**4. Pancreatic metastases from renal cell carcinoma**

(this subtype being the most frequently reported in the present study); therefore, among 177 patients submitted to surgery for pancreatic metastases from renal cell cancer, the median survival was 70 months, while the 2 year and 5 year overall survival rates were of 78 and 65%, respectively. These data suggest the potential benefit of pancreatic resections for metastatic lesions; it seems that the short-term outcomes are not significantly influenced by the metastatic character of the lesion, while the long-term outcomes seem to reveal significant long-

In a study conducted by Reddy et al. on 49 patients with metastatic pancreatic lesions, the main included primaries were renal cell carcinoma (in 21 cases), gallbladder cancer (in 6 cases), pulmonary cancer (in 4 cases), ovarian cancer (in 4 cases), sarcomas (in 4 cases), melanomas (in 3 cases), colorectal cancer (in 2 cases), breast cancer (in 1 case), hepatocellular carcinomas (in 1 case), seminomas (in 1 case), Langerhans cell histiocytosis (in 1 case) and nonpancreatic endocrine cancers (in one case). The study was conducted for a 38 year time period and reviewed data from 3830 patients submitted to pancreatic surgery; among these cases, the metastatic origin of the tumor was demonstrated in 1.6% of cases. The median age at the time of resection of pancreatic lesions was 60 years, while the most commonly encountered symptoms were abdominal pain (in 48% of cases), followed by jaundice (in 31% of cases). When it comes to the most commonly performed surgical procedures, they consisted of pancreatoduodenectomy in 31 cases, distal pancreatectomies in 14 cases and total pancreatectomy in 4 cases; among the 14 cases submitted to distal pancreatic resections, splenectomy was associated in 13 patients. When it comes to the short-term outcomes, the reported morbidity rates were 52% after pancreaticoduodenectomy, 46% after distal pancreatectomy and 25% after total pancreatectomy; however, the overall mortality rate was 0. The most often reported complications were wound infections, followed by delayed gastric emptying or pulmonary complications. When it comes to the histopathological findings, the most often reported lymph node metastases originated from renal cell carcinomas, gallbladder carcinomas, lung, colorectal carcinomas, melanomas, seminomas, sarcomas and nonpancreatic endocrine tumors, while perineural and vascular invasion were reported in gallbladder, lung, renal cell cancers and melanomas. As for the longterm outcomes, the authors reported a median overall survival rate after pancreatic resection of 3.7 years. Among long-term survivors (defined as a longer than 10 year survival after pancreatic resection), the most commonly reported origins were renal cell carcinomas, followed by Langerhans histiocytosis and seminomas. When performing an univariate analysis, the most important prognostic factors affecting the long-term survival were represented by the presence of perineural invasion and vascular invasion; surprisingly, the diameter of the metastatic tumor or lymph node metastases did not significantly influence survival. Moreover, patients who experienced any type of surgical complication as well as male patients trended to report a poorer outcome. When it comes to the influence of the cancer type on the overall prognostic, a significant influence was reported. The poorest outcomes were reported in patients submitted to surgery for pancreatic metastases originating from melanomas, followed by cases with breast cancer. No patient diagnosed with pancreatic metastases from colorectal, lung cancer or sarcoma did experience an overall survival longer than 5 years. The best outcome was reported by the patient diagnosed with metastatic Langerhans cell histiocytosis and by the patient diagnosed with seminoma, both cases being alive more than 11 years after pancreatic surgery.

term survival especially in oligometastatic lesions from renal primaries [11].

134 Advances in Pancreatic Cancer

Renal cell carcinomas represent almost 2% of all malignant tumors in adults, being the third most common genitourinary tract cancer [13]. Although renal cell carcinoma is associated with an overall good prognostic, with 5-year survival rate of up to 95%, patients presenting distant metastases report a significant poorer outcome, with 5-year survival rates lower than 10%.

Pancreatic metastases with renal cell carcinoma origin can be diagnosed at the time of the diagnostic of the primary tumor (as synchronous lesions) or after a disease free interval (as metachronous lesions). In the second case, it seems that the prognostic is significantly influenced by the disease free survival interval, a longer period of time between the initial diagnostic and the diagnostic of metastatic lesions being associated with a lower biological aggressivity and better chances of long-term survival [14, 15]. However, it should not be omitted that pancreatic metastases from renal cell carcinoma can occur even at 10–32 years from the diagnostic of the primary tumor, so that differential diagnosis should be kept in mind any moment in which a patient known with previous history of renal cell carcinoma is diagnosed with a metachronous pancreatic tumor [16].

Patients with pancreatic metastases from renal cell carcinomas can remain asymptomatic for a long period of time or can develop signs and symptoms such as weight loss, abdominal pain, jaundice or even pancreatitis due to the Wirsung duct obstruction caused by tumor growth; in certain cases lesions located in the pancreatic head will lead to the apparition of upper gastrointestinal bleeding [17, 18].

Once a pancreatic metastasis with renal cell carcinoma origin is suspected at the imagistic studies, a fine needle biopsy might be needed in order to confirm the origin of the lesion and to decide which should be the therapeutic protocol. However, pancreatic metastases from renal cell carcinoma are the most common situation in which pancreatic resection for metastatic disease has been proposed.

When it comes to the most important prognostic factors after pancreatic resections for pancreatic metastases with renal cell carcinomas, it seems that the disease free survival plays a central role; patients diagnosed with pancreatic metastases with a disease free survival longer than 2 years seem to have an improved outcome. Other factors which seem to influence the long-term outcomes are represented by the diameter of the tumor (tumors larger than 5 cm being associated with poorer outcomes), stage at the initial diagnostic and the tumoral degree of differentiation [19, 20].

The largest series of cases submitted to pancreatic resections for metastatic renal cell carcinomas was conducted by Schwarz et al. and was published in 2014 in *Annals of Surgical Oncology* [21]. The study was conducted between May 1987 and June 2003 in 12 Franco-Belgian surgical centers and involved 62 patients submitted to surgery for pancreatic metastases from renal cell carcinomas. The median age at diagnostic was 54 years (range 31–75 years) while the most common reported symptoms were abdominal pain (in 24% of cases), anemia and gastrointestinal bleeding (in 13% of cases) and jaundice (in 10% of cases). The mean interval from the diagnostic of the primary tumor to the diagnostic of the pancreatic lesion was 9.8 years (range 0–25 years—two patients presenting with synchronous pancreatic lesions). When it comes to the most commonly performed surgical procedures, they consisted of pancreatoduodenectomy in 31% of cases, distal pancreatectomies in 40% of cases, total pancreatectomies in 23% of cases and enucleation in 6% of cases. In order to achieve negative resection margins, in six cases major vascular resections with reconstruction were performed, while *en bloc* visceral resections were needed in other four cases (consisting of colonic resections in three cases and omentectomy in one case); in other six patients the presence of other distant metastases imposed performing other visceral resections such as liver resection in three cases, contralateral adrenalectomy in three cases and contralateral nephrectomy in other two cases. The histopathological studies confirmed an unique pancreatic lesion in 39 cases, while in the other 23 cases, 2 or more metastatic lesions were described. Moreover lymph node involvement was reported in 27% of cases submitted to lymph node dissection. During the early postoperative period, the authors reported an overall mortality rate of 6.4%; after a median follow-up of 91 months, 32 patients were dead of disease, 11 cases died of other non-malignant causes and 15 patients were still alive (5 cases being alive with disease while the remaining 10 cases were alive with no signs of recurrent lesions). The authors reported a 3 year, a 5 and a 10 year survival rate of 72, 63 and 32%, respectively. Among the 37 patients who experienced recurrences, 9 cases presented pancreatic relapse, the median time to recurrence being of 44 months. Pancreatic relapsed presented as isolated metastases in five cases and as part of systemic relapse—in association with lung and liver metastases in other four patients; therefore four cases were submitted to pancreatic re-resection, the median survival time after re-resection being of 52.6 months (significantly higher compared to the one reported after conservative therapy—11.2 months, *p* = 0.019). When it comes to the most important prognostic factors influencing survival, it seems that the presence of extrapancreatic disease as well as the presence of lymph node metastases significantly decreased survival. Surprisingly, the study failed to demonstrate a significant influence of the disease free survival interval on the overall survival rate, this fact being explained by the authors by the limited number of patients introduced in the current study [21].

reported in 12 cases while the postoperative overall mortality was 7.5%. When it comes to the long-term outcomes, the authors reported a mean overall survival of 147.9 months; however, none of the studied factors (including body mass index, sex, time of resection, synchronous/ metachronous lesions, symptomatic/asymptomatic lesions, resection status, existence of other extrapancreatic lesions, tumor dimension or lymph node status) did not significantly influenced survival. This fact was explained by the authors by the relative small number of cases introduced in the current study [22]. Another important aspect pointed out of these authors is the one regarding the lymph node status: among the 21 patients who benefited from lymph node resection 5 patients were diagnosed with lymph node metastases; therefore the authors

underlined the necessity of association of lymph node dissection in such cases [22].

