**3.2.2 Multi-layer deposition**

154 Electrochemical Cells – New Advances in Fundamental Researches and Applications

Fig. 9. (a) SEM image of the film obtained from ethanol and 2-methoxy, 1-propanol on the substrate at 350 °C after heat treatment at 700 °C for 2 hours; (b) magnification of (a).

**(a) (b)**

**(a) (b)**

**(a) (b)**

Cracks

Small cracks

film and show that the use of this solvent alone is not enough for complete densification of

Fig. 10. (a) SEM image of the film obtained from ethanol and diethylene glycol monobutyl

Fig. 11. (a) SEM image of the film obtained from ethanol and diethylene glycol monobutyl ether on the substrate at 350 °C, after heat treatment at 700 °C for 2 hours; (b) magnification of (a).

ether on the substrate at 350 °C, without heat treatment; (b) magnification of (a).

the deposited layer.

From the results obtained in depositions with different solvents, the solution (ethanol and diethylene glycol monobutyl ether) was chosen to use in the protocol of multi-layer depositions with intermediate heat treatment.

Figure 12 shows the film after the first layer deposition, where the surface is completely covered. After heat treatment (Figure 12b) there is a homogenization of the surface morphology, however, this homogenization is accompanied by the appearance of some discontinuities distributed throughout the film.

Fig. 12. SEM images of the film obtained from intermittent deposition at substrate temperature of 350 °C: (a) after the first deposition; (b) after the first heat treatment at 700 °C for 2 hours.

Fig. 13. SEM images of the film obtained from intermittent deposition at substrate temperature of 350 °C: (a) after the second deposition; (b) after the second heat treatment at 700 °C for 2 hours.

Fuel Cell: A Review and a New Approach

**5. Acknowledgments**

**6. References**

724.

Brazil.

111, pp. 131.

*Research*. Vol. 50, pp. 365.

*Science*. Vol. 12, pp. 1285.

Vol. 159, pp. 159.

1808.

*Ionics*. Vol. 53, pp. 597.

About YSZ Solid Oxide Electrolyte Deposition Direct on LSM Porous Substrate by Spray Pyrolysis 157

This work was supported by CAPES, the Brazilian Government agency for the development

Akorede, M.F., Hizam, H. & Pouresmaeil, E. (2010). Distributed energy resources and

Andrade, I. M. de. (2006). Zircônia Estabilizada com a adição de Cério e Neodímio. *17º*

Aruna, S.T. & Rajam, K.S. (2008). A study on the electrophoretic deposition of 8YSZ coating

Arya, S.P.S. & Hintermann, H.E. (1990). Growth of Y-Ba-Cu-O Superconducting Thin Films

Balkenende, A.R., Bogaerts, A., Scholtz, J.J., Tijburg, R.R.M. & Willems, H.X. (1996). Thin

Brinker, C.J., Hurd, A.J., Frye, G.C., Ward, K.J. & Ashley, C.S. (1990). Sol-Gel Thin Film

Bryant, W.A. (1977). The fundamentals of chemical vapour deposition. *Journal of Materials*

Canales-Vázquez, J., Tao, S. W. & Irvine, J. T. S. (2003). Electrical properties in

Carter, S., Selcuk, A., Chater, R. J., Kajda, J., Kilner, J. A. & Steele, B. C. H. (1992). Oxygen

Chamberlin, R.R. & Skarman, J.S. (1966). Chemical Spray Deposition Process for Inorganic

Chen, C.H., Kelder, E.M., Van der Put, P.J.J.M. & Schoonman, J. (1996). Morphology control

Cooper, L., Benhaddad, S., Wood, A. & Ivey, D.G. (2008). The effect of surface treatment on

Ellis, M. W., Von Spakovsky, M.R. & Nelson D.J. (2001). Fuel cell systems: efficient,

Farhikhte, S., Maghsoudipour, A. & Raissi, B. (2010). Synthesis of nanocrystalline YSZ

by Ultrasonic Spray Pyrolysis. *Thin Solid Films*. Vol. 193, pp. 841.

