**Recent Developments in Non-conventional Welding of Materials**

Editors

**Rui Manuel Leal Ivan Galv˜ao**

MDPI • Basel • Beijing • Wuhan • Barcelona • Belgrade • Manchester • Tokyo • Cluj • Tianjin

*Editors* Rui Manuel Leal ESAD.CR/Polytechnic Institute of Leiria Portugal CEMMPRE/University of Coimbra Portugal

Ivan Galvao˜ ISEL/Polytechnic Institute of Lisbon Portugal CEMMPRE/University of Coimbra Portugal

*Editorial Office* MDPI St. Alban-Anlage 66 4052 Basel, Switzerland

This is a reprint of articles from the Special Issue published online in the open access journal *Materials* (ISSN 1996-1944) (available at: https://www.mdpi.com/journal/materials/special issues/ Recent Materials).

For citation purposes, cite each article independently as indicated on the article page online and as indicated below:

LastName, A.A.; LastName, B.B.; LastName, C.C. Article Title. *Journal Name* **Year**, *Volume Number*, Page Range.

**ISBN 978-3-0365-3873-0 (Hbk) ISBN 978-3-0365-3874-7 (PDF)**

Cover image courtesy of Ivan Galvao and Rui Manuel Leal ˜

© 2022 by the authors. Articles in this book are Open Access and distributed under the Creative Commons Attribution (CC BY) license, which allows users to download, copy and build upon published articles, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications.

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*2.4. Spectral-Domain Optical Coherence Tomography (Sd-OCT)*

Cross-sectional analysis was performed with a commercial OCT device, Thorlabs Telesto-II, using a superluminescent diode (central wavelength: 1300 nm, bandwidth: about 100 nm) with axial resolution of 5.5 μm in air, and lateral resolution of 13 μm. The maximum field of view (FOV) is 10.0 × 10.0 mm2, with 3.5 mm imaging depth. The detector consists of a spectrograph made of a diffraction grating and a fast camera. The system is controlled via a 64-bit software preinstalled on a high-performance computer. The 3D scanning path probe with integrated video camera performs high-speed imaging (76 kHz) for rapid volume acquisition and live display. The sample stage provides XY translation and rotation of the sample along with axial travel of the probe.


**6.6 Diagnostic feasibilities of polarization mapping of optically thin layers of BTs**

To look for the feasibilities for differentiation of geometrical/optical structure of architectonics of BTs, comparative study of statistical and fractal structures of BT maps has been carried out [103, 119 - 121]. There are BTs of interest: (i) physiologically normal and dystrophically changed muscular tissue (MT), i.e. structured BT with ordered architectonics; (ii) physiologically normal and septically inflamed pulmonary tissue (PT), i.e. BT with island architectonics. The set of figures (Figs. 23 and 24) illustrates polarization maps of the mentioned objects.

Fig. 23. Polarization maps of physiologically normal (left part) and dystrophycally changed (right part) MT: (a), (b) – 2D distributions (in degrees) of the azimuth of polarization and ellipticity; (c), (d) – histograms of polarization parameters.

Potentialities for statistical differentiation of polarization maps are illustrated by comparison of magnitudes of the statistical moments of the 1st to the 4th orders for the azimuth of polarization and ellipticity at images of physiologically normal and pathologically changed BTs, represented in Tables 2 and 3.

Table 2. Statistical moments of the 1st to the 4th orders for the coordinate distributions of the azimuth of polarization and ellipticity at images of histological tomes of normal and dystrophically changed MT

Fig. 24. Polarization maps of physiologically normal (left part) and septically inflamed (right part) PT: (a), (b) – 2D distributions (in degrees) of the azimuth of polarization and ellipticity; (c), (d) – histograms of polarizarion parameters.

One can see from the represented data that magnitudes of asymmetry and excess of the coordinate distributions of the azimuth of polarization and ellipticity at BT images with ordered architectonics (Table 2) exceed by 3 to 5 times the magnitudes of the corresponding parameters characterizing statistics of the 3rd and the 4th orders of inhomogeneous in polarization BT images with island architectonics (Table 3).

Potentialities for statistical differentiation of polarization maps are illustrated by comparison of magnitudes of the statistical moments of the 1st to the 4th orders for the azimuth of polarization and ellipticity at images of physiologically normal and pathologically changed

(c) (d)

(a) (b)

*Norm (21 samples) Pathology (22 samples)*

azimuth of polarization and ellipticity at images of histological tomes of normal and

Fig. 24. Polarization maps of physiologically normal (left part) and septically inflamed (right part) PT: (a), (b) – 2D distributions (in degrees) of the azimuth of polarization and ellipticity;

One can see from the represented data that magnitudes of asymmetry and excess of the coordinate distributions of the azimuth of polarization and ellipticity at BT images with ordered architectonics (Table 2) exceed by 3 to 5 times the magnitudes of the corresponding parameters characterizing statistics of the 3rd and the 4th orders of inhomogeneous in

*M*1 *0,26 0,013 0,12 0,01 M*1 *0,21 0,001 0,18 0,011 M*2 *0,12 0,01 0,08 0,004 M*1 *0,19 0,013 0,12 0,006 M*3 *6,7 0,469 4,9 0,294 M*1 *9,4 0,846 6,2 0,434 M*4 *17,9 1,61 14,5 1,595 M*1 *25,4 2,54 21,6 2,592*  Table 2. Statistical moments of the 1st to the 4th orders for the coordinate distributions of the

*M*1

BTs, represented in Tables 2 and 3.

(c) (d)

(c), (d) – histograms of polarizarion parameters.

polarization BT images with island architectonics (Table 3).

(a) (b)

dystrophically changed MT

*M*1

Table 3. Statistical moments of the 1st to the 4th orders for the coordinate distributions of the azimuth of polarization and ellipticity at images of histological tomes of normal and septically inflamed PT

On the other hand, structured BTs possess hierarchical, self-similar structure of architectonics [97, 113, 120]. That is why one must determine optical manifestations of such geometry of anisotropic component of structured BTs. The study of self-similarity of polarization maps of BTs has been carried out for skin derma.

Figure 25 shows the set of log-log dependences, log *P d* ( ) lo g(1 / ) , log *P d* ( ) lo g(1 / ) , for power spectra of the distributions of polarization parameters at images of physiologically normal and pathologically changed skin derma.