**Period of the study**

1987– 2003

1993– 2014

2000– 2011

1997– 2012

1998– 2006

1999– 2013

**No. of patients**

40 patients 125.4

8 patients 12.42

20 patients 130 ± 59

15 patients 13.4

**Name, year of the study**

Schwarz, 2014

Ruckert, 2016 [22]

Markinez, 2013 [23]

Benhaim, 2015 [24]

Zerbi, 2008 [25]

Yuasa, 2015 [26]

[21]

The outcomes after pancreatic resection for pancreatic metastases with renal cell origin are

**Type of pancreatic resection**

DP: 25 cases TP: 14 cases Enucleation: 4 cases

PD: 15 cases DP: 12 cases Enucleation: 3 cases Broad papillary resection: 1 case

TP: 6 cases DP: 1 case

PD: 6 cases DP: 5 cases TP: 3 cases

DP: 11 cases TP: 2 cases

MP: 1 case

TP: 2 cases

Atypical resection: 1 case

Metastasectomy: 6 cases

Metastasectomy: 5 cases

Metastasectomy: 13 cases

**Early postoperative**

Pancreatic Resections for Metastatic Disease http://dx.doi.org/10.5772/intechopen.75571 137

**Long-term outcomes**

Overall survival after pancreatic resections: 52.6 months

Overall survival after pancreatic resections: 147.9 months

Survival between 6 months and 95 months

72%

Overall survival rate at 4 years:

Overall survival after pancreatic resections: 44 months

Overall survival after pancreatic resections: not reached at 3.5 year follow-up

**outcomes**

Postoperative mortality: 4 cases

Postoperative mortality: 3 cases

Postoperative mortality: 1 case

Postoperative mortality: 1 case

Postoperative mortality: 0

Postoperative mortality: 0

In a similar study conducted by Ruckert et al. and published in 2016 in the *International Journal of Surgery,* the authors reviewed data from 40 patients submitted to surgery for pancreatic metastases from renal cell carcinomas in 2 German centers between January 1993 and October 2014. These cases were submitted to surgery for pancreatic disease after a median period of 125.4 months, the most commonly performed surgical procedures consisting of pancreatoduodenectomy (in 37.5% of cases), total pancreatectomies (in 22.5% of cases), distal pancreatectomies (in 30% of cases), segmental resections (in 7.5 cases) and papillary resections (in 2.5% of cases). The most commonly encountered complication was pancreatic leak and it was reported in 12 cases while the postoperative overall mortality was 7.5%. When it comes to the long-term outcomes, the authors reported a mean overall survival of 147.9 months; however, none of the studied factors (including body mass index, sex, time of resection, synchronous/ metachronous lesions, symptomatic/asymptomatic lesions, resection status, existence of other extrapancreatic lesions, tumor dimension or lymph node status) did not significantly influenced survival. This fact was explained by the authors by the relative small number of cases introduced in the current study [22]. Another important aspect pointed out of these authors is the one regarding the lymph node status: among the 21 patients who benefited from lymph node resection 5 patients were diagnosed with lymph node metastases; therefore the authors underlined the necessity of association of lymph node dissection in such cases [22].

The largest series of cases submitted to pancreatic resections for metastatic renal cell carcinomas was conducted by Schwarz et al. and was published in 2014 in *Annals of Surgical Oncology* [21]. The study was conducted between May 1987 and June 2003 in 12 Franco-Belgian surgical centers and involved 62 patients submitted to surgery for pancreatic metastases from renal cell carcinomas. The median age at diagnostic was 54 years (range 31–75 years) while the most common reported symptoms were abdominal pain (in 24% of cases), anemia and gastrointestinal bleeding (in 13% of cases) and jaundice (in 10% of cases). The mean interval from the diagnostic of the primary tumor to the diagnostic of the pancreatic lesion was 9.8 years (range 0–25 years—two patients presenting with synchronous pancreatic lesions). When it comes to the most commonly performed surgical procedures, they consisted of pancreatoduodenectomy in 31% of cases, distal pancreatectomies in 40% of cases, total pancreatectomies in 23% of cases and enucleation in 6% of cases. In order to achieve negative resection margins, in six cases major vascular resections with reconstruction were performed, while *en bloc* visceral resections were needed in other four cases (consisting of colonic resections in three cases and omentectomy in one case); in other six patients the presence of other distant metastases imposed performing other visceral resections such as liver resection in three cases, contralateral adrenalectomy in three cases and contralateral nephrectomy in other two cases. The histopathological studies confirmed an unique pancreatic lesion in 39 cases, while in the other 23 cases, 2 or more metastatic lesions were described. Moreover lymph node involvement was reported in 27% of cases submitted to lymph node dissection. During the early postoperative period, the authors reported an overall mortality rate of 6.4%; after a median follow-up of 91 months, 32 patients were dead of disease, 11 cases died of other non-malignant causes and 15 patients were still alive (5 cases being alive with disease while the remaining 10 cases were alive with no signs of recurrent lesions). The authors reported a 3 year, a 5 and a 10 year survival rate of 72, 63 and 32%, respectively. Among the 37 patients who experienced recurrences, 9 cases presented pancreatic relapse, the median time to recurrence being of 44 months. Pancreatic relapsed presented as isolated metastases in five cases and as part of systemic relapse—in association with lung and liver metastases in other four patients; therefore four cases were submitted to pancreatic re-resection, the median survival time after re-resection being of 52.6 months (significantly higher compared to the one reported after conservative therapy—11.2 months, *p* = 0.019). When it comes to the most important prognostic factors influencing survival, it seems that the presence of extrapancreatic disease as well as the presence of lymph node metastases significantly decreased survival. Surprisingly, the study failed to demonstrate a significant influence of the disease free survival interval on the overall survival rate, this fact being explained by the

136 Advances in Pancreatic Cancer

authors by the limited number of patients introduced in the current study [21].

In a similar study conducted by Ruckert et al. and published in 2016 in the *International Journal of Surgery,* the authors reviewed data from 40 patients submitted to surgery for pancreatic metastases from renal cell carcinomas in 2 German centers between January 1993 and October 2014. These cases were submitted to surgery for pancreatic disease after a median period of 125.4 months, the most commonly performed surgical procedures consisting of pancreatoduodenectomy (in 37.5% of cases), total pancreatectomies (in 22.5% of cases), distal pancreatectomies (in 30% of cases), segmental resections (in 7.5 cases) and papillary resections (in 2.5% of cases). The most commonly encountered complication was pancreatic leak and it was The outcomes after pancreatic resection for pancreatic metastases with renal cell origin are shown in **Table 1**.

with an extremely poor prognostic. Less than 2% of patients with pancreatic metastases from melanomas will be diagnosed with oligometastatic disease, most often the primary tumor

Pancreatic Resections for Metastatic Disease http://dx.doi.org/10.5772/intechopen.75571 139

As for the long-term outcomes, patients presenting pancreatic metastases originating from melanomas with various locations seem to have a poorer prognostic when compared to other primaries due to the aggressive biological behavior of melanomas [19]. However, compared to patients treated in a conservative manner, it seems that patients submitted to surgery might benefit from a better outcome especially in cases in which complete resection of the pancreatic lesion is feasible [32, 33]. When it comes to the most important prognostic factors which might influence the long-term outcomes, it seems that a long disease free survival interval is usually associated with a lower biological aggressivity of the primary tumor, and, therefore, with a better outcome [34]. In a case series of two patients diagnosed with pancreatic metastases from melanomas at *Melbourne University*, *Austin Hospital*, *Victoria*, *Australia* published in 2003, the authors reported encouraging results; the first case was the one of a 45-year-old woman with personal history of ocular melanoma treated by transscleral resection 12 years earlier, the histopathological studies revealing at that moment a 10 mm mixed spindle and epithelioid cell melanoma; however, she experienced an early local recurrence 1 year postoperatively, laser therapy being performed at the time of relapse. About 11 years later (after the first local relapse), the patient was diagnosed with a pancreatic head tumor in association with three to four well defined hepatic nodules measuring 5–10 mm, while the fine needle biopsy confirmed the metastatic character of the tumor originating from the melanoma. The patient was submitted to a pylorus preserving pancreatoduodenectomy and segmental liver resection, the histopathological studies confirming the metastatic character of all the resected tumors. The patient was free of disease at 6 months follow-up. The second reported case from the same authors was the one of a 55-year-old patient known with a previous history of ocular melanoma enucleated 13 years earlier who complained of epigastric pain and was diagnosed with a tumoral mass at the level of the pancreatic head; intraoperatively multiple pigmented lesions were seen on the whole surface of the pancreas, so the patient was submitted to total pancreatectomy and remained free of disease 7 months later [34]. Wood's series conducted on a group of six patients with pancreatic metastases forming melanomas, complete surgical resection of the pancreatic lesion was associated with a median overall survival rate of 24 months, significantly higher than the survival rates after palliative chemotherapy (where the median overall survival rate does not surpass 12 months) [35, 36]. However, in Woods' study one of the most important prognostic factors was related to the resection margins, patients presenting with positive resection margins or incomplete resection being associated with a significantly poorer outcome (in fact in these cases the median survival rate was 8 months, similar to the one reported after palliative chemotherapy) [35]. In

conclusion incomplete resection has no benefit in terms of survival.