Formation. *Journal of Non-Crystalline Solids*. Vol. 121, pp. 294.

Films. *Journal of the Electrochemical Society*. Vol. 113, pp. 86.

technique. *Journal of Materials Chemistry*. Vol. 6, pp. 765.

*Journal of Power Sources*. Vol. 184, pp. 220.

*Compounds*. Vol. 491, pp. 402.

benefits to the environment. *Renewable and Sustainable Energy Reviews*. Vol 14, pp.

*CBECIMat - Congresso Brasileiro de Engenharia e Ciência dos Materiais*, Foz do Iguaçu,

using mixture of acetone and ethanol solvents. *Materials Chemistry and Physics*. Vol.

MgO Layers for Effective Hopping Transport of Electrons. *Philips Journal of*

La2Sr4Ti6O19−δ: a potential anode for high temperature fuel cells. *Solid State Ionics*.

transport in selected nonstoichiometric perovskite-structure oxides. *Solid State*

of thin LiCoO2 films fabricated using the electrostatic spray deposition (ESD)

the oxidation ferritic stainless steels used for solid oxide fuel cell interconnects.

flexible energy conversion for the 21st century. *IEEE Proceedings*. Vol. 89, pp.

(ZrO2–8Y2O3) powder by polymerized complex method. *Journal of Alloys and*

of human resources. The authors also thank the financial support of CNPq.

After the second layer deposition, the film covered most of these irregularities, achieving the aimed goal of the intermediate deposition protocol. However, the second and first layer overlapping, led to the formation of an even more irregular layer, both before (Figure 13a) and after heat treatment (Figure 13b).

The same behavior was observed after the last deposition. This layer apparently had some leveling effect on the film, slightly reducing the surface irregularities (Figure 14a). There were no significant morphological changes after the final heat treatment (Figure 14b). For the protocol of multi-layer depositions, with intermediate heat treatment, a crack-free film was obtained, but the surface presented a roughness increase.

Fig. 14. SEM images of the film obtained from intermittent deposition at substrate temperature of 350 °C: (a) after the final deposition; (b) after the final heat treatment at 700 °C for 2 hours.


**2.2 Mucosal layers of rectal wall**

Another anatomical landmark is differentiating the mucosal layers (**Figure 4**) in relation to the TNM classification of the rectal cancer.

**Figure 4.** *Mucosal layers of rectal wall (axial T2 weigted MR image).*

T1- submucosal invasion.

T2- invasion of muscularis propria.

T3- through the muscularis propria to the submucosa.

T4- perforation of the visceral peritoneum or direct invasion of the peritoneum.

Important fact is that T3 and T4 tumors are associated with extramural invasion. The more pronounced penetration of the mesorectum is associated with a worse prognosis and a higher probability of local recurrence. Many tumors are staged as pT3, but there is actually a heterogeneous T3 group, which is why a subclassification of T3 has been created:

T3a - minimal invasion <1 mm by muscularis propria.

T3b- light-walled invasion 1-5 mm from muscularis propria.

T3c- moderate invasion 5-15 mm from muscularis propria.

T3d- extensive invasion>15 mm by muscularis propria.

T3a and T3b are associated with better outcome for the patient compared with T3c and T3d stages, suggested they are T4 tumors because of worse outcome and poor prognosis [1].

When talking about staging it is important to notice that low rectal cancer is a separate subgroup again due to different anatomical features- the anorectal sling:

Staging of low rectal cancer with MRI (recently validated in the prospective study Mercury II: Low Rectal Cancer study [2].

stage 1 - the tumor is visualized in the rectal wall, but not throughout its thickness (preserved outer muscle layer).

stage 2- the tumor displaces the muscle layer without crossing the intersphincteric line.