Fig. 25. log-log dependences of power spectra of the azimuth of polarization and ellipticity at images of physiologically normal (a), (b) and pathologically changed (c), (d) skin derma.

The dependence log *P d* ( ) lo g(1 / ) manifests two slopes within three decades of scales of architectonics of skin derma's elements; the dependence log *P d* ( ) lo g(1 / ) consists of the part with constant slope and statistical part, as it is seen from Fig. 1.6 (a) and (b). Pathological state of such BT manifests itself in randomization of distributions of polarization parameters at images of the corresponding histological tomes, i.e. for approximating curves (Fig. 25 (c) and (d)) steady slope is absent.

#### **6.7 Degree of mutual polarization of laser images of BTs**

For laser light fields scattered by BTs, coordinate changes of polarization characteristics can be characterized by the complex degree of mutual polarization, CDMP, at two points *r r* 1 2 ; [6]:

$$\mathcal{W}(r\_1, r\_2) = \frac{\left(\mathcal{U}\_x(r\_1)\mathcal{U}\_x(r\_2) - \mathcal{U}\_y(r\_1)\mathcal{U}\_y(r\_2)\exp\left(i\left(\mathcal{S}\_2(r\_2) - \mathcal{S}\_1(r\_1)\right)\right)\right)^2}{\left(\mathcal{U}\_x^2(r\_1) + \mathcal{U}\_y^2(r\_1)\right)\left(\mathcal{U}\_x^2(r\_2) + \mathcal{U}\_y^2(r\_2)\right)}.\tag{27}$$

The following interconnections between the real part of the CDMP, Re , *W Wrr* 1 2 , and the magnitudes at the azimuth of polarization, *r* , ellipticity, *r* , at points *r* of BT's image, and orthogonal components , *U IU I x x y y* of the complex amplitude with phase difference between them *r* have been established in study [100]:

$$\overline{\mathcal{W}}\left(r\_2, r\_1\right) = \frac{\left(\left(I\_x\left(r\_2\right)I\_x\left(r\_1\right)\right)^{\frac{1}{2}} - \left(I\_y\left(r\_2\right)I\_y\left(r\_1\right)\right)^{\frac{1}{2}}\cos\left(\delta\_2\left(r\_2\right) - \delta\_1\left(r\_1\right)\right)\right)^2}{I\left(r\_2\right)I\left(r\_1\right)}\,\tag{28}$$

where

$$\mathcal{S}\left(r\_1\right) = \tan^{-1}\left[\frac{\tan\left[2\,\mathcal{J}\left(r\_1\right)\right]}{\tan\left[\,\alpha\left(r\_1\right)\right]}\right]; \quad \mathcal{S}\left(r\_2\right) = \tan^{-1}\left[\frac{\tan\left[2\,\mathcal{J}\left(r\_2\right)\right]}{\tan\left[\,\alpha\left(r\_2\right)\right]}\right].\tag{29}$$

#### **6.8 Statistical approach to analysis of coordinate distributions of the CDMP at BT images**

Normal and dystrophycally changed tissues of skeleton muscle has been investigated in paper [100]. Coordinate distributions of the CDMP *W x*(,) *y* at images of histological tomes of such samples are shown in Figure 26.

Statistical analysis of the coordinate distributions of magnitudes *W x*(,) *y* shows for the map of tissue of skeleton muscle differences between the statistical moments of the 1st to the 3rd orders (within 30%-50%), while magnitudes of excess (the 4th order statistical moment) differ by 2 to 2.5 times.

part with constant slope and statistical part, as it is seen from Fig. 1.6 (a) and (b). Pathological state of such BT manifests itself in randomization of distributions of polarization parameters at images of the corresponding histological tomes, i.e. for

For laser light fields scattered by BTs, coordinate changes of polarization characteristics can be characterized by the complex degree of mutual polarization, CDMP, at two points *r r* 1 2 ;

The following interconnections between the real part of the CDMP, Re , *W Wrr* 1 2 ,

*r* of BT's image, and orthogonal components , *U IU I x x y y* of the complex

1 2 2 22 2

exp , *xx yy*

*x yx y*

*Ur Ur Ur Ur*

*U rU r U rU r i r r*

112 2

*Ir Ir*

1 1 1 2

tan 2 tan 2 tan ; tan . tan tan

Normal and dystrophycally changed tissues of skeleton muscle has been investigated in paper [100]. Coordinate distributions of the CDMP *W x*(,) *y* at images of histological tomes

Statistical analysis of the coordinate distributions of magnitudes *W x*(,) *y* shows for the map of tissue of skeleton muscle differences between the statistical moments of the 1st to the 3rd orders (within 30%-50%), while magnitudes of excess (the 4th order statistical moment) differ

**6.8 Statistical approach to analysis of coordinate distributions of the CDMP at BT**

*xx yy IrIr IrIr r r*

2 1

(29)

*r r*

1 2

*r r*

2 2 2 1 2 1 22 11

. (27)

2 1 1

cos

, (28)

*r* , ellipticity,

1 2 1 2 22 11

architectonics of skin derma's elements; the dependence log *P d* ( ) lo

approximating curves (Fig. 25 (c) and (d)) steady slope is absent.

**6.7 Degree of mutual polarization of laser images of BTs**

and the magnitudes at the azimuth of polarization,

1 2

*r r*

amplitude with phase difference between them

g(1 / ) manifests two slopes within three decades of scales of

g(1 / ) consists of the

2

*r* have been established in study

  *r* , at points

The dependence log *P d* ( ) lo

*Wrr*

*Wr r*

of such samples are shown in Figure 26.

,

2 1

[6]:

[100]:

where

**images**

by 2 to 2.5 times.

Fig. 26. Coordinate distributions of the CDMP at images of histological tomes of normal (a) and dystrophycally changed (b) tissue of skeleton muscle.

Table 4. Statistical moments of the 1st to the 4th orders for distributions of magnitudes *W x*(,) *y* at images of histological tomes of normal and dystrophically changed tissues of skeleton muscle.

Figure 27 shows autocorrelation functions of the coordinate distributions of magnitudes of the CDMP at images of histological tomes of samples of normal (a) and pathologically changed (b) muscular tissues.

