very bad air quality. Traffic jams are common in cities worldwide, including the majority of the in some countries. In big cities, it is common that people travel several hours daily in order to access the workplace. The level of motoring has in many places reached a point where the problems are no longer possible to accept. Today, there are hundreds of millions of motor vehicles in the world, and many hundred thousands of people are killed on the roads each year [23]. In some countries, the goal is for every household to get a car. The trend in many countries is that the number of cars increases as income increases, households are divided and cities are expanding. Another problem is the poor connectivity between human settlements due to the poor quality of road infrastructure. Agenda 2030 addresses these issues by upgrading the transport system so that it can better connect cities and settlements and make it affordable, including financially and durable, to ensure that all world citizens benefit from the urbanization process. The focus is also on increasing access to green and public spaces, reducing the negative impact of cities on the environment per capita and reducing direct economic losses caused by disasters.

#### *4.10.1. Suburbans have to connect with the cities objectively*

**4.7. Applying for new business for new opportunities**

18 Sustainable Cities - Authenticity, Ambition and Dream

There is still a need for ports and shipping.

environmentally.

**whole**

**4.8. Paying attention to underground construction concept**

Business development in the last two to three decades has been of major importance for urban development. Retail trade is an important factor in urban life. Wherever shops are placed, they dramatically affect traffic and trade patterns. Large sections of the industry have moved or disappeared, more may follow in the coming years. The abandoned industrial areas at the ports, in the city center or in their periphery open up opportunities for building closer and greener for the benefit of both city life and sustainability. Shipping and fishing have also changed; therefore, in many port cities, it is necessary to consider how the areas can be recycled. Even though many jobs have been closed, even population of people has increased. It is typical in industries that do not pollute or disrupt. There are industries that can be more easily mixed with, for example, housing, and can contribute to a good urban environment. This makes it necessary to consider whether existing rules and planning traditions to regulate coexistence between businesses and housing are still appropriate [19]. There are also professions that necessarily have to be in the cities and in the ports. Many of these companies are venture companies that cannot be instantly integrated with homes and other common urban activities. It is essential to ensure that these companies can continue to function and develop, and it must be ensured that there are sufficient safety distances around these companies—for the sake of both the companies themselves and their neighbors. It also means that the ports should not only be emptied for business and converted into, for example residential areas [20].

In many countries such as Japan, Malaysia and China, planning to take advantage of surfaces of the inner parts more effectively have begun in these countries. A solution for creating a sustainable future for the Earth's growing population is building on several floors, that is, to use surfaces above and below ground level. The compact city is seen as a model for future low-energy society. Japan, for instance, are looking at building whole cities down the mountain. The most important subject which required a clear answer is a way to cope with the transport problems in the largest cities. In order to accommodate all the facilities needed in the metropolitan areas, underground construction is being increasingly used for warehouses, business centers, shelters and facilities for work, leisure and cultural activities [21]. There are obvious environmental benefits. When an underground project is to be evaluated in an environmental impact assessment way, the aforementioned option should also be evaluated

**4.9. Paying particular attention to "negative areas" in the context of the city as a**

Cities face major challenges, particularly in connection with changes in economic and social structures and globalization. Specific issues, among others, are a high unemployment rate and social exclusion phenomena. Within a city, there may be considerable differences not only in terms of economic and social opportunities but also in terms of the quality of the The oldest suburbs were based on modes such as trams, city busses and trains. The newer suburbs are often based on the car as the dominant mode of transport. The vehicle is a minimal sustainable mode of transportation—especially if it only has the driver on board. The most of the crowds on the landing roads and in the big cities come from the suburbs. The suburb of the future must also be based on modes other than the car. Suburbs can be connected to the city center with light railways or modern trams that can transport a lot of passengers with a modest width. In other places, frequent and fast buses can reduce the need for driving. Attractive bicycle parking at stations and stops can encourage more to use bus or train.

#### *4.10.2. Local stations in the suburbs*

However, the vehicle cannot be avoided. On the other hand, it can be used more appropriately. Municipalities with suburbs can build larger parking spaces at the local stations in the suburbs, thus encouraging the drive not to go all the way to work or to the city center. They can promote partial arrangements and intercourse, resulting in fewer cars on the streets.

