Professional Documents
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INSTITUTULUI
POLITEHNIC
DIN IAI
2012
Editura POLITEHNIUM
Editorial Board
President: Prof. dr. eng. Ion Giurma, Member of the Academy of Agricultural
Sciences and Forest, Rector of the Gheorghe Asachi Technical University of Iai
Editor-in-Chief: Prof. dr. eng. Carmen Teodosiu, Vice-Rector of the
Gheorghe Asachi Technical University of Iai
Honorary Editors of the Bulletin: Prof. dr. eng. Alfred Braier,
Prof. dr. eng. Hugo Rosman,
Prof. dr. eng. Mihail Voicu Corresponding Member of the Romanian Academy,
President of the Gheorghe Asachi Technical University of Iai
Editors in Chief of the MATHEMATICS. THEORETICHAL MECHANICS.
PHYSICS Section
Prof. dr. phys. Maricel Agop, Prof. dr. math. Narcisa Apreutesei-Dumitriu,
Prof. dr. eng. Radu Ibnescu
Honorary Editors: Prof. dr. eng. Ioan Bogdan, Prof. dr. eng. Gheorghe Nag
Associated Editor: Associate Prof. dr. phys. Petru Edward Nica
2012
SUMAR
Pag.
2012
CONTENTS
Pp.
MUGUR B. RU
Al. I. Cuza University of Iai,
Department of Physics
Received: November 28, 2011
Accepted for publication: December 5, 2011
1. Introduction
The Modified Newtonian Dynamics theory, MOND, was proposed by
(Milgrom 1983) as an alternative manner to explain the form of the galaxy
rotation curves. When the uniform velocity of galaxies was first observed it was
unexpected because this fact came in conflict with Newtonian theory of gravity
predictions. The farther out are the moving objects the lower velocities they
had. Later in the 70s the theory of dark matter seemed to solve this mystery.
According to this theory each galaxy contains an exterior halo, like a
contracting shell, of a special type of matter, dark matter. Consequently the
normal matter rotates more as a rigid body than as a fluid, as the Newtonian
theory suggests.
e-mail: m_b_raut@yahoo.com
Mugur B. Ru
(1)
The right term is the Newtonian gravitational acceleration, the left term is
an interpolating function which is 1 for large accelerations and a/a0 for low
accelerations ( a 0 been a constant).
One immediate consequence of Eq. (1) is that the asymptotic rotational
speed of a galaxy becomes independent of radius
v = (GMa0
1
)4
(2)
This is the general case and it has an axiomatic validity, especially for flat
galaxies. Certainly, the goal of this theory is very easy to accomplish if there is
only one interpolating function. In reality there are many effective interpolating
functions, been dependent on the type of galaxy rotation curve we study. For
instance the spiral-type rotational galaxies curves can be explained with
( x) =
x
1 + x2
(3)
This fact makes MOND theory a little peculiar, but there is nothing
peculiar in a phenomenological theory, except only its lack of physical basis. If
we observe that Eq. (3) tends to x for law values of x, maybe we get used to its
peculiarity. The most significant tests of MOND are provided by disc-galaxy
rotation curves (Begeman et al., 1991; Sanders & Verheijen, 1998; Sanders,
1996 ; de Blok & McGaugh, 1998). However, the dark matter theory seems to
be the favorite regarding the galaxy rotation problem. The scientific community
prefers it instead MOND, although the correct in many aspects predictions of no
matter each of it is the comparison basis for the other, (McGaugh, 2004;
Famaey et al., 2007).
This paper is an attempt to find an alternative to MOND theory, in order
to explain the form of the galaxies rotation curves.
GM
A +1
+
r ,
r
+1
(4)
= 4G ( + ue ) .
(5)
The second term on the right side of Eq. (4) is an empirical term attached
to the Newtonian gravitational potential, a term that describes the action of an
unknown repulsive energy. We have therefore A> 0.
With this potential (4) we try to show that this undefined energy may
cause the radial movement of the discoid galaxies observed in reality. From (4)
we find the expression of the first derivative of this equation
g =
GM
r
+ Ar ,
(6)
l ( r ) = Al r l + Bl r l 1 ,
(7)
= 0 .
(8)
Note that the potential (4) does not satisfy the condition (7), because
l 0, 1 , so there may be local configurations of potentials (4) where there
may be maxima or minima. Hence g = 0 in (6). From this condition we can
determine the critical radius whence equality occurs
GM
rc2
= Arc .
(9)
Mugur B. Ru
1
GM + 2
rc =
.
(10)
GM
with g N = 2 and forces expression
r
r + 2
F = FN 1 + 2
r
GMm
deriving from the potential (4). Note that for distances
with FN = 2
r
smaller than the critical radius there will be attractive accelerations and forces,
after the critical radius the accelerations and forces become repulsive.
On reaching the critical radius the equilibrium of the galaxy will be the
result of the galaxy accelerations balance
a=
v 2 GM
= 2
rc
rc
v = ( GM )
1
1
2 2( + 2)
1
2( + 2)
(11)
v L M ,
1
vM ,
corresponding to =1 and the case in which we have a particular interest
(12)
v M 4,
(13)
corresponding to =0. Note that both potentials obtained from (4) with
expressions (12) and (13) provides the shape of the rotation curves of discoid
galaxies close to observations. But the form (4) with (13) it leads us
unexpectedly closer to the MOND theory. Indeed if we take A = a 0 we obtain
from (10) exactly
GM
rc =
a0
2
,
(14)
the critical radius from which the small accelerations approximation occurs in
the MOND theory. From (11) and (14) it results
v 4 = GMa0 ,
(15)
which is the well-known expression obtained in the MOND theory for the radial
velocities independent from the galaxies radius. What is important here is that
we got this result in the approximation
g = g N + a0 ,
and not in the approximation
g = ( g N a0 )1/2 ,
like in MOND theory. The difference lies in the fact that our theory has not
worked out with an expression of a modified inertia like in MOND theory,
Newton's Second Law remaining unchanged. So with (4) and (13) MOND
theory results can be obtained without the need to change the law of inertia like
in (1). We just need to change the definition of constant a 0 as an artifact of
galaxies.
3. Dark Energy and the Dynamics of the Galaxies
We might ask now what is the nature of this unknown energy responsible
for the observed shapes of rotation curves of galaxies. In (4), condition (12)
leads to = 1. Although this form of the potential (4) may explain the dynamics
of discoid galaxies, we still do not accidentally deflect the discussion on this
path. It shows that in (4), with = 1, the additional part of the gravitational
potential can be conceived as a Newtonian equivalent to the cosmological
constant
Mugur B. Ru
A=
c 2
.
3
From this we can infer only that Ar would express a repulsive force due
to expansion of the universe. It can be either dark energy or vacuum energy.
Assuming that the expansion of the universe would somehow influence the
dynamics of galaxies we reach the role of dark matter in this regard. So we can
think of a galaxy as being surrounded by a halo composed of dark matter.
c 2
r tends to divide
Expansion of the universe expressed by the force
3
galaxies but the dark matter they are "wrapped" opposes with a reactive force
which is opposite to the force of expansion. In this way the galaxies keep their
c 2
r leads to
form and their dynamics is the observed one. The force
3
observations of the form v M 1 / 3 but the form v M 1 / 4 can not be
explained by the same reactive force. Things get more complicated if we
consider A = a 0 . The acceleration a 0 is four orders of magnitude higher than
c 2
r (for example, our galaxy have r = 1020 m ). So dark energy,
3
that causes the expansion of the universe, is almost four orders of magnitude
smaller than the energy that causes the galaxy dynamics. The acceleration a 0
can not be attributed to expansion of the universe but it can be related to an
internal expansion force of the galaxy. Let us admit that this force would be due
to the generation of new matter in the galaxy (exploding stars, matter that tends
to be extended in the galaxy). In such conditions the expansion force of the
galaxy will find its reaction in the blanket of dark matter that surrounds it. This
will "push" the galaxy with a constant force, equal and opposite, of value a 0 .
This might explain the anomaly of Pioneer 10 spacecraft. There is an attractive
constant force in our galaxy, supplementary to the Newtonian one, which is
indirectly due to expansion trend of the galaxy and directly due to the blanket of
dark matter that surrounds it. Eq. (15) is valid because dark matter is opposing
to the trend of the dispersion caused by the rotation of the galaxy.
Under these conditions Eqs. (14) and (15) are valid without the need to
consider MOND theory. If we admit that a 0 have not the same meaning as in
the MOND theory but totally due to other causes, having no connection with the
expansion of the universe but only with internal dynamics of galaxies, is a
constant specific to each galaxy in part, then all we have talked so far is valid.
Otherwise the place of a 0 may be taken by the general value A which can be
determined from experimental curves. Amazingly, if we do this we get to the
the force
10
1. Introduction
During the past quarter century, tremendous steps have been made in the
diagnosis and treatment of cancer. Technology now allows the diagnosis and
treatment of tumors of ever-diminishing size, as with breast cancers; ductal
carcinoma in situ now comprises 2530% of all newly diagnosed breast
cancers at most medical centers (Armstrong et al., 2000). With earlier detection,
an understanding of growth patterns reflective of the natural biological
characteristics of these tumors must also evolve. Surgeons have always led the
fields of technological and basic scientific medical advances. Current concepts,
be they either the physiological characteristics of shock, organ transplantation,
antisepsis, wound healing, or gene therapy, have been forged by surgical
investigators.
The field of mathematics has undergone a similar evolution. Topology,
fractals, chaos theory, and development of nonlinear descriptive methods have
provided mathematicians new creative tools that permit the development of
models of tumor growth and behavior at the microenvironmental level
(Friedman & Reitich, 1999; Waliszewski et al.,1998). Specific formulas have
been described for growth, angiogenesis (Orme & Chaplain, 1997), cell-to-cell
adhesion (Perumpanani et al, 1997) and even pH regulation and drug delivery
(Secomb et al, 2001). From a clinical viewpoint many of these formulas may
seem oversimplified, but they collectively form an important foundation for
descriptive insight.
What has been lacking is the linkage of these two naturally and mutually
beneficial research endeavors. For oncologic surgeons, the ability to
mathematically describe (or, even better, predict) patterns of tumor behavior
provides an exciting, new, and precise method that may benefit both current and
future therapies. For the mathematician, an understanding of the clinical factors
essential for tumor development and metastasis provides realistic insight into
these complex biological processes, in turn permitting the development of
accurate, clinically relevant mathematical formulas.
In most medical centers, surgeons lead the team that provides
comprehensive cancer care. Oncologic mathematics provides surgeons another
opportunity to expand their leadership role and to better understand tumor
behavior and optimize cancer treatment.
In this paper we aim to envisage a new concept of carcinogenesis and
tumor progression. Consequently, we use the natural environment where
malignant tumors grow, space(-time) with non-integer fractal dimension, in
quest for further applications of the newly discovered and intriguing
phenomenon of tumor self-seeding by circulating cancer cells (CTC). More
precisely, we assume that the metastasic tumor cells move (through the systemic
circulation, yet not necessarily only there) as a coherent wave, or even more
precisely, a chemically pumped travelling wave laser with oxygen. The
11
12
made cancer the second cause of death in the industrialised countries (see any
cancer statistics). Nevertheless, cancer it is not a modern disease and it was
known since the antiquity: Egyptians of the New Kingdom (Olson et al., 2002),
Greeks (Porter, 1997) and Romans (Hajdu, 2004) accurately described medical
treatments for tumour removal. It is only within the last two centuries however,
that due to the higher standards of living, cancer has become one of the main
life-threatening diseases.
13
Fig. 2 Example of self-signaling (autocrine): the cell produces its own growth factors
which stimulate the growth receptors on the surface (Dr. W.H. Moolenaar, Netherlands
Cancer Institute).
14
able to form a tumour. That is because of the intrinsic proliferation limit of all
mammalian cells. All chromosomes have an ending cap called telomere, a Tloop non-coding DNA sequence (2...50 Kb) that prevents the end of the
chromosomes from attaching to other genetic material. At every mithosis the
cell loses a small part of its telomeres because of the impossibility for DNA
duplication enzymes, for instance DNA-polymerase, to continue working until
the very end of the genome (Fig. 3). This limitation is due to the fact that
enzymes like DNA-polymerase always move in the 53 direction of the
DNA sequence, so when the side of the replication is opposite, a small part of
the genome is lost. The shortening of the telomeres induces cell senescence, a
state of cellular elderly where division no longer occurs. This avoids genetically
unstable cells to replicate. Senescence starts after the so called Hayflick limit
(Hayflick, 1997) of about 50 cell divisions. In cancer cells instead, the disabling
of the pRb and the p53 pathways allows unlimited replication, until the point
when the telomeres are completely absent. Once having entirely consumed the
telomeres, the cell population is believed to undergo a phase of massive
genomic instability, causing extended cell death. The high selective pressure
induced by this crisis may permit specific resistant clones to emerge (Fig. 4).
Those survivor cells would be immortalised (unlimited proliferative potential)
by finding ways to maintain their telomeres long enough. A possible way is the
overexpression of the telomerase gene (Shay & Bacchetti, 1997) which appears
to take place in 8590 % of cancers. Telomerase is a telomere-rebuilding
enzyme normally expressed in germline cells and stem cells, in which
immortalisation is an essential feature. Once immortalised, malignant cells have
made a further step towards the formation of cancer.
Fig. 3 Illustration of the end replication problem: at both sides of the copying, the
leading DNA strand has lost part of the telomeric sequence, which stops at the 5 end of
the parental strand, whereas the lagging strand results completed until the very end
(Dr. R. Beijersbergen, Netherlands Cancer Institute).