Table 5. Correlation parameters of the distributions of the CDMP, *W x*(,) *y* , for normal and pathologically changed osseous muscular tissues.

Fig. 27. Autocorrelation functions *Gxy* (,) of 2D distributions of the CDMP, *W x*(,) *y* , at images of histological tomes of muscular tissues.

Correlation analysis of 2D distributions of magnitudes *W x*(,) *y* leads to the following conclusions: (*i*) differences between magnitudes of a half-width *L* of autocorrelation functions for distributions *W x*(,) *y* at polarization/correlation maps of muscular tissue's maps are within the interval 0.65 to 2 times; (*ii*) differences between dispersions of the distributions for extrema of power spectra for *W x*(,) *y* reach one order of magnitude.

Thus, the analysis of approaches and metrological techniques of modern polarimetric diagnostics of birefringent nets of BTs leads to the following conclusions.

#### **7. Conclusions**

Thus, new approaches to metrology of partially coherent and partially polarized light fields are derived proceeding from singular optics concept. The first of them concerns to exploring

Fig. 27. Autocorrelation functions *Gxy* (,) of 2D distributions of the CDMP, *W x*(,) *y* , at

distributions for extrema of power spectra for *W x*(,) *y* reach one order of magnitude.

diagnostics of birefringent nets of BTs leads to the following conclusions.

Correlation analysis of 2D distributions of magnitudes *W x*(,) *y* leads to the following conclusions: (*i*) differences between magnitudes of a half-width *L* of autocorrelation functions for distributions *W x*(,) *y* at polarization/correlation maps of muscular tissue's maps are within the interval 0.65 to 2 times; (*ii*) differences between dispersions of the

Thus, the analysis of approaches and metrological techniques of modern polarimetric

 higher-order statistical moments (asymmetry and excess) characterizing the distributions of polarization/correlation parameters of laser images of BTs are of the highest sensitivity in respect to changing optical properties of nets of biological crystals

 interconnection between the real part of the CDMP and parameters of anisotropy (such as direction of an optical axis and phase difference between orthogonal components of scattered laser radiation) at different points of birefringent matrix provides reliable tool for correlation optical diagnostics of pathological changes of biological tissues and, as a consequence, for early and non-invasive diagnostics of wide-spread diseases, which

Thus, new approaches to metrology of partially coherent and partially polarized light fields are derived proceeding from singular optics concept. The first of them concerns to exploring

images of histological tomes of muscular tissues.

of normal and pathologically changed BTs;

challenge Humanity in the Third Millenium.

**7. Conclusions**

the spatial modulated time-averaged Poynting vector in completely and partially coherent non-paraxial light fields for control the motion of nano- and microparticles in optical currents. The second approach reveals interconnection between polarization singularities inherent in completely polarized and partially polarized optical beams for the general case of partially mutual coherence of orthogonally polarized components. Further, we have shown the feasibility for experimental analysis of the Poynting vector components by combining interferometric and polarimetric metrological techniques. At last, we have demonstrated potentialities of laser 2D Stokes-polarimetric metrological technique developed and implemented in previous consideration in non-invasive pre-clinic diagnostics of physiological state of biological tissues. The represented approaches show fruitfulness of attracting the concepts and metrological tools of singular optics in formation and investigation of unconventional polarization distributions that can be of usefulness in problems of optical correlation diagnostics and optical telecommunications.

There are the important next steps in developing the direction of Metrology represented in this chapter. The study of optical currents using light-scattering particles of nano-scale will provide vital data both on microstructure of light and on intimate processes of interaction of optical beams with extremely small (in scale of a wave length) particles and ensembles of them. It is in prospect to investigate experimentally in more details influence of varying degree of coherence of optical fields on some phenomena considered in this review and associated with peculiarities (*singularities*) of the Poynting vector in complex inhomogeneous optical fields beyond the paraxial approximation. Also, it is important to obtain experimental verification, *viz.* visualization, of the mechanical action of the spin moment in optical beams. The study of influence of polarization characteristics of light field on motion of nanoparticles will be continued, as well as development of biomedical application of notion and techniques of completely/partially coherent, inhomogeneously polarized fields.

Another branch of the following R&D must be focused, in our opinion, on overcoming some disadvantages intrinsic to digital optical data surveying due to automatic gain control applied in the most of register tools, including CCD cameras. Really, dealing with differentiation metrology (such as 2D Stokes polarimetry) one wants to have comparable data in the set of measurements that is not always achievable with self-controlled in sensitivity digital registering devices. As compromise, one can consider combination of analog data recording and digital processing of these data. Nevertheless, this important point is worthy separate investigation for providing higher accuracy and reliability of modern optical metrology.


**2.1 Pharmaceuticals**

Finasteride and dutasteride are both 5-ARI medications used to successfully inhibit prostate growth. These two agents are both currently accepted for treating benign prostatic hypertrophy (BPH). The difference between the two medications is minimal, however potentially significant. 5-α-Reductase has two isoenzymes. Finasteride inhibits the type 2 isoenzyme while dutasteride inhibits both the type 1 and type 2 isoenzymes. Dutasteride thus has more complete inhibition of DHT, roughly 90% as compared to finasteride's 70% reduction of serum DHT.5,6 It has been proposed that expression of the type 1 isoenzyme is increased with prostate cancer while the type 2 isoenzyme is unaffected with prostate cancer.7 5-ARI medications focus on inhibiting androgen receptor (AR) activation. Research on BPH has shown that consistent use of finasteride or dutasteride decreases prostatic volume 30% and reduce PSA levels 50-60%.8 Both 5-ARI medications have been tested for chemopreventative benefits with multicenter, randomized, double blind, placebo controlled trials. The thrust of this paper will discuss the 5-ARI medications and their current role in prostate cancer prevention.

Other pharmaceutical agents potentially used for prostate cancer prevention include statins, nonsteroidal anti-inflammatory drugs (NSAIDS), and toremifene. Statins inhibit HMG-CoA, the rate limiting step of cholesterol synthesis. Statin use over 2 years has been associated with a decrease in prostate specific antigen.9 By inhibiting prostatic cellular growth and promoting apoptosis, statins also decrease cellular growth. No large double blind study has evaluated the effect of statin use on prostate cancer but a meta-analysis did find a protective effect.10 Further studies are needed to substantiate current evidence.