**61**

*Role of Magnetic Resonance Imaging in Patients with Rectal Cancer*

stage 3- the tumor invades the intersphincteric line or is 1 mm from the

For understanding of the neoplastic behavior of rectal cancer it is of great importance to analyze the pathways of spreading of tumorous tissue. They are:

2.involvement of local lymph vessels and lymph node metastases,

3.venous invasion (intra- and extramural venous invasion- EMVI) and

Demonstration of any invasion both histologically and by MRI [3] is always associated with a poor prognosis. The detection of EMVI is associated with the presence of synchronous distant metastases. Involvement of extramural venous vessels is more closely associated with poor prognosis, as well as invasion of larger veins. This leads to the conclusion, that detection of EMVI on MRI is of great prognostic

Explaining the anatomy by the radiologists helps the surgeons plan the surgical

2.TME- Total Mesorectal Excision is the universally established standard for optimal oncological surgery in rectal cancer [4]. TME is an independent predictor of local recurrence. TME includes excision of the rectum and surrounding adipose tissue, the lymphovascular cuff, the mesorectum, in which the locoregional lymph nodes are located. The outermost border of the mesorectum, the mesorectal fascia, plays the role of an oncological barrier. Thus, if the surgical principles for TME are followed, the prognostic effect of regional lymph nodes

may be neglected [5], as they themselves are removed en block in TME.

4.No surgery and stoma placement in locally advanced and unresectable T4b

Before discussing the imaging of rectal cancer one should understand the treatment options for the disease. The ideal prognostic stage allows selection of the

3.Deferral of surgery or Watch and Wait strategy- novel strategy based on organ preservation if complete clinical response is achieved by neoadjuvant therapy (references on EURECCA (European Registration of Cancer Care [6] and

stage 4- the tumor invades the external anal sphincter and infiltrates the levator

*DOI: http://dx.doi.org/10.5772/intechopen.94868*

ani and/or invades neighboring organs.

1.direct invasion in the rectal wall,

importance and it is explained in details below.

1.TEM- Transanal Endoscopic Microsurgery in T1 stage

**2.3 Pathways of spreading**

4.tumor deposits.

**2.4 Surgery of rectal cancer**

TRIGGER) [7].

tumors.

**2.5 Treatment options**

procedure. Surgeons have 3 options:

levator ani.

stage 3- the tumor invades the intersphincteric line or is 1 mm from the levator ani.

stage 4- the tumor invades the external anal sphincter and infiltrates the levator ani and/or invades neighboring organs.


**3.2 Retinoic acid (RA) related cell signalling machineries might be involved in the cortical barrel patterning**

RA signalling regulates many of the morphogenetic events at the early embryonic stage, such as A-P axis formation, the establishment of L-R asymmetry and so on (Kiecker & Lumsden, 2005; Niederreither & Dolle, 2008). It has recently been suggested that RA might also have physiological roles in cortical development at the later embryonic stages (Siegenthaler et al., 2006; Smith et al., 2001). We thus next tried to examine the possible roles of RA related cell signalling machinery in the cortical area pattering during development. By using the same BAC clone *RP23-78N21*, we replaced the *Cdh6*-ATG exon to an expression cassette for the membrane-bound form of enhanced green fluorescent protein (GAP43-EGFP) by means of homologous recombination and generated transgenic

stable, independent BAC transgenic (Tg) mouse founders from Construct #1 and five from Construct #2. In the former founders, none of them recapitulated the reporter expression in S1-barrel layer IV neurons (Fig. 1, white arrow heads), which are strongly marked by the original BAC trans-genesis (Fig. 1, black arrow heads). In contrast, four out of five founders reproduced the intense expression profile of S1-barrel layer IV neurons, while one of them showed no reporter expression in the brain (probably due to the positional effect of the BACs' integration site). From these results, it is strongly suggested that the most 5 prime third of Segment X (region a in Fig. 1) is responsible for *Cdh6* expression in the S1-barrel

In order to further to narrow down the responsible territory, we designed the Construct #3 in which a fragment containing the most 3 prime third of region a is excluded from the original BACs. Among seven Tg founders generated from Construct #3, we could not observe the intense reporter expression of S1-barrel layer IV neurons at all (white arrow heads in Fig. 1), while we found that neurons in the other cortical layers (i.e. layers II/III) and/or areas at P7 maintained their conspicuous expression compared to the original *Cdh6*- BAC-Tg lines (Fig. 1). Taken together, we concluded that a 5,884 bp territory containing 11