**Author details**

Amjad Almusaed<sup>1</sup>

Sweden

**References**

2000. p. 30

2004. p. 154

intechopen.77971

\* and Asaad Almssad<sup>2</sup>

\*Address all correspondence to<EMAIL_ADDRESS>
Washington, D.C., United States: Island Press; 2011. p. 2

[7] Baker S. Sustainable Development. New York: Routledge; 2006. p. 26

Republic of Ecuador. 2017. p. 3, 4, 7, 41

Ahmedabad: CEPT University; 2014

University College Dublin; 2008

1 Department of Construction Engineering and Lighting Science, Jönköping University,

Introductory Chapter: Overview of Sustainable Cities, Theory and Practices

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21

[1] Cucu V. Geografia orasului. In: Fundatiei "Dimitrie Bolintineanu". Romania: Bucuresti;

[2] Almusaed A. Introductory chapter: A general reading process on landscape architecture. London, England: Intechopen; p. 3-7. [Accessed: September 19 2018]. DOI: 10.5772/

[3] Slavin MI, editor. Sustainability in America's Cities Creating the Green Metropolis.

[4] Almusaed A. Intelligent Sustainable Strategies Upon Passive Bioclimatic Houses: From Basra (Iraq) to Skanderbeg (Denmark). Aarhus, Denmark: Aarhus School of Architecture;

[5] United Nations. New Urban Agenda, Habitat III., Supported by the Government of the

[6] Almusaed A, Almssad A, editors. Sustainable Building, Interaction between a Holistic Conceptual Act and Material Properties. London, England: IntechOpen; 2018. p. 5

[8] Bojinski S, Doherty SJ. Lessons learned from IPCC AR4 [internet], American Meteorological Society. 2009. Available from: http://journals.ametsoc.org/doi/abs/10.1175/2008BAMS2643.1

[9] Almusaed A, Almssad A. Urban biophilic theories upon reconstructions process for Basrah City in Iraq. In: The 30th International Plea Conference, December 16-18, 2014.

[10] Almusaed A. Towards a zero energy house strategy fitting for south Iraq climate. In: The 25th Passive, and Low Energy Architecture (PLEA). October 2008. Dublin, England:

2 The Head Department of Building Technology, Karlstad University, Sweden

#### *4.10.3. Using of subways as environmental solutions*

The interest in concealing road traffic is increasing in the century with environmental requirements. One way is to build tunnels. Many of the world's most complex tunnel projects are conducted in Asia's fast-growing metropolitan areas. There are many examples of traffic tunnels in several floors, subways, tunnels for district heating, telephone lines and so on. Subways are expected to be very important in the future. In many areas, there are also plans for car traffic in tunnels, including in Stockholm. All technical systems that utilize pipes or pipelines are built underground for its distribution network: telecommunications, electricity, district heating, gas, water and sewage [24].

#### *4.10.4. Promote efficient and cheap urban transport*

Many disadvantaged neighborhoods also lead to the lack of transport links and environmental influences, which are likely to reduce their attractiveness. The development of an efficient and inexpensive transport system will provide residents of these neighborhoods with opportunities for mobility and equal access to those of other citizens. To achieve this, transport planning and traffic management in these areas must progressively reduce the negative impact of transport on the environment and organize transport in a manner that integrates these neighborhoods into the city and region as a whole. Suitable networks for pedestrian traffic and cyclists will be useful for this purpose. The better we manage to economically stabilize disadvantaged areas, integrate them socially and improve the physical environment and transport infrastructure, the greater our chances are that our cities will remain points of social progress, growth and innovation [25].

#### **4.11. Activation of training education policies for children's and young's residences**

A crucial starting point for improving the situation of disadvantaged areas in cities is to improve the situation of education and training in local communities in line with proactive policies focused on children and young people. More opportunities for education and training should be provided for disadvantaged areas, and they must be tailored to the needs and deficiencies of children and young people in those areas. Through a policy focused on children and young people built to the requirements of the social area in which they live, we must contribute to increasing the chances of children and young people living in deprived areas to achieve and provide equal opportunities in the long run.