NSAIDS inhibit cyclooxygenase-2 (COX-2), which is a key enzyme found in prostate cancer which converts arachidonic acid to prostaglandins. Experimental evidence demonstrated a regression of PIN after NSAID use, but the planned trial with rofecoxib was withdrawn after safety concerns.11,12

Selective estrogen modulators (SERMs) are best known for their effects on breast cancer. Toremifene has decreased prostate cancer in the TRAMP model. A phase 2b study found that 20mg doses of toremifene resulted in a 48% decrease in prostate cancer at one year.13 However, the phase III trial demonstrated no significant risk reduction.14

### **2.2 Micronutrients**

430 Cancer Prevention – From Mechanisms to Translational Benefits

In December of 2010, the Federal Drug Administration's (FDA) Oncology Drugs Advisory Committee (ODAC) reviewed 5-ARI's indication for the prevention of prostate cancer in men at increased risk for prostate cancer. This committee ruled against the use of 5-ARI's for the use of prostate chemoprevention. Advocacy groups have since issues statements disagreeing with the FDA's ruling, highlighting the fact that controversy continues to exist. The goal of this paper is to examine the available agents and the current environment.

**2. Current chemopreventative agents - pharmaceuticals and micronutrients**  The ideal chemopreventative agent should be minimally expensive, nontoxic and effective. Having multiple preventative benefits is considered a plus; however it should not potentiate other causes of morbidity or mortality. Pharmaceutical agents, most notably 5-ARIs, and micronutrients have been studied to better establish their potential role in cancer

Finasteride and dutasteride are both 5-ARI medications used to successfully inhibit prostate growth. These two agents are both currently accepted for treating benign prostatic hypertrophy (BPH). The difference between the two medications is minimal, however potentially significant. 5-α-Reductase has two isoenzymes. Finasteride inhibits the type 2 isoenzyme while dutasteride inhibits both the type 1 and type 2 isoenzymes. Dutasteride thus has more complete inhibition of DHT, roughly 90% as compared to finasteride's 70% reduction of serum DHT.5,6 It has been proposed that expression of the type 1 isoenzyme is increased with prostate cancer while the type 2 isoenzyme is unaffected with prostate cancer.7 5-ARI medications focus on inhibiting androgen receptor (AR) activation. Research on BPH has shown that consistent use of finasteride or dutasteride decreases prostatic volume 30% and reduce PSA levels 50-60%.8 Both 5-ARI medications have been tested for chemopreventative benefits with multicenter, randomized, double blind, placebo controlled trials. The thrust of this paper will discuss the 5-ARI medications and their current role in

Other pharmaceutical agents potentially used for prostate cancer prevention include statins, nonsteroidal anti-inflammatory drugs (NSAIDS), and toremifene. Statins inhibit HMG-CoA, the rate limiting step of cholesterol synthesis. Statin use over 2 years has been associated with a decrease in prostate specific antigen.9 By inhibiting prostatic cellular growth and promoting apoptosis, statins also decrease cellular growth. No large double blind study has evaluated the effect of statin use on prostate cancer but a meta-analysis did find a protective

NSAIDS inhibit cyclooxygenase-2 (COX-2), which is a key enzyme found in prostate cancer which converts arachidonic acid to prostaglandins. Experimental evidence demonstrated a regression of PIN after NSAID use, but the planned trial with rofecoxib was withdrawn

Selective estrogen modulators (SERMs) are best known for their effects on breast cancer. Toremifene has decreased prostate cancer in the TRAMP model. A phase 2b study found that 20mg doses of toremifene resulted in a 48% decrease in prostate cancer at one year.13

effect.10 Further studies are needed to substantiate current evidence.

However, the phase III trial demonstrated no significant risk reduction.14

prevention.

**2.1 Pharmaceuticals**

prostate cancer prevention.

after safety concerns.11,12

Micronutrients have long been sought after to provide a chemotherapeutic benefit for the development or prevention of prostate cancer. Antioxidants in vitro can inhibit cellular proliferation, induce apoptosis and modulate genes leading to the suppression of prostatic tumor. 15,16 The largest scale trial on micronutrients was for selenium and vitamin E in the Selenium and Vitamin E Cancer Prevention Trial *(*SELECT).

The interest in selenium began with the Nutritional Prevention of Cancer Trial, which used oral selenium for nonmelanoma skin cancer. Men were randomized to selenium versus placebo and were found to have a 65% reduction in prostate cancer incidence after a 4.5 year follow up. Vitamin E interest developed after a 32% reduction in prostate cancer in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Trial (ATBC) trial, which was a double blind randomized placebo controlled trial for lung cancer incidence and mortality.

These studies paved the way for the SELECT trial, published in 2009, which was a randomized, placebo controlled population based primary prevention trial focused on the effects of selenium and vitamin E on preventing prostate cancer. SELECT randomized 35,533 men to four treatment arms: selenium with placebo, selenium with vitamin E, Vitamin E with placebo, placebo with placebo. Study supplements included 200 micrograms l-selenomethionine, 400mg racemic alpha-tocopherol and an optional multivitamin containing no selenium or vitamin E. Eligible men were at least 50 years of age for African-Americans, at least 55 for Caucasians, negative DRE, PSA less than 4ng/mL, and normal blood pressure.

The primary endpoint was the presence of prostate cancer found on for cause biopsies. The indications for biopsy were not indicated in the protocol and were at the discretion of the physician.

During the second interim analysis seven years after initiation of the trial, the independent Data and Safety Monitoring Committee recommended discontinuation of the SELECT because the data demonstrated no significant differences between groups. No statistically significant effects were reported on primary or secondary analyses of the data, suggesting no prostate cancer prevention benefits from selenium or vitamin E.17 Unfortunately, selenium and vitamin E, which initially demonstrated promise, was eventually found to not have a significant effect on preventing prostate cancer. 17-19

Other chemopreventative micronutrients include lycopene, green tea, soy, DIM and curcumin. Molecular targets these agents affect include nuclear factor-KB, AKt, Wnt, Hedgehog and Notch.20

Lycopene is a biologically occurring carotenoid that is a potent antioxidant. It has been shown to be associated with lower prostate cancer risk in a number of epidemiologic studies.21 Using the preclinical TRAMP mouse model, prostate cancer was significantly decreased 60% vs. 95% (P=.01). However, no correlation was found with prostate cancer in a PLCO trial examining 29,000 men.