Intra-abdominal breast cancer metastases are usually diagnosed at the level of the liver, spleen or axial skeleton [37]. When reported, pancreatic metastases from breast cancer are

**7. Pancreatic metastases from breast cancer**

being an ocular melanoma [30, 31].

*Abbreviations*: DP, distal pancreatectomy; PD, pancreatoduodenectomy; TP, total pancreatectomy; MP, middle pancreatectomy.

**Table 1.** Outcomes after pancreatic resections for pancreatic metastases from renal cell carcinomas.


Contents

Preface

Application fields of supercapacitors are expanding because they have a very large charge/discharge current density and a cycle durability of tens of thousands of cycles or more compared to secondary batteries. There are various kinds of supercapacitor: electric double layer capacitors with a relatively long history, pseudocapacitors that utilize electrochemical reactions, and the progress of hybrid capacitor technology that combines double layer capacity and electrochemical reactions. Development of electrode materials and electrolytes and new cell design for constructing devices support the performance improvement and expansion of new applied fields such as automobiles, heavy machinery, and energy harvesting. This book aims to provide engineers with the opportunity to review the latest information by integrating cutting-edge papers on the science, technology, and the

The first chapter reviews the properties of carbon nanomaterials such as activated carbon, graphene, and carbon nanotubes. The author evaluates the current state of carbon nanomaterials and their composite materials for supercapacitor applications and describes future prospects (Khalid et al.). Chapters 2 and 3 focus on device flexibility and introduce the latest material technologies for developing wearable supercapacitors (Shanov et al.). In the fourth chapter, a constant voltage charge test is performed using a conventional electric double layer capacitor, and the relationship between the applied voltage and the deterioration behavior of the capacitor is considered from a practical point of view (Tashima). Chapter 5 explains the lithium doping method, which can increase cell capacity while maintaining the output and cycle characteristics of the capacitor. The author discusses the lithium ion hybrid capacitor, which has attracted attention in the field of capacitor technology (Sun et al.). In Chapters 6 and 7, two authors introduce high-capacity pseudocapacitors by using metal oxide nanomaterial and chromium nitride as electrode materials (Das et al. and Singh et al.). In the last chapter, the authors explain the application of supercapacitors to hybrid buses by drawing a realistic solution related to the controlling method for capacitor and power train based on precise energy efficiency

**Takaya Sato**

Japan

Tsuruoka College,

National Institute of Technology,

application of supercapacitors.

calculation and simulation (Wang et al.).


**4.3 Experimental results**

### **4.3.1 Formation of 20 nm x 20 nm pitched dot arrays [16]**

Figure 4. 4 shows the SEM images of 20 nm x 20 nm pitch dot arrays patterns drawn by 30 keV electron beam at a dosage of 16 mC/cm2 using various resist thicknesses of 11.8 to 16.3 nm. In Figs. 4. 4(a) and (b), there are many defects such as the dots combined with neighbor dots. On the other hand, the number of defect decreases with the thickness. At the resist thickness of 13.1 nm, the 20 nm x 20 nm pitch dot array have completely been drawn as shown in Fig. 4. 4(c). Furthermore, using further thin resist film, the dot arrays appear unclearly (Fig. 4. 4(d)) because the SEM contrast becomes poor due to thin thickness. Therefore, the resist thickness of about 13 nm is very suitable for formation of 20 nm x 20 nm very fine pitch dot arrays.

Fig. 4.4. SEM images of 20nm x 20nm fine pitch dot arrays formed by 30keV EB lithography at a dosage of 16 mC/cm2, (a) with a resist thickness of 16.1 nm, (b) 14.7, (c) 13.1 nm and (d) 11.8 nm**.**

The conventional EB drawing system was used as described in section 3. 1. The drawing was done on a resist layer coating on a piece of Si after we set the sample on the XY table in the system. The EB drawing was done under a probe current of 100 pA at an acceleration voltage of 30 kV. In the other system parameters, the address resolution was 2.5 nm in a

The calixarene resist films on Si substrate with a thickness of 11.8 nm to 16.9 nm, which were controlled by the spin coating at a speed of 3000 rpm to 8000 rpm for 190 s was prepared as shown in Fig. 4. 3. The thicknesses were measured by contact mode atomic force microscope

The resist process is as follows. After coating the resist on the Si substrate, pre-baking was done at the 110 oC for 3 min in air. Then, the EB drawing was done by raster scanning with the CAD data. After the developing and rinsing with a developer of ZEP-RD and isopropanol, respectively, The pattern quality was checked whether complete formation of the

> **2500 3500 4500 5500 6500 7500 8500 Rotation r(rpm)**

Fig. 4.3. Thicknesses of 11.8 nm to 16.9 nm controlled by the spin coating at a speed of 3000

Figure 4. 4 shows the SEM images of 20 nm x 20 nm pitch dot arrays patterns drawn by 30 keV electron beam at a dosage of 16 mC/cm2 using various resist thicknesses of 11.8 to 16.3 nm. In Figs. 4. 4(a) and (b), there are many defects such as the dots combined with neighbor dots. On the other hand, the number of defect decreases with the thickness. At the resist thickness of 13.1 nm, the 20 nm x 20 nm pitch dot array have completely been drawn as shown in Fig. 4. 4(c). Furthermore, using further thin resist film, the dot arrays appear unclearly (Fig. 4. 4(d)) because the SEM contrast becomes poor due to thin thickness. Therefore, the resist thickness of

about 13 nm is very suitable for formation of 20 nm x 20 nm very fine pitch dot arrays.

Fig. 4.4. SEM images of 20nm x 20nm fine pitch dot arrays formed by 30keV EB lithography at a dosage of 16 mC/cm2, (a) with a resist thickness of 16.1 nm, (b) 14.7, (c) 13.1 nm and (d) 11.8 nm**.**

**4.2 EB drawing and sample preparation**

drawing field of 25 µm x 25 µm.

drawn dot arrays was done or not.

**10**

**4.3.1 Formation of 20 nm x 20 nm pitched dot arrays [16]**

**12**

**14**

**Thickness t(nm)**

**16**

**18**

(AFM).

rpm to 8000 rpm

**4.3 Experimental results**

Fig. 4.5. Variations of average calixarene dot size with thicknesses for various exposure dosages.

Fig. 4.6. SEM images of 20nm x 20nm pitched calixarene resist dot arrays formed by 30keV EB drawing on Si substrate (1.6 Tb/in2) in 9 shots/dot drawing.

From Fig. 4. 4, the variations of average calixarene dot size for various thicknesses and exposure dosages were obtained as shown in Fig. 4. 5. The figure shows that the dot diameter decreases with not only thickness but also exposure dosage. Although the diameter variation with exposure dosage means that proximity effect occurs in the EB writing, the thin resist layer contributes to get small drawing probe. In order to draw the 20 nm x 20 nm pitch dot arrays pattern, we need a dot size of 15 nm at least. From Fig. 4. 5, it is neccessary to choose an exposure dosage of < 16 mC/cm2 and a resist thickness of < 13 nm for the fine pitch arrays formation.

Figure 4. 6 shows the result of the 20 nm x 20 nm pitch dot arrays patterns drawing with a thickness of 11.8-14.7 nm at some exposure dosages. The exposure dosages were 14 mC/cm2, 16 mC/cm2 and 18 mC/cm2. At a dosage of 14 mC/cm2, there are some vacancies as defects. It may be caused by that the dosage is not enough to make the resist molecular link. When using commercial developer, the insufficient exposed resist part was solved so

Electron Beam Lithography for Fine Dot Arrays with Nanometer-Sized Dot and Pitch 17

when a thinner resist film on Si substrate was used in the 30-keV-EB drawing. Nevertheless, a complete 20 nm x 20 nm pitch dot array was successfully achieved using the unique EB drawing condition for EB drawing with a resist thickness of 13.1 nm and an exposure dosage of 16 mC/cm2 as described above. The exposure dosage is dependent on dot pattern data. In the experiment, we used the dot pattern data of 3 x 3 shots/dot. We have also

Fig. 4.8. SEM images of 20x20, 25x25, 30x30 nm2 pitched calixarene resist dot arrays formed

Fig. 4.9. A proper region of 30-keV-EB drawing available for very fine pitch dot arrays in a relationship between exposure dosage and unit cell area (square pitch) in 9 shots/dot

From the above results, we can obtain an available drawing margin with regard to dot packing and exposure dosage for 30-keV EB drawing. The margin indicates that a minimum pitch exists for 30-keV EB drawing of the dot array pattern. In the 30-keV EB drawing and calixarene resist system, the smallest pitch is about 18 x 18 nm2. The dosage margin of about 6% is estimated at the pitch. This means that we need a stable EB-drawing system including the EB source, resist material and its thickness. Figure 4. 10 shows that there is the possibility of forming 18 x 18 nm2 pitch dot arrays using EB drawing. Our results demonstrate that 18 x 18 nm2 pitch dot arrays can be partially drawn. It is clarified that the

indicated the exposure dosage with a unit of C/dot, as shown in Fig. 4. 9.

by 30keV EB drawing on 13.1-nm-thick resist film on Si substrate.

drawing.

that the completed dots could not be formed. At a dosage of 16 mC/cm2, it is enough to makes complete dots. In a case of a dosage of 18 mC/cm2, the dot was combining together with neighbor dots because the dot size becomes larger than that at 16 mC/cm2. Figure 4. 7 shows the variations of the dot size with exposure dosage of the 20 nm x 20 nm dot arrays pattern at a resist thickness of 13.1 nm. The fluctuation of the dot size between minimum and maximum dot sizes are about 3 nm. This is as small as that in previous section. The experimental results demonstrated that 30 keV EB drawing can form 20 nm x 20 nm very fine pitch dot arrays pattern using optimal resist thickness and exposure dosage.