To our knowledge, this is the first time that a distinct gene regulatory fragment for a defined layer and/or area has been observed, suggesting that separable genetic programs may serve the pattering of each cortical layer and/or area during development. The further characterisation of the gene regulatory elements that directly interact with the 5,884 bp territory would be an important next step in understanding how the cortical layer and/or area identity is strictly determined during development. In this connection, it is noticeable that the 5,884 bp territory contains many of the transcription factor binding motifs, such as *RORbeta*, whose expression is already known to be restricted to defined sets of cortical layers and/or areas (Dye et al., 2011; Hirokawa et al., 2008; Nakagawa & O'leary, 2003). Since recent reports suggest that *RORbeta* harbours an instructive role in elaborating barrel cytoarchitecture and/or circuitries (Jabaudon et al., 2011), it would be of great interest to rigorously evaluate how these transcription factors are involved in establishing *Cdh6* expression along S1-barrel layer IV neurons at P7 which might have functional significance in driving cell segregations to form and/or maintain the barrel

**3.2 Retinoic acid (RA) related cell signalling machineries might be involved in the**

RA signalling regulates many of the morphogenetic events at the early embryonic stage, such as A-P axis formation, the establishment of L-R asymmetry and so on (Kiecker & Lumsden, 2005; Niederreither & Dolle, 2008). It has recently been suggested that RA might also have physiological roles in cortical development at the later embryonic stages (Siegenthaler et al., 2006; Smith et al., 2001). We thus next tried to examine the possible roles of RA related cell signalling machinery in the cortical area pattering during development. By using the same BAC clone *RP23-78N21*, we replaced the *Cdh6*-ATG exon to an expression cassette for the membrane-bound form of enhanced green fluorescent protein (GAP43-EGFP) by means of homologous recombination and generated transgenic

ECRs is required for *Cdh6* expression in S1-barrel layer IV neurons at P7.

layer IV neurons at P7.

cytoarchitecture.

**cortical barrel patterning**

Fig. 2. Possible involvement of retinoic acid (RA) related cell signalling machineries in the cortical barrel patterning.

A BAC clone *RP23-78N21* is modified to harbour a membrane-bound form of EGFP cassette and SV40 polyadenylation signal (GAP43-EGFP-pA) in frame to the *Cdh6* gene via homologous recombination (Rec) in a recombinogenic bacterial strain (upper most part of the figure). (A-D) A Tg mouse with EGFP modified BACs recapitulated *Cdh6* expression at P7. OB, olfactory bulb; S1 primary somatosensory area. The boxed area d in panel C is magnified in panel D. Note that Layer IV barrels in S1 are illuminated in this Tg mouse line. (E-H) Effects of RA on barrel development. RA is intraperitoneally injected into the mother (E, F) or the pups (G, H) and the EGFP expression profile is evaluated at P7. Note that this is only the case with E14.5 injections, which affect the formation of barrel cytoarchitecture, highlighting the role of RA in early neocortical development.

mouse founders (Inoue et al., 2009). In the Tg cerebral cortex, we found that GFP expression shows exactly the same patterns as with the original LacZ-Tg mice (Fig 1 and 2). In particular, this GFP-BAC-Tg mouse line illuminated the S1 barrel structure of the whole mount brain preparations, allowing us to easily image the S1-barrel territory whose identification generally requires specific histological staining processes, such as the CO staining method.

We then administrated RA to the mothers or pups for GFP-BAC-Tg, with the concentration reported to induce abnormality in the cortex (Smith et al., 2001) and evaluated how RA affects the GFP expression patterns at P7. As a result of this, no drastic change was observed for the cortical barrel patterning when RA was administrated later than embryonic day 17.5 (E17.5). However, RA administration at E14.5 resulted in massive perturbation of S1 barrel patterning, with ambiguous area boundaries illuminated by GFP expression. Noticeably, the intensity of the GFP expression appeared to be decreased due to the qualitative and quantitative differences among *Cdh6*::*GFP* positive cortical cells and/or thalamocortical axon terminals. These results imply that the role of RA in regulating *Cdh6* expression and/or cortical area pattering is just limited to those embryonic stages earlier than E14.5.