Green tea contains several catechins believed to inhibit oncogenesis and provide antioxidants. Epidemiologic studies between Asian men with a high intake of green tea first suggested that green tea may provide a protective benefit against prostate cancer. Three

The Changing Landscape of Prostate

biopsies were reviewed by a blinded pathologist.

reduced the risk of HGPIN compared to placebo.

given a new indication for prostate cancer prevention.

**3.2 The Reduction by Dutasteride of Prostate Cancer Events (REDUCE)**

comparing finasteride to dutasteride for the prevention of prostate cancer.

Dutasteride, then, theoretically could enhance the anti-tumor effect.

Cancer Chemoprevention: Current Strategies and Future Directions 433

study site every six months for side effect evaluation and medication refills. Annual PSA and DRE were performed. Biopsy was recommended if the DRE was abnormal or PSA was greater than 4.0ng/ml in the placebo arm or 2.0 times PSA (adjusted to 2.3x in year 4) in the finasteride arm. At the completion of the trial in year seven, all participants were recommended to undergo an end of study prostate biopsy with at least six cores. All

The primary endpoint of the study was the prevalence of prostate cancer as diagnosed by biopsy for cause or end of study biopsies. Prostate cancer was found in 24.4% of the placebo group (1,147/4,692) and 18.4% of the finasteride group (803/4,368), representing a 24.8% risk reduction (CI 19-31, p<0.001). Finasteride's relative benefit was found across all groups including age, race/ethnicity, family history and entry PSA. In addition, Finasteride also

Interestingly, tumors with a Gleason grade of 7-10, high grade tumors, were found to be more prevalent in the finasteride group (37%), 280 of 757 graded tumors, as compared to the placebo group (22%), 237 of 1,068 graded tumors. This was statistically significant (P<.001). The increased prevalence of high grade tumors in the treatment group has generated tremendous speculation and sub-analysis. Forty of the excess high grade tumors were found in the "for cause" biopsies, clinically indicated due to increasing PSA or changes in the DRE. Secondary analyses have found a detection bias demonstrating a net reduction in highgrade cancers and a 53% reduction in low grade cancers.26 However, due disagreement in the medical community regarding finasteride's effect on high-grade cancers, it was not

Published in the *New England Journal of Medicine* in April of 2010, the REDUCE trial, was a 4 year multicenter, randomized, double-blind, placebo-controlled, parallel-group study. 8,231 men were randomized equally to dutasteride 0.5mg daily versus placebo. This trial was begun prior to the completion of the PCPT trial. Eligible patients were randomized to receive either Dutasteride or placebo. There has never been a large randomized trial

An important distinction between dutasteride and finasteride is the effect on 5-alpha reductase. Unlike finasteride, dutasteride affects the expression of both type 1 and type 2 isoenzymes of 5-alpha reductase inhibitors. Animal studies demonstrate that compared to finasteride, dutasteride has an increased reduction in both DHT and tumor growth.27

Eligible participants were required to be 50-75 years old, have a serum PSA between 2.5ng/mL-10mg/mL for men aged 50-60 years or 3.0-10ng/mL for men aged >60 years, and had undergone a prostate biopsy within six months of enrollment. Men were excluded if they had more than one biopsy, had prostate cancer of any grade, HGPIN, atypical small acinar proliferation, or a prostate volume of more than 80 grams, had previous prostate surgery of any kind, or had an international prostate symptom score (IPSS) of 25 or higher. During the trial 6726 men (82.6%) underwent at least 1 biopsy and 1516 men (22.5%) were diagnosed with prostate cancer. The primary endpoint was the presence of prostate cancer

clinical trials suggest a benefit.22 A small clinical trial (n=60) using oral green tea catechins (GTC) found that patients with HGPIN randomized to GTC vs. placebo had no change in PSA levels, but did have less progression of prostate cancer: 1 patient vs. 9 patients progress.23

Soy, like green tea, was also found to demonstrate lower prostate cancer in epidemiologic studies between diets high in soy versus western diets. The benefit is potentially a 70% reduction of prostate cancer.24 Soy affects signaling pathways, specifically Wnt and Hh signaling. Randomized studies are currently being performed.

DIM (the dimeric product of indole-3-carbinol) is found in a variety of plants and has been shown to inhibit alpha reductase suggesting that it may have an inhibitory role in prostate cancer. Curcumin is a bioavailable agent in turmeric and is also an alpha reductase inhibitor. Other regulators along the tumor pathway are inhibited by these two substances. Clinical trials are required to evaluate their effects.

Currently no biologically available micronutrients have been proven to provide chemoprevention benefits of prostate cancer. As such, current patient recommendations are to eat healthy foods and pursue healthy lifestyle changes.25


3.3 Bleaching susceptibility

One of the most devastating consequences of global warming is coral bleaching. Bleaching occurs when scleractinian corals, hydrocorals and octocorals lose their photosynthetic symbiotic algae or pigments [21, 111, 123–125], which leads to the white calcium carbonate skeleton being visible through the transparent host tissue. The frequency and severity with which coral bleaching occurs have increased in recent years [126]. Numerous investigations have demonstrated that coral bleaching events are a serious threat to coral reefs worldwide, where they have caused a severe deterioration in reef health (e.g. increase in coral disease, decrease in reef calcification and loss of habitat for related reef organisms [25, 123, 127–129]. The severity of coral bleaching depends on several factors, including specific coral species impacted [130], symbiotic algae assemblages [131] and thermal history [132].