Fig. 4.7. Variation of the resist dot size measured from the 20 nm x 20 nm pitch resist dot arrays formed by EB-drawing with 30 keV incident electron.

#### **4.3.2 Challenge to form 18 nm x 18 nm pitched dot arrays [5, 16]**

#### *(1) Dependences of resist thickness and exposure dosage on 20-nm-pitch EB drawing*

Initially, we studied the effects of resist thickness and exposure dosage on 30-keV EB drawing of the dot arrays with a pitch of 20 nm x 20 nm. Figure 4. 6 indicates that the optimal thickness and exposure dosage were about 13.1 nm and 16 mC/cm2, respectively. On the other hand, we did not obtain good results using a thickness of 11.8 nm, although the thickness was as thin as possible. This may be caused by insufficient contrast of SEM images due to an excessively thin resist and poor focus adjustment. Thus, it is necessary to use a thin resist film to suppress the scattering of the primary electrons in the resist. The tendency that finer dot arrays patterns can be drawn with thinner resists are demonstrated, and agrees with the simulation result. Nevertheless, there exists a critical thickness for fine evaluation of the drawn pattern as described above.

#### *(2) Possibility of forming 18 nm pitch dot arrays pattern*

To anticipate the ultimate pitch of the dot arrays using 30-keV EB drawing, we studied the EB drawing margin by EB drawing of highly packed dot arrays with pitches of 20 x 20, 25 x 25, and 30 x 30 nm2 by ranging the exposure dosages between 14 and 40 mC/cm2. Figure 4. 8 shows the SEM images of the 20 x 20, 25 x 25, and30 x 30 nm2 pitch dot arrays patterns formed using various dosages at a constant resist thickness of 13.1 nm. The experimental results indicate that the optimal condition for drawing becomes narrow as dot packing increases. We successfully formed 20 x 20 nm2 pitch dot arrays at an exposure dosage of 16 mC/cm2. In contrast, the available proper exposure dosages increased to 14-22 and 14-30 mC/cm2 for the pitchs of 25 x 25 and 30 x 30 nm2, respectively. The results show that it is very difficult to form 20 x 20 nm2 pitch dot arrays in the resist film on Si substrates even

that the completed dots could not be formed. At a dosage of 16 mC/cm2, it is enough to makes complete dots. In a case of a dosage of 18 mC/cm2, the dot was combining together with neighbor dots because the dot size becomes larger than that at 16 mC/cm2. Figure 4. 7 shows the variations of the dot size with exposure dosage of the 20 nm x 20 nm dot arrays pattern at a resist thickness of 13.1 nm. The fluctuation of the dot size between minimum and maximum dot sizes are about 3 nm. This is as small as that in previous section. The experimental results demonstrated that 30 keV EB drawing can form 20 nm x 20 nm very

fine pitch dot arrays pattern using optimal resist thickness and exposure dosage.

Fig. 4.7. Variation of the resist dot size measured from the 20 nm x 20 nm pitch resist dot

Initially, we studied the effects of resist thickness and exposure dosage on 30-keV EB drawing of the dot arrays with a pitch of 20 nm x 20 nm. Figure 4. 6 indicates that the optimal thickness and exposure dosage were about 13.1 nm and 16 mC/cm2, respectively. On the other hand, we did not obtain good results using a thickness of 11.8 nm, although the thickness was as thin as possible. This may be caused by insufficient contrast of SEM images due to an excessively thin resist and poor focus adjustment. Thus, it is necessary to use a thin resist film to suppress the scattering of the primary electrons in the resist. The tendency that finer dot arrays patterns can be drawn with thinner resists are demonstrated, and agrees with the simulation result. Nevertheless, there exists a critical thickness for fine

To anticipate the ultimate pitch of the dot arrays using 30-keV EB drawing, we studied the EB drawing margin by EB drawing of highly packed dot arrays with pitches of 20 x 20, 25 x 25, and 30 x 30 nm2 by ranging the exposure dosages between 14 and 40 mC/cm2. Figure 4. 8 shows the SEM images of the 20 x 20, 25 x 25, and30 x 30 nm2 pitch dot arrays patterns formed using various dosages at a constant resist thickness of 13.1 nm. The experimental results indicate that the optimal condition for drawing becomes narrow as dot packing increases. We successfully formed 20 x 20 nm2 pitch dot arrays at an exposure dosage of 16 mC/cm2. In contrast, the available proper exposure dosages increased to 14-22 and 14-30 mC/cm2 for the pitchs of 25 x 25 and 30 x 30 nm2, respectively. The results show that it is very difficult to form 20 x 20 nm2 pitch dot arrays in the resist film on Si substrates even

arrays formed by EB-drawing with 30 keV incident electron.

evaluation of the drawn pattern as described above. *(2) Possibility of forming 18 nm pitch dot arrays pattern*

**4.3.2 Challenge to form 18 nm x 18 nm pitched dot arrays [5, 16]**

*(1) Dependences of resist thickness and exposure dosage on 20-nm-pitch EB drawing*

when a thinner resist film on Si substrate was used in the 30-keV-EB drawing. Nevertheless, a complete 20 nm x 20 nm pitch dot array was successfully achieved using the unique EB drawing condition for EB drawing with a resist thickness of 13.1 nm and an exposure dosage of 16 mC/cm2 as described above. The exposure dosage is dependent on dot pattern data. In the experiment, we used the dot pattern data of 3 x 3 shots/dot. We have also indicated the exposure dosage with a unit of C/dot, as shown in Fig. 4. 9.

Fig. 4.8. SEM images of 20x20, 25x25, 30x30 nm2 pitched calixarene resist dot arrays formed by 30keV EB drawing on 13.1-nm-thick resist film on Si substrate.

Fig. 4.9. A proper region of 30-keV-EB drawing available for very fine pitch dot arrays in a relationship between exposure dosage and unit cell area (square pitch) in 9 shots/dot drawing.

From the above results, we can obtain an available drawing margin with regard to dot packing and exposure dosage for 30-keV EB drawing. The margin indicates that a minimum pitch exists for 30-keV EB drawing of the dot array pattern. In the 30-keV EB drawing and calixarene resist system, the smallest pitch is about 18 x 18 nm2. The dosage margin of about 6% is estimated at the pitch. This means that we need a stable EB-drawing system including the EB source, resist material and its thickness. Figure 4. 10 shows that there is the possibility of forming 18 x 18 nm2 pitch dot arrays using EB drawing. Our results demonstrate that 18 x 18 nm2 pitch dot arrays can be partially drawn. It is clarified that the

Electron Beam Lithography for Fine Dot Arrays with Nanometer-Sized Dot and Pitch 19

function to Eq. (3.1), the 1, 2, C1/C2, and values are about 5 nm, 15 nm, 0.03 and 0.27, respectively. In the Monte Carlo simulation, we obtained EDD in 15-nm-thick resist on Si substrate (Fig. 4. 11(b)). When roughly fitting it to the EID function, they are about 2 nm, 10 nm, 0.02 and 0.5 nm, respectively. Although the resist materials are difficult in the experiments and simulations, the values of 1, 2, C1/C2 in the experiment are almost same as those in the simulation. Comparing between experimental and simulated results, the values of 1 in both cases agree well because the electron probe size of 2 nm and the resist molecular size of 1 nm can be considered in the EB drawing. According small 1 and values, the system is very suitable for very fine dot and very fine pitch dot arrays drawing. Figures 4.12(a)-(d) show SEM images of very fine pitch resist dot arrays on Si substrate with various pitches of 20 x 20 nm2 to 40 x 40 nm2. The exposure dosage was 16 mC/cm2. In these experiments, we succeeded in obtaining the highest-packed dot array pattern with a pitch of 20 x 20 nm2 (Fig. 4. 12(a)), which corresponds to the ultrahigh recording density of about 1.61 Tb/in2 in patterned media. The dot sizes of about 12.5 to 18 nm are changed as shown in Fig. 4. 12(e). The size fluctuation is about 2 nm and almost constant in a range of 0.4 to 1.6 Tb/in2. This shows that the drawings are carried out in no relation with the dot pitch. Figures 4. 13(a) and (b) show SEM images of 25 x 25 nm2 pitched resist dot arrays at side and corner of the drawing area Fig. 4.13 SEM images (a), (b) and histograms (c)-(e) of 25 nm x 25 nm pitch resist dot arrays on Si substrate at a dosage of 16 mC/cm2, (a) at side of the written pattern area, (b) at corner, (c) at center, (d) at

at an exposure dosage of 16 mC/cm2. The dot sizes histograms are shown in Figs. 4. 13(c)- (e). Comparing the distributions at center, side and corner of the drawing area, the histograms and the mean values are almost same. These experimental results demonstrate the proximity effect is extremely small in this system. The system is suitable for formation of very fine pitch dot arrays with very fine dot. From the results, a curvature of corner in the

In addition, using 50 keV EB lithography, we can consider that the 1 and values will be improved small to a twice of those in 30 keV EB lithography. This is because the forward scattering area in 50 keV EB lithography is suppressed to a twice of that in 30 keV EB lithography. Therefore, 50 keV lithography is more suitable for fine dots patterning than 30

Fig. 4.11. Experimental result (a) and Monte Carlo calculation (b) of EID function and roughly fitting to EID function in 30 keV EB drawing and 15 nm thick calixarene resist on Si substrate.

side and (e) at corner.at an exposure dosage of 16 mC/cm2.

drawing pattern could be sharp shape with a radius of 7-8 nm.

keV EB lithography.