15
For this reason, the initial exponential growth of a newborn malignant neoplasm
causes a shortage of nutrients among cancer cells. Local pre-existent
vascularisation is never enough to sustain growth for more than 108 cells. The
colony must therefore develop angiogenesis-triggering capabilities (Bouck et
al., 1996; Hanahan & Folkman, 1996). Angiogenesis is the process of formation
of new blood vessels in response to a stimulus secreted by poor vascularised
tissues. Angiogenesis is important for the organism morphogenesis and even
later maintains the correct supply of nutrients for all tissues. Fast growing cells,
such as cancer cells, start soon to starve, and have the need of additional blood
supply in order to keep expanding. A possible solution is the production by
cancer cells of vascular endothelial growth factors (VEGF) and fibroblast
growth factors (FGF1/2) which bind to the transmembrane receptors of
endothelial cells (cells covering the interior surface of blood vessels)
stimulating their growth towards the signal concentration gradient (Veikkola &
Alitalo, 1999). Angiogenesis is the principal mechanism that transforms a
microscopic malignancy into a macroscopic tumour and, also in the later stages,
it is necessary for a lesion to grow and sustain itself. This implies that
angiogenesis is an important target for anti-cancer drugs like thrombospondin-1
(Bull et al., 1994) and bevacizumab (Shih & Lindley, 2006), also known as
avastin.
Fig. 4 The progressive shortening of the telomeres leads to a massive cell death due to
the induced genomic instability (death by genomic catastrophe while duplicating). From
such process of intense genetic mutation and selection an immortalised clone could
emerge (Dr. R. Beijersbergen, Netherlands Cancer Institute).
16
unable to travel outside their own tissue due to their necessity to be anchored
and reside among similar cells. An eventual detachment from the extracellular
matrix or ECM (a complex structure of proteins and specific cells forming the
tissue scaffold and microenvironment see Sec. 6.1) would occur in a form of
apoptosis called anoikis (Frisch & Screaton, 2001). Contrary to their normal
counterparts, cancer cells are able to survive the loss of anchorage, to travel
through the vascular system and form distant tumours elsewhere (Fig. 5). The
traits expressed by invasive and metastatic cancer cells are principally loss of
cell-to-cell adhesion, anchorage-independence, chemotaxis (migration towards a
diffusible substance gradient), haptotaxis (migration towards a non-diffusible
substance gradient) and production of matrix degrading enzymes (e.g. Matrix
metalloproteinase) which cleave the extracellular matrix (Fidler, 2003;
Matrisian, 1992; Mignatti & Rifkin, 1993) making space for invasion and
freeing growth and angiogenic factors trapped inside.
Fig. 5 Tissue invasion is a multi-step process that requires the cancer cell to have
developed many malignant traits, necessary for the formation of new distant colonies
called metastases (Fidler, 2003).
3. Mathematics of Cancer
In comparison to molecular biology, cell biology, and drug delivery
research, mathematics has so far contributed relatively little to the area. A
search in the PubMed bibliographic database (http://www.ncbi.nlm.
17
nih.gov/PubMed/) shows that out of 1.5 million papers in the area of cancer
research, approximately 5% are related to mathematical modeling. However, it
is clear that mathematics could make a huge contribution to many areas of
experimental cancer investigation since there is now a wealth of experimental
data which requires systematic analysis.
Nevertheless, over the last decade, the activity in mathematical modeling
and computational simulation of cancer has increased dramatically (e.g.,
reviews such as (Araujo et al., 2004; Byrne et al., 2006; Adam, 1996; Bellomo
et al., 2003; Quaranta et al., 2005; Sanga et al., 2006). A variety of modeling
strategies have been developed, each focusing on one or more aspects of cancer.
Cellular automata and agent-based modeling, where individual cells are
simulated and updated based upon a set of biophysical rules, have been
developed to study genetic instability, natural selection, carcinogenesis, and
interactions of individual cells with each other and the microenvironment.
Because these methods are based on a series of rules for each cell, it is simple to
translate biological processes (e.g., mutation pathways) into rules for the model.
However, these models can be difficult to study analytically, and computational
costs can increase rapidly with the number of cells. Because a 1-mm tumor
spheroid may have several hundred thousand cells, these methods could become
unwieldy when studying tumors of any significant size. See (Alarcn et al.,
2005; Anderson, 2003; Mallett et al., 2006) for examples of cellular automata
modeling and (Abbott et al., 2006; Mansury et al., 2002) for examples of agentbased modeling. In larger-scale systems where the cancer cell population is on
the order of 106 or more, continuum methods may provide a more suitable
modeling technique. Early work, including (Byrne et al., 1996; Byrne et al.,
1996; Greenspan et al., 1976), used ordinary differential equations to model
cancer as a homogeneous population, as well as partial differential equation
models restricted to spherical geometries. Linear and weakly nonlinear analyses
have been performed to assess the stability of spherical tumors to asymmetric
perturbations (Araujo et al., 2004; Byrne et al., 2006), (Byrne et al., 2002;
Chaplain et al., 2001; Cristini et al., 2003; Li et al., 2007) in order to
characterize the degree of aggression. Various interactions of a tumor with the
microenvironment, such as stress-induced limitations to growth, have also been
studied (Ambrosi et al., 2002; Ambrosi et al., 2002; Ambrosi et al., 2002;
Araujo et al., 2004; Araujo et al., 2005; Jones et al., 2000; Roose et al., 2003).
Most of the modeling has considered single-phase (e.g., single cell species)
tumors, although multiphase mixture models have also been developed to
provide a more detailed account of tumor heterogeneity (Ambrosi et al., 2002;
Byrne et al., 2003; Chaplain et al., 2006).
Recently, nonlinear modeling has been performed to study the effects of
morphology instabilities on both avascular and vascular solid tumor growth.
(Cristini et al., 2003) used boundary integral methods to perform the first fully
nonlinear simulations of a continuum model of tumor growth in the avascular
18
19
On the other hand, of great use in our further reasonings, will be the fact
that in many biological systems it is possible to empirically demonstrate the
presence of attractors that operate starting from different initial conditions
(Ivancevic). Some of these attractors are points, some are closed curves, while
the others have noninteger, fractal dimension and are termed strange
attractors (Guarini et al., 1993). It has been proposed that a prerequisite for
proper simulating tumor growth by computer is to establish whether typical
tumor growth patterns are fractal. The fractal dimension of tumor outlines was
empirically determined using the box-counting method (Sedivy, 1996). In
particular, fractal analysis of a breast carcinoma was performed using a
morphometric method, which is the box-counting method applied to the
mammogram as well as to the histologic section of a breast carcinoma (Sedivy
& Windischberger, 1998).
If tumor growth is chaotic, this could explain the unreliability of
treatment and prediction of tumor evolution. More importantly, if chaos is
established, this could be used to adjust strategies for fighting cancer. Treatment
could include some form of chaos control and/or anti-control.
4. A Few Words about Holography
A hologram is usually recorded on a photographic plate or a flat piece of
film, but produces a three-dimensional image. In addition, making a hologram
does not involve recording an image in the conventional sense. To resolve this
apparent paradox and understand how holography works, we have to start from
first principles.
In conventional imaging techniques, such as photography, what is
recorded is merely the intensity distribution in the original scene. As a result, all
information about the optical paths to different parts of the scene is lost.
The unique characteristic of holography is the idea of recording both the
phase and the amplitude of the light waves from an object. Since all recording
materials respond only to the intensity in the image, it is necessary to convert
the phase information into variations of intensity. Holography does this by
using coherent illumination and introducing, as shown in Fig. 6, a reference
beam derived from the same source. The photographic film records the
interference pattern produced by this reference beam and the light waves
scattered by the object.
Since the intensity at any point in this interference pattern also depends
on the phase of the object wave, the resulting recording (the hologram) contains
information on the phase as well as the amplitude of the object wave. If the
hologram is illuminated once again with the original reference wave, as shown
in Fig. 7, it reconstructs the original object wave.
An observer looking through the hologram sees a perfect threedimensional image. This image exhibits all the effects of perspective, and depth
of focus when photographed, that characterized the original object.
20
Fig. 6 Hologram recording: the interference pattern produced by the reference wave
and the object wave is recorded.
21
22
I ( x, y ) = r + o( x, y ) = r 2 + o( x, y ) + ro( x, y ) + ro ( x, y ),
2
(1)
t = t 0 + TI ,
(2)
(3)
u ( x, y ) = rt( x, y ) = r (t 0 + Tr 2 ) + Tr o( x, y ) +
+ Tr 2 o( x, y ) + Tr 2 o ( x, y ).
(4)
The right-hand side of (4) contains four terms. The first of these,
r(t0+Tr2), which represents a uniformly attenuated plane wave, corresponds to
the directly transmitted beam.
The second term, Tr |o(x, y)|2, is extremely small, compared to the other
terms, and can be neglected.
The third term, Tr2o(x, y), is, except for a constant factor, identical with
the complex amplitude of the scattered wave from the object and reconstructs an
image of the object in its original position. Since this image is formed behind
the hologram, and the reconstructed wave appears to diverge from it, it is a
virtual image.
The fourth term, Tr2o*(x, y), represents a wave similar to the object
wave, but with the opposite curvature. This wave converges to form a real
image (the conjugate image) at the same distance in front of the hologram.
With an in-line hologram, an observer viewing one image sees it
superimposed on the out-of-focus twin image as well as a strong coherent
background. Another drawback is that the object must have a high average
transmittance for the second term on the right-hand side of (4) to be negligible.
23
Fig. 9 Optical system used to reconstruct the image with an in-line hologram,
showing the formation of the twin images.
4.3. Off-axis Holograms
The complex amplitude at any point (x, y) on the photographic plate due to
the reference beam can then be written as
r ( x, y ) = r exp(i2x ),
(5)
where =(sin)/, since only the phase of the reference beam varies across the
photographic plate, while that due to the object beam, for which both the
amplitude and phase vary, can be written as
24
o( x, y ) = o( x, y ) exp[i( x, y )].
(6)
I ( x , y ) = r ( x , y ) + o ( x, y ) = r ( x , y ) + o ( x, y ) +
+ r o( x, y ) exp[i( x, y )]exp(i2x ) + r o( x, y ) exp[i( x, y )]exp(i2x ) = (7)
2
= r 2 + o( x, y ) + 2r o( x, y ) cos[2x + ( x, y )].
The amplitude and phase of the object wave are encoded as amplitude and
phase modulation, respectively, of a set of interference fringes equivalent to a
carrier with a spatial frequency of .
If, as in (2), we assume that the amplitude transmittance of the processed
photographic plate is a linear function of the intensity, the resultant amplitude
transmittance of the hologram is
t( x, y ) = t '0 + T o( x, y ) 2 + Tr o( x, y ) exp[i( x, y )]exp(i2x ) +
+ Tr o( x, y ) exp[i( x, y )]exp(i2x ),
(8)
(9)
The first term on the right-hand side of (9) corresponds to the directly
transmitted beam, while the second term yields a halo surrounding it, with
approximately twice the angular spread of the object. The third term is identical
to the original object wave, except for a constant factor Tr2, and produces a
virtual image of the object in its original position. The fourth term corresponds
to the conjugate image which, in this case, is a real image. If the offset angle of
the reference beam is made large enough, the virtual image can be separated
from the directly transmitted beam and the conjugate image.
In this arrangement, corresponding points on the real and virtual images
are located at equal distances from the hologram, but on opposite sides of it.
Since the depth of the real image is inverted, it is called a pseudoscopic image,
as opposed to the normal, or orthoscopic, virtual image. It should also be noted
that the sign of only affects the phase of the reconstructed image, so that a
positive image is always obtained, even if the hologram recording is a
photographic negative.
25
Material
Table 1
Recording materials for holography
Exposure Resolution
mm-1
Processing
J/m2
10000
Normal
Bleach
Wet
Amplitude
Phase
Phase
(diffraction
efficiency)
0.06
0.60
0.90
102
10-104
10-1
3000
5000
500-1200
Wet
Dry
Dry
Phase
Phase
Phase
0.30
0.90
0.30
10
10000
None
Phase
0.20
Photographic
1.5
5000
DCG
(dichromated gelatin)
Photoresists
Photopolymers
PTP
(photothermoplastics)
102
BSO
( Bi12SiO20
photorefractive
crystals)
max
Type
26
27
Alarcn T., Byrne H. M., Maini P. K., A Cellular Automaton Model for Tumour Growth
in Inhomogeneous Environment. J. Theor. Biol., 225, 257-274 (2003).
Ambrosi D, Guana F., Stress-modulated Growth. Math. Mech. Solids (in press)
doi:10.1177/1081286505059739.
Ambrosi D., Mollica F., On the Mechanics of a Growing Tumor. Int. J. Eng. Sci., 40,
1297-1316 (2002).
Ambrosi D., Preziosi L., On the Closure of Mass Balance Models for Tumor Growth.
Math. Mod. Meth. Appl. Sci., 12, 737-754 (2002).
Anderson A. R. A., A Hybrid Mathematical Model of Solid Tumour Invasion: The
Importance of Cell Adhesion. IMA Math. Appl. Med. Biol., 22, 163-186 (2005).
Anderson A. R. A., Chaplain M. A. J., Continuous and Discrete Mathematical Models
of Tumor-induced Angiogenesis. Bull. Math. Biol., 60, 857-900 (1998).
Araujo R. P., McElwain D. L. S., A Linear-elastic Model of Anisotropic Tumor Growth.
Eur. J. Appl. Math., 15, 365-384 (2004).
Araujo R. P., McElwain D. L. S., A Mixture Theory for the Genesis of Residual Stresses
in Growing Tissues. (II) Solutions to the Biphasic Equations for a Multicell
Spheroid. SIAM J. Appl. Math., 66, 447-467 (2005).
