**7. Concluding Remarks**

Can we define a common denominator for the function of FAS1 proteins? The characterization of HsTgfbi structure and function demonstrates the versatility of the FAS1 domain in binding multiple ligands, which might be a conserved feature. The frequent assumption that FAS1 proteins are involved in "cell adhesion," however, is more context-dependent. It is derived from insightful experiments performed with animal cell cultures; however, it might be misleading for "hard-shelled" cells such as bacteria, fungi and plants that usually adhere to their ECM as a result of turgor pressure and build up adhesive materials such as pectin. By contrast, the designation of Tgfbi and Pn as matricellular proteins, defined as non-structural ECM-components that interact with cell surface receptors as mediators between the cell and its microenvironment [77,182], seems a more productive concept for approaching the common function of FAS1 proteins in all kingdoms of life including plants. The crucial challenge for future work on plant FAS1 proteins will be the identification of molecular interactors both of the FAS1 domain and of their abundant but enigmatic glycan modifications.

**Funding:** This research was funded by the Austrian Science Fund FWF (Grant number I1182-B22).

**Conflicts of Interest:** The author declares no conflict of interest.


*5.3.1 Habitat*

Climate change can cause habitat degradation or loss for several species (e.g., polar bears, koalas, and birds). Polar bears are dependent on sea ice. The increased temperature is causing the arctic sea ice to melt, damaging the polar bears' habitat (**Figure 10**) [23]. Koalas are dependent on eucalyptus tree. The increased temperature and drought are causing wildfire, destroying the koalas' habitat [24]. Lake Urmia (Iran) is a bird habitat and used to be a popular tourist destination. The lake is drying up mainly because of climate change.

**Figure 10.** *Climate change causes loss of habitat for polar bear.*

### *5.3.2 Nutrition*

Survival of species can be affected by water/food availability/quality beyond those that species can tolerate. Unpredictability/shortage of water and food caused by climate change may lead to greater prevalence of torpor and hibernation in small mammals and hypometabolism in large mammals.

Polar bears will have trouble finding food as the sea ice thins and melts earlier. With limited food supply, the polar bears rely on their stored fat. They have to swim longer distances in the water and many young cubs die because of their inability to swim. Koalas' main food source is eucalyptus leaves. Each koala eats

approximately 1 kg of eucalyptus leaves per day. Climate change reduces the amount of water in the eucalyptus tree. The increased carbon dioxide level causes decrease protein levels in the tree affecting plant nutritional quality. All these changes create dehydration, malnutrition, and starvation. Koalas are risking their lives by climbing down from their trees in search of water and food. This leaves them vulnerable to predators and the risk of being hit by cars. Koalas' population has declined by more than 30% over their last three generations (**Figure 11**) [24]. Elephants require 150–300 liters of water per day for drinking in addition to the amount needed for bathing and playing. Droughts can cause population decline (**Figure 12**) [25].

**Figure 11.** *Climate change is responsible for dehydration and malnutrition of koala.*

**209**

**Figure 14.**

*Impact of Climate Change on Life*

(**Figure 14**).

**Figure 13.**

*Climate change promotes early avian migration.*

*Climate change leads to female sea turtle overpopulation and domination.*

*DOI: http://dx.doi.org/10.5772/intechopen.94538*

*5.3.3 Migration, breeding, and gender determination*

Warmer springs have promoted advanced timing of migration and breeding in most avian species in the last decades (**Figure 13**) [26]. Rising sea levels threaten the sea turtle eggs as most turtles lay their eggs on beaches. Climate change can affect sex determination in several animals [27, 28]. The sex of the sea turtles is determined by the nest temperatures. Cool temperatures produce more males while warm temperatures produce more females. Climate change alters the sea turtles' gender population (females outnumbering males). Certain areas could end up producing only female turtles, with the possibility of local species extinction since there will be no mating partners for female turtles

**Figure 12.** *Climate change causes decline in elephant population.*

#### *Impact of Climate Change on Life DOI: http://dx.doi.org/10.5772/intechopen.94538*

*Environmental Issues and Sustainable Development*

(**Figure 12**) [25].

**Figure 11.**

*Climate change is responsible for dehydration and malnutrition of koala.*

approximately 1 kg of eucalyptus leaves per day. Climate change reduces the amount of water in the eucalyptus tree. The increased carbon dioxide level causes decrease protein levels in the tree affecting plant nutritional quality. All these changes create dehydration, malnutrition, and starvation. Koalas are risking their lives by climbing down from their trees in search of water and food. This leaves them vulnerable to predators and the risk of being hit by cars. Koalas' population has declined by more than 30% over their last three generations (**Figure 11**) [24]. Elephants require 150–300 liters of water per day for drinking in addition to the amount needed for bathing and playing. Droughts can cause population decline

**208**

**Figure 12.**

*Climate change causes decline in elephant population.*


**6. CFD Simulation Results and Nusselt Number Correlations**

The CFD simulation results of average mass flow temperatures behind the tube rows are shown in Table 2.