30-keV EB drawing has the potential to form 18 x 18 nm2 pitch dot array patterns in thinner resist films on Si substrates by accurately selecting the optimum EB drawing conditions. For the formation of complete dot arrays pattern with 18 x 18 nm2 pitch, stability in the EB system is also required. At least, we have to use stable electron probe current with a deviation within 6% for 2 Tbit/in2 magnetic storage using 30-keV EB drawing.

The exposure dosages were 10-11 mC/cm2, which are smaller than the dosage estimated in 18 x 18 nm2 pitch drawing (Fig. 4.9). The small exposure dosages are caused by using different exposure shot numbers per square pattern as a dot. In Fig. 4. 10, we increased the number of shots/dot from 9 to 16 (4x4) for fast EB drawing. The dosage of 10 mC/cm2 in 16 shots/dot drawing corresponds to about 18 mC/cm2 in 9 shots/dot drawing. The 18 mC/cm2 almost agrees with the estimated dosage in Fig. 4. 9.

Fig. 4.10. SEM images of 18 x 18 nm2 pitched resist dot arrays formed by 30 keV EB drawing on Si substrate (about 2.0 Tb/in2).

#### **4.3.3 Small proximity effect using calixarene resist [17]**

The proximity effect of the EB drawing and thinner calixarene resist system is considered using the EID in the experiment and the EDD in Monte Carlo simulation.

Assuming that the EID function is defined with 2 Gaussian distributions as described in previous section, the 1st and 2nd terms in Eq. (3. 1) represent the energy depositions due to electron forward scattering (FS) and backward scattering (BS), respectively. For the miniaturization of the bit size, very small proximity effect and small 1 and 2 values are crucial. The ratio of the total energies due to FS and BS is very important.

$$\eta = \left[\mathbf{C}\_1 \exp(-\frac{r^2}{\sigma\_1^2}) dr \;/\int \mathbf{C}\_2 \exp(-\frac{r^2}{\sigma\_2^2}) dr = \left(\frac{\mathbf{C}\_2}{\mathbf{C}\_1}\right) \left(\frac{\sigma\_2}{\sigma\_1}\right)^2\tag{4.1}$$

The value has to be less than 1 because the drawing energy due to FS becomes dominant for very fine dot arrays formation. On the other hand, considering EB drwing of square, the drawing energy due to BS at side and corner of the square becomes a half and a quarter of that at center, respectively, based on reciprocity principle [9]. The variation of BS drawing energy on exposure dosage at everywhere of the drawing area is suppressed to be negligible small if the value is less than 1.

In the experiments, the exposure dosages were changed from 10 C/cm2 to 5 C/cm2. We obtained the EID using calixarene as shown in Fig. 4. 11(a) [23]. When we roughly fit the EID

30-keV EB drawing has the potential to form 18 x 18 nm2 pitch dot array patterns in thinner resist films on Si substrates by accurately selecting the optimum EB drawing conditions. For the formation of complete dot arrays pattern with 18 x 18 nm2 pitch, stability in the EB system is also required. At least, we have to use stable electron probe current with a

The exposure dosages were 10-11 mC/cm2, which are smaller than the dosage estimated in 18 x 18 nm2 pitch drawing (Fig. 4.9). The small exposure dosages are caused by using different exposure shot numbers per square pattern as a dot. In Fig. 4. 10, we increased the number of shots/dot from 9 to 16 (4x4) for fast EB drawing. The dosage of 10 mC/cm2 in 16 shots/dot drawing corresponds to about 18 mC/cm2 in 9 shots/dot drawing. The 18

Fig. 4.10. SEM images of 18 x 18 nm2 pitched resist dot arrays formed by 30 keV EB drawing

The proximity effect of the EB drawing and thinner calixarene resist system is considered

Assuming that the EID function is defined with 2 Gaussian distributions as described in previous section, the 1st and 2nd terms in Eq. (3. 1) represent the energy depositions due to electron forward scattering (FS) and backward scattering (BS), respectively. For the miniaturization of the bit size, very small proximity effect and small 1 and 2 values are

2 2 2

1 2 1 1

  2 2

*C*

(4.1)

deviation within 6% for 2 Tbit/in2 magnetic storage using 30-keV EB drawing.

mC/cm2 almost agrees with the estimated dosage in Fig. 4. 9.

**4.3.3 Small proximity effect using calixarene resist [17]**

using the EID in the experiment and the EDD in Monte Carlo simulation.

crucial. The ratio of the total energies due to FS and BS is very important.

1 2 2 2

exp( ) / exp( ) *r rC <sup>C</sup> dr C dr*

The value has to be less than 1 because the drawing energy due to FS becomes dominant for very fine dot arrays formation. On the other hand, considering EB drwing of square, the drawing energy due to BS at side and corner of the square becomes a half and a quarter of that at center, respectively, based on reciprocity principle [9]. The variation of BS drawing energy on exposure dosage at everywhere of the drawing area is suppressed to be negligible

In the experiments, the exposure dosages were changed from 10 C/cm2 to 5 C/cm2. We obtained the EID using calixarene as shown in Fig. 4. 11(a) [23]. When we roughly fit the EID

on Si substrate (about 2.0 Tb/in2).

small if the value is less than 1.

function to Eq. (3.1), the 1, 2, C1/C2, and values are about 5 nm, 15 nm, 0.03 and 0.27, respectively. In the Monte Carlo simulation, we obtained EDD in 15-nm-thick resist on Si substrate (Fig. 4. 11(b)). When roughly fitting it to the EID function, they are about 2 nm, 10 nm, 0.02 and 0.5 nm, respectively. Although the resist materials are difficult in the experiments and simulations, the values of 1, 2, C1/C2 in the experiment are almost same as those in the simulation. Comparing between experimental and simulated results, the values of 1 in both cases agree well because the electron probe size of 2 nm and the resist molecular size of 1 nm can be considered in the EB drawing. According small 1 and values, the system is very suitable for very fine dot and very fine pitch dot arrays drawing. Figures 4.12(a)-(d) show SEM images of very fine pitch resist dot arrays on Si substrate with various pitches of 20 x 20 nm2 to 40 x 40 nm2. The exposure dosage was 16 mC/cm2. In these experiments, we succeeded in obtaining the highest-packed dot array pattern with a pitch of 20 x 20 nm2 (Fig. 4. 12(a)), which corresponds to the ultrahigh recording density of about 1.61 Tb/in2 in patterned media. The dot sizes of about 12.5 to 18 nm are changed as shown in Fig. 4. 12(e). The size fluctuation is about 2 nm and almost constant in a range of 0.4 to 1.6 Tb/in2. This shows that the drawings are carried out in no relation with the dot pitch. Figures 4. 13(a) and (b) show SEM images of 25 x 25 nm2 pitched resist dot arrays at side and corner of the drawing area Fig. 4.13 SEM images (a), (b) and histograms (c)-(e) of 25 nm x 25 nm pitch resist dot arrays on Si substrate at a dosage of 16 mC/cm2, (a) at side of the written pattern area, (b) at corner, (c) at center, (d) at side and (e) at corner.at an exposure dosage of 16 mC/cm2.

at an exposure dosage of 16 mC/cm2. The dot sizes histograms are shown in Figs. 4. 13(c)- (e). Comparing the distributions at center, side and corner of the drawing area, the histograms and the mean values are almost same. These experimental results demonstrate the proximity effect is extremely small in this system. The system is suitable for formation of very fine pitch dot arrays with very fine dot. From the results, a curvature of corner in the drawing pattern could be sharp shape with a radius of 7-8 nm.

In addition, using 50 keV EB lithography, we can consider that the 1 and values will be improved small to a twice of those in 30 keV EB lithography. This is because the forward scattering area in 50 keV EB lithography is suppressed to a twice of that in 30 keV EB lithography. Therefore, 50 keV lithography is more suitable for fine dots patterning than 30 keV EB lithography.

Fig. 4.11. Experimental result (a) and Monte Carlo calculation (b) of EID function and roughly fitting to EID function in 30 keV EB drawing and 15 nm thick calixarene resist on Si substrate.