It is now widely accepted that cortical area patterning begins as early as mouse E12.5 when the counter-gradient of the transcription factors Pax6 and Emx2 is established in the cortical ventricular zones (Bishop et al., 2000; Hamasaki et al., 2004). This gradation pattern, as generated by such secreted molecules as *Fgf8*, is shown to be the basis of cortical arealisation yet other transcriptional factors, such as *Coup-TFI,* could regulate the area-specific differentiation of distinct subtypes of cortical neurons independently of *Fgf8*-*Pax6*/*Emx*2 gene functions (Armentano et al., 2007; Fukuchi-Shimogori & Grove, 2001, 2003). Our results, together with a previous series of studies, thus suggest that RA accumulated earlier than E14.5 might play a role in cortical arealisation by affecting the production, migration, positioning and/or circuit formation of the cortical S1 barrel layer IV neurons that eventually express *Cdh6*. The next critical step would be to examine whether RA-related signalling could be interactive with the 5,884 bp territory identified in this study that contains *RORbeta* related transcription factor binding motifs.


*Edited by Sai Praveen Haranath and Samiya Razvi*

Bronchoscopy has become an essential part of modern medicine . Recent advances in technology have allowed integration of ultrasound with this tool. The use of lasers along with bronchoscopes has increased the therapeutic utility of this device. Globally an increasing number of pulmonary specialists, anaesthesiologists and thoracic surgeons are using the bronchoscope to expedite diagnosis and treatment. The current volume on bronchoscopy adds to the vast body of knowledge on this topic. The democratic online access to this body of knowledge will greatly increase the ease with which both trainees and expert bronchoscopists can learn more .The contributions from around the world cover the breadth of this field and includes cutting edge uses as well as a section on pediatric bronchoscopy . The book has been an effort by excellent authors and editors and will surely be a often reviewed addition to your digital bookshelf. . In summary, this book is a great testament to the power of collaboration and is a superb resource for doctors in training, ancillary team members as well as practicing healthcare providers who have to perform or arrange for bronchoscopy or the associated procedures.

ISBN 978-953-51-0642-5

Global Perspectives on Bronchoscopy

Photo by Pablo\_K / iStock

## Global Perspectives on Bronchoscopy

*Edited by Sai Praveen Haranath and Samiya Razvi*

**GLOBAL PERSPECTIVES**

**ON BRONCHOSCOPY**

Edited by **Sai Praveen Haranath**

and **Samiya Razvi**


*Microwave-Assisted Extraction of Bioactive Compounds (Review) DOI: http://dx.doi.org/10.5772/intechopen.96092*

**Number**

**24**

54.

55.

56.

 Noni plant roots (*Morinda*

*citrifolia*)

 Tomato paste

 Purple corn (*Zea mays* L.) cob

 **Plant sample**

**Results obtained**

 MAE: Microwave

HCl-ethanol

Extraction time = 19 min

UMAE:

Microwave

KHz of ultrasonic processing,

ratio = 10.6, Extraction time = 367 s

MAE:

Anthraquinones

 (95.91%)

 A higher yield has been obtained with higher

[54]

antioxidant

 activity.

Microwave

 power = 720 W,

Temperature

ethanol (80%), Extraction time = 15 min

MAE:

Phenolic constituents

23.5 mg GAE/g)

Rutin compound (365 mg/g)

 (9.3–

Higher yields.

[85]

*Microwave Heating - Electromagnetic Fields Causing Thermal and Non-Thermal Effects*

Microwave

 power = 150 W,

Temperature

ethanol, time = 20 min

MAE:

Microwave

water (20 mL, 80/20, v/v), ratio = 15, Extraction time = 3 min

MAE:

Polyphenolic

 compounds

 Several phenolic compounds

 were extracted.

 [87]

Microwave

water (76/24% v/v),

Solvent/feed

time = 4 min

MAE:

Total phenolic

content = 85.64

GAE/g d.w.