**Table 2.** CFD simulation data.

Presented correlations for air-side Nusselt numbers relate to Reynolds numbers. The Reynolds number (Equation (5) is related to the hydraulic diameter, which is calculated using the definition proposed by Kays and London [23], where *wmax* is given by Equation (6). Parameter *wmax* has been calculated for the minimum airflow cross-section between tubes and it can exist in a different place in case of different PFTHE construction. The hydraulic diameter has been calculated by assumption dividing the volume through which air flows in one row by the surface area in contact with the air. Most often, this hydraulic diameter in the case of PFTHE is a bit smaller than double the fin pitch, and using geometry from Figure 1, equals 5.35 mm.

Reynolds numbers (*Redh*,*a*) (Equation (5) and maximal velocities (*wmax*) (Equation (6)) have been calculated for each row separately, due to a different maximum air velocity caused by higher air temperature causing increased air volume. The calculated parameters such as Reynolds numbers, HTCs, Nusselt numbers, and Colburn factors are presented in Tables 3–6.

$$Re\_{d\_{\hbar},a} = \frac{w\_{\text{max}} \cdot d\_{\hbar}}{\nu\_a} \tag{5}$$

**Table 3.** Calculated thermal parameters for the first row of PFTHE.

**Table 4.** Calculated thermal parameters for the second row of PFTHE.

**Table 5.** Calculated thermal parameters for the third row of PFTHE.

**Table 6.** Calculated thermal parameters for the first row of PFTHE.

The following designations are used in Equation (5): *Re dh*,*a* is the Reynolds number in case of air hydraulic diameter; *dh* is the air hydraulic diameter; *νa* is the air kinematic viscosity.

$$w\_{\text{max}} = \frac{(s \cdot p\_l)}{\left(s - \delta\_f\right) \cdot (p\_l - d\_{o,\text{min}})} \cdot \frac{\left(\overline{T}\_a^i\right)}{\left(\overline{T}\_{a,o}\right)} \cdot w\_o \tag{6}$$

The symbol *wmax* designates the air velocity in the least cross-section of the air flow. The symbol *s* denotes fin pitch. Other symbols represent: *pl* the longitudinal fin pitch *δf* the fin thickness, *do*,*min* the minimal dimension between tubes, *Ti a* the mass average air temperature in *i*-th row of PFTHE, and *Ta*,*o* the inlet mass average air temperature.

The approximation function was determined using the least-squares method. Using this function, the Nusselt number was approximated, depending on the Reynolds and Prandtl numbers, according to Equation (7). The range of Reynolds numbers considered is factored in the present study, and is also present in Equation (7).

$$Nu\_a = \varkappa\_1 \cdot Re^{\varkappa\_2} \cdot Pr^{\frac{1}{3}} \qquad \quad 140 \; < \; Re \; < \; 1500 \tag{7}$$

The heat transfer correlation for the entire heat exchanger is shown in Figure 6. The Nusselt numbers for the first and second rows of tubes as a function of the Reynolds number, calculated separately for each row, are illustrated in Figure 7a,b. The heat transfer correlations for the third and fourth rows of tubes are shown in Figure 8a,b. Figures 6–8 also show the confidence intervals for the Nusselt number calculated using Equation (7). The legend of each figure shows the corresponding correlation, either for the whole exchanger (Figure 6) or for a given row of tubes (Figures 7 and 8). Each figure also shows the limits of the 95% confidence intervals for the Nusselt number on a given tube row, where the coefficients *x*1 and *x*2 are determined by the least-squares method. For the 95% confidence interval, the values of the Nusselt number calculated for a given Reynolds number (Equation (7)) differ by +/−2 *σ*, where the symbol *σ* denotes the mean standard deviation of the Nusselt numbers obtained by the CFD modelling. The process of determining 95% confidence intervals for correlations per Nusselt number obtained by least-squares is detailed in Chapter 11 of Taler's book [24].

**Figure 6.** The average value of the Nusselt number as a function of the Reynolds number for the entire PFTHE.

**Figure 7.** The Nusselt number as a function of the Reynolds number: (**a**) for the first row of PFTHE; (**b**) for the second row of PFTHE.

**Figure 8.** The Nusselt number as a function of the Reynolds number: (**a**) for the third row of PFTHE; (**b**) for the fourth row of PFTHE.


**1. Introduction**

The expanded mindfulness about sustainability and requests for eco-friendly products has constrained the manufacturing firms to reevaluate their business activities [1]. Ventures are embracing the conventional strategies for manufacturing and petroleum products in the majority of the world [1]. The manufacturing enterprises in developed countries discharge multiple times carbon dioxide when contrasted with the developing nations [2]. The current arrangements on environmental change uncover that the normal surface temperature of the earth will increase to 3°C until the finish of this century [2]. This temperature increment is far away from the aggressive objective of the Paris Agreement that plans to confine it up to 2°C [3].