substratum [51, 91]. Millepora spp. are also found in many environments and waves, water movement, light intensity and habitat depth were identified as key factors influencing their distribution and growth forms [51, 82, 91–93]. On barrier reefs, the amount of wave energy is highest on the reef crest, where wave breaking first occurs and subsequently attenuates towards fore reef and lagoonal environments (Figure 5) [94, 95]. This gradient in wave energy, combined with Millepora's sensitivity to wave-induced breakage, were showed to strongly influence colony and size distributions of M. cf. platyphylla at Moorea (French Polynesia), with highest densities recorded on the fore reef and larger colonies on nearshore reefs [91]. M. cf. platyphylla colonies occurred in a contagious pattern of distribution (i.e. colonies close to one another), as described for other Caribbean species [96], and colony breakage and subsequent fragment re-attachment were suggested as explanations for such colony aggregations [58]. Three Millepora species were also identified on the reefs of Reunion Island [97], where each species is distributed according to their proximity with the shore and reef crest, mostly related to the wave energy dispersal. M. cf. exaesa is the first species encountered close to shore on the shallow reef flat (2 m depth), replaced by M. tenera when approaching the reef crest, and M. cf. platyphylla colonies live from the crest to 35 m depth on the outer slope. Millepores are important reef framework builders, second only after scleractinian hard corals [51, 82]. Their complex structure is a habitat for other species adapted to stinging cells, including scavenger crustaceans (e.g. crabs, shrimps and barnacles, [51, 98–100]), as well as fish [38, 101–103], serpulids [104, 105], spionid polychaetes [51] and scleractinian corals [106]. Interestingly, high fire coral cover on Caribbean reefs was associated with increased fish richness species [86]. Many studies have described hydrocorals as opportunistic species that show rapid growth rates with high fecundity [51] and the ability for clonal propagation through fragmentation [58]. Fire corals are capable of colonizing both natural and artificial substrates, including dead gorgonians, rocks and ships [107, 108], as well as living seagrass stems, hydrocorals, gorgonians, scleractinian corals and other reef invertebrates (e.g. giant clams) through pursuit, contact and overgrowth

Invertebrates - Ecophysiology and Management

Wave energy dispersal on a barrier reef (modified from [94, 95]). The fore reef experiences strong wave action from incoming waves that break on the reef crest, near the upper slope, with a significant decrease in swell exposure towards deeper waters. The reef crest dissipates 70% of the incident swell wave energy with gradual

wave attenuation from the back reef to nearshore fringing reefs.

Figure 5.

22

Zooxanthellate hydrocorals are thought to be extremely sensitive to bleaching [130, 133] and can be threatened by future climate change. Millepora spp. have been reported to be among the first cnidarians to lose their zooxanthellae symbionts during widespread bleaching events [134] and they have suffered local or regional extinctions from bleaching in the Pacific [78, 85, 135]. Numerous investigations of bleaching events on Caribbean and Florida Keys reefs have reported bleaching of Millepora colonies [133, 136–139], with M. alcicornis, a finely branched species, being the most severely affected reef corals. Such coral morphology has been described to be more susceptible to bleaching than encrusting and massive species [140]. Yet, bleached colonies of M. alcicornis remained alive during a bleaching event affecting a north-eastern Brazilian reef [133], which is in accordance with previous reports that Millepora species are also the first to recover from short-term bleaching [136, 137]. In the Maldives Archipelago (Indian Ocean), Millepora was reported to be the major reef-building coral in shallow reefs (7 m depth), producing some 'Millepora zones' [141]. Three species were well documented, the massive species M. cf. platyphylla [46, 142] and two branching ones, M. tenera [51, 143, 144] and M. latifolia [143]. However, many recent surveys of the Maldivian reefs have identified another pattern of distribution, where none to low abundances of Millepora species were recorded (1–2 depending on the species) [145–148]. Gravier-Bonnet and Bourmaud [148] suggested that milleporids were extirpated from several Maldives atolls, following the 1997–1998 El-Nino Southern Oscillation event (ENSO). ENSO has induced a strong bleaching and massive coral mortality (of up to 90%) in the tropical Indian Ocean, including the Maldives [145, 149]. On the Great Barrier Reef, Millepora spp. were also the most susceptible taxa to the mass bleaching event of 1998, with 85% of mortality [130], while they showed no evidence of bleaching at Moorea, although scleractinian corals were severely bleached at this location [150]. During 2014–2017, the worst documented bleaching event observed [26, 27], M. cf. platyphylla showed no sign of bleaching at Moorea, although about 60% of scleractinian corals were bleached on the fore reefs (Figure 6A). Since February 2019, Moorea's reefs are suffering from another mass bleaching event, with colonies of M. cf. platyphylla showing sign of bleaching and mortality (Figure 6B). Differential susceptibilities to this bleaching event were also observed between M. cf. platyphylla colonies (Figure 6C). Ongoing surveys will help quantifying bleaching susceptibility and mortality among coral taxa and locations, as well as between fire coral growth forms and genotypes (Dubé et al. in prep). Nevertheless, a previous study has shown that temperature is the primary factor related to bleaching in M. alcicornis, but that synergism with exposure to solar radiation may play a key role in hydrocoral bleaching [151]. Also, multifocal bleaching in hydrocorals, consisting of numerous scattered bleached spots, has been first described as a syndrome caused by an infectious disease affecting several colonies of M. dichotoma in the Red Sea [152]. 16S rRNA gene sequencing showed that affected tissues match sequences of bacteria belonging to Alphaproteobacteria and Bacteroidetes members previously associated with various diseases in scleractinian corals [153]. Yet the mechanisms of multifocal bleaching, its aetiology and mode of transmission remain unknown. Nevertheless, many studies have addressed the aetiology and effects of bleaching in Anthozoan species, wherein changes in the expression of genes and proteins were observed, and particularly heat shock proteins and transcription factors [154–159]. A recent study demonstrated that bleached specimens of M. alcicornis in Mexican Caribbean undergo a moderate decrease in symbiont's density and photosynthetic pigments, in addition to differential expression of 17 key proteins, such as calmodulin, actin and collagen

often coupled with calcium homeostasis, exocytosis and cytoskeleton organization

Bleaching susceptibility of M. cf. platyphylla during massive bleaching events occurring on the fore reefs at Moorea Island (French Polynesia). (A) View of the fore reef at Moorea during the bleaching event of 2016, showing healthy colonies of M. cf. platyphylla and bleached colonies of scleractinian corals, mostly of the Pocillopora genus. M. cf. platyphylla was sensitive to the recent bleaching event of 2019 at Moorea, where colonies bleached and died (B) from the rise in temperature, while other colonies showed sign of resistance to bleaching on the same reef (C). Photographs are courtesy of Yannick Chancerelle (A) and Yann Lacube

Ecology, Biology and Genetics of Millepora Hydrocorals on Coral Reefs

DOI: http://dx.doi.org/10.5772/intechopen.89103

Coral reefs are also threatened by ocean acidification associated with the increasing CO2 partial pressure, which depresses net calcification of corals and hydrocorals [160, 161]. Physiological responses of reef organisms to ocean acidification are relatively well known [162, 163]. Examples include changes in gene expression consistent with metabolic suppression, increased oxidative stress, antioxidant system, apoptosis and symbiont loss [164, 165]. Yet little information on the effects of ocean acidification on the physiology of fire corals is available in the current literature. Luz and colleagues [166] demonstrated that the antioxidant defense system of M. alcicornis is capable of coping with acidic conditions for a short period of time, while long-term exposure induces oxidative stress with consequent oxidative damage to lipids and proteins, which could compromise hydrocoral health and influence negatively the zooxanthellae-coral symbiosis and ultimately lead to bleaching [167].

in Anthozoan species [139].