Araujo R., McElwain D., A History of the Study of Solid Tumour Growth: The
Contribution of Mathematical Modelling. Bull. Math. Biol., 66, 1039-1091
(2004).
Armstrong K., Eisen A., Weber B., Assessing the Risk of Breast Cancer. N. Engl. J.
Med., 342, 564-571 (2000).
Bartolini R. A., Photoresists, in: Holographic Recording Materials. In Topics in
Applied Physics, Vol. 20, H. M. Smith (Ed.), Springer-Verlag, Berlin, 1977, pp.
209-27.
Bellomo N., de Angelis E., Preziosi L., Multiscale Modelling and Mathematical
Problems Related to Tumor Evolution and Medical Therapy. J. Theor. Med., 5,
111-136 (2003).
Bjelkhagen H. I., Silver Halide Materials for Holography & Their Processing.
Springer-Verlag, Berlin, 1993.
Booth B. L., Photopolymer Laser Recording Materials. Journal of Applied
Photographic Engineering, 3, 24-30 (1977).
Bouck N., Stellmach V., Hsu S., How Tumors Become Angiogenic. Adv. Cancer Res.
69, 135174 (1997).
Bull H., Brickell P., Dowd P., Src-related Protein Tyrosine Kinases are Physically
Associated with the Surface Antigen cd36 in Human Dermal Microvascular
Endothelial Cells. FEBS Lett., 351, 41-44 (1994).
Byrne H. M., Alarcon T., Owen M. R., Webb S. D., Maini P. K., Modelling Aspects of
Cancer Dynamics: A Review. Phil. Trans. Roy. Soc., A364, 1563-1578 (2006).
Byrne H. M., Chaplain M. A. J., Growth of Necrotic Tumors in the Presence and
Absence of Inhibitors. Math. Biosci., 135, 187-216 (1996).
Byrne H. M., Chaplain M. A. J., Modelling the Role of Cell-cell Adhesion in the Growth
and Development of Carcinomas. Math. Comput. Model., 24, 1-17 (1996).
Byrne H. M., Matthews P., Asymmetric Growth of Models of Avascular Solid Tumors:
Exploiting Symmetries. IMA J. Math. Appl. Med. Biol., 19, 1-29 (2002).
Byrne H., Preziosi L., Modelling Solid Tumour Growth Using the Theory of Mixtures.
Math. Med. Biol., 20, 341-366 (2003).
28
29
Hogea C. S., Murray B. T., Sethian J. A., Simulating Complex Tumor Dynamics from
Avascular to Vascular Growth Using a General Level-set Method. J. Math. Biol.,
53, 86-134 (2006).
Huignard J. P., Micheron F., High Sensitivity Read-write Volume Holographic Storage
in Bi12SiO20 and Bi12GeO20 Crystals. Applied Physics Letters, 29, 591593
(1976).
Huignard J. P., Phase Conjugation, Real Time Holography and Degenerate Four-wave
Mixing in Photoreactive BSO Crystals. In Current Trends in Optics, Arecchi &
Aussenegg (Eds.), Taylor & Francis, London, 1981, pp. 15060.
Ivancevic T., Jain L., Pattison J., Hariz A., Nonlinear Dynamics and Chaos Methods in
Neurodynamics and Complex Data Analysis. Nonl. Dyn. (Springer) (to appear).
Jones A. F., Byrne H. M., Gibson J. S., Dold J. W., A Mathematical Model of the Stress
Induced During Avascular Tumor Growth. J. Math. Biol., 40, 473-499 (2000).
Kinzler K., Vogelstein B., Lessons from Hereditary Colorectal Cancer. Cell, 87(2),
159-170 (1996).
Leith E. N., Upatnieks J., Reconstructed Wavefronts and Communication Theory.
Journal of the Optical Society of America, 52, 1123-30 (1962).
Leith E. N., Upatnieks J., Wavefront Reconstruction with Continuous-tone Objects.
Journal of the Optical Society of America, 53, 1377-81 (1963).
Leith E.N., Upatnieks J., Wavefront Reconstruction with Diffused Illumination and
Three-dimensional Objects. Journal of the Optical Society of America, 54, 1295301 (1964).
Li X., Cristini V., Nie Q., Lowengrub J. S., Nonlinear Three Dimensional Simulation of
Solid Tumor Growth. Disc. Cont. Dyn. Sys., B7, 581-604 (2007).
Lin L. H., Beauchamp H. L., Write-read-erase in Situ Optical Memory Using
Thermoplastic Holograms. Applied Optics, 9, 208892 (1970).
Macklin P., Lowengrub J., A New Ghost Cell/Level Set Method for Moving Boundary
Problems: Application to Tumor Growth. J. Scientific Comp. (in review).
Macklin P., Lowengrub J., Nonlinear Simulation of the Effect of Microenvironment on
Tumor Growth. J. Theor. Biol., 245, 677-704 (2007).
Mallett D. G., de Pillis L. G., A Cellular Automata Model of Tumor Immune System
Interactions. J. Theor. Biol., 239, 334-350 (2006).
Mansury Y., Kimura M., Lobo J., Deisboeck T.S., Emerging Patterns in Tumor
Systems: Simulating the Dynamics of Multicellular Clusters with an Agent-based
Spatial Agglomeration Model. J. Theor. Biol., 219, 343-370 (2002).
Matrisian L., The Matrix-degrading Metalloproteinases. Bioessays, 14, 455-463 (1992).
Medema R., Bos J., The Role of p21ras in Receptor Tyrosine Kinase Signaling. Crit.
Rev. Oncog., 4(6) 615-661 (1993).
Mignatti P., Rifkin D., Biology and Biochemistry of Proteinases in Tumor Invasion.
Physiology Rev., 73, 161-195 (1993).
Nottale L., Fractal Space-Time and Microphysics: Towards a Theory of Scale
Relativity. World Scientific, Singapore, 1993.
Olson J., Bathshebas Breast: Women and Cancer and History. John Hopkins
University Press, Baltimore, 2002.
Orme M. E., Chaplain M. A. J., Two-dimensional Models of Tumor Angiogenesis and
Antiangiogenesis Strategies. IMA J. Math. Appl. Med. Biol., 14, 189-205 (1997).
30
Pennington K. S., Harper J. S., Laming F. P., New Phototechnology Suitable for
Recording Phase Holograms and Similar Information in Hardened Gelatine.
Applied Physics Letters, 18, 80-84 (1971).
Perumpanani A.J., Sherratt J. A., Norbury J. et al., Biological Inferences from a
Mathematical Model for Malignant Invasion. Invasion Metastasis, 16, 209-221
(1996).
Porter R., The Greatest Benefit to Mankind: A Medical History of Humanity from
Antiquity to the Present. Harper Collins Publishers, London, 1997.
Quaranta V., Weaver A. M., Cummings P. T., Anderson A. R. A., Mathematical
Modeling of Cancer: The Future of Prognosis and Treatment. Clin. Chem. Acta,
357, 173-179 (2005).
Roose T., Netti P. A., Munn L. L., Boucher Y., Jain R., Solid Stress Generated by
Spheroid Growth Estimated Using a Linear Poroelastic Model. Microvasc. Res.,
66, 204-212 (2003).
Sanga S., Sinek J.P., Frieboes H. B., Fruehauf J. P., Cristini V., Mathematical Modeling
of Cancer Progression and Response to Chemotherapy. Expert. Rev. Anticancer
Ther., 6, 1361-1376 (2006).
Sedivy R., Fractal Tumours: Their Real and Virtual Images. Wien Klin. Wochenschr.,
108(17), 547-551 (1996).
Sedivy R., Windischberger C., Fractal Analysis of a Breast Carcinoma Presentation
of a Modern Morphometric Method. Wien Klin. Wochenschr., 148(14), 335-337
(1998).
Shay J., Bacchetti S., A Survey of Tolomerase Activity in Human Cancer. Eur. J.
Cancer, 33, 787-791.
Shih T., Lindley C., Bevacizumab, An Angiogenesis Inhibitor for the Treatment of Solid
Malignancies. Clinical Therapeutics, 28(11), 1779-1802 (2006).
Sinek J., Frieboes H., Zheng X., Cristini V., Two-dimensional Chemotherapy Simulations Demonstrate Fundamental Transport and Tumor Response Limitations
Involving Nanoparticles. Biomed. Microdev., 6, 197-309 (2004).
Smith H.M. (Ed.), Holographic Recording Materials. Springer-Verlag, Berlin, 1977.
Smothers W. K., Monroe B. M., Weber A. M., Keys D. E., Photopolymers for
Holography. In Practical Holography IV, Proceedings of the SPIE, Vol. 1212, S.
A. Benton (Ed.), SPIE, Bellingham, 1990, pp. 20-29.
Sporn M., The War on Cancer. Lancet, 347, 1377-1381 (1996).
Urbach J. C., Thermoplastic Hologram Recording. In: Holographic Recording
Materials, Topics in Applied Physics, Vol. 20, H. M. Smith (Ed.), SpringerVerlag, Berlin, 1977, pp. 161207.
Veikkola T., Alitalo K., Vegfs and Receptors and Angiogenesis. Semin. Cancer Biol., 9,
211-220 (1999).
Waliszewski P., Konarski J., Molski M., On the Modification of Fractal Self-space
During Cell Differentiation or Tumor Progression. Fractals, 8, 195-203 (2000).
Waliszewski P., Molski M., Konarski J., On the Holistic Approach in Cellular and
Cancer Biology: Nonlinearity, Complexity, and Quasi-determinism of the
Dynamic Cellular Network. J. Surg. Oncol., 68, 70-78 (1998).
Waliszewski P., Molski M., Konarski J., On the Relationship Between Fractal
Geometry of Space and Time in which a Cellular System Exists and Dynamics of
Gene Expression. Acta Biochimol., 48, 209-220 (2001).
31
Waliszewski P., Molski M., Konarski J., Self-similarity, Collectivity and Evolution of
Fractal Dynamics During Retinoid-induced Differentiation of Cancer Cell
Population. Fractals, 7, 139-149 (1999).
Weinberg R., The Retinoblastoma Protein and Cell Cycle Control. Cell, 81, 323-330
(1995).
Wise S. M., Lowengrub J. S., Frieboes H. B., Cristini V., Three Dimensional Diffuseinterface Simulation of Multispecies Tumor Growth- I: Numerical Method. Bull.
Math. Biol. (in review).
Wyllie A., Kerr J., Curri A., Cell Death: The Significance of Apoptosis. Int. Rev. Cytol.,
68, 251-306 (1980).
Zheng X., Wise S. M., Cristini V., Nonlinear Simulation of Tumor Necrosis, Neovascularization and Tissue Invasion Via an Adaptive Finite Element/Level Set
Method. Bull. Math. Biol., 67, 211-259 (2005).
Abstract. Starting from a basic model for solid tumors growth, a chaotic
multi-scale cancer-invasion model is manufactured, which embeds a Lorenz
attractor in its solutions. Furthermore we show how a laser can be expressed in
terms of a Lorenz system and correspondences between the laser and the above
mentioned chaotic multi-scale cancer-invasion model are proposed. Also, we
show that the basic model for solid tumors growth admits a travelling wave
solution and we suggest that metastatic tumor cells which move through the
systemic circulation, and not necessarily there, are similar to a coherent wave,
i.e. a travelling wave, chemically pumped oxygen type laser.
Keywords: carcinogenesis, tumor, fractal, travelling wave, holography.
1. Basic Model
1.1. The PDE Cancer-invasion Model
34
35
the single cell level within the hybrid discrete-continuum model. The
conservation equation for the tumour cell density n is therefore given by
n
+ J rand + J hapto = 0,
t
and hence the partial differential equation governing tumour cell motion (in the
absence of cell proliferation) is
n
= Dn 2 n ( nf ) .
t
(1)
(2)
(3)
36
c
= Dc 2 c + f n c,
t
(4)
n
=
t
Dn 2 n
haptotaxis
( nf ) ,
degradation
f
= mf ,
t
diffusion
decay
production
m
2
= Dm m + n m ,
t
(5)
diffusion
uptake decay
production
c
2
= Dc c + f n c,
t
where Dn, Dm and Dc are the tumour cell, MDE and oxygen diffusion
coefficients, respectively, is the haptotaxis coefficient and , , , , and
are positive constants. We should also note that cellmatrix adhesion is
modelled here by the use of haptotaxis in the cell equation, i.e. directed
movement up gradients of MM. Therefore, maybe considered as relating to
the strength of the cellmatrix adhesion.
2. Non-dimensionalisation and Parameterisation
In order to use realistic parameter values, one must first of all nondimensionalise the equations in the standard way. We rescale distance with an
appropriate length scale L (e.g. the maximum invasion distance of the cancer
cells at this early stage of invasion, approximately 1 cm), time with (e.g. the
average time taken for mitosis to occur, approximately 824 h (Calabresi et
al., 1993)), tumour cell density with n0, ECM density with f0, MDE
concentration with m0 and oxygen concentration with c0 (where n0, f0, m0 and c0
are appropriate reference variables). Therefore, setting
n =
n
f
m
c
x
t
=
, f = , m
, c = , x = , t = ,
n0
f0
m0
c0
L
in (5) and dropping the tildes for notational convenience, we obtain the scaled
system of equations
n
=
t
dn2 n
f
=
t
37
haptotaxis
( nf ) ,
deg radation
mf
diffusion
decay
production
m
= d m 2 m + n m ,
t
(6)
diffusion
uptake decay
production
c
= d c 2 c + f
n c ,
t
38
diffuse through water at a rate of Dc = 105 cm2 s1 and cells consume oxygen at
a rate of 6.25 1017 M cells1 s1 (Casciari et al., 1992). The background
oxygen concentration within the tissue was somewhat difficult to estimate as
this depends on how well the tissue is vascularised. If we take the concentration
of oxygen in the blood supplying the tumour/tissue to be 0.15 ml O2 per ml of
blood and since we know that 1 M of oxygen occupies 22400 ml then there is
0.15/22400 M O2 ml1 = 6.7 x 106 M O2 ml1, and since 1 ml = 1 cm3 then we
calculate c0 = 6.7 x 106 M O2 cm3 (Sherwood, 2001). Clearly, this would be an
overestimate, since not all of the domain will be fully vascularised but this at
least gives us a reference value. The values of the non-dimensional parameters
were given as
f = 0.025.