The hazard related to the atmosphere will increase in the offing because of expanded risk recurrence and increasingly powerless populace. Subsequently, for the government assistance of society and environmental assurance, enterprises must remember green innovations for their tasks. The presence of present-day businesses relies on their fitness to change with the external environment [4]. In this way, to stay practical in the market, manufacturing firms must create and actualize low carbon emanation advancements. Thus, the firms are spending huge money to devise sustainable techniques for creation and utilization [5].

Since the most recent couple of decades, numerous thoughts and approaches have been created such as Lean, Green, Six Sigma, and so forth [6, 7] to create the top quality items. Gaikwad and Sunnapwar [8] introduced critical achievement factors for executing incorporated LGSS rehearses in the manufacturing industry.

Yet, an individual methodology cannot address all the issues comprehensively identified with sustainability [9]. Along these lines, a coordinated methodology is required that lessens wastes and varieties and mitigates negative ecological effects [3]. Sreedharan and Raju [10] opined that GLS (Green Lean Six Sigma) is a comprehensive methodology that reduces ecological outflows through 3R's (reduce, reuse, and recycle).

LGSS comprises of three remarkable methodologies viz., Green, Lean, and Six Sigma that expand profitability elements through reduced emissions, wastes, and rework [11]. Lean promotes the efficient evacuation of wastes through excellence at all levels inside the firm [12, 13]. Green innovation diminishes the negative ecological effect of the item by making it all the more ecofriendly [14–16]. Six Sigma decreases varieties in the process that prompts diminished dismissal of products [17]. However, consolidated Green Lean Six Sigma is fit for creating an item that is not just of high caliber and ease yet in addition eco-friendly [18].

In the literature, there is significant proof of the combination and system of Lean and Green, Lean, and Six Sigma. In any case, the literature needs enough proof of the integration and structure of LGSS. There exist hardly any investigations related to the LGSS structure; however, the concerned associations confronted difficulties to execute the equivalent because of the conventional nature of the system [19]. In addition, in the literature, there exists no examination on the LGSS structure that can be applied independently of the size, type, and culture of the firm. For this, the current study gives reconciliation and system of LGSS for accomplishing greatness in profitability and environmental sustainability.

Lean Six Sigma is an approach that identifies the customer expectations, eliminates wastages, and reduces variability. It combines Six Sigma's problem-solving approach with statistical tools with a Lean effect on flow improvement [20]. Hence, the objective of industrial engineering to improve productivity through optimization techniques has been fulfilled.

Evidence suggests that LGSS approaches make a positive impact on social, economical, and environmental (i.e., sustainability) performance of the firm [21]. Therefore, industrial engineering practitioners make an effort toward the deployment of such types of approaches into their business. The industrial engineering field has also tremendous pressure to improve production efficiency concerning social and environmental responsibility, and also market dynamics have changed [15, 16]. Bergmiller and McCright [22] opined that the three elements of sustainability (economic, social, and environmental) should be mulled over by firms to keep their competitive edge. In this situation, the confront for firms is to meet all their stakeholders' requirements through achieving positive financial execution while finding the correct equilibrium among the triple bottom line of sustainability [23, 24].

### **2. Literature review**

The historical backdrop of GLS followed back to the advancement of Lean way of the thinking. The Lean idea was contrived in Japan after the Universal War II to contend with the large scale manufacturing arrangement of the USA [5, 25]. The

**87**

and execution of LGSS.

effects [26].

**Figure 1.**

*Radar chart of LGSS tools.*

radar chart.

**3. Integration of lean green six sigma**

*Integrated Lean-Green-Six Sigma Practices to Improve the Performance of the Manufacturing…*

cutting edge idea of Lean philosophy originated from the Toyota Production System (TPS), spearheaded by Japanese specialists Taiichi Ohno and Shigeo Shingo [3]. The Lean methodology diminishes wastes; it cannot lessen the unfriendly natural

The execution of Green innovations can defeat this confinement of the Lean. Green innovation adds to Lean as it diminishes negative natural effects and other related wastes [27]. Green innovation decreases natural discharges; it cannot lessen the lean wastes [1]. Along these lines, there is a requirement for a consolidated Green Lean (GL) approach that limits Lean wastes as well as decreases the carbon footprint. There is a decent arrangement of similitude between the two strategies

The majority of the investigations discover that there is an absence of metrics,

The GLS has gotten due consideration as of late due to its capacity to improve efficiency, and profitability and alleviate environmental concerns [19]. LGSS framework proposes a hypothetical incorporation model of the LGSS dependent on the blend of hypothetical components. **Figure 2** delineates a coordinated LGSS framework. The reconciliation model's principle point is to depict the basic realities required for the manufacturing industry to improve sustainable execution. The proposed model speaks to the theoretical likenesses between the three methodologies. The empowering influences function as the key data sources that invigorate the incorporation of LGSS while the exhibitions in trade-off fill in as yield. The difficulties for the LGSS combination are the limitations that confine the hierarchical interests to improve the manageability elements. The apparatuses and related LGSS framework are considered as the supporting mechanism that bolsters the joining