Figure 6.

(B and C).

25

#### Figure 6.

Zooxanthellate hydrocorals are thought to be extremely sensitive to bleaching [130, 133] and can be threatened by future climate change. Millepora spp. have been reported to be among the first cnidarians to lose their zooxanthellae symbionts during widespread bleaching events [134] and they have suffered local or regional extinctions from bleaching in the Pacific [78, 85, 135]. Numerous investigations of bleaching events on Caribbean and Florida Keys reefs have reported bleaching of Millepora colonies [133, 136–139], with M. alcicornis, a finely branched species, being the most severely affected reef corals. Such coral morphology has been described to be more susceptible to bleaching than encrusting and massive species [140]. Yet, bleached colonies of M. alcicornis remained alive during a bleaching event affecting a north-eastern Brazilian reef [133], which is in accordance with previous reports that Millepora species are also the first to recover from short-term bleaching [136, 137]. In the Maldives Archipelago (Indian Ocean), Millepora was reported to be the major reef-building coral in shallow reefs (7 m depth), producing some 'Millepora zones' [141]. Three species were well documented, the massive species M. cf. platyphylla [46, 142] and two branching ones, M. tenera [51, 143, 144] and M. latifolia [143]. However, many recent surveys of the Maldivian reefs have identified another pattern of distribution, where none to low abundances of Millepora species were recorded (1–2 depending on the species) [145–148]. Gravier-Bonnet and Bourmaud [148] suggested that milleporids were extirpated from several Maldives atolls, following the 1997–1998 El-Nino Southern Oscillation event (ENSO). ENSO has induced a strong bleaching and massive coral mortality (of up to 90%) in the tropical Indian Ocean, including the Maldives [145, 149]. On the Great

Invertebrates - Ecophysiology and Management

Barrier Reef, Millepora spp. were also the most susceptible taxa to the mass bleaching event of 1998, with 85% of mortality [130], while they showed no evidence of bleaching at Moorea, although scleractinian corals were severely bleached at this location [150]. During 2014–2017, the worst documented bleaching event observed [26, 27], M. cf. platyphylla showed no sign of bleaching at Moorea, although about 60% of scleractinian corals were bleached on the fore reefs

and Bacteroidetes members previously associated with various diseases in

24

scleractinian corals [153]. Yet the mechanisms of multifocal bleaching, its aetiology and mode of transmission remain unknown. Nevertheless, many studies have addressed the aetiology and effects of bleaching in Anthozoan species, wherein changes in the expression of genes and proteins were observed, and particularly heat shock proteins and transcription factors [154–159]. A recent study demonstrated that bleached specimens of M. alcicornis in Mexican Caribbean undergo a moderate decrease in symbiont's density and photosynthetic pigments, in addition to differential expression of 17 key proteins, such as calmodulin, actin and collagen

(Figure 6A). Since February 2019, Moorea's reefs are suffering from another mass bleaching event, with colonies of M. cf. platyphylla showing sign of bleaching and mortality (Figure 6B). Differential susceptibilities to this bleaching event were also observed between M. cf. platyphylla colonies (Figure 6C). Ongoing surveys will help quantifying bleaching susceptibility and mortality among coral taxa and locations, as well as between fire coral growth forms and genotypes (Dubé et al. in prep). Nevertheless, a previous study has shown that temperature is the primary factor related to bleaching in M. alcicornis, but that synergism with exposure to solar radiation may play a key role in hydrocoral bleaching [151]. Also, multifocal bleaching in hydrocorals, consisting of numerous scattered bleached spots, has been first described as a syndrome caused by an infectious disease affecting several colonies of M. dichotoma in the Red Sea [152]. 16S rRNA gene sequencing showed that affected tissues match sequences of bacteria belonging to Alphaproteobacteria

Bleaching susceptibility of M. cf. platyphylla during massive bleaching events occurring on the fore reefs at Moorea Island (French Polynesia). (A) View of the fore reef at Moorea during the bleaching event of 2016, showing healthy colonies of M. cf. platyphylla and bleached colonies of scleractinian corals, mostly of the Pocillopora genus. M. cf. platyphylla was sensitive to the recent bleaching event of 2019 at Moorea, where colonies bleached and died (B) from the rise in temperature, while other colonies showed sign of resistance to bleaching on the same reef (C). Photographs are courtesy of Yannick Chancerelle (A) and Yann Lacube (B and C).

often coupled with calcium homeostasis, exocytosis and cytoskeleton organization in Anthozoan species [139].

Coral reefs are also threatened by ocean acidification associated with the increasing CO2 partial pressure, which depresses net calcification of corals and hydrocorals [160, 161]. Physiological responses of reef organisms to ocean acidification are relatively well known [162, 163]. Examples include changes in gene expression consistent with metabolic suppression, increased oxidative stress, antioxidant system, apoptosis and symbiont loss [164, 165]. Yet little information on the effects of ocean acidification on the physiology of fire corals is available in the current literature. Luz and colleagues [166] demonstrated that the antioxidant defense system of M. alcicornis is capable of coping with acidic conditions for a short period of time, while long-term exposure induces oxidative stress with consequent oxidative damage to lipids and proteins, which could compromise hydrocoral health and influence negatively the zooxanthellae-coral symbiosis and ultimately lead to bleaching [167].


*Fundamentals of Irrigation Methods and Their Impact on Crop Production DOI: http://dx.doi.org/10.5772/intechopen.105501*

Though there is no specific way of designing an irrigation system for sustainable integrated pest management, what matters is making sure it is designed in a way that will reduce water usage without hampering the efficacy of the pesticide and also protecting the environment. The use of chemigation systems is an advancement that could help in achieving the goals for integrated pest management.