(7)
39
polarization vector of the environment, equals the vectorial sum of all the dipole
moments from the unit volume, and will be given by
P = N a = 0 E ,
(9)
= H,
t
(10)
where H is the Hamiltonian operator and the wave function of the atom.
Since a monochromatic field of frequency 0, not very intense, interacts
with the atom inducing transitions between two of its energetic levels, E1 and E2
i.e. E2 - E1 = 0, it is usual to neglect the other levels and to approximate the
atom as a system with two energy levels. If the wave functions of the atom in
the two states are 1 and 2, respectively, then we have
= C11 + C22 ,
(11)
where C1, C2 are the time dependent complex amplitude probabilities for the
atom to find itself on the energy levels E1 and E2, respectively. In other words
11 = C1C1 C1 represents the probability of the atom to find itself in the state
2
1, and 22 = C2C2 C2 the probability of the atom to find itself in the state
2
H = H 0 + H ' .
(12)
H 01 = E11 , H 02 = E22 ,
(13)
Replacing (11), (12) and (13) into the Schrdinger equation, and after
some standard calculus, we get the equations
40
C2 ,
iC1 = E1C1 + H12
C1 ,
iC 2 = E2C2 + H 21
(14)
= 2 H 1dV .
H 21
(15)
It has been taken into account the orthonormal property of the wave
functions 1 and 2
i j dV = ij
(i, j = 1, 2),
(16)
where ij is Kroenekers symbol, and the fact that the interaction matrix H`ij has
no diagonal elements.
It is common to introduce the following simplification: if one chooses the
zero energy value at the center of the interval between the two energies, then
they become
E2 =
0
,
2
E1 =
0
,
2
(17)
0C1
C2 ,
+ H12
2
0C2
C1.
+ H 21
2
iC 2 =
(18)
1 ex 2 dV .
(19)
= 12 E.
H12
(20)
41
(21)
P = N a 12 X = N a 12 12 + c.c.,
(22)
Y = i(C1C2 C1C2 ) i( 12 21 ),
2
Z = C2 C1 22 11.
(23)
(24)
(25)
2
Y = 0 X + 12 EZ ,
(26)
2
Z = 12 EY ,
(27)
where in Eq. (25) the second form was obtained taking into account H`12 = H`21.
By multiplication of Eq. (25) with Na12, it transforms into an equation
for P , namely
P = N a 12 X = N a 12 ( 12 + 21 ) = N a 12 12 + c.c.
(28)
The equation for 12 is obtained from Eqs. (25) and (26), taking into
account Eqs. (21) and (23). It results
12 = i0 12 + i
12
EZ .
(29)
42
(30)
+ P + 2 P = 20 2 EN .
P
0
12
T2
(31)
12
EZ ,
(32)
where 12 =1/T2.
By multiplication of Eq. (27) with Na the left side becomes N . Replacing
Y from (25) in (27), we get
N
2
=
EP .
t 0
(33)
Eq. (33) shows that, at the disappearance of the electromagnetic field, the
inversion of population must remain constant. However, an electromagnetic
field resonant with the considered transition ( 0) is composed of quanta
which can be absorbed by atoms, so may have the effect of a transfer of
population between the two levels. It is obvious that, at the canceling of the
field, the inversion of population must evolve towards an equilibrium value Ne
which is obtained by a process of pumping and by spontaneous relaxation
processes. They imply the presence of other energetic levels besides those
already considered. We proceed again by phenomenological reasonings. We
suppose that this evolution is again exponentially, thus we add a term of the
43
(34)
Eq. (34), together with (28) coupled with (32), or with (31) represents the
substance equations. They must be associated with the electromagnetic field
equation which we transcribe here
2E
2 2 E
c 2 t 2
= 0
2P
t 2
(35)
(36)
where k = c/c, c being the frequency of the considered mode (index c from
cavity). For simplification, in what follows, we consider =1 (gaseous
environment).
We suppose the oscillation is produced on a single mode described by a
spatial dependence of the form W(x, y, z). This dependence will characterize
both the field and polarization, so we can write
(t )W ( x, y, z )exp(i t ) + c.c.
E=E
c
(37)
P = P (t )W ( x, y, z )exp(ic t ) + c.c.
(38)
and
44
dE ic
=
P.
dt 2 0
(39)
It is necessary to include the loss by radiation which are due to, in the
first place, mirrors imperfections. We do that by introducing a term E in the
left hand side, so the field equation becomes
i
dE
+ E = c P .
dt
20
(40)
The equation for polarization is obtained comparing Eqs. (22) and (38).
It results
12 =
exp(i t )
PW
c
,
N a 12
12 =
1 dP
+ ic P W exp(ic t ),
N a 12 dt
(41)
which introduced in Eq. (32), and after multiplying both sides with W*exp(-ict)
and integrating over the entire volume (mode) of the cavity, leads to
i 2
dP
+ ( 12 + i(c 0 )) P = 12 EN
,
dt
(42)
where, in the left hand side, we introduced the first term from (37) and where N
represents the inversion of population from the volume occupied by the cavity
mode, defined by the relation
N=
N a ( 22 11 )W WdV
WdV
(43)
We then introduce the relations for the field and polarization (37) and
(38) into the equation for the inversion (34). Using the approximation P = ic P ,
neglecting the rapidly varying terms (which contain exp (2ict)), multiplying
by WW* and integrating over the volume of the cavity, we get
2iA0
N
+ 11 ( N N e ) =
( E P EP ),
t
(44)
45
A0 =
N a (W W )2 dV
WdV
(45)
Eqs. (40), (42) and (44) form the Bloch-Maxwell system and describe a
unimodal laser oscillator. If we make the change of variables
t=
i12
1
t , E =
A,
12
2 A0 12
(46)
212 0
12 0
P =
R, N N e =
n,
c 122
c A0 12
the Bloch-Maxwell equations gets the form of the Lorenz system. They become
dA
= A + R,
dt
dR
= rA R(1 + i) An,
dt
(47)
dn
1
= bn + 2 ( AR + A R),
dt
where the following notations were used
0
2 N e
, = c
, b = 11 , r = c 12 .
12
12
12
20 12
(48)
In the form (47) the equations make up a complex Lorenz system. This
was discussed in detail in the paper (Fowler et al., 1982). The complex Lorenz
system transforms into the well known real Lorenz system if the resonance is
~
~
exact (c = 0 = 0) and the phases of the amplitudes E and P are
chosen so the functions A and R to be real
46
dA
= ( R A),
dt
dR
= A(r n) R,
dt
(49)
dn
= AR bn.
dt
The fact that a unimodal laser oscillator is described by the Lorenz
system was remarked for the first time by Haken (Haken, 1975). Therefore, it
was demonstrated that the imense variety of dynamical behaviors, including the
chaotic ones, presented by a Lorenz system, must be expected to occur in a
laser. Among the first who reported Lorenz type chaotic behaviors in a laser,
were Weiss and Brock (Weiss & Brock, 1986).
Equations of the same form are obtained also when one consideres a
travelling wave laser, such as laser amplificators where the wave passes only
one time the environment, or a circular unidirectional laser (Milonni et al.,
1987; Newell et al., 1992).
3.2. A Chaotic Multi-scale Cancer-invasion Model
(50)
dc
= f n c.
dt
When simulated, the temporal system (50) with the set of parameters (7)
exhibits a virtually linear temporal behavior with almost no coupling between
47
the four concentrations that have very different quantitative values (all phase
plots between the four concentrations, not shown here, are virtually onedimensional). To see if a modified version of the system (50) could lead to a
chaotic description of tumor growth, and following the method in (Ivancevic et
al., 2008), four new parameters, a1, a2, a3, and a4 are introduced. The resulting
model is
dn
= 0,
dt
df
= a1( m f ),
dt
dm
= f ( a3 c ) m + a2 n,
dt
(51)
dc
= fm a4 c n.
dt
The introduction of the parameters (a1, a2, a3, a4) was motivated by the
fact that tumor cell shape represents a visual manifestation of an underlying
balance of forces and chemical reactions (Olive & Durand, 1994). Specifically,
the parameters represent the following quantities: a1 = tumor cell volume
(proliferation/non-proliferation fraction), a2 = glucose level, a3 = number of
tumor cells, a4 = diffusion from the surface (saturation level).
A tumor is composed of proliferating (P) and quiescent (or nonproliferating) (Q) cells. Tumor cells shift from class P to class Q as the tumor
grows in size (Kozusko & Bourdeau, 2007). Model dependence on the ratio of
proliferation to non-proliferation is introduced via the first parameter, a1. The
discretization of Eq. (6a) leads to cell density being modelled as a constant in
Eq. (51a). Accordingly, cell density does not play a role in the dynamics. In
(51) the cell density is re-introduced into the dynamics via the cell number, a3.
The importance of introducing a3 also appears in connection with the cyclindependent kinase (Cdk) inhibitor p27, the level and activity of which increase in
response to cell density. Levels and activity of Cdk inhibitor p27 also increase
with differentiation following loss of adhesion to the ECM (Chu et al., 2008).
The ability to estimate the growth pattern of an individual tumor cell type
on the basis of morphological measurements should have general applicability
in cellular investigations, cellgrowth kinetics, cell transformation and
morphogenesis (Castro et al., 2003).
Cell spreading alone is conducive to proliferation and increases in DNA
synthesis, indicating that cell morphology is a critical determinant of cell
48
Fig. 1 A 3D Lorenz-like chaotic attractor from the modified tumor growth model (59
b-d). The attractor effectively couples the MMconcentration f, the MDE
concentration m, and the oxygen concentration c in a masklike fashion.
49
50
(52)
m
= d m 2 m + a2 kn + f ( a3 c ) m,
t
c
= d c 2 c + fm n a4 c.
t
The new tumorgrowth model (52) retains all the qualities of the original
model (6) plus includes the temporal chaotic butterflyattractor. This chaotic
behavior may be a more realistic view on the tumor growth, including
stochasticlike longterm unpredictability and uncontrollability, as well as
sensitive dependence of a tumor growth on its initial conditions.
Now, if we compare (51) with (49) and make a one-to-one
correspondence between these two systems of equations, we see that A which is
the electric field amplitude corresponds to f, the MM concentration, R which is
the polarization amplitude corresponds to m, the MDE concentration and n the
inversion of population corresponds to c, the oxigen concentration. Since both
systems, the laser and the tumor invasion can be written in the form of a Lorenz
system, we can suppose that the metastatic cancer cells moving through the
systemic circulation form a coherent wave, i.e. a particular type of chemically
pumped (since it may obtain its energy from chemical reactions) laser with
oxygen. In the following section we show moreover, that this coherent wave can
be identified with a travelling wave laser with oxygen.
4. Travelling Waves in the Multiscale Diffusion
Cancer-invasion Model
Let us write the system (6) again. We assume the model studies the
averaged behaviour of the tumor cells in the direction of invasion only and
ignores variations in a plane perpendicular to the direction of invasion.
51
52
n
=
t
f
k3 n
x x
F ( n)
proteolysis
f
= G ( f , m),
t
(53)
m
=
t
protease production
H ( n, f )
natural decay
Km
diffusion
production and uptake decay
c
2c
= dc 2 +
I ( f , n)
c ,
t
x
G ( f , m) = k4 mf ,
(54)
H (n, f ) = k5 nf , I ( f , n) = k6 f k7 n.
53
4.1. Nondimensionalisation
After making the substitutions for F, G, H and I from (54) into equations
(53 a)(53 d) and eliminating m using m = H(n, f) and c using c = I(f, n) we
nondimensionalise the resulting equations using
12
k
n
f
t
x
n = , f = , t = , x = , L = 3 ,
n
f
T
L
k 2 k 4 k5
T=
k
1
, n = k2 , f = 1 .
k1k2
k 4 k5
Dropping tildes for notational convenience then gives rise to the system
n
f
= n(1 n) n ,
t
x x
(55)
f
= nf 2 .
t
4.2. Spatially Homogeneous System
(56)
f (t ) = [t c1 + log[1 + exp( t + c2 )]]1 ,
54
state n = 0 ahead of the wave and the fully malignant state n = 1, f = 0 behind
the wave. This is confirmed by numerical solutions of (55 a) and (55 b), which
are not discussed here. Such travelling wave solutions can be studied
analytically using the travelling wave differential equations. We look for
constant shape travelling wavefront solutions of (55 a) and (55 b) by setting
n( x, t ) = N ( z ),
f ( x, t ) = F ( z ), z = x t ,
(57)
dN
2 NF 2
dz
2N 3F 3
N
(1
N
)
,
=
(58)
dF NF
=
.
dz
The analysis of (58 a) and (58 b) involves the study of the (N, F) phase
plane. Since we are looking for travelling waves connecting (1, 0) and (0, F ) in
the (N, F) phase plane we look for solutions of (58 a) and (58 b) with boundary
conditions
N ( ) = 1, F ( ) = 0, N () = 0, F ( ) = F ,
(59)
which requires (1, 0) to have an unstable manifold while (0, F ) must have a
stable manifold. In order to study this we look at the stability of the system (58
a) and (58 b).