Electron Beam Lithography for Fine Dot Arrays with Nanometer-Sized Dot and Pitch 21

The possibility of forming very fine pits or dots with a pitch of less than 25 nm was researched using reactive ion etching (RIE) and nano-imprinting with EB drawn pattern as a mask for the future process. We were able to fabricate ultrahighly packed dot arrays with a dot diameter of less than 15 nm and a dot pitch of 25 nm x 25 nm in negative calixarene resist using EB drawing. We also formed nan-Si dot arrays patterns by CF4 RIE. Furthermore, pit arrays were formed in polymer film through nano-imprinting by the photo-polymer method using a Si dot arrays pattern as the master mold. We demonstrated that the EB-drawn dot arrays resist pattern is very suitable for the fabrication of Si dot arrays and pit arrays with a pitch of 25 nm x 25 nm in this polymer. The Si dot and pit diameters

RIE O2 ashing EB drawing

We tried to apply the EB drawing to dry etching process. We checked if the pattern is available for reactive ion etching (RIE) process, and we carried out CF4-RIE using the resist patterns. We performed to do RIE of the Si substrate with the resist dot arrays pattern after post baking of the resist pattern, and to remove the remained resist by O2 ashing. The process flow is shown in Fig. 5. 1. The experiments conditions are represented in Table 5. 1.

Table 5.1. RIE and ashing conditions for Si dot formation and resist removal, respectively. As the experimental results, we obtained very fine Si dot arrays with a pitch of 30 nm x 25 nm to 25 nm x 25 nm (Fig. 5. 2). The minimum diameter of the Si dot is < 10 nm, and the height is about 20 nm. Figure 5. 3 shows histograms of the EB drawn resist dot and the RIE Si dot sizes in a pitch of 25 nm x 25 nm. According RIE and ashing, the resist dot size is

Fig. 5.1. Process flow for Si nano-dot arrays by RI etching and ashing.

**5. Application of EB drawing to formation of nano-Si-dot and nano-polymerpit arrays with a pitch of 25 nm x 25 nm using EB drawing, reactive ion**

**etching (RIE) and nano-imprinting [23, 25]**

were less than 10 nm.

calixarene

**5.1 Dry etching (RIE and ashing)**

The EB writing with thin calixarene resist promises to open the way toward ultrahighdensity recording at >1 Tb/in2 and quantum devices.

Fig. 4.12. SEM images (a)-(d) and the dot size variation (e) of very fine pitch resist dot arrays at center of the drawing area on Si substrate at a dosage of 16 mC/cm2 with a pitch of (a) 20 nm x 20nm, (b) 25 nm x 25 nm, (c) 30 nm x 30 nm and (d) 40 nm x 40 nm.

Fig. 4.13. SEM images (a), (b) and histograms (c)-(e) of 25 nm x 25 nm pitch resist dot arrays on Si substrate at a dosage of 16 mC/cm2, (a) at side of the written pattern area, (b) at corner, (c) at center, (d) at side and (e) at corner.


**3. The role of hypertension in the progression of NASH**

SHRSP5/Dmcr rats are hypertensive, making this strain an ideal model in which to study the correlation between hypertension and NASH. In our previous study, we investigated the mechanism underlying the development of hypertension-associated NASH using three strains of a rat: normotensive WKY, hypertensive SHR and SHRSP5/Dmcr [28]. As mentioned previously, SHRSP5/Dmcr was established from the SHRSP strain, which was derived from SHR strain that was developed from normotensive WKY rats by selective inbreeding of the rats with spontaneously high systolic blood pressure in normal conditions [29]. Male rats with a blood pressure of 150–175 mmHg persisting for more than 1 month, and females with a blood pressure of 130– 140 mmHg were mated, and the offspring with high blood pressure (over 150 mmHg persisting for more than 1 month) were selected for further inbreeding. The severity of hypertension was elevated from generation to generation, and all the rats from the third to sixth generation developed spontaneous hypertension by 15 weeks of age. Since the SHR and WKY originated from the same parental outbred Wistar rats, the WKY strain was used as the normotensive control for the SHR and SHRSP5/Dmcr strains. The blood pressure in the adult male rats of the three strains, WKY, SHR, and SHRSP5/Dmcr, were 130, 235, and 180 mmHg, respectively [28].

In our study, the normotensive WKY strain, and two hypertensive SHR and SHRSP5/Dmcr strains were fed either the HFC or control diet for 8 weeks. Changes to liver pathology and expression of proteins associated with inflammation and oxidative stress were determined [28]. We evaluated serum levels of AST, ALT, and γ-GTP, and confirmed that mild liver damage occurred in the hypertensive strains in the absence of HFC feeding, suggesting that hypertension may be a risk factor for chronic liver disease. The HFC diet induced more severe lobular inflammation and hepatic fibrosis in the hypertensive strains compared with the normotensive strain. The severity of the hepatic fibrosis observed in the SHRSP5/Dmcr strain was even higher compared with that of the SHR strain. The HFC diet induced elevation of serum inflammatory cytokines, TNF-α and TGF-β1, in the hypertensive strains, whereas an increase in TGF-β1 was not observed in the normotensive rats. The combination of TNF-α and TGF-β1 may trigger a more severe inflammatory response in the hypertensive rats by regulating the activation of downstream inflammatory signaling such as NF-κB and mitogen-activated protein kinase (MAPK) pathways. Increased activation of NF-κB and MAPK (p38 and JNK) signaling occurred in the hypertensive strains, which may have contributed to the more severe lobular inflammation observed in these rats. In addition, oxidative stress, defined as an imbalance between the production of reactive oxygen species (ROS) and their elimination by antioxidant defenses, may lead to cellular injury and chronic inflammation [30]. An increase in oxidative stress in NASH patients was previously reported [31, 32]. We measured serum thiobarbituric acid reactive substances levels and found that oxidative stress was significantly elevated in hypertensive strains fed an HFC diet but not in normotensive rats (unpublished data). Meanwhile, in hypertensive rats, the HFC diet suppressed the nuclear factor erythroid 2-related factor 2 (Nrf2)/ Kelch-like ECH-associated protein 1 (Keap1) pathway, involved in antioxidative defenses [33]. We also found that hepatic levels of superoxide dismutase-1 (SOD-1) [25] and SOD-2 [28], that contribute to antioxidant defense by catalyzing the dismutation of superoxide anions [34], were decreased in hypertensive SHRSP5/Dmcr rats fed the HFC diet. The decrease in SOD-2 expression induced by HFC feeding was not observed in normotensive WKY and hypertensive SHR strains [28]. This could suggest that an increase in oxidative stress and a lower antioxidative capacity may trigger a more severe inflammatory response and liver damage in hypertensive rat strains following HFC feeding, compared with normotensive strains.

cell (HSC) activation, which results in the production and deposition of extracellular matrix (ECM) [27]. The HFC diet induced the upregulation of transforming growth factor-β1 (TGFβ1), a profibrotic cytokine that promotes HSC activation, prior to the appearance of obvious hepatic fibrosis (at 2 weeks). Its upregulation was also observed at subsequent stages (at 8 and 16 weeks). Expression of alpha smooth muscle actin (α-SMA) and platelet-derived growth factor-B, involved in hepatic fibrosis, were elevated at 8 weeks of HFC feeding, indicating extensive activation of HSC at this time point. Alpha-1 type I collagen, the major component of ECM, was produced by activated HSC (myofibroblast) and was markedly elevated at 8 and 16 weeks, corresponding to the appearance of extensive liver fibrosis observed at the same time points.

In order to investigate the role of dietary cholesterol in the pathogenesis of HFC diet-induced NASH in SHRSP5/Dmcr rats, we compared hepatic histological changes induced by a high fat (HF) diet and those by an HFC diet (unpublished). As described above, the HFC diet induced severe steatosis, lymphocyte infiltration, ballooned hepatocytes, and fibrosis in the livers of the rats. In contrast, HF feeding only led to mild hepatic steatosis and lymphocyte infiltration, while liver fibrosis was not observed. It was suggested that dietary cholesterol may play a key role in the transition from simple steatosis to fibrotic steatohepatitis, the progressive stage,

SHRSP5/Dmcr rats are hypertensive, making this strain an ideal model in which to study the correlation between hypertension and NASH. In our previous study, we investigated the mechanism underlying the development of hypertension-associated NASH using three strains of a rat: normotensive WKY, hypertensive SHR and SHRSP5/Dmcr [28]. As mentioned previously, SHRSP5/Dmcr was established from the SHRSP strain, which was derived from SHR strain that was developed from normotensive WKY rats by selective inbreeding of the rats with spontaneously high systolic blood pressure in normal conditions [29]. Male rats with a blood pressure of 150–175 mmHg persisting for more than 1 month, and females with a blood pressure of 130– 140 mmHg were mated, and the offspring with high blood pressure (over 150 mmHg persisting for more than 1 month) were selected for further inbreeding. The severity of hypertension was elevated from generation to generation, and all the rats from the third to sixth generation developed spontaneous hypertension by 15 weeks of age. Since the SHR and WKY originated from the same parental outbred Wistar rats, the WKY strain was used as the normotensive control for the SHR and SHRSP5/Dmcr strains. The blood pressure in the adult male rats of the three strains, WKY, SHR, and SHRSP5/Dmcr, were 130, 235, and 180 mmHg, respectively [28].