Total flavonoid

 0.52 mg

Recovery of higher yield in a shorter time

[21]

compared to Soxhlet extraction technique.

Microwave

water (47/53% v/v), Extraction time = 2 min

Solvent/feed

 ratio = 14,

 power = 444 W, Solvent = ethanol/

60.

 Purple fleabane

 ratio = 10, Extraction

Temperature

 = 70 °C,

 power = 558 W, Solvent = ethanol/

Solvent/feed

Aloe-emodin

Higher yield compared to other extraction

[86]

methods.

 power = 340 W, Solvent = ethanol/

 = 60 °C, Solvent = 50 mL of

Solvent/feed

 ratio = 10, Extraction

57.

 Seeds, leaves, pulp, and fruits of

sea buckthorn (*Hippophae*

*rhamnoides*)

58.

59.

 Bitter leaves

 Aloe (Liliaceae)

Solvent/feed

 ratio = 100,

 = 60 °C, Solvent = 10 mL of

Solvent/feed

Lycopene (97.4%)

More efficient and rapid than UAE.

[84]

 power = 98 W, Frequency = 40

 (95%),

Solvent/feed

 ratio = 20,

 power = 555 W, Solvent = of 1.5 M

**Bioactive compounds**

Anthocyanins

100 g)

 (185.1 mg/

 **Remarks**

More efficient and rapid than CSE.

**Reference**

[83]


**3. Necessity for drug repurposing in cancer treatment and availability of attractive candidates**

Comparing cancer with other disease that takes much time to develop and working insidiously. Every cancer begins with few mutations that suppress tumor suppression gene and promoting oncogene that leads to abnormal cell proliferation, escape of apoptosis, immune evasion, inflammation, defects in DNA damage repair mechanism, Warburg effects, angiogenesis and lack of differentiation of cell with most of the cells remain immature. As there is progress happen the picture of tumor microenvironment become more and more complicated. At this time tumor is no more homogenous but packed with heterogeneous cells and changing itself to more resistance form. The cancer might be supported by systemic condition of the body or in the other words internal anti-cancer mechanism become compromised to eradicate the tumor. The tumor microenvironment begins to secret many immunosuppressive cytokines and inflammatory mediators that sustain the tumor growth and save this corrupted cellular structure against honest immune system that work in the form of vigilance. After dominate at local region, tumor intrude to the other favorable region. Later on, metastasis start based on seed and soil theory of Stephan Paget, where cancer cells work as "seeds" and the specific organ microenvironments work as "soil." The success interaction between these two entities determines the development of a secondary tumor [11].

After get metastasis, the most of the patients give response to first line treatment not more than 50% for various cancers. At advance stages of cancer, majority of patients will develop anti-cancer resistance due to drastic abnormal genetic, epigenetic changes and surviving of cancer stem cells that not killed even after the death of tumor cells [12, 13]. So, it becomes important to repurpose drugs that able to act at multiple targets in tumors in patient that display genetic heterogeneity.

**125**

**Figure 3.**

*Hall marks of cancer.*

*Drug Repurposing in Oncotherapeutics DOI: http://dx.doi.org/10.5772/intechopen.92302*

Artemisinins Induce formation of

Doxycycline Protein synthesis in

*Repurposed drug for the cancer treatment.*

bacteria

Chlorpromazine

[19]

**Table 1.**

**Drug First approved target Approved in**

Dopamine receptor antagonist

reactive oxygen species (ROS) within the infected red blood cells (RBC)

**3.1 Various anti-cancer targets that can be used for repurposing of drug**

repurposing in oncotherapeutics (**Figure 3**).