4.4. Stability Analysis
The steady states (N0, F0) of (58 a) and (58 b) are (0, F ) and (1, 0),
where F represents a continuum of steady states. We study their stability by
looking at the eigenvalues of the stability matrix linearised about the steady
states. The eigenvalues about (0, F ) are 1/ and 0. The corresponding
eigenvectors are (1, F ) and (0, 1). The negative eigenvalue indicates that there
is a stable manifold along (1, F ) . The zero eigenvalue represents translations
along the continuum of steady states.
55
REFERENCES
Anderson A.R.A., Chaplain M.A.J., Newman E.L., Steele R.J.C., Thompson A.M.,
Mathematical Modelling of Tumour Invasion and Metastasis. J. Theor. Med., 2,
129-154 (2000).
Aznavoorian M., Stracke L., Krutzsch H., Schiffman E., Liotta L. A., Signal
Transduction for Chemotaxis and Haptotaxis by Matrix Molecules in Tumour
Cells. J. Cell Biol., 110, 1427-1438 (1990).
Boudreau N., Jones P. L., Extracellular Matrix and Integrin Signaling: The Shape of
Things to Come. Biochem. J., 339 (1999).
Bray D., Cell Movements. Garland Publishing, New York, 1992.
Calabresi P., Schein P. S. (Eds.), Medical Oncology. 2nd Edn., McGraw-Hill, New
York, 1993.
Carter S.B., Principles of Cell Motility: The Direction of Cell Movement and Cancer
Invasion. Nature, 208, 1183-187 (1965).
Casciari J. J., Sotirchos S. V., Sutherland R. M., Variation in Tumour Cell Growth
Rates and Metabolism with Oxygen-concentration, Glucose-concentration and
Extracellular pH. J. Cell. Physiol., 151, 386-394 (1992).
Castro M.A.A., Klamt F., Grieneisen V.A., Grivicich I., Moreira J.C.F., Gompertzian
Growth Pattern Correlated with Phenotypic Organization of Colon Carcinoma,
Malignant Glioma and Non-small Cell Lung Carcinoma Cell Lines. Cell Prolif.
36(2), 65-73 (2003).
Chambers A. F., Matrisian L. M., Changing Views of the Role of Matrix
Metalloproteinases in Metastasis. J. Natl. Cancer Inst., 89, 1260-1270 (1997).
Chu I. M., Hengst L., Slingerland J. M., The Cdk Inhibitor p27 in Human Cancer:
Prognostic Potential and Relevance to Anticancer Therapy. Nature Rev. Cancer,
8, 253-287 (2008).
Debruyne P.R., Bruyneel E.A., Karaguni I.-M. et al., Bile Acids Stimulate Invasion and
Haptotaxis in Human Corectal Cancer Cells through Activation of Multiple
Oncogenic Signalling Pathways. Oncogene, 21, 6740-6750 (2002).
56
57
Sargent M. III, Scully M. O., Lamb W. E. Jr., Laser Physics. Addison Wesley Publ.
Co., Reading, Massachusetts, 1977.
Schwartz M., A Biomathematical Approach to Clinical Tumour Growth. Cancer, 14,
(1961).
Sherwood L., Human Physiology: From Cells to Systems. 4th Ed., Pacific Grove,
California, Brooks/Cole, 2001.
Stetler-Stevenson W. G., Hewitt R., Corcoran M., Matrix Metallo-proteinases and
Tumour Invasion: From Correlation to Causality to the Clinic. Cancer Biol., 7,
147-154 (1996).
Terranova V.P., Diflorio R., Lyall R.M., Hic S., Friesel R., Maciag T., Human
Endothelial Cells are Chemotactic to Endothelial Cell Growth Factor and
Heparin. J. Cell Biol., 101, 2330-2334 (1985).
Vaidya V.G., Alexandro F.J. Jr., Evaluation of Some Mathematical Models for Tumour
Growth. Int. J. Biomed. Comput., 13, 19-35 (1982).
Weiss B. O., Brock J., Phys. Rev. Lett., 57, 2804 (1986).
Werb Z., ECM and Cell Surface Proteolysis: Regulating Cellular Ecology. Cell, 91,
439-442 (1997).
Xie B., Bucana C. D., Fidler I. J., Density-dependent Induction of 92-kd Type Type-IV
Collagenase Activity in Cultures of A431 Human Epidermoid Carcinoma Cells.
Am. J. Pathol.,144, 1958-1967 (1994).
Zervoudaki A., Economou E., Pitsavos C., Vasiliadou K. et al., The Effect of Ca2+
Channel Antagonists on Plasma Concentrations of Matrix Metallopro ases
in Metastasis. J. Natl. Cancer Inst., 89, 1260-1270 (1997).
60
ii) the interstitial matrix, which exists within intercellular space. The
ECM serves multiple functions that are critical for embryonic development and
wound repair. These functions include providing tissues with shape and
flexibility and acting as a cushion to absorb external pressure. The ECM also
serves as a base for cell anchorage, which mediates cell polarity, intercellular
signaling, and assists in migration. The key to the ECM function lies in its
unique composition and structure. The ECM is constructed in a specific pattern
that is critical to its ability to carry out these functions and alterations in the
expression level or arrangement of proteins within the ECM can be used to
manipulate its function.
The most obvious function of the ECM is to provide structural support,
shape, and stability for tissues. It does this by functioning as a base for cell
anchorage. This base consists of three main structural components collagen,
fibronectin, and elastic fibres, which bind to one another building a protein
lattice upon which cells adhere.
Cell adherence to the ECM lattice provides cells support needed for cell
migration. This is particularly important during embryonic development when
cells are required to migrate into surrounding regions and differentiate into
specific tissues (Svoboda et al., 2008). A less obvious yet possibly more
important function of the ECM in regards to tissue homeostasis and disease is
its ability to mediate intracellular signaling. The ECM affects signaling through
three main mechanisms:
i) cell ECM interaction;
ii) regulation of the bioavailability of growth factors;
iii) the function of matricellular proteins. Cell attachement to the ECM via
integrins induces signaling cascades that promote survival. Loss of cell-ECM
contact can result in a form of apoptosis termed anoikis (Giannoni et al., 2008).
Anchorage-dependent survival is observed in most cells with the exception of
red blood cells and inflammatory cells. However, tumor cells are often resistant
to anoikis and can survive without a physical attachment to the ECM allowing
them to successfully metastasize to distant tissues (Chiarugi & Giannoni, 2008).
The ECM also affects cellular activity by serving as a reservoir for
proteins required for propper tissue function and repair. This includes a plethora
of growth factors and proteases. These pleiotropic molecules have been shown
to robustly affect proliferation, survival and migration in numerous cell types.
Once growth factors are secreted from cells, they often become embeded within
the ECM and require ECM degradation by proteases such as elastase to release
the active protein allowing it to interact with surrounding and transduce
downstream signaling. The ability of the ECM to control the bioavailability of
growth factors provides another means of regulating cellular activities and
further explains how alterations in the makeup of the ECM as observed in
diseases such as cancer affect cell response.
61
Matricellular proteins also reside in the ECM. They are a unique family
of proteins that do not function as structural proteins but rather orchestrate the
deposition of the ECM and mediate cell-cell and cell-ECM interactions. To do
this, matricellular proteins interact directly with cell surface receptors, structural
proteins, growth factors and proteases found within the ECM (Framson & Sage,
2004). Their expression is found in every tissue, begins early in development,
persist throughout adulthood and is increased durring tissue remodeling events.
Matricellular proteins are critical regulators of many aspects of cell function
including differentiation, survival, proliferation and migration making them
necessary for proper tissue function. Not surprisingly, given their affect on cellECM mediated signaling pathways, matricellular proteins have been shown to
strongly influence tumor growth.
For tumor cells to metastasize, the local ECM must be remodeled to
create an environment conducive to tumor survival and progression. This
includes altering the architecture and compozition of the tumor-associated ECM
or tumor microenvironment (TME) to facilitate tumor cell dissemination (Pupa
et al., 2002). Changes in ECM architecture are primarely carried out by enzimes
such as MMPs which assist in remodeling of the TME by degrading structural
proteins such as colagen and fibronectin allowing tumor cells to freely navigate
through the surrounding ECM. MMPs and other proteases assist in destruction
of the first barrier tumor cells face to successful metastasis, the basement
membrane. They degrade the underlying basement membrane allowing tumor
cells to escape the primary tumor and invade into surrounding non-neoplasic
tissues. MMPs continue to breakdown barriers in the surrounding ECM clearing
a path to blood vessels where tumor cells will intravasate into the circulatory
system and seed secondary tumors (Hofmann et al., 2005). Destruction of the
ECM by proteases also promotes tumor progression by facilitating the release of
angiogenic and mitogenic factors bound within the ECM (von Kempen et al.,
2003). In a surprising unexpected twist, studies revealed that the breakdown of
ECM proteins by MMPs was more complex than anticipated. In fact it is a
highly organized process which results in the generation of both protumor and
antitumor cleavage products (Lopez-Otin et al., 2009).
Presence of the ECM is required for cellular survival therefore increased
degradation of the ECM within the TME must be balanced by an increase in
ECM synthesis. The development of a tumor, much like a wound, provokes a
robust inflammatory response causing an influx of mast cells, macrophages and
neutrophils into the TME (Wu & Zhou, 2009).
We may summarize that the extracellular matrix provides signalling cues
that regulate cell behaviour and orchestrate functions of cells in tissue formation
and homeostasis. The composition of the ECM, its three-dimensional
organization and proteolytic remodelling are major determinants of the
microenvironmental signalling context that controls cell shape, motility, growth,
survival and differentiation. In recent years, the importance of ECM signalling
62
( 2 ) 1
= +V
iD (dt ) D ,
t t
F
(1)
where
= V iU.
V
(2)
The real part V of the complex speed field V represents the standard classical
speed, which is differentiable and independent of the resolution, dt , while the
imaginary part U is a new quantity arising from fractality, which is nondifferentiable and resolution-dependent. The quantity D is the Nottales
coefficient and corresponds to the transition fractal non-fractal (Agop et al.,
2008; Agop et al., 2010; Agop et al., 2010).
We are now able to write the equation of geodesics (a generalization of
the first Newtons principle) in the form,
V
V
)V
iD (dt )( 2 D ) 1 V
= 0.
=
+ (V
t
t
F
(3)
This means that the global complex acceleration field, V t , depends on the
, on the non-linearity (convective) term,
local complex acceleration field, t V
)V
, and on the dissipative one, V . Moreover, the behavior of a fractal
(V
fluid is of viscoelastic or of hysteretic type which means that the fractal fluid
has memory. Such a result is in agreement with the opinion given in (Agop et
al., 2010; Agop et al., 2008): the fractal fluid can be described by Kelvin-
63
Voight or Maxwell rheological model with the aid of complex quantities e.g. the
complex speed field, the complex acceleration field etc.
3. Tumor-associated ECM as a Non-differential Medium has
Interference Abilities
The Eq. (1) is a Navier-Stokes type equation with an imaginary viscosity
coefficient
0 = iD(dt )( 2/ D
) 1
(4)
= 0 , we can choose
If the motions of the fractal fluid are irrotational, i.e. V
of the form
V
= 2iD (dt )
V
ln ,
(5)
( 2/ DF ) 1
U = D(dt )(2/ DF ) 1 ln .
By substituting (6) in (3) and separating the real and the imaginary parts, up to
an arbitrary phase factor which may be set zero by a suitable choice of the phase
of , we obtain
m0
+ (V )V = -Q,
t
(7)
+ ( V) = 0,
t
with Q the fractal potential,
Q = 2m0 D 2 (dt ) ( 4/ D
)2
m0 U
m0 D (dt ) ( 2/ D
2
) 1
(8)
64
and m 0 the rest mass of the fractal fluid particle. Eq.(7a) is the momentum
conservation law, Eq. (7b) is the density conservation law, and they define
together a fractal hydrodynamics (FHD).
In the one-dimensional case, using the substitutions
t = , kx = ,
v
=V,
v0
k 3D2
= N , 2 =
(dt ) D
0
v0
(9)
,
N ,
(10)
N ( NV )
+
= 0.
t
Using the method from (Agop et al., 2010) with the initial conditions
V ( 0 , = 0) = c,
N ( 0 , = 0) =
0 2
exp
= N 0 ( 0 ),
(11)
V ( 0 = c , ) = c,
N ( 0 = , ) = N ( 0 = +, ) = 0,
(12)
2
c + ( 0 )
V ( 0 , ) =
,
2
2 2
2
+
2
2
( 0 c )
1
exp
,
N ( 0 , ) =
2 2 2 2
2 2 2 2
+
+
(13)
65
2
c 2 +
( 0 )
0 c
,
2i
V ( 0 , ) =
2
2
2 2
2 2
2
2
+
+
(14)
2
c 2 + ( 0 )
2
( 0 c )
j ( 0 , ) =
exp
,
3/
2
2 2 2 2
2 2 2 2
+
+
2
( 0 c )
0 c
2i
exp
,
3/ 2
2
2 2 2 2
2 2 2
+
+
(15)
Q ( 0 , ) = 0 2i 2
( 0 , c ) 2
2 2 2 2
+
+ 2i 2
1
2
2
+ 2
(16)
2 2
F ( 0 , ) = 0 + 4i ( 0 c ) 2 +
.