In our study, the normotensive WKY strain, and two hypertensive SHR and SHRSP5/Dmcr strains were fed either the HFC or control diet for 8 weeks. Changes to liver pathology and expression of proteins associated with inflammation and oxidative stress were determined [28]. We evaluated serum levels of AST, ALT, and γ-GTP, and confirmed that mild liver damage occurred in the hypertensive strains in the absence of HFC feeding, suggesting that hypertension may be a risk factor for chronic liver disease. The HFC diet induced more severe lobular inflammation and hepatic fibrosis in the hypertensive strains compared with the normotensive

during the progression of NAFLD/NASH.

112 Cholesterol - Good, Bad and the Heart

**3. The role of hypertension in the progression of NASH**


**Acknowledgements**

The authors are grateful to the Ministry of Electronics and Information Technology, Government of India, for financial support to develop the surveillance system (Grant No. 13(2)/2013-CC&BT). They are also immensely indebted to the General Manager and other concerned officials of North Eastern Coalfields, Margherita, Assam, India to provide the necessary data, extend logistic support, and permit field experimentation of the developed system at Tirap Opencast Coal Mine. The authors are also thankful to the Director, CSIR-Central Institute of Mining and Fuel Research, Dhanbad, India, for his valuable guidance.


**4. Inverse F-Transform**

In this section, we omit the assumption (6) stating every point of the universe *X* must be covered by at least one basic function. Admitting this degenerated case allows us to express a useful characterization of the case when the inverse F-transform, given by Definition 10, provides a solution to the preimage problem.

**Lemma 10.** *Let the assumptions of Lemma 3 be satisfied. If*

$$\mathcal{W}\mathcal{W}^{\top} = D \,, \tag{17}$$

*then the inverse F-transform v* = *F*ˆ[*u*] *given by Definition 10 is a solution to the preimage problem according to Definition 11, DF*[*v*] = *Wv* = *Wu* = *DF*[*u*] = *b for any vector u* ∈ *A.*

**Proof.** We see that the inverse F-transform is a solution to the preimage problem if and only if for any *u* ∈ *A*, it holds:

$$\mathcal{W}u = DF[u] = b \quad = \quad \mathcal{W}v = \mathcal{W}\mathcal{F}[u] = \mathcal{W}\mathcal{W}^\top F[u] = \mathcal{W}\mathcal{W}^{-1}D^{-1}\mathcal{W}u,$$

which holds if

$$WW^\top D^{-1} = I\_{\prime\prime}$$

or equivalently if (17) holds true.

**Corollary 3.** *Condition* (17) *holds true if both of the following equations are fulfilled:*

*i*=1

*1.* ∀*t* ∈ *Y*: *dtt* = *L* ∑ *i*=1 *wti* = *L* ∑ *i*=1 *w*2*ti , 2.* ∀*t*,*s* ∈ *Y*, *t* = *s*: *dts* = 0 = *L* ∑ *wtiwsi*

Recalling that *wti* = *W*(*t*, *xi*) = *At*(*xi*) ∈ [0, 1], we infer that condition 1 is equivalent to stating that ∀*t* ∈ *Y*, *xi* ∈ *X* : *wti* ∈ {0, 1}, i.e., only simple-minded assignment of closeness is possible to be used. Condition 2 is equivalent to stating that every column of the matrix *W* contains at most one non-zero value—let us denote the system of all such matrices as W. Putting these two conditions together, we obtain the following corollary.

 *.*

**Corollary 4.** *If the matrix W* ∈ W *contains only values 0 and 1, then the inverse F-transform v* = *F* ˆ[*u*] *given by Definition 10 is a solution to the preimage problem.*

This property is demonstrated in Examples A2 and A3 in the Appendix A.

#### **5. New Set of Basic Functions**

This section was inspired by the paper [17] where one of the main goals consists in finding conditions under which a noisy signal must be sampled so that it can be reconstructed from its F-transform components. The authors showed that a fuzzy partition adjoint to the partition (with the same nodes) that determined the F-transform components, ensures that the associated inverse F-transform provides the best approximation of the original, continuous function in a certain space.

We analyzed a possible connection between discrete fuzzy partitions on the closeness space and decided to address the following question: can we find a solution to the preimage problem *Wv* = *b* by creating a new set of basic functions, s.t. they determine a linear transformation of the vector *b* that would solve the problem? If so, what are the conditions that this new set of basic functions must satisfy?

Throughout this section, assume that the sets *X* = {1, ... , *L*}, *Y* and {*At* : *X* → [0, 1] | *t* ∈ *Y*}, the matrices *W* and *D* and the vector *b* are related as in Lemma 3 and fixed.

We are looking for a new set of basic functions (a new fuzzy partition) {*Bt* : *X* → R | *t* ∈ *Y*}, written in rows of a newly created matrix *M* ∈ R*l*×*L*, i.e.,

$$\forall t \in \mathcal{Y}, \mathbf{x} \in \mathcal{X} \colon m\_{t\mathbf{x}} = B\_t(\mathbf{x}) \,, \tag{18}$$

s.t. the vector *v* = *Mb* solves the preimage problem.

Therefore, we require that *WMb* = *b* and from this, we deduce properties of the matrix *M* and express them in terms of basic functions *At*'s and *Bt*'s. Let for an arbitrary matrix *N*, *Nt* denote its *t*-th row, *Nt* denote its *t*-th column and *Nts* denote its entry *nts*.

Hence, we require that

$$\forall t \in \mathcal{Y} \colon (\mathcal{W}\mathcal{M}^{\top})^{t} b = \sum\_{s \in \mathcal{Y}} (\mathcal{W}\mathcal{M}^{\top})\_{ts} b\_{s} = \sum\_{s \in \mathcal{Y}} \mathcal{W}^{t} (\mathcal{M}^{\top})\_{s} b\_{s} = b\_{t} \dots$$

Recalling that *Wtx* = *At*(*x*) and (*M*)*xs* = *Msx* = *Bs*(*x*), for *t*,*s* ∈ *Y*, *x* ∈ *X*, we have

$$\forall t \in \mathcal{Y} \colon \sum\_{s \in \mathcal{Y}} \left( b\_s \sum\_{x \in X} A\_t(x) B\_s(x) \right) = b\_t \,. \tag{19}$$

Substituting the constants

$$\mathfrak{c}\_{\mathfrak{ts}} = \sum\_{\mathfrak{x} \in X} \mathcal{A}\_{\mathfrak{t}}(\mathfrak{x}) B\_{\mathfrak{s}}(\mathfrak{x}), \quad (\mathfrak{t}, \mathfrak{s}) \in \mathcal{Y} \times \mathcal{Y}\_{\mathfrak{s}}.$$

in (19), we obtain that

=

$$\forall t \in \mathcal{Y} \colon \sum\_{s \in \mathcal{Y}} b\_s c\_{ts} = b\_t \dots$$

In the other words, by creating the matrix *C* = *WM* ∈ R*l*×*l* from the constants *cts*, (*t*,*s*) ∈ *Y* × *Y*, we solve *Cb* = *b*. As *B* can be the whole space R*l*, we generally demand that *C* is an identity matrix *I* (in the special case of rank *W* < *l*, this requirement would be unnecessarily strong but leads again to a good choice of new basic functions *Bt*'s). demand

$$\begin{aligned} \text{This means that for all } (t, s) \in \mathcal{Y} \times \mathcal{Y}\_\prime \text{ we denote} \\ 1. \qquad \forall t = s \text{; } \mathfrak{c}\_{t\star} = \ \Gamma \quad A\_t(\mathfrak{x}) B\_t(\mathfrak{x}) = 1. \text{ and} \end{aligned}$$

$$\begin{aligned} 1. \quad \forall t = s \colon c\_{ts} &= \sum\_{\mathbf{x} \in X} A\_{t}(\mathbf{x}) B\_{s}(\mathbf{x}) = 1, \mathbf{a},\\ 2. \quad \forall t \neq s \colon c\_{ts} &= \sum\_{\mathbf{x} \in X} A\_{t}(\mathbf{x}) B\_{s}(\mathbf{x}) = 0. \end{aligned}$$

=

This observation motivates the following definition.