Based on global statistics, more than 20 million individuals will be detected with cancer in 2025. Certain cancer like breast cancer, colorectal, prostate is mostly remaining incurable in advanced stages with existing treatment and that leads to increase in number of cases. Thus, addressing these present and future challenges requires more effective cancer drugs [29]. Traditional anti-cancer therapy like Chemotherapy and radiation have dangerous side effects that range from bone marrow suppression, oral mucositis, arising of secondary cancer to vomiting, diarrhea and organ specific toxicity that drastically decrease the quality life and overall survival of cancer patients [30]. From this point of view, drug repositioning option is promising strategy to identify non-cancer drugs like aspirin and chlorpromazine which have anti-tumor activity with less side effects comparable to traditional anti-cancer drugs. Traditionally limited targets were identified for anti-cancer drugs that involve cell cycle inhibitors, anti-metabolites, anti-angiogenesis, growth factor inhibitors, pro-apoptotic. But today many new targets identified that work in more specific way and reduce dangerous side effects of anti-cancers. Some novel drug target mentioned in following diagram that might be work well for future drug

**disease**

In psychosis, bipolar disorder, schizophrenia

Anti-malarial [25]

**Repurposed in cancer (preclinical/clinical)**

[24]

effects [26]

Antibiotics Down regulation of MMP-2 and

Increase in p21 [23], p51 expression

Anti-proliferative, pro-apoptotic

MMP-9 expression in leukemia [27] and colorectal cancer cells [28]

The following table (**Table 1**) consists of brief reviews of available good drug candidates for drug repurposing and some of that already approved.

**Table 1.**

*Drug Repurposing - Hypothesis, Molecular Aspects and Therapeutic Applications*

candidates for drug repurposing and some of that already approved.

**disease**

Nausea, vomiting of pregnant woman (banned

now)

Type-II diabetes mellitus

suppressant

breast cancer

aggregation in cardiovascular disease

reduce heart rate

diseases

COX-1 Prevent Platelets

**Repurposed in cancer (preclinical/clinical)**

TNF-α

Multiple myeloma by targeting

Mitochondrial respiration, reducing insulin and insulin-like growth factor levels, inhibits mTOR and activate p53, AMPK pathway

In Pancreatic neuroendocrine by targeting mTOR signaling pathway

For HER2-positive metastatic

Prostaglandin E2 (PGE2) decreased in colon cancer [18], inhibition of platelets to suppress NK cellmediated lysis of cancer cells [19]

Reduced 57% risk of metastasis in Breast cancer by blocking cyclic AMP (cAMP), focal adhesion

Rise in intracellular Na + and Ca2+ in human prostate adenocarcinoma cells, lead to activation of calcineurin and transcriptional upregulation of Fas ligand cause apoptosis. Also, suppression nuclear factor-kappa B and inhibition of DNA topoisomerase II are well documented.

gastric cancer

kinase (FAK)

**Drug First approved target Approved in**

medullary control centers (the vomiting center and the chemoreceptive trigger zone) or affect the peripheral receptors

monophosphate activated protein kinase (AMPK) signaling pathway

Everolimus [16] mTOR Immuno-

Trastuzumab [17] HER2 HER2-positive

Propranolol [20] β-receptor blocker Cardiovascular

Digoxin [21, 22] Na + -K + -ATPase Heart failure, to

Thalidomide [14] Might affect the

Metformin [15] Activate the adenosine

Aspirin (low dose; 50–100 mg daily)

Warburg effects, angiogenesis and lack of differentiation of cell with most of the cells remain immature. As there is progress happen the picture of tumor microenvironment become more and more complicated. At this time tumor is no more homogenous but packed with heterogeneous cells and changing itself to more resistance form. The cancer might be supported by systemic condition of the body or in the other words internal anti-cancer mechanism become compromised to eradicate the tumor. The tumor microenvironment begins to secret many immunosuppressive cytokines and inflammatory mediators that sustain the tumor growth and save this corrupted cellular structure against honest immune system that work in the form of vigilance. After dominate at local region, tumor intrude to the other favorable region. Later on, metastasis start based on seed and soil theory of Stephan Paget, where cancer cells work as "seeds" and the specific organ microenvironments work as "soil." The success interaction between these two entities determines the development of a secondary tumor [11]. After get metastasis, the most of the patients give response to first line treatment not more than 50% for various cancers. At advance stages of cancer, majority of patients will develop anti-cancer resistance due to drastic abnormal genetic, epigenetic changes and surviving of cancer stem cells that not killed even after the death of tumor cells [12, 13]. So, it becomes important to repurpose drugs that able to act at multiple targets in tumors in patient that display genetic heterogeneity. The following table (**Table 1**) consists of brief reviews of available good drug