(17)
66
a)
ReV
N
1
0.75
0.5
0.25
0
-10
10
10
5
0
-5
10
5
-10
10
-5
5
2.5
0
-2.5
-5
10 -10
c)
5
10 -10
d)
ImV
-5
Re J
10
5
0
-5
-10
-10
10
-5
1
100.75
0.5
5
0.25
0
-10
10
10
5
0
-5
5
10 -10
e)
-5
-5
5
10 -10
f)
Im J
0.4
0.2
0
-0.2
-0.4
-10
10
10 0
-25
5
-50
-75
10
5
-5
-5
-10
10
-5
g)
5
10
-10
-5
5
10
-10
10
5
0
-5
-10
-10
10
10
5
0
-5
-5
5
10 -10
67
This means that the particle of fluid in free motion polarizes the fractal
medium behind himself, 0 c , and ahead of itself, 0 c , in such a
form that the resulting forces are symmetrically distributed with respect to the
plane through the observable particle position, 0 = c at any time - see
the symmetry of the curves in Figs. (1 a-g). In such context, the presence of a
perturbation e.g. one given by a laser beam, induces an asymmetry of the
force field, having as an effect the excitation of a specific mode of structuring
matter.
The solution (13 b) corresponds to the density of time-dependent Gaussian
scalar potential speed packet associated to a free particle, having the scalar
potential speed function,
[ ( ) c ]2
1
0
exp
( 0 , ) =
2 2 1 + i 2
1/ 4
+i
(19)
c2
c ( 0 )
exp i
+i
.
2
4
Moreover, through Eq. (13b), the phase, S, of this scalar potential speed
function is connected with the real part (observable ) of complex velocity field.
Now, let us assume the particle interaction with an external potential
(which can be approximately modeled, for example, by an infinite square-well
potential), resulting in a discontinuous change in momentum. Localized timedependent solutions for this problem, i.e. bouncing scalar potential speed
packets, can be constructed in a very straightforward way from solutions of the
free-particle problem (Agop et al., 2010). With 0 = 0 the wall position, the
simple difference solutions of the form ( 0 , ) (( 0 ), ) not only
satisfy the free-particle Schrdinger equation or the equivalent form (given by
the system of Eq. (7) of the fractal hydrodynamics) for all ( 0 ) values (if
( 0 , ) does), but also accommodate the new boundary condition at the
wall, namely that (0, ) = 0 . Then, the probability density is
68
N R ( 0 , ) = ( 0 , ) (( 0 ), ) =
= N + ( 0 , ) + N ( 0 , )
2 N + ( 0 , ) N ( 0 , ) cos
N + ( 0 , ) = N ( 0 , ) ,
where
(20)
2 2
2
0 c
,
2
2
2
N ( 0 , ) = N (( 0 ), )
and
N ( 0 , ) are given by Eq. (13b). The result (20) is equivalent with the
interference of a progressive scalar potential speed packet (for > 0 ) with a
regressive one (for < 0 ) see Figs. (2 a-c).
~
b) c = 7
a) c = 5
1
1
0.5
0.75
0.5
0.4
0.25
0
0.3
0.75
0.5
0.25
0
-4
0.5
0.4
0.3
-4
0.2
-2
0.2
-2
0.1
0.1
Regressive scalar
potential speed packet
4
c) c = 9
N ( 0 , )
Progressive scalar
potential speed
-0
0.5
0.75
0.5
0.25
0
0.4
0.3
-4
0.2
-2
0
0.1
2
4
Fig. 2 Progressive scalar potential speed packet ( > 0 ), and a regressive one ( < 0 )
for various values of normalized speed, c.
The interference term from Eq. (20) gives local maxima and minima see
Figs. (3 a-c) and Figs. (4 a-c). Their space-time positions depend on the initial
velocity c . From Figs. (3 a-c) and (4 a-c) it results that the multi-peak structure
can be observed both for the spatial component and for the temporal one, but in
the last case only for << 2 Figs. (4 a-c).
a)
c~ = 5
b)
1.5
69
c~ = 7
1.5
0.5
0.4
0.5
0
0.5
0.4
0.5
0
0.3
-4
0.3
-4
0.2
0.2
-2
-2
0
0.1
2
2
4
N R ( 0 , )
0.1
4
c)
c~ = 9
2
1.5
0.5
1
0.4
0.5
0
0.3
-4
0.2
-2
-0
0.1
2
4
E = ln dx,
(21)
where (x) is the density of distributions, and we note by x, on the whole, the
random variables of the problem, dx being the elementary measure of their field.
This functional represents a measure of the uncertainty degree, when
defining the probabilities, i.e. it is positive, it increases when uncertainty also
incresases taken in the sense of expanding distribution and it is additive for
sources that are independent as compared to uncertainity. If we admit the
maximum of informational energy in the inference against probabilities, having
at our disposal only a partial piece of information this is equivalent to frankly
admitting the fact that we cannot know more. Through this, the distributions
that we obtain must be at least displaced, as compared to the real ones, because
there is no restrictive hypothesis regarding the lack of information. In other
70
( x) f ( x)dx.
c~ = 0.1
b)
0.5
(22)
c~ = 0.2
0.5
10
0.25
0
8
-0.25
6
-0.5
0
0
-0.5
0
4
0.2
10
8
6
4
0.2
0.4
0.4
2
0.6
0.6
0.8
1
N R ( 0 , )
0.8
c) c = 0.3
0.5
0.25
0
-0.25
-0.5
0
10
8
6
4
0.2
0.4
-0
0.6
0.8
1
( x)dx = 1,
(23)
are now constraints the variation of the functional (21) has to subject to, in order
to offer the distribution density corresponding to the maximum of informational
energy. In this concrete case, Lagranges non determined multipliers method
directly leads to the well known exponential distribution
( x ) = exp( x f ( x )).
(24)
Let us notice that through the fractal component of the complex scalar
potential of the speed field
= D ln .
(25)
71
Eq. (21), ignoring the scale factor D, is identical with the average mean of (25)
E=
= ln dx.
D
(26)
( r ) rdr ,
(27)
(r )dr 1,
(28)
r=
(29)
or in notations
exp( ) 0 ,
2
,
a
2r
( r ) = 0 exp .
a
(30)
(31)
d
2D
(ln ) =
= const.
dr
a
(32)
Q=
=
m0u 2
2 d
d2
m0 D 2 2 (ln ) +
(ln ) =
r dr
2
dr
2m0 D 2 1 2
,
a a r
(33)
4m D 2
dQ
(34)
= 02 .
dr
ar
Consequently, the fractal medium by maximization of the
informational energy becomes a source of central forces (Ibnescu et al., 2006;
Ibnescu et al., 2006).
F (r ) =
72
( x, t ) ln ( x, t )dx 0.
(35)
The spread of cancer cells from their original location to other sites in the
body, known as metastasis, has long been thought of as a one-way journey. But
some researchers also believe that metastatic cancer cells can fuel primary
tumor growth, with potentially important implications for the timing and nature
of cancer treatment.
The concept of tumor self-metastasis, or tumor self-seeding, originated
at Memorial Sloan-Kettering Cancer Center, based on a series of studies led by
Drs. Joan Massagu, head of the Metastasis Research Center, and Larry Norton,
deputy physician-in-chief of the centers breast cancer programs. In studies of
mice, Dr. Massagu observed that breast tumors expressing genes associated
with metastasis were growing faster than tumors that did not express these
genes, even though the genes had no apparent role in increased cell division or
decreased cell death (Fig. 5). These results did not fit in with the standard
theories of tumor growth. In 2006, the two researchers proposed that cells which
break free from a tumor and colonize distant tissues may also return home via
the circulatory system to the welcoming microenvironment in which they first
developed (Norton, 2006). The two researchers tested their hypothesis in a
mouse model of cancer and published their results in 2009 in Cell (Kim et al.,
2009).
73
Fig. 5 In the self-seeding concept of cancer growth and metastasis, a mobile tumor
cell can take one of five different pathways in the body. A evade and return to the
primary tumor, using only the close ECM and not the systemic circulation; B escape
into the systemic circulation and then return to the original tumor; C migrate through
the systemic circulation and grow a metastatic tumor elsewhere in the organism; D
evade and return to the metastatic tumor, not using the systemic circulation; E escape
and return to the metastatic tumor through the systemic circulation.
For one experiment, they chose a non-metastatic breast cancer cell line
and an isolated set of daughter cells from that line that had gained the ability
over time to metastasize to the lungs. When the researchers implanted the parent
cells in one mammary gland and the metastatic daughter cells in the opposite
gland to serve as donor tumors, the daughter cells migrated to the lungs and to
the tumors that were being formed by the parent cells in the opposite gland,
accounting for 5 to 30 percent of the eventual size of the parent tumors. Parent
tumors seeded by daughter cells grew faster than parent tumors that were
implanted alone without daughter cells in the opposite gland.
The researchers observed this same seeding behavior with daughter cells
that metastasize to the bones and brain, and with colon cancer and melanoma
cell lines, but they did not see the effect when they transplanted daughter cells
that were not metastatic.
In a set of follow-up experiments performed in the laboratory, the
researchers showed that cells from primary tumors can attract circulating
metastatic tumor cells, and they identified several proteins that likely encourage
this migration. They also found that the returning metastatic cells promoted
primary tumor growth by releasing proteins that change the tumor
microenvironment, including blood vessels and immune cells.
74
Their hypothesis began to get support from other researchers who were
testing it in their own laboratories. In 2009, Dr. Philip Hahnfeldt and his
colleagues published the results of computer modeling studies designed to look
at the intersection of two biological phenomena found in tumors (Enderling et
al., 2009). One of these phenomena is that a small population of cancer cells
may act like stem cells; they may have the ability to reproduce an infinite
number of times, creating more cells like themselves with the capability for
endless proliferation but also producing daughter cancer cells that eventually
lose the ability to divide. The second phenomenon is that tumor growth is
limited by the space available for expansion. Normally, healthy cells have an
amount of space between them that is not available in a tumor. Cancer cells
grow tightly together in a dense mass until all available space has been
occupied, at which point cell division stops. But at the edges of the tumor,
where the normal tissues are less dense, cancer cells continue to multiply and
push outward, expanding the tumor size.
Their models showed an important and counterintuitive relation
between cell migration, cell death, and tumor growth. When the progeny of a
cancer stem cell in the model did not migrate or die spontaneously, tumor
growth stagnated at around 110 cells. In contrast, a combination of high death
rate among the non-stem cell progeny and a high cell migration rate produced
the largest tumors in the shortest amount of time, to almost 100,000 cells in just
over 3 years.
This theoretical phenomenon accelerated tumor growth jump-started by
a high rate of tumor cell death has potential implications for the clinical
treatment of cancer. Traditional cytotoxic chemotherapy drugs kill large
numbers of rapidly dividing cancer cells, but may not affect cancer stem cells in
every tumor type. Currently, no anticancer drugs exist that specifically interfere
with the process of metastasis, though researchers are actively working on
understanding the genetic changes that drive a cancer cells ability to break
away from a tumor and survive in the blood stream, in the hopes of making
metastasis a valid therapeutic target.
In the light of the above, we think of the CTC returning to the initial
tumor site and fueling the primary tumor growth or even grow a new tumor as a
particular case of complete holography (i.e. a hologram which does not
represent only the virtual objects image, but becomes the very object - which
we believe, is a characteristic of the living organisms).
5.2. Hypoxia and Cancer
75
environment as well as initiate the vascularisation process that will increase the
local oxygen supply. Central in the hypoxic response is the angiogenic shift,
with production of potent angiogenic factors such as vascular endothelial
growth factor (VEGF). Hypoxia is present in many solid malignancies, and the
mean oxygen level in tumours corresponds to approximately 1.5% (Vaupel et
al., 2001). This is partly due to the abnormal vascularisation in tumours, which
is insufficient in supplying oxygen to the sometimes rapidly expanding
malignant lesion. Besides the generally impaired oxygen supply, there are also
areas with an acute lack of oxygen, resulting in necroses and widespread cell
death. In breast cancer these types of necrotic processes are often associated
with clinically aggressive behaviour. Markers for hypoxia such as HIF-1a have
also been linked to highly malignant features and are potentially relevant
prognostic markers for identifying subgroups of breast cancer with certain
malignant properties (Harris, 2002; Kimbro & Simons, 2006). There is an
ongoing debate whether hypoxia contributes to more aggressive tumours or if
aggressive tumours have more widespread hypoxia, and seemingly one
explanation does not necessarily exclude the other. Recent research focusing on
hypoxic responses and delineation of important regulators of hypoxia has
clearly indicated that the hypoxia response in tumours can be used to define
novel treatment strategies (ODonnell et al., 2006). The future arsenal of novel
cancer therapies will most certainly include specific targeting of hypoxic
processes.
Human cancers are characterized by intratumoral hypoxia that results
from dysregulated cell proliferation. Physiological responses triggered by
hypoxia impact on all critical aspects of cancer progression, including
immortalization,
transformation,
differentiation,
genetic
instability,
angiogenesis, metabolic adaptation, autocrine growth factor signaling, invasion,
metastasis, and resistance to therapy.
We assume the relationship between hypoxia and aggressive tumors may
be due to the presence of the coherent wave laser with oxygen of metastatic
tumor cells in the area, where the produced oxygen gradients lead to oxygen
consumption. It has been already shown that laser photocoagulation is effective
in the treatment of diabetic retinopathy, in a series of major studies (Lovestam
et al., 2000; McCarty et al., 2000; Fong et al., 1999; Dogru et al., 1999). The
oxygen-consumption may be based on a multilayer solution to Ficks law of
diffusion, yet the essence is that the oxygen consumption is greatest where the
oxygen gradient changes most rapidly (Yu et al., 2005; Cringle et al., 2002;
Cringle et al., 2002).
All the above considerations and hypoxias impact on all critical aspects
of cancer progression support the ideea that, the metastatic tumor cells moving
through the systemic circulation (and not necessarily inthere), may be
considered a travelling wave chemically pumped type laser with oxygen.