=

**Definition 13** (Compatible Set of Basic Functions)**.** *Let the assumptions of Lemma 3 be satisfied. We say that the set* {*Bt* : *X* → R | *t* ∈ *Y*} *is a compatible set of basic functions with respect to* {*At* : *X* → R | *t* ∈ *Y*} *in the closeness space* (*X*, *w*)*, if*

$$\forall t \in \mathcal{Y} \colon \sum\_{\mathbf{x} \in \mathcal{X}} A\_t(\mathbf{x}) B\_t(\mathbf{x}) = 1\_{\mathcal{X}}$$

*and*

$$\forall t, \mathbf{s} \in \mathcal{Y}, \ t \neq \mathbf{s} \colon \sum\_{\mathbf{x} \in \mathcal{X}} A\_t(\mathbf{x}) B\_{\mathbf{s}}(\mathbf{x}) = \mathbf{0} \dots$$

**Theorem 2** (Solution Determined by a Compatible Set of Basic Functions)**.** *Let the assumptions of Lemma 3 be satisfied and let* {*Bt* : *X* → R | *t* ∈ *Y*} *be a compatible set of basic functions with respect to* {*At* : *X* → R | *t* ∈ *Y*} *in the closeness space* (*X*, *w*)*. Let b* ∈ *B and a matrix M* ∈ R*l*×*L be defined by Mtx* = *Bt*(*x*)*, t* ∈ *Y, x* ∈ *X, then the vector v* = *Mb is a solution to the preimage problem Wv* = *b.*

**Proof.** *Wv* = *WMb* ∈ R*l* and for each of its components, we have

$$\begin{aligned} \forall t \in Y \colon \mathcal{W}^t \boldsymbol{\upsilon} &= (\mathcal{W}\mathcal{M}^\top)^t \boldsymbol{b} = \sum\_{s \in Y} (\mathcal{W}\mathcal{M}^\top)\_{ts} \boldsymbol{b}\_s = \sum\_{s \in Y} \mathcal{W}^t (\mathcal{M}^\top)\_s \boldsymbol{b}\_s \\ &= \sum\_{s \in Y} \sum\_{\mathbf{x} \in \mathcal{X}} \mathcal{W}\_{tx} \mathcal{M}\_{s\mathbf{x}} \boldsymbol{b}\_s = \sum\_{s \in Y} \sum\_{\mathbf{x} \in \mathcal{X}} A\_t(\mathbf{x}) B\_s(\mathbf{x}) \boldsymbol{b}\_s = \boldsymbol{b}\_t \dots \boldsymbol{b}\_s \end{aligned}$$

This proves that *Wv* = *b*.

If we can find a set of new basic functions *Bt*'s compatible with *At*'s, then the vector *v* = *Mb* can be described as an inverse F-transform of an unknown vector *u* ∈ *A*, s.t. *b* = *DF*[*u*], with respect to {*Bt* : *X* → R | *t* ∈ *Y*} written in the rows of *M*.

In other words, the direct mapping between the vector spaces *A* and *B* is given by *W* (*W* : *A* → *B*) and any *M* gives an element of the induced inverse relation, i.e., (*b*, *Mb*) ∈ *W*−1 where *W*−1 ⊆ *B* × *A* is the inverse relation to the mapping *W*. This leads to multiple solutions forming a subset of the affine subspace described in Lemma 9.

**Lemma 11.** *Let the assumptions of Lemma 3 be satisfied. If* rank *W* = *l, then there always exists a compatible set of basic functions with respect to* {*At* : *X* → R | *t* ∈ *Y*} *in the closeness space* (*X*, *w*)*.*

**Proof.** Following Lemma 8, *W*−1 = *W*(*WW*)−1 is a right inverse to *W*. By setting *M* = *W*−1, we found a compatible set of basic functions {*Bt* : *X* → R | *t* ∈ *Y*} given by (18).

To conclude, we found the inverse-F-transform-like procedure associated with the system of new basic functions that, applied on *b*, gives a solution to the preimage problem. Examples A4 and A5 in the Appendix A illustrate the proposition of this section.


2.2.1. Parameter Estimation

In the current study, the parameter estimation is done based on a full Bayesian analysis framework, where the appropriate prior distributions have to be assigned to all unknown parameters. In this study, diffuse priors *p*(*β*) ∝ *const* are assigned to all fixed regression parameters and the second-order Gaussian random walk priors were assigned to non-parametric continuous covariates [20]. The structured spatial effects *si* were modeled through a Gaussian Markov random field specified as an intrinsic conditional autoregressive (ICAR) prior distribution [21].


**3. Conclusion and recommendations**

As a result, the place of metacognition in education is very important. Metacognitive skills help students develop skills such as problem-solving, critical thinking, leadership, and responsibility. Metacognition enables students to be more active by allowing them to take more responsibility in their learning and increases the meaningfulness of their learning. Additionally, the development of metacognition increases cognitive competencies and helps students make the best use of their mental resources. Students with metacognition can manage their learning processes, which increases their academic success. Therefore, the importance and place of metacognitive skills should be emphasized in education.

The following suggestions can be given to educators and students to improve metacognitive skills:

*Cognition and Metacognition in Education DOI: http://dx.doi.org/10.5772/intechopen.114857*

As a result, various suggestions can be offered to educators and students to improve metacognitive skills. With these suggestions and guidance from educators, significant progress will be made in the development of students' skills such as problem-solving, critical thinking, leadership, and responsibility.


Preface

The global landscape of economics and business continually evolves, with emerging markets playing an increasingly pivotal role in shaping the world's economic future. In this edited volume, *New Topics in Emerging Markets*, we delve into a diverse array of subjects that encapsulate the dynamism and complexity of these markets. We aim to provide a comprehensive and accessible exploration of critical issues in emerging markets for a general readership, offering insights into their challenges and opportunities.

Emerging markets, often characterized by rapid growth, changing demographics, and evolving business environments, are at the forefront of global economic discourse. Our contributors come from various academic and professional backgrounds, and their research spans a broad spectrum of topics, reflecting the multifaceted nature of emerging markets.

Chapter 1, "Hodrick-Prescott Filtering of Large Emerging Economies and Decoupling Hypothesis", begins by exploring economic trends in large emerging economies and the intriguing concept of decoupling. Are these economies becoming increasingly independent of their developed counterparts or are they still intricately linked to global economic cycles?

Chapter 2, "The Global Business Cycle within the New Commodities and the Financial Cycle: An Empirical Evidence Based on a Multivariate Unobserved Components Model (UCM)", delves into the intricate relationship between commodities and the global business cycle. As commodities become increasingly vital in today's interconnected world, understanding their impact on the worldwide economy is paramount.

Chapter 3, "Emerging Financial Markets in Ghana and Public Financial Management Crisis Uncertainties Amidst Debt Restructuring", uses Ghana's experience with emerging financial markets as a case study, shedding light on the challenges and uncertainties that arise during debt restructuring and their impact on public financial management.

Chapter 4, "How to Successfully Select the Best-Performing Bank Based on the Best Auditor's Choice Quality in Islamic and Conventional Banks?", explores the intricate process of selecting the best-performing bank, considering the quality of auditors in both Islamic and conventional banking systems.

Chapter 5, "Impacts of Board Quality on Financial Performance in Conventional and Participatory Banks during and after the Covid-19 Crisis: Evidence from Emerging and Developing Countries", investigates the role of board quality in influencing the financial performance of banks in emerging and developing countries during and after the COVID-19 pandemic, which disrupted global economies.

Chapter 6, "Causal Relationship Among Bank Capitalization, Efficiency, and Risk-Taking in ASEAN Commercial Banks", explores the intricate relationships among bank capitalization, efficiency, and risk-taking in ASEAN commercial banks, as banking stability and efficiency are essential to economic growth.

Chapter 7, "Policies for Improving the Efficiency of Innovative Clustering in an Emerging Market", discusses policies to enhance the efficiency of innovation clusters, which are hubs of creativity and entrepreneurship, in emerging markets.

Chapter 8, "Exploiting Technology during Pandemics in Sub-Saharan Africa", investigates how Sub-Saharan Africa leveraged technology to mitigate the impact of the COVID-19 pandemic.

Chapter 9, "Technological Adoption in Emerging Economies: Insights from Latin America and the Caribbean with a Focus on Low-Income Consumers", explores the phenomenon of technological adoption as a crucial driver of economic growth in Latin America and the Caribbean, focusing on low-income consumers.

Chapter 10, "Dynamics of Innovation Ecosystems: Orchestrating Actors and Interactions in Emerging Economies", uncovers the intricate dynamics of innovation ecosystems in emerging economies.

Chapter 11, "Perspective Chapter: eCommerce in the Web3 Era", provides insights into the intersection of e-commerce and the emerging Web3 world, which is spurring the rapid evolution of future commerce.

Chapter 12, "Fashion-Strategizing Leadership in Sports", explores the unique dynamics of leadership in the sports industry within emerging markets.

Chapter 13, "The Future of Education: Writing Exams in the Metaverse at South African Universities", explores the future of education in the Metaverse. Education is transforming, and South African universities are at the forefront of this change.

Chapter 14, "MNC Strategy in Contested Environments: Stay Put or Stay Foot?", examines multinational corporations' strategic decisions when faced with contested markets.

As you embark on this journey through *New Topics in Emerging Markets*, we hope you gain valuable insights into the intricacies, challenges, and opportunities that define these dynamic and rapidly evolving economies. Whether you are an academic, business professional, or simply an inquisitive reader, this volume offers a thoughtprovoking exploration of the issues shaping the future of emerging markets.

We would like to thank IntechOpen for allowing us to become the editors of this book. We appreciate that they believed we could provide the necessary knowledge and technical assistance. We together managed to find the other great colleagues who contributed to this volume. We thank each author for their valuable contributions

that resulted in this book; it will be an asset to the professional community. We also thank our technical reviewers and colleagues at IntechOpen. We could not have done it without you.