The goal is to maximize stakeholder value, by achieving customer satisfaction, process speed, cost, and quality through the tools and techniques [29]. This

dependent on waste decrease procedures and management practices [22].

top management backing, and standard method for execution of LGSS in the firm. The LGSS instruments can possibly discover the wastages, abandons, and undesirable exercises that lead to the advancement of resources [28]. As suggested by Kaswan and Rathi [4], LGSS tools are presented in **Figure 1** in the form of a

*DOI: http://dx.doi.org/10.5772/intechopen.93276*

*Integrated Lean-Green-Six Sigma Practices to Improve the Performance of the Manufacturing… DOI: http://dx.doi.org/10.5772/intechopen.93276*

**Figure 1.** *Radar chart of LGSS tools.*

*Concepts, Applications and Emerging Opportunities in Industrial Engineering*

not just of high caliber and ease yet in addition eco-friendly [18].

plishing greatness in profitability and environmental sustainability.

tion techniques has been fulfilled.

sustainability [23, 24].

**2. Literature review**

Since the most recent couple of decades, numerous thoughts and approaches have been created such as Lean, Green, Six Sigma, and so forth [6, 7] to create the top quality items. Gaikwad and Sunnapwar [8] introduced critical achievement factors for executing incorporated LGSS rehearses in the manufacturing

Yet, an individual methodology cannot address all the issues comprehensively identified with sustainability [9]. Along these lines, a coordinated methodology is required that lessens wastes and varieties and mitigates negative ecological effects [3]. Sreedharan and Raju [10] opined that GLS (Green Lean Six Sigma) is a comprehensive methodology that reduces ecological outflows through 3R's (reduce, reuse,

LGSS comprises of three remarkable methodologies viz., Green, Lean, and Six Sigma that expand profitability elements through reduced emissions, wastes, and rework [11]. Lean promotes the efficient evacuation of wastes through excellence at all levels inside the firm [12, 13]. Green innovation diminishes the negative ecological effect of the item by making it all the more ecofriendly [14–16]. Six Sigma decreases varieties in the process that prompts diminished dismissal of products [17]. However, consolidated Green Lean Six Sigma is fit for creating an item that is

In the literature, there is significant proof of the combination and system of Lean and Green, Lean, and Six Sigma. In any case, the literature needs enough proof of the integration and structure of LGSS. There exist hardly any investigations related to the LGSS structure; however, the concerned associations confronted difficulties to execute the equivalent because of the conventional nature of the system [19]. In addition, in the literature, there exists no examination on the LGSS structure that can be applied independently of the size, type, and culture of the firm. For this, the current study gives reconciliation and system of LGSS for accom-

Lean Six Sigma is an approach that identifies the customer expectations, eliminates wastages, and reduces variability. It combines Six Sigma's problem-solving approach with statistical tools with a Lean effect on flow improvement [20]. Hence, the objective of industrial engineering to improve productivity through optimiza-

Evidence suggests that LGSS approaches make a positive impact on social, economical, and environmental (i.e., sustainability) performance of the firm [21]. Therefore, industrial engineering practitioners make an effort toward the deployment of such types of approaches into their business. The industrial engineering field has also tremendous pressure to improve production efficiency concerning social and environmental responsibility, and also market dynamics have changed [15, 16]. Bergmiller and McCright [22] opined that the three elements of sustainability (economic, social, and environmental) should be mulled over by firms to keep their competitive edge. In this situation, the confront for firms is to meet all their stakeholders' requirements through achieving positive financial execution while finding the correct equilibrium among the triple bottom line of

The historical backdrop of GLS followed back to the advancement of Lean way of the thinking. The Lean idea was contrived in Japan after the Universal War II to contend with the large scale manufacturing arrangement of the USA [5, 25]. The

**86**

industry.

and recycle).

cutting edge idea of Lean philosophy originated from the Toyota Production System (TPS), spearheaded by Japanese specialists Taiichi Ohno and Shigeo Shingo [3]. The Lean methodology diminishes wastes; it cannot lessen the unfriendly natural effects [26].

The execution of Green innovations can defeat this confinement of the Lean. Green innovation adds to Lean as it diminishes negative natural effects and other related wastes [27]. Green innovation decreases natural discharges; it cannot lessen the lean wastes [1]. Along these lines, there is a requirement for a consolidated Green Lean (GL) approach that limits Lean wastes as well as decreases the carbon footprint. There is a decent arrangement of similitude between the two strategies dependent on waste decrease procedures and management practices [22].

The majority of the investigations discover that there is an absence of metrics, top management backing, and standard method for execution of LGSS in the firm. The LGSS instruments can possibly discover the wastages, abandons, and undesirable exercises that lead to the advancement of resources [28]. As suggested by Kaswan and Rathi [4], LGSS tools are presented in **Figure 1** in the form of a radar chart.