**2.3. Feedstock combustion for gasifier**

as biogas production and second purpose may be as a fertilizer. The seed cake of jatropha can be used as organic fertilizer because it still has nutrients and mineral needed by the plant. Jatropha seed cake could be used in combustion process but considering air emission pro-

In this section, use of jatropha as a fertilizer or green manure has been presented. Green manure can reduce loss of nutrients from soil and give sustainable nutrient supply for long period as compared to chemical fertilizer. Chemical fertilizers can get solubilize in water and will drift together with water especially during the rainy seasons. Patolia et al. [10] reported after 2 years

also reported that dry matter of sandy loam soil could be increased upto 120% by adding 3 tons

Biogas (methane) is produced by anaerobic digestion. Biogas has wide utilities as it can be applied directly for cooking, heating and stationary engine operation in dual fuel mode. The biogas is purified, compressed and stored in cylinder as CNG (Compressed Natural Gas) for automotive transport purposes, power generation as well as in agricultural unit operation. Jatropha seed cake has good potential as biogas feedstock due to confer 60% higher biogas and also better calorific value than the cattle dung [11]. Chandra et al. [11] reported jatropha seed cakes have biogas generation potential in the range of 220–250 and 240–265 L/kg of cake respectively (under mesophilic temperature range of anaerobic digestion). C, H, and N composition was 48.8; 6.20 and 3.85% with C/N ratio of 12.70. The methane content of biogas derived from non-edible oil seed cakes has been found to range between 65 and 70% against 55% from the cattle dung. The best dilution ratio of cake is at 1:4 (cake:water) for *J. curcas* seed cakes. Production of biogas from *J. curcas* seed cakes is one of easy ways for waste management. It can also be used to fulfill energy need for rural areas. According to Kumar [12], in India ~2550 million cubic meters of biogas has been produced from 10.2 lakh metric tons of *J. curcas* seed cakes. Visser and Adriaans [13] studied anaerobic digestion of *J. curcas* press cake. The cake was from cold pressing jatropha seed including the husk. Digestion was carried out at temperature 20°C, pressure 1 bar during 60 days. Jatropha cake that pressed with nozzle (aperture size

application. Ghosh et al. [6]

O.

/kg dry matter, with

and 1.4% K2

O5

duced by burning, its use as a fertilizer would be a better choice.

that N45 application could increase the dry matter compared to No

of seedcake/ha as manure. *J. curcas* L. seedcake contain 2% N, 1.2% P2

of 7 mm) contain 33% hull produced a cumulative biogas yield of 0.95 m3

mesh. Other parts of *J. curcas* plant as a biogas feedstock is presented in **Figure 3**.

0.23 L/g VS added, it shows oil has potential with 0.739 L/g Volatile Solid added.

85% carbon conversion. Gunaseelan [8] reported energy biomass from part of fresh *J. curcas*. The feedstocks were dried at 60°C before use and subsequently grained to become 2 mm

**Figure 3** suggests not only jatropha cake, but also all parts of the jatropha plant could be utilized for producing biogas (methane). The highest yield was achieved from seed kernel 0.969 L/g Volatile Solid added. If compared to the yield from de-oiled cake, which is just

**2.1. Jatropha as a fertilizer (green manure)**

**2.2. Biogas production**

276 Advances in Biofuels and Bioenergy

Vyas and Singh [14] reported that jatropha seed husk could be used successfully as feedstock for open core down draft gasifier, although the gasifier has to be induced by 1 kg charcoal and 3.2 kg wood. Jatropha seed husk analysis contains 3.97% dry basis ash, 71.04% dry basis volatile matter and 24.99% dry basis fixed carbon. Gasifier was able to run on jatropha seed husk for 340 minute at 2 flow rates (4.5 and 5.5 m3 /h) without any problems. Gasification efficiency of 68.31% was achieved at gas flow rate of 5.5 m3 /h and biomass consumption rate of 2.2 kg/h. Gasification efficiency can possibly be increased 2.35% by increasing 1 m3 /h of gas flow rate and by adding 0.4 kg/h biomass consumption rate.