76
6. General
1. Cancer does not conform to simple mathematical principles. Its
irregular mode of carcinogenesis, erratic tumor growth, variable response to
tumoricidal agents, and poorly understood metastatic patterns constitute highly
variable clinical behavior. Defining this process requires an accurate
understanding of the interactions between tumor cells and host tissues and
ultimately determines prognosis. Applying time-tested and evolving
mathematical methods to oncology may provide new tools with inherent
advantages for the description of tumor behavior, selection of therapeutic
modes, prediction of metastatic patterns, and providing an inclusive basis for
prognostication. Mathematicians describe equations that define tumor growth
and behavior, whereas surgeons actively deal with biological processes.
Mathematics in oncology applies these principles to clinical settings.
2. The main conclusions of this paper are as follows:
i) mathematics of cancer proves to be chaotic and highly non-linear,
justifying the use of space(-time) non-differentiability as a starting base model;
ii) a chaotic multi-scale cancer-invasion model is manufactured, which
embeds a Lorenz attractor in its solutions;
iii) since laser can be expressed as a Lorenz system, we may assume
some correspondences between the laser and the above mentioned chaotic
multi-scale cancer-invasion model;
iv) the basic model for solid tumor growth admits a travelling wave
solution;
v) we suggest that metastatic tumor cells which move through the
systemic circulation are similar to a coherent wave, i.e. a travelling wave
chemically pumped type laser with oxygen;
vi) we assume the extracellular matrix and in particular, the tumor
microenvironment are non-differential media endowed with holographic
properties (capacity to memorize, interference abilities and source of forces);
vii) the two well known phenomena: tumor self-seeding by CTC and
hypoxia, in our opinion, both support the ideea of complete holography (a
hologram which becomes the very object in the particular case of living
organisms).
3. Experimentally testable, mathematics applied in oncology may provide
a framework to determine clinical outcome on a patient-specific basis and
increase the growing awareness that mathematical models help simplify
seemingly complex and random tumor behavior.
REFERENCES
***
77
Agop M., Forna N., Casian-Botez I., Bejenariu I. C., J. Comput. Theor. Nanosci., 5,
483-489 (2008).
Agop M., Nica P. E., Gurlui S., Foca C., Pun V. P., Colotin M., Implications of an
Extended Fractal Hydrodynamic Model. Eur. Phys. J., D, 56(3) 405-419 (2010).
Agop M., Nica P. E., Ioannou P. D., Antici A., Pun V. P., Fractal Model of the Atom
and Some Properties of the Matter through an Extended Model of Scale
Relativity. Eur. Phys. J. D., 49, 239-248 (2008).
Agop M., Niculescu O., Timofte A. et al., Non-Differentiable Mechanical Model and
Its Implications. Int. J. Theor. Phys., 49(7), 1489-1506 (2010).
Chiarugi P., Giannoni E., Anoikis: A Necessary Death Program for Anchoragedependent Cells. Biochemical Pharmacology, 76, 1352-1364 (2008).
Cringle S..J., Yu D.-Y., Yu P. K., Su E.-N., Intraretinal Oxygen Consumption in the Rat
in Vivo. Invest. Ophthalmol. Vis. Sci., 43, 1922-1927(2002).
Cringle S..J., Yu D-Y., A Multi-layer Model of Retinal Oxygen Supply and
Consumption Helps Explain the Muted Rise in Inner Retinal PO2 During
Systemic Hyperoxia. Comp. Biochem Physiol., 132, 61-66 (2002).
Dogru M., Nakamura M., Inoue M., Yamamoto M., Long-term Visual Outcome in
Proliferative Diabetic Retinopathy Patients after Panretinal Photo-coagulation.
Jpn. J. Ophthalmol., 43, 217-224 (1999).
Enderling H., Anderson A.R.A., Chaplain M.A.J., Beheshti A., Hlatky L., Hahnfeldt P.,
Paradoxical Dependencies of Tumor Dormancy and Progression on Basic Cell
Kinetics. Cancer Research, 69(22), 8814-8821 (2009).
Fong D. S., Ferris F. L. III, Davis M. D., Chew E. Y., Causes of Severe Visual Loss in
the Early Treatment Diabetic Retinopathy Study. ETDRS Report no. 24, Early
Treatment Diabetic Retinopathy Study Research Group. Am. J. Ophthalmol.,
127, 137-141 (1999).
Framson P. E., Sage E. H., SPARC and Tumor Growth: Where the Seed Meets the Soil.
Journal of Cellular Biochemistry, 92, 679-690 (2004).
Giannoni E., Buricchi F., Grimaldi G. et al., Redox Regulation of Anoikis: Reactive
Oxygen Species as Essential Mediators of Cell Survival. Cell Death and
Differentiation, 15, 867-878 (2008).
Harris A. L., Hypoxia A Key Regulatory Factor in Tumour Growth. Nat. Rev. Cancer,
2, 38-47 (2002).
Hofmann U. B., Houben R., Brocker E. B., Becker J. C., Role of Matrix Metalloproteinases in Melanoma Cell Invasion. Biochimie, 87, 307-314 (2005).
Ibnescu R., Hanganu L. C., Modeling and Simulation of Mechanical Systems (I) The
Bond-Graph Model and The Block Diagram Model. Bul. Inst. Polit. Iai,
L(LIV), 6A, s. Construcii de Maini, 271-276 (2006).
Ibnescu R., Hanganu L. C., Modeling and Simulation of Mechanical Systems. (I)
Comparison Between the Lagranges Equations Method and The Bond- Graph
Method. Bul. Inst. Polit. Iai, L(LIV), 6A, s. Construcii de Maini, 263-270
(2006).
Kim Mi-Y., Oskarsson T., Acharyya S., Nguyen D. X., Zhang X. H.-F., Norton L.,
Massagu J., Tumor Self-seeding by Circulating Cancer Cells. Cell, 139, 13151326 (2009).
Kimbro K.S., Simons J.W., Hypoxia-inducible Factor-1 in Human Breast and Prostate
Cancer. Endocr. Relat. Cancer, 13, 739-749 (2006).
78
Lopez-Otin C., Palavalli L. H., Samuels Y., Protective Roles of Matrix Metalloproteinases: From Mouse Models to Human Cancer. Cell Cycle, 8, 3657-3662
(2009).
Lovestam M.A, Agardh E., Photocoagulation of Diabetic Macular Oedema: Complications and Visual outcome. Acta Ophthalmolm. Scand., 78, 667-671 (2000).
Mazilu N., Agop M., Fizica Procesului de Masur. Ed. tefan Procopiu, Iai, 1994.
McCarty C. A., McKay R., Keeffe J. E., Management of Diabetic Retinopathy by
Australian Ophthalmologists. Working Group on Evaluation of the NHMRC
Retinopathy Guideline Distribution, National Health and Medical Research
Council. Clin. Exp. Ophthalmol., Vol. 28, 2000, pp. 107-112.
Norton L., Massagu J., Is Cancer a Sisease of Self-seeding? Nature Medicine, 12, 875878 (2006).
ODonnell J. L., Joyce M. R., Shannon A. M., Harmey J., Geraghty J., Bouchier-Hayes
D., Oncological Implications of Hypoxia Inducible Factor-1alpha (HIF-1alpha)
Expression. Cancer Treat. Rev., 32, 407-416 (2006).
Pupa S. M., Menard S., Forti S., Tagliabue E., New Insights into the Role of
Extracellular Matrix During Tumor Onset and Progression. Journal of Cellular
Physiology, 192, 259-267 (2002).
Svoboda K. K., Fischman D. A., Gordon M. K., Embryonic Chick Corneal Epithelium:
A Model System for Exploring Cell-matrix Interactions. Developmental
Dynamics, 237, 2667-2675 (2008).
Vaupel P., Kelleher D. K., Hockel M., Oxygen Status of Malignant Tumors:
Pathogenesis of Hypoxia and Significance for Tumor Therapy. Semin. Oncol.,
28, 29-35 (2001).
Vaupel P., The Role of Hypoxia-induced Factors in Tumor Progression. Oncologist, 9,
Suppl. 5, 10-17 (2004).
von Kempen L. C., Ruiter D. J., van Muijen G. N., Coussens L. M., The Tumor Microenvironment: a Critical Determinant of Neoplastic Evolution. European Journal
of Cell Biology, 82, 539-548 (2003).
Wu Y., Zhou B. P., Inflammation: A Driving Force Speeds Cancer Metastasis. Cell
Cycle, 8, 3267-3273 (2009).
Yu D.-Y., Cringle S. J., Su E., Yu P. K., Humayun M. S., Dorin G., Laser-Induced
Changes in Intraretinal Oxygen Distribution in Pigmented Rabbits. Invest.
Ophthalmol. Vis. Sci., 46(3), 988-999 (2005).
UN NOU MODEL AL CARCINOGENEZEI I PROGRESIEI TUMORALE N
CADRUL DINAMICII NELINIARE (III)
(Rezumat)
Se arat c matricea extracelular i n particular micromediul tumoral se
comport ca un mediu fractal ce prezint proprieti holografice, capacitate de
memorizare, coeren, surs de for prin intermediul energiei informaionale etc. Se
trag concluziile generale asupra modelului.
2"
80
1. Introduction
Modification of polymers has received greater attention in light of the
scarcity of starting materials required for the synthesis of new monomers to
deliver better polymeric materials (Bhattacharya et al., 2009). Modification is
essential to meet various challenges, as it is very difficult to get new polymers
(Gupta et al., 2003). Surface and bulk properties can be improved easily by
modifying conventional polymers (Kato et al., 2003). The grafting method is
extremely attractive as the modified biomaterial is obtained in the purest form
possible (Ulbricht, 2006). The grafting is applicable to almost all polymermonomer combinations with enormous possibilities of physico-chemical and
biological characteristics both on the surface and in the bulk matrix (Kato K. et
al. 2003). The degree of grafting may be easily controlled by the careful
variation of the radiation exposure (Gupta B. et al., 2003). Although there are
different ways to synthesize graft copolymers, radiation methods have become
the most versatile in terms of the physico-chemical behavior of the modified
materials (Ulbricht, 2006). These methods provide materials with high level of
purity; they are surface-selective or may lead to the bulk modification of the
matrix as well (Gao et al., 2005). The modification involves treatment of the
polymer surface with UV radiation to activate the surface or the bulk,
respectively. This activated surface is subsequently treated with a polymerizable
monomer under appropriate conditions so that the monomer is grafted on the
polymer (Praschak et al., 1998).
Grafting has several advantages: (1) the ability to modify the polymer
surface to have very distinct properties through the choice of different
monomers, (2) the ease and controllable introduction of graft chains with a high
density and exact localization of graft chains to the surface with the bulk
properties unchanged, and (3) covalent attachments of graft chains onto a
polymer surface assuring long-term chemical stability of introduced chains, in
contrast to physically coated polymer chains (Ulbricht, 2006; Praschak et al.,
1998; Gopal et al., 2007).
UV irradiation method: UV radiation interacts with the substance in the
primary stages by the mechanism of excitation of its atoms and molecules.
Exposure of polymers to ultraviolet radiation can lead to extensive physical and
chemical modification of polymeric materials (Jiangxi, 2008; Safrany, 2002).
These changes in properties may have both detrimental and beneficial
consequences in determining the end uses of polymer. It is beneficial in the
sense that it can cause cross-linking and grafting on the surface of the polymers
but on the other hand it may cause chain scission (breaking of bond) as well,
thus damaging the polymer (Gopal et al., 2007).
81
2. Experimental
Commercial Polypropylene (PP) membranes with thickness = 80 m
were purchase from SC CEPROINV SA. The monomer used was acrylamide
82
83
kinetics of drug release into human body from DDS with different forms and
shapes.
In this paper we analyzed how the surface energy of polypropylene
membranes are modified when different method for UV grafting were applied.
The contact angle of water and ethanol for PP membranes was measured before
and after physical treatments, and some important parameters for surface energy
were evaluated:
1. Work of Adhesion. Defined as the work required separating the liquid
and solid phases, or the negative free energy associated with the adhesion of the
solid and liquid phases. It is used to express the strength of the interaction
between the two phases. It is given by the Young-Dupre equation as
Wa = LV (1 + cos ) ,
(1)
WS = LV (cos 1) .
(2)
T = LV cos .
(3)
This value, the product of the cosine of the contact angle and the surface
tension, also represents the wetting force normalized for length. It allows for a
characterization of the strength of the wetting interaction without separate
measurement of surface tension.
4. Critical Surface Tension. Using a series of homologous liquids of
differing surface tensions a graph of cos versus LV is produced. It will be
found that the data form a line which approaches cos = 1 at a given value of
C .
5. Surface polarity represent the ratio of SP to S , where S is the surface
free energy, and SP and SD the contributions of non-polar and polar forces,
respectively.
In Figs. 2 and 3 are represented contact angle of water and ethanol, for all
three methods of grafting, versus UV exposure time.
From these representations we can se that the contact angles of water
decrease after UV grafting process. The UV-photo grafted membranes which
contain glucose as template are maintained hydrophobic but the contact angle
84
decrease from 113.32 degree to 108 but no more than 93.03. A decrease, for 15
minutes of UV irradiation, followed by an increase of water contact angle, for
30 minutes than can be seen for Method I and III. The reverse can be seen for
Method II. This phenomenon can be explained taking into account the
preparation methods. In Methods I and II the polymeric membranes were
irradiated in the same time or immediately after the immersion in
template/monomer solution, so this could explain why at the surface of the
polymeric films are more polar groups. This phenomenon is sustained by the
comportment of surface polarity, represented in Fig. 3. The ethanol contact
angle decrease with UV irradiation time, for all three methods used to graft
polypropylene membranes. A little increase of contact angle can be seen for
Method III.