### **3. Integration of lean green six sigma**

The GLS has gotten due consideration as of late due to its capacity to improve efficiency, and profitability and alleviate environmental concerns [19]. LGSS framework proposes a hypothetical incorporation model of the LGSS dependent on the blend of hypothetical components. **Figure 2** delineates a coordinated LGSS framework. The reconciliation model's principle point is to depict the basic realities required for the manufacturing industry to improve sustainable execution. The proposed model speaks to the theoretical likenesses between the three methodologies. The empowering influences function as the key data sources that invigorate the incorporation of LGSS while the exhibitions in trade-off fill in as yield. The difficulties for the LGSS combination are the limitations that confine the hierarchical interests to improve the manageability elements. The apparatuses and related LGSS framework are considered as the supporting mechanism that bolsters the joining and execution of LGSS.

The goal is to maximize stakeholder value, by achieving customer satisfaction, process speed, cost, and quality through the tools and techniques [29]. This

#### **Figure 2.**

*Integrated framework of LGSS.*

#### **Figure 3.**

*Execution steps of LGSS framework.*

initiative depends upon collaborative team effort to improve performance of the firm [30] to identify the need of the customers and to eliminate unwanted activities within the process [31]. The individual LGSS approach shares some similarities such as employee involvement, customer satisfaction, and continuous improvement [32]. Aqlan and Alfandi [33] opined that each of the practice has been carried out by many forms to improve their processes. Some researchers focus on Lean achievement in excellence through the reduction of waste and unwanted activities [34].

Following **Figure 3** depicts the Six Sigma DMAIC (Define-Measure-Analyze-Improve-Control)-based framework that can be adopted by all business firms. The proposed integrated framework has executed in the following five steps.

**89**

the company.

*Integrated Lean-Green-Six Sigma Practices to Improve the Performance of the Manufacturing…*

In this step, the project may be selected based on wastage, defect rate, environmental issues faced by the organization, social issues, financial issues, and voice of the customers. The selected project can be classified into different departments/ sections of the company that is initiated the LGSS project. Gupta et al. [35] stated that most of the projects fail due to improper selection. Selection of the LGSS project depends upon sustainability need and global competitive pressure that force the firm to select the project. So, based on the customer demand, environmental concern, and socio-economic need, the final project is selected. After identification of a feasible project, a charter is prepared based on the scope of the project, sched-

In this step, the current state of nature of the selected project has been estimated. Here, the performance of the selected project is compared with the indices of Lean, Green, and Six Sigma practices. Based on the collected data, the std. deviation, sigma level, and Cpk can be estimated using statistical tools. Estimations such as CO2 emission, material consumption, Green energy coefficient are estimated using green energy technology tools like life cycle assessment. VSM is the best tool of Lean practices for evaluating the current degree of waste in the process. The blend of significant VSM and life cycle assessment lead to the evaluation of Lean-

In this progression, the underlying drivers of the wastefulness identified with wastages, emanation, and imperfection rate in the task have been distinguished. From the client and business perspective, the worth included and nonvalue included activities have been distinguished, and afterward, the procedure cycle effectiveness is resolved to contrast with world-class benchmarking value which

In the interim, the imperatives and bottlenecks are discovered in the chosen project and investigations identified with deformity rate, discharge rate, and varieties in the process are discovered. Advanced measurable quality tools, such as fishbone diagram, 5 Why, FMEA, and so on, are utilized to discover the main driver of the issue.

Once the causes of inefficiency and wastages are find out, potential solutions are proposed and tested, and the best solution is applied to diminish the prominent reasons. All the sources of information such as customers, staff, stakeholders, project sponsors are used to determine the evaluation criteria. To evaluate the proposed solution against the criteria, tools such as pug matrix, DOE (Design of experiment), LCA, etc. are used. The estimation of time-saving, improved quality, and other quality measures is also made with enhanced VSM. After launching the best solution as a pilot solution, the task to be performed is documented, and pilot participants are trained in various aspects of the best solution. After that, the pilot solution is executed in a selected section or department of

*DOI: http://dx.doi.org/10.5772/intechopen.93276*

**3.1 Execution steps of LGSS framework**

*3.1.1 Step 1: project identification based on LGSS*

ule, and team members that involved in the project.

*3.1.2 Step 2: assessment of the current state of the project*

Green wastes that gives the source to assist improvement.

*3.1.3 Step 3: find out the root causes of the inefficiency*

decides how much improvement is required.