**124**

*Repurposed drug for the cancer treatment.*


**2. History**

In the early years of endovascular techniques, the main method for the treatment of wide-neck aneurysms was surgical. Attempts at embolization presented significant risks of coil herniation, migration, parent artery occlusion and poor mid-term morphological results with high recurrence rates. A great effort has been made by engineers and manufacturers to develop coils that present a better arrangement inside the aneurysm sac and fulfil two important conditions: a good apposition with the aneurysm wall, and a stable three-dimensional conformation, so that loops do not herniate through the aneurysm neck.

The first issue was approached by the development of coils with a geometry intended to fill the aneurysm sac, even if it is irregular. A good apposition with all regions of the cavity may improve the aneurysm embolization ratio and increase the stability of the coil mass, preventing migration. The second issue was approached through the development of coils with a memory of their three-dimensional shape, so that they may be used to create a

© 2012 Maldonado and Bonafé, licensee InTech. This is an open access chapter distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2012 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

relatively predictable cage that would keep the subsequent coils inside. As one may imagine, the above properties are relatively antagonistic. A coil that penetrates irregular spaces and has a good position to the aneurysm wall is also a coil that may herniate through a large aneurysm neck. In this context of technical difficulty, balloon and stent-assisted techniques have been used to provide protection for the parent artery as well as to treat coil mass herniation.

Intracranial stents also serve as scaffolding for neo-endothelization, providing additional reduction of the flow into the aneurysm. Consequently, their use improves intrasaccular thrombosis and decreases the risk of recanalization.

Even if these concepts seem attractive, manufacturers were rapidly confronted with technical difficulties, such as the narrowness and fragility of the intracranial vasculature, the need to navigate tortuous vessels, and the obligation to provide materials that were thin enough so that a microcatheter could be placed simultaneously in the vasculature.

The first case of intracranial stenting for treating a brain aneurysm was reported by Higashida et al. in 1997 (Higashida et al., 2005). In that occasion, the authors used a balloonexpandable cardiac stent in combination with Guglielmi detachable coils to treat a fusiform aneurysm of the vertebrobasilar junction. At that time, other authors had already attempted the placement of stent and coils in a fusiform aneurysm in an experimental context in pigs. Soon after, different groups reported a number of strategies using a combination of balloonmounted stents and coils. In 2000, the use of stents for managing coil migration during the treatment of wide neck aneurysms was reported (Fessler et al., 2000, Lavine et al., 2000) and the case series became progressively larger.

The first stent specifically designed for the intracranial area to obtain Food and Drug Administration (FDA) approval was the NeuroformTM (Boston Scientific Corporation, Natick, USA). The device was approved for 'humanitarian device exemption' in 2002. This means that its use was complicit to the additional approval of an Institutional Review Board and was supposed to be limited to use on no more than 4000 individuals per year in the United States of America (USA).

Outside the USA, especially in Europe and in the context of clinical research, other stents became rapidly available. That was the case with the LeoTM (Balt, Montmorency, France), the first self-expanding closed cell design stent released in Europe in 2003, and then the EnterpriseTM (Cordis Neurovascular I., Miami Lakes, USA), which was approved by the FDA in the US in 2007.

Flow diverters are the last technical advances bringing the concept of 'reverse remodeling' for intracranial aneurysm treatment. SilkTM (Balt, Montmorency, France) and PipelineTM (Chestnut Medical Technologies Incorporation, Menlo Park, CA, USA) are in this category. These devices are intended to exclude the aneurysm sac from the parent artery by creating significant flow disruption, so that blood significantly stagnates inside the aneurysm sac and thromboses.


Acknowledgments

This work is partly supported from Okasan-Kato Foundation. The presented works have been carried out with graduate students who formerly belonged and currently belong to our research group, Okajima, Omura, and Yoshida.


# **The Mutual Influence of Religion and Science in the Human Understanding and Exploration of Outer Space**

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