In Figs. 6 and 7 are represented the negative free energy associated with
spreading liquid (water and ethanol respectively) over solid surface of
polypropylene membranes functionalized with Glucose.
As we can notice for water work of spreading decrease for 15 minutes
UV irradiation and than increase for 30 minutes, in cases of Method I and III.
The reverse can be observed for Method II. The ethanol work of spreading
increase for all protocol of UV grafting, but a slow decrease can be seen in case
II and III.
85
As we can see the wetting tension for water and ethanol respectively,
from Figs. 7 and 9, have the same behavior like water and ethanol work of
spreading.
Fig. 8 Wetting tension for water versus Fig. 9 Wetting tension for ethanol versus
UV exposure time.
UV exposure time.
Table 1
Contributions of non-polar and polar forces to the surface free energy
of PP membranes
Sample
SP
SD
Ungrafted
SI_15
SI_30
SI_60
SII_15
SII_30
SII_60
SIII_15
SIII_30
SIII_60
28.6
32.38
71.9
22.96
66.41
37.78
51.55
30.88
45.12
32.52
12.05
4.15
65.17
0.003
50.1
5.65
24.32
2.71
22.97
4.18
40.65
36.53
137.07
22.963
116.51
43.43
75.87
33.59
68.09
36.7
In Table 1 are listed the contributions of non-polar and polar forces to the
surface free energy of PP membranes. The samples were noted: I, II, and III,
means the preparation methods, 15, 30 and 60 means UV irradiation time.
86
87
He D., Susanto H., Ulbricht M., Photo-irradiation for Preparation, Modification and
Stimulation of Polymeric Membranes. Progress in Polymer Science, 34, 62-98
(2009).
Jiangxi D. H., Surface-selective and Controllable Photo-grafting for Synthesis of
Tailored Macroporous Membrane Adsorbers. Essen, 2008.
Kato K., Uchida E., Kang E., Uyama Y., Ikada Y., Polymer Surface with Graft Chains.
Prog. Polym. Sci., 28, 209-259 (2003).
Lisboa P., Gilliland D., Ceccone G., Valsesia A., Rossi F., Surface Functionalisation of
Polypyrrole Films Using UV Light Induced Radical Activation. Applied Surface
Science, 252(13), 4397-4406 (2006).
Praschak D., Bahners T., Schollmeyer E., PET Surface Modifications by Treatment with
Monochromatic Excimer UV Lamps. Appl. Phys. A, 66, 69-75 (1998).
Romero-Sancheza M. D., Pastor-Blasa M. M.,. Martn-Martneza J. M., Walzak M.J.,
Addition of Ozone in the UV Radiation Treatment of a Synthetic Styrenebutadiene-styrene (SBS) Rubber. International Journal of Adhesion & Adhesives,
25(44), 358-371 (2005).
Rou L., Cacaval C.N., Rou D., Effect of UV Radiation on Some Polymeric Networks
Based on Vinyl Ester Resin and Modified Lignin. Polymer Testing, 28(3), 296300 (2009).
Safrany A., Preparation of Patterned Surfaces and Microspheres Using Radiation
Processing Techniques, Radiation synthesis and modification of polymers for
Biomedical Applications. IAEA, Vienna, 2002, pp. 179-191.
Ulbricht M., Advanced Functional Polymer Membranes. Polymer, 47, 2217-2262
(2006).
Waldman W., De Paoli M., Photodegradation of Polypropylene/polystyrene Blends:
Styrenee Butadienee Styrene Compatibilisation Effect. Polymer Degradation and
Stability, 93(1), 273-284 (2008).
STUDIUL ENERGETICII SUPRAFEEI MEMBRANELOR DE POLYPROPILEN
FUNCIONALIZATE CU GLUCOZ OBINUTE PRIN GREFARE CU
AJUTORUL RADIAIILOR UV
(Rezumat)
n aceast lucrare s-a urmrit modul n care se modific principalii parametrii ce
caracterizeaz energia de suprafa a membranelor din polipropilen ca urmare a
funcionalizrii acestora cu ajutorul radiaiilor din domeniul UV. Membanele
comerciale din polipropilen (PP), cu grosime = 80 m au fost grefate cu glucoz
folosind radiaiile din domeniul UV emise de o lamp de vapori de mercur de tip HBO200, n aer, la temperatura camerei. n acest scop s-au aplicat trei metode diferite de
preparare. Metoda I: iradierea UV a membranei de PP imersat ntr-o soluie omogen
de monomer/template timp de 15, 30 i 60 minute. Metoda II: membranele de PP sunt
iradiate UV acelai timp, iar apoi au fost imersate timp de 24 de ore n soluia
monomer/template. Metoda III: filmele polimere au fost inute n soluia
monomer/template pentru 24 de ore, apoi iradiate UV timp de 15, 30 i 60 minute.
Soluia omogen monomer/template const din: 2mm Acrylamid (AAm), 80mm
N , N , -Methylen(bis) acrylamid MBAAm, 2mm Glucoz i ap. Toate membranele
88
90
1. Introduction
In recent years there is an increasing in the elaboration of new tools for elearning to prepare students for a useful career. Concerning the development of
powerful tools for the students who study Physics we point out the elaboration
of physics simulations, Virtual Physics Laboratories, Virtual Physics Tests and
video presentations that are used for improving the students knowledge
(Escalada et al., 1996; Radinschi et al., 2008; Murariu & Toma; Murariu;
Radinschi et al., 2007; Radinschi et al., 2010; Macas-Daz & Puri, 2007). All
these e-learning tools play the important role of acquire and transmit
knowledge. They are very useful for all the students, and especially for the
students who are away from the universities and for the students from
campuses. With the aid of these tools a rapid interaction can be also established
between teacher and students and between students, through the attached chat
window or Forum. The teacher and the students themselves can also interact by
e-mail.
We consider that a good student has to be prepared for the demands of
college work, well informed and guided and participate in activities to enhance
knowledge of physics. For this purpose we have developed a useful physics
environment creating a Virtual Physics Laboratory (Radinschi & Aigntoaie,
2010), and making a completion of our Virtual Physics Test that was designated
to the first-semester course in Physics. The results obtained by our students who
participated in these online activities make us to elaborate the online Physics
Test for the second-semester course in Physics at our faculty. We have
elaborated the on-line material taking into account the discussions with our
students and their needs for improving the level of knowledge.
The online Physics Test is developed in Adobe Flash CS4 and can be
used in pre-seminar activities, in parallel or after these and the Physics course.
The test allows students to train themselves. Together with the Virtual Physics
Laboratory contributes at the improving of students knowledge and support
them to make a real progress in the learning process.
2. Online Physics Test Developed in Adobe Flash CS4
After the experience that we had with the implementation of the first part
of the Virtual Physics Test that was integrated in the Physics curriculum we
decided to develop the second part that is designated to our students who attend
the second-semester course in Physics at our faculty. The material of our
Physics course of the second semester was adapted for the elaboration of the
online Physics Test and in this way we improve the e-learning environment that
we created in the first semester. The online Physics Test is elaborated in Adobe
Flash CS4 and contains questions from the chapters Mechanics II, Electricity
and Magnetism, Electromagnetic Waves and Solid Body Physics. The online
91
test offers students a supportive environment for learning Physics and engages
them to test their knowledge without the direct guidance of the teacher. In this
way they can easy learn the content of the Physics course and prepare for the
seminars and exams. There is a continue communication with the teacher and
with the colleagues using e-mail, the chat window and Forum. Because this
activity is free of choice and we do not impose to our student the use of the
online Physics Test we are satisfied because most of them choose to use this elearning tool. For the students who choose to use the online Physics Test the
final grade will be an average between the grade obtained in the exam and the
grade obtained in the online Physics Test. The questionnaire can be taken as
follows: the students have to access each page and choose the answer to each
question by clicking on the button. Each question has five answers and only one
of them is correct. The students have to choose the answer within a specified
time period and then they can access the next page of the questionnaire. With
the help of this application the teacher has the opportunity of testing his
students; however, the students can also test themselves, without the guidance
of a teacher. After the quiz has been scored, an information page will appear,
comprising the description of the results for the scores. Thus, at the end of the
test the students will be provided with an overview of their answer s and they
will be able to see the points they have gained.
In Fig. 1 we present a page of the online Physics Test.
92
We present below the main part of the code developed in Adobe Flash
CS4 for the example page of the online Physics Test.
// The setup function removes the old question & answers and places current
questions & answers in qHolder.
function setup():void
// declare local useful variables
var j:int;
// remove all of qHolder's children to clear content of the previous question.
while (qHolder.numChildren > 0)
{
qHolder.removeChild(qHolder.getChildAt(0));
}
// update question counter
txtCounter.text = "[ " + String(index+1) + " / " + String(nrOfQuestions) + " ]";
//
clear
feedback
for
the
new
question
txtFeedback_txt.text="";
//
text
formatting
of
the
questions
var qFormat:TextFormat = new TextFormat('Arial', qSize, qColor);
//
text
formatting
of
the
answers
var aFormat:TextFormat = new TextFormat('Arial', aSize, aColor);
// We build the text field according to specified parameters and add it as a child of
qHolder.
var qField:TextField = new TextField();
displayWidth;
//qField.height=qHeight;
// question field properties: position, size, formationg and content
qField.x=10;
qField.y=5;
qField.multiline=true;
qField.wordWrap=true;
qField.defaultTextFormat=qFormat;
//
set
the
format
qField.text = String(index+1) + ". " + arrQuestionsText[index]; // content
//
add
question
text
field
to
qHolder
qHolder.addChild(qField);
mcChoice1_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice1_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*0;
mcChoice2_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice2_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*1;
mcChoice3_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice3_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*2;
mcChoice4_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice4_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*3;
mcChoice5_mc.x
=
qHolder.x
+
qField.x
+
50;
mcChoice5_mc.y = qHolder.y + qField.y + 50 + qSize + (aSize+60)*4;
// create array to hold radio buttons for all choices
if(arrQuestionsType[index] == 0) // text
{
arrChoicesRb = new Array(arrChoicesText[index].length);
// add choices to qHolder
for (j=0; j<arrChoicesText[index].length; j++)
{
// set up each radio button
arrChoicesRb[j] = new RadioButton();
arrChoicesRb[j].label = arrChoicesText[index][j];
arrChoicesRb[j].value = j;
arrChoicesRb[j].width = qField.width;
arrChoicesRb[j].x = qField.x + 20;
arrChoicesRb[j].y = qField.y + 40 + qSize + (aSize+20)*j;
arrChoicesRb[j].group = rbg;
// add each as a child of qHolder
qHolder.addChild(arrChoicesRb[j]);
mcChoice1_mc.visible = false;
mcChoice2_mc.visible = false;
mcChoice3_mc.visible = false;
mcChoice4_mc.visible = false;
mcChoice5_mc.visible = false;
}
}
else // formula, use the mc
{
arrChoicesRb = new Array(arrQuestionsType[index]);
for (j=0; j<arrQuestionsType[index]; j++)
{
// set up each radio button
arrChoicesRb[j] = new RadioButton();
arrChoicesRb[j].label = "";
arrChoicesRb[j].value = j;
arrChoicesRb[j].width = qField.width;
arrChoicesRb[j].x = qField.x + 20;
arrChoicesRb[j].y = qField.y + 40 + qSize + (aSize+60)*j;
arrChoicesRb[j].group = rbg;
// add each as a child of qHolder
qHolder.addChild(arrChoicesRb[j]);
mcChoice1_mc.visible = true;
mcChoice2_mc.visible = true;
mcChoice3_mc.visible = true;
mcChoice4_mc.visible = true;
mcChoice5_mc.visible = true;
mcChoice1_mc.gotoAndStop(index.toString());
mcChoice2_mc.gotoAndStop(index.toString());
mcChoice3_mc.gotoAndStop(index.toString());
mcChoice4_mc.gotoAndStop(index.toString());
93
94
mcChoice5_mc.gotoAndStop(index.toString());
switch(j)
{
case 0: { mcChoice1_mc.mcQ_mc.gotoAndStop(j+1); } break;
case 1: { mcChoice2_mc.mcQ_mc.gotoAndStop(j+1); } break;
case 2: { mcChoice3_mc.mcQ_mc.gotoAndStop(j+1); } break;
case 3: { mcChoice4_mc.mcQ_mc.gotoAndStop(j+1); } break;
case 4: { mcChoice5_mc.mcQ_mc.gotoAndStop(j+1); } break;
default: {} break;
}
}
}
arrChoicesRb[arrChoicesUser[index]].selected = true;
//trace("User choice: " + arrChoicesUser[index] );
// Set the initial selection for the radio button group.
//arrChoicesRb[arrChoicesUser[index]].selected = true;
// Move the check button (already on the stage) to an appropriate spot below qHolder.
if(0 == index){ // first question
btnPrevQ_btn.visible = false;
btnNextQ_btn.visible = true;
mcResults_mc.visible = false;
}
else if(nrOfQuestions-1 == index){ // last question
btnPrevQ_btn.visible = true;
btnNextQ_btn.visible = false;
mcResults_mc.visible = true;
}
else{ // intermediate question
btnPrevQ_btn.visible = true;
btnNextQ_btn.visible = true;
mcResults_mc.visible = false;
}
95
the number of male students is greater that the increasing in the number of
female students.
Students percentage (%)
100
90
80
70
60
50
40
30
20
10
0
First semester 2010
Fig. 2 Statistic about the students who used the online Physics Test,
performed by semester.
96
Second semester
2010 female
First semester
2010 male
Second semester
2010 male
Fig. 3 Percentage of students who