#### **2.4. Bioactive compost production**

Bioactive compost can be produced from *J. curcas* hull. Sharma et al. [15] produced bioactive compost from jatropha hull biomass by using lingocellulolytic fungi. Bioactive compost is for increasing the added value compared to ordinary manure. Within 1 month, carbon to nitrogen (C/N) ratio of hull decreases from 66.93 to 12–16. From C/N ratio point of view, composting of jatropha hull in 1 month has indicated a better composition of bioactive compost. However, it takes nearly 4 months for complete compost maturation. After 4 months, phytotoxicity of compost can be reduced, thus compost will be ready to use. Bioactive compost from jatropha hull is alkaline, so it is suitable for acidic soil. It can balance the pH of the acidic soil.


**4.7 HOX genes**

Another important set of genes in regulating EMT is the homeobox (HOX) gene family, master players in regulating embryonic development and maintaining homeostasis through strictly regulated expression in various tissues and organs during adult life. Several studies have demonstrated the association of HOX genes in the pathogenesis of multiple cancers.  In one study 60% of their breast cancers had no HOXA5 expression (Raman et al., 2000) which causes p53-dependent apoptosis. HOXA5 was reported to cause cell death through the activation of the caspase pathways in HS578T cells expressing mutant p53 (Chen et al., 2004). HOXD10 was extensively reduced as malignancy increased in epithelial cells, and restoring its expression in MDA-MB-231 could significantly reduce the migration capacity of these highly aggressive cells (Carrio et al., 2005). HOXB13 over-expression was associated with increased MCF10A cell motility and invasion *in vitro*, while its ratio to interleukin-17β receptor was predictive of tumour recurrence during adjuvant tamoxifen monotherapy. HOXB7 is involved in tissue remodeling of the normal mammary gland (Ma et al., 2004) and is expressed at higher levels in metastatic breast tumours (Care et al., 1998, 2001). Furthermore, regulation of the expression of several growth and angiogenic factors, including basic FGF, VEGF, IL8, ANG1, ANG2, and MMP9 in SKBR3 breast cancer cells, depends on the over-expressed levels of HOXB7 which can result in the formation of vascularised tumours when grown as xenografts in nude mice. HOXB9 like HOXB7 can lead to increased cell motility and EMT (Hayashida et al., 2010).

Endocrine Resistance and Epithelial Mesenchymal Transition in Breast Cancer 467

internal ribosomal entry site sequence and thereby increasing the translational efficiency of ZEB2 which then directly inhibits E-cadherin expression, maintaining an EMT state (Beltran

Although these RNA molecules are associated with the regulation of EMT and MET, other miRNAs such as miR-10b are reportedly associated with metastasis and invasion. It inhibits HOX10 translation while increasing RHOC when induced by TWIST (Ma et al., 2007). Another miRNA that seems to increase the metastatic potential of cancer cells is miR-29a; up-regulated in a mesenchymal metastatic RASXT mammary cell line compared to epithelial EpRas cells. In addition, over-expression of miR-29a suppresses expression of tristetraprolin, a regulator of epithelial polarity and metastasis, and leads to EMT and metastasis through RAS signalling. This correlates with data from breast cancer patients showing enhanced miR-29a and reduced tristetraprolin levels (Gebeshuber et al., 2009). In contrast to miR-10b, miR-335 was found to be a suppressor of invasion and metastasis through modulation of the expression of the 'six gene signature' set: COL1A1, MERTK, PLCB1, PTPRN2, TNC and SOX4 which are considered predictive markers of metastasis and invasion. miR-335 was also reported to suppress invasion and metastasis in MDAMB231, a

highly metastatic and invasive ER-ve breast cancer cell line (Tavazoie et al., 2008).