*3.1.4 Step 4: find out and apply the best solution*

*Integrated Lean-Green-Six Sigma Practices to Improve the Performance of the Manufacturing… DOI: http://dx.doi.org/10.5772/intechopen.93276*

### **3.1 Execution steps of LGSS framework**

*Concepts, Applications and Emerging Opportunities in Industrial Engineering*

initiative depends upon collaborative team effort to improve performance of the firm [30] to identify the need of the customers and to eliminate unwanted activities within the process [31]. The individual LGSS approach shares some similarities such as employee involvement, customer satisfaction, and continuous improvement [32]. Aqlan and Alfandi [33] opined that each of the practice has been carried out by many forms to improve their processes. Some researchers focus on Lean achievement in excellence through the reduction of waste and

Following **Figure 3** depicts the Six Sigma DMAIC (Define-Measure-Analyze-Improve-Control)-based framework that can be adopted by all business firms. The

proposed integrated framework has executed in the following five steps.

**88**

**Figure 3.**

**Figure 2.**

*Integrated framework of LGSS.*

unwanted activities [34].

*Execution steps of LGSS framework.*

## *3.1.1 Step 1: project identification based on LGSS*

In this step, the project may be selected based on wastage, defect rate, environmental issues faced by the organization, social issues, financial issues, and voice of the customers. The selected project can be classified into different departments/ sections of the company that is initiated the LGSS project. Gupta et al. [35] stated that most of the projects fail due to improper selection. Selection of the LGSS project depends upon sustainability need and global competitive pressure that force the firm to select the project. So, based on the customer demand, environmental concern, and socio-economic need, the final project is selected. After identification of a feasible project, a charter is prepared based on the scope of the project, schedule, and team members that involved in the project.

#### *3.1.2 Step 2: assessment of the current state of the project*

In this step, the current state of nature of the selected project has been estimated. Here, the performance of the selected project is compared with the indices of Lean, Green, and Six Sigma practices. Based on the collected data, the std. deviation, sigma level, and Cpk can be estimated using statistical tools. Estimations such as CO2 emission, material consumption, Green energy coefficient are estimated using green energy technology tools like life cycle assessment. VSM is the best tool of Lean practices for evaluating the current degree of waste in the process. The blend of significant VSM and life cycle assessment lead to the evaluation of Lean-Green wastes that gives the source to assist improvement.

### *3.1.3 Step 3: find out the root causes of the inefficiency*

In this progression, the underlying drivers of the wastefulness identified with wastages, emanation, and imperfection rate in the task have been distinguished. From the client and business perspective, the worth included and nonvalue included activities have been distinguished, and afterward, the procedure cycle effectiveness is resolved to contrast with world-class benchmarking value which decides how much improvement is required.

In the interim, the imperatives and bottlenecks are discovered in the chosen project and investigations identified with deformity rate, discharge rate, and varieties in the process are discovered. Advanced measurable quality tools, such as fishbone diagram, 5 Why, FMEA, and so on, are utilized to discover the main driver of the issue.

#### *3.1.4 Step 4: find out and apply the best solution*

Once the causes of inefficiency and wastages are find out, potential solutions are proposed and tested, and the best solution is applied to diminish the prominent reasons. All the sources of information such as customers, staff, stakeholders, project sponsors are used to determine the evaluation criteria. To evaluate the proposed solution against the criteria, tools such as pug matrix, DOE (Design of experiment), LCA, etc. are used. The estimation of time-saving, improved quality, and other quality measures is also made with enhanced VSM. After launching the best solution as a pilot solution, the task to be performed is documented, and pilot participants are trained in various aspects of the best solution. After that, the pilot solution is executed in a selected section or department of the company.

#### *3.1.5 Step 5: sustain the best results*

In this step, the results are sustained in the process or system if the considerable improvement is observed. The whole process is reevaluated using lifecycle assessment (LCA) and value stream mapping (VSM) techniques to judge the level of emissions and waste reduction. Also, various observations, control charts, and data collection techniques are used to reassess the sigma level, Cpk, electricity, water, material consumption, etc. If the sustained results are not found, then an action plan is also initiated to select an appropriate solution. Through the execution of LGSS, the firm can gain improved sustainability, reputation, and global market through the delivery of eco-friendly products.


**5. Conclusion**

RCC of > 4 cm. can be treated with elective NSS providing optimal long-term outcome. The surgeon's decision for organ-preserving surgery should depend on the tumor location and

Pahernick S. *et al.* compared the results of NSS for the tumors of less and more than 4 cm. in size. Out of 474 treated patients 102 had the tumor of more than 4 cm. The mean follow-up was 4.7 years. The 5 and 10-year cancer-specific survival for small and large tumors were: 97.9% and 95.8%, 94.9% and 95.8%, respectively. In contrast to the tumor size, stage pT3a was associated with a significantly higher risk of tumor related death. The authors advocat‐ ed that the surgeon's decision with regard to the organ preservation should consider the tu‐ mor location and safe surgical resectability, rather than the tumor size [17]. This conclusion

Joniau S. *et al.* presented their results of NSS for the patients with bigger than 4 cm renal tumors. The following data have been collected and analyzed: surgical indication, tumor characteristics, complications, serum creatinine level, time to recurrence and time to the pa‐ tient death. Local cancer control has been achieved in the vast majority of patients. The renal function was preserved in the patients with elective indications. NSS for absolute indica‐ tions was significantly correlated with the loss of renal function but not with a cancer-specif‐