**The Impact of Epilepsy on Reproductive Functions**

Cemal Tamer Erel and Onur Guralp *Istanbul University, Cerrahpasa School of Medicine, Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology*

*Turkey*


**3.3. Relation between isotopic composition and origin of natural gas**

The isotopic composition of natural gas depends on the type and maturity of source rock [27, 28]. Stable isotope geochemistry helps to differentiate the original gas derived from a single source rock. The methane carbon isotope compositions range between \_ 65.6 ‰ and \_ 41.1‰. Methane hydrogen isotope data ranges from \_ 193 ‰ to \_ 149‰. The isotopically lightest δ 13C sample was obtained from the SEM-1 well, while the heaviest δ 13C value was received from AQ-16 well. Many of the δ 13C values have intermediate positions between these end members, which are consistent with what is commonly interpreted as mixed microbial and thermogenic gas [14, 28]. A general increase in the δ 13C values with depth from Miocene to Plio-Pleistocene reservoir is consistent with the increasing thermal maturity and the decreasing relative concentration of biogenic gas.

All the study gas samples that exhibit higher oleanane index ranging from 19% and 42% strongly support the enrichment of angiosperm higher land plants input to the siliciclastic source kerogen which is thought to be derived from Late Cretaceous to Tertiary age [21, 22]. The medium concentration of moretane index in all the study samples ranges between 11% and 16% and the absence of gammacerane index strongly supports a terrestrial input [23, 24].

and C29 αßß/(αßß+ααα) which according to Seifert and Moldowan [25] are genetically related to the effect of thermal maturity processes. The average sterane isomerization ratios C29ααα 20*S*/(*S+R*) and C29αßß/(αßß+ααα) of natural gas are 0.6 and 0.5 respectively indicating a medium stage of thermal maturation equivalent to the main peak of oil generation window (0.85 Ro%) [18]. The medium sterane isomerization ratios may reflect the rapid rates of subsidence and sedimentation in the Nile Delta and appear to have been generated during the

**Figure 6.** Carbon and Hydrogen isotope ratios of natural gases. Genetic fields according to Schoell[27, 31] and Whiticar

The isotopic composition of natural gas depends on the type and maturity of source rock [27, 28]. Stable isotope geochemistry helps to differentiate the original gas derived from a single

sample was obtained from the SEM-1 well, while the heaviest δ 13C value was received from

193 ‰ to \_

**3.3. Relation between isotopic composition and origin of natural gas**

source rock. The methane carbon isotope compositions range between \_

Methane hydrogen isotope data ranges from \_

III kerogen [26].

C29 ααα20S/(S+R),

65.6 ‰ and \_

149‰. The isotopically lightest δ 13C

41.1‰.

Biomarker maturity parameters, include the sterane isomerization ratios\_

early stage of source rock maturation from type-

34 Advances in Petrochemicals

et al. [32].

The wet gas (C2+) components also display a significant variability in their isotopic composi‐ tions. The δ 13C of ethane (δ 13C2) ranges from \_ 37.5‰ to \_ 27.9‰ but that of propane (δ 13C3) ranges from \_ 32.2‰ to \_ 11.1‰.

Natural gases become isotopically heavier and contain relatively more methane with increas‐ ing thermal maturity. Thermogenic methane is generally enriched in δ 13C compared with microbial methane [27].

Figure 5 represents the Bernard plot in which the molecular ratio C1/ (C2 + C3) is plotted versus methane's stable carbon isotope ratio according to Bernard et al.[29] and Faber and Stahl [30]. The relationship between these two parameters allows distinguishing microbially generated methane from thermogenic hydrocarbon gases. The figure provides a strong indication for gas mixing of thermogenic and early microbial methane.

The δ 13C methane versus δ D methane plot (Figure 6) represents a scheme for the carbon and hydrogen isotope ratios of methane and their genetic implications. Although this diagnostic plot was initially established for determining the thermogenic origin of methane [31] it is useful for the discrimination of microbial methanogenesis, i.e. carbon dioxide (CO2) reduction versus acetate fermentation [32]. The δ 13C values between \_ 65.6 ‰ to \_ 41.1‰ and δ D values between \_ 193 ‰ and \_ 149‰ obtained for the methane of the samples from this study classify methane as mixtures between thermogenic and biogenic origin. Figure 7 gives a good matching with the published regional gas data. The relatively heavy hydrogen isotopic compositions (Figure 7) suggest that the microbial gas proportions are probably generated through CO2 reduction [31, 32].

In the offshore Nile Delta and Mediterranean Sea, the Oligocene to Early Miocene sedimentary sequence is considered as the primary source of natural gas and condensate characterized as mixed type II/III kerogen [8, 26].

The isotopic composition of the individual gas components is a function of thermal maturity of the generated source rock kerogen. Stahl [33] proposed an empirical relationship between methane carbon isotopic composition and vitrinite reflectance. Berner et al. [34] and Berner and Faber [35] illustrated a model between the carbon isotopic compositions of methane, ethane, and propane and source rock maturities represented by vitrinite reflectance measure‐ ments. In this study we used the isotope maturity models developed by Berner and Faber [35] to estimate the type and maturity of the precursor (source) material (Figures 7and 8). The geochemical characteristics of natural gas from the Nile Delta indicating a derivation from source rocks rich in terrestrial precursors [8, 36, 37]. Consequently, the admixture of light microbial methane to the thermogenic hydrocarbon gas takes place during secondary proc‐ esses, such as migration, microbial oxidation, or mixing. These processes usually affect the gas properties within the reservoir [28, 40].

**Figure 7.** Isotopic composition of methane and ethane in natural gases of the western and eastern Nile Delta. The ma‐ turity line is according to Berner and Faber [35]. The terrestrial organic matters indicate the maturity of the source rock in vitrinite reflectance measurements

**Figure 8.** Isotopic composition of ethane and propane in natural gases of the western and eastern Nile Delta. The ma‐ turity line is according to Berner and Faber [35].

Isotopic compositions of ethane and propane from the west and east Nile Delta samples proved their mixing origin and derivation from terrestrial organic matter with a source rock maturity between 0.1% and 2.0% Vitrinite Reflectance measurements.