An interesting idea that has emerged recently suggests the possibility that cancer cells undergoing EMT acquire stem cell-like characteristics.  It was first reported by Al-Hajj et al., (2003) when they showed that a CD44+/CD24−/low sub-population of breast cancer cells could produce tumours in a xenograft model more effectively. These cells are regarded as the 'metastatic component' of the cancer, particularly in breast neoplasms as they are the only subset of cells with potential to initiate new tumour growth. This was further supported by analysis of genetic profiles of CD44+ breast cancer cells which showed enrichment with stem-cell markers and displayed activated TGFβ signalling with lung metastasis and poor clinical outcomes (Sheridan et al., 2006; Shipitsin et al., 2007). Furthermore, it has been reported that metaplastic and claudinlow breast cancers are enriched with markers of EMT and display stem cell characteristics suggesting that cancer cells undergoing EMT exhibit stem cell-like characteristics (Prat et al., 2010). In addition to that, inducing EMT in immortalized human mammary epithelial cells with either TGFβ, SNAIL1 and TWIST confers stem cell characteristics with increased formation of mammospheres in three dimensional culture and ductal outgrowths in xenotransplants (Mani et al., 2008; Morel et al, 2008). Interestingly, BCSCs isolated from primary tumors and normal breast tissue showed an increased expression of the mesenchymal markers TWIST1 and 2, FOXC2, SNAIL1, ZEB2, vimentin and fibronectin

not (Mani et al., 2008). Furthermore, hypoxia-induced SNAIL2 expression has also been associated with acquisition of a basal-like breast cancer phenotype with high levels of the stem cell regulatory genes CD133 and BMI1 (Storci et al., 2008). Inhibition of WNT signalling through LRP6 was found to reduce stem cell-like properties and cause EMT reversal, restoration of the epithelial phenotype, and suppression of SNAIL2 and TWIST expression (DiMeo et al., 2009) in a mouse model of breast cancer metastasis to the lung.

/CD24+) isolated from differentiated carcinoma do

**4.11 Epithelial to mesenchymal transition and breast cancer stem cells**

et al., 2008).

stem cell-like properties.

while epithelial cells (which are CD44-


*3.1. Defining the Compensatory Reserve*

The compensatory reserve is a concept that represents the sum total of all physiological mechanisms that contribute to the maintenance of systemic DO2 to the body's tissue. Conceptually, a compensatory reserve can be calculated as the difference between a baseline value at rest (100% reserve) and the value at the onset of hemodynamic instability (i.e., 0% reserve) [14,22–25,30,34–36]. In this regard, each individual has a finite 'reserve' consisting of physiological feedback mechanisms designed to compensate for low blood flow states. The complexity of this compensatory reserve is reflected by the reported observation that the physiology of integrated compensation is unique for each individual [37]. When this capacity to compensate becomes depleted, a state of decompensated shock occurs. Clinically, a compensatory reserve measurement (CRM) can be obtained from assessment of changing arterial pressure waveform morphology associated with changes in compensation [14,18,21,23,30,38–54]. Figure 2 illustrates that each arterial waveform consists of two primary waves: (1) an 'ejected' wave with features that are dictated by all compensatory mechanisms that influence myocardial function; and (2) a 'reflective' wave with features that are influenced by all compensatory mechanisms involved in the control of peripheral blood flow [14,22]. The LBNP model of hemorrhage has been used to generate a large reference database of more than 650,000 arterial pressure analog waveforms generated from noninvasive photoplethysmographic techniques and collected from more than 260 healthy men and women with age range of 18 to 55 years across various stages of reduced central blood volume to the point of decompensated shock (0% compensatory reserve) [22]. With application of advanced machine-learning technology to this large physiologically-diverse database, the CRM algorithm has 'learned' to provide rapid and continuous measures of changing arterial pressure waveform morphology to the clinical caregiver with the ability to gain an early and accurate assessment of the individual patient's medical status without the need for demographic data or measures of the patient's baseline physiology (as depicted in Figure 3) [21,24].

**Figure 2.** Illustration of changes in features of the ejected and reflected arterial waveforms progressing from a normal blood volume state to a state of reduced central blood volume (i.e., hypovolemia) such as that experienced during hemorrhage. The red line indicates the integrated waveform that is clinically observed. Modified from Convertino et al. [14,22,23].

**Figure 3.** Diagram illustrating the overall framework envisioned for using the compensatory reserve measurement (CRM) in pre-hospital care, including the details on the CRM machine learning algorithm for assessing beat-to-beat analog arterial pressure waveform features in an individual patient unknown to the algorithm. The unknown arterial waveform is compared to a large waveform "library" collected from a diversity of human subjects exposed to progressive reductions in central blood volume. The algorithm identifies the most similar waveform in the waveform library with the unknown sample to generate a CRM value. Modified from Convertino et al. [14,18,21–23,55].