In our study the local disease recurrence was detected in 2 (3.5%) and the systemic recur‐ rence in 4 (7%) patients. We could not reveal any changes in the serum creatinine level preand postoperatively in the both groups, despite cold ischemia which was used in all patients. Both, the cancer-specific and overall survival was significantly better in the groups of relative and elective indications as compared with the absolute indication (p<0.014 and p<0.023, respectively). These data are similar to the results of the eight-institution multicen‐

It has been shown by Badalato GM. *et al*. in their recent publication that the oncological effi‐ cacy of NSS for pT1b renal tumors was comparable to that of radical nephrectomy [20]. The authors compared the NSS with radical nephrectomy in the patients with T1b RCC using a propensity scoring approach. 11 256 cases of 4-7 cm. tumors that underwent partial or radi‐ cal nephrectomy have been evaluated. The propensity score analysis was used to adjust for the potential differences in the baseline characteristics of the patients between the two groups. Overall and disease-free survival of the patients was compared in stratified and ad‐ justed analysis, controlling for propensity scores. For the entire patient cohort, no difference in the survivals was found in the NSS and radical nephrectomy groups. The survival differ‐ ence between the groups in a propensity-adjusted cohort of patients could not be confirmed

We've observed that the NSS for centrally located tumors was associated with a higher com‐ plication rate. This goes in accordance with the data of Ficarra V. *et al.* who recently pro‐ posed a new tumor scoring system [21]. According to the authors this system can better

technical feasibility rather than on the tumor size [16].

has been later supported by Antonelli A. *et al.* [18].

tre review of 1048 NSS procedures [13].

even when stratified by the tumor size and patient age.

predict the complications after NSS than linear tumor size.

ic survival [19].

92 Renal Tumor

In conclusion, the NSS is a feasible procedure for RCCs of 4-7 cm in size. The local cancer control can be achieved in most patients. Oncological outcome of the treatment is negatively related with the tumor size. Long-term prospective studies on the higher number of patients are required to prove the similar oncological efficacy of NSS and radical nephrectomy in the RCCs of 4-7 cm. in size.


**5. Exosomes as biomarkers and therapeutic targets**

All cells in the body secrete ExMVs, a heterogeneous population of bilayer vesicles with membrane that transport and deliver loads of proteins and nucleic acids to the recipient cells, allowing cell-cell communication. The exosomes, of endosomal origin, regulate normal and pathological processes. Healthy subjects and patients with different diseases release exosomes with different RNA and protein contents into the circulation, which can serve as biomarkers [45]. Compared to conventional biomarkers in serum or urine samples, exosomal biomarkers have greater sensitivity and specificity due to their high stability. They are present in almost all body fluids that harbor molecular components, exosomal proteins, and miRNA, and they are carriers of genetic information, which can be used for diagnosis. Although most RNAs found in exosomes are nucleotide fragments of degraded RNA with a length of <200 nm, some full-length RNA may be present. For example, circulating exosomal miRNAs are equivalent to those of the cancer cells of origin [45].

The power of nanovesicles as biomarkers depends on the enrichment of the exosomal classification markers, which otherwise only represent a very small proportion (<0.01%) of the total proteome of body fluids. The enrichment of the exosomal biomarkers of diagnosis will help in the discovery of new biomarkers to provide more precise information related to the origin of each exosome. A proteomic analysis and characterization of the plasma exosomes is essential, and gel permeation chromatography has been used to purify TNFR1 exosomal-like vesicles from the low-density lipoprotein (LDL) fraction. With this multistage purification scheme, it was possible to identify the 66 proteins of the circulating healthy exosomes, in the plasma, including proteins, both cytosolic and membrane-associated, as extracellular secreted proteins and associated with the cells identified with vesicular trafficking. The advantage of this analysis is that it allows the separation of different populations of vesicles according to their size. This reduces complexity in the identification of proteins in the plasma sample that may contain more than 1 million different intermixed proteins, and the discovery of peroxisome proliferator-activated receptor gamma (PPARγ) as a component of plasma exosomes will allow identifying a new pathway for the paracrine transfer of nuclear receptors specific in each pathology [46].

### **5.1. Exosomal proteins as diagnostic biomarkers**

The molecular content of exosomes is the fingerprint of the cell type that released it and its current status; most viable cells release extracellular environment, protein secretions of exosomes, and when fused with the plasma membrane, appear in the blood and urine, so they are easily accessible, and can be used as biomarkers, for the diagnosis and prognosis of malignant tumors and other pathologies [47, 48].

Due to their cellular origin, exosomes express protein markers specific to the endosomal pathway, such as tetraspanins (CD63, CD9 and CD81), heat shock proteins (Hsp70), proteins of the Rab family, Tsg101 and Alix, which are not found in other vesicles of similar size. Their function is to eliminate damaged or aged cellular molecules, to protect cells from the accumulation of waste or drugs, participate in physiological and pathological processes, and have a wide variety of clinical applications, ranging from biomarkers to cancer therapy [49]. Proteomic and biochemical analysis of the purified exosomes revealed that the bilayer membrane of phospholipids is embedded with various proteins and lipids originating in the parental cells. These can serve as surface markers for the characterization and differentiation of exosomes from other types of microvesicles [50]. Exosomes contain various proteins, which express specific cellular functions, so they can serve as biomarkers for the diagnosis of liver, kidney, and cancer diseases [51]. Proteins in urinary exosomes are easily available through nontoxic means, are invasive, and are useful in diagnosis, especially for diseases of the urinary tract [52].

## **5.2. Exosomal nucleic acids as diagnostic biomarkers**

A new generation of drug delivery systems can be mediated by exosomes and ExMVs; because they have high administration efficiency and low immunogenicity, new therapies can be implemented, and standardization is achieved with isolation techniques, with high functional efficiency, solid performance, scalable production, adequate storage, and efficient loading methods, which do not damage its molecular integrity and the movement of the elements *in vivo* as novel "nano-vehicles" [43]. The elements derived from cells generate an endogenous mechanism for intercellular communication; they are vehicles with the capacity to transfer biological information and the potential use can be as means of drug delivery [44].

All cells in the body secrete ExMVs, a heterogeneous population of bilayer vesicles with membrane that transport and deliver loads of proteins and nucleic acids to the recipient cells, allowing cell-cell communication. The exosomes, of endosomal origin, regulate normal and pathological processes. Healthy subjects and patients with different diseases release exosomes with different RNA and protein contents into the circulation, which can serve as biomarkers [45]. Compared to conventional biomarkers in serum or urine samples, exosomal biomarkers have greater sensitivity and specificity due to their high stability. They are present in almost all body fluids that harbor molecular components, exosomal proteins, and miRNA, and they are carriers of genetic information, which can be used for diagnosis. Although most RNAs found in exosomes are nucleotide fragments of degraded RNA with a length of <200 nm, some full-length RNA may be present. For example, circulating exosomal miRNAs are equivalent

The power of nanovesicles as biomarkers depends on the enrichment of the exosomal classification markers, which otherwise only represent a very small proportion (<0.01%) of the total proteome of body fluids. The enrichment of the exosomal biomarkers of diagnosis will help in the discovery of new biomarkers to provide more precise information related to the origin of each exosome. A proteomic analysis and characterization of the plasma exosomes is essential, and gel permeation chromatography has been used to purify TNFR1 exosomal-like vesicles from the low-density lipoprotein (LDL) fraction. With this multistage purification scheme, it was possible to identify the 66 proteins of the circulating healthy exosomes, in the plasma, including proteins, both cytosolic and membrane-associated, as extracellular secreted proteins and associated with the cells identified with vesicular trafficking. The advantage of this analysis is that it allows the separation of different populations of vesicles according to their size. This reduces complexity in the identification of proteins in the plasma sample that may contain more than 1 million different intermixed proteins, and the discovery of peroxisome proliferator-activated receptor gamma (PPARγ) as a component of plasma exosomes will allow identifying a new

pathway for the paracrine transfer of nuclear receptors specific in each pathology [46].

The molecular content of exosomes is the fingerprint of the cell type that released it and its current status; most viable cells release extracellular environment, protein secretions of

**5. Exosomes as biomarkers and therapeutic targets**

194 Stromal Cells - Structure, Function, and Therapeutic Implications

to those of the cancer cells of origin [45].

**5.1. Exosomal proteins as diagnostic biomarkers**

Exosomes contain exosomal RNAs, especially miRNAs that function as diagnostic biomarkers, are protected from RNase-dependent degradation, are detected in circulating plasma, and serve for the diagnosis of ovarian cancer [53, 54]. Nanostructure analysis and study of the transcriptome of exosomes that transport RNA are diagnostic and found in breast milk, saliva, blood, urine, malignant ascites, amniotic fluid, bronchoalveolar secretion, and synovial fluid [55, 56].

Urinary extracellular vesicles (uEV) are released in the nephron of the kidney and urinary tract. Specific proteomic and transcriptomic markers provide information on the cell of origin and are a reservoir for the discovery of biomarkers in kidney diseases. The uEV are a new means of cell signaling, renal tubular cells, and can provide exosomal markers not detectable in urine. Renal biopsy is an invasive technique with complications such as infection and hemorrhage. The analysis of proteomic and transcriptomic changes of uEV in different disease states as a biomarker can be a noninvasive alternative to biopsy [57].

In conclusion, the most important biomedical utility of exosomes is their application as biomarkers in clinical diagnosis. Compared with those detected in conventional samples, such as serum or urine, exosomal biomarkers provide comparable or superior sensitivity and specificity, attributed to their excellent stability, and the exosomal biomarkers of biofluids can be easily obtained. Recent technical advances in the isolation of exosomes will make diagnostics more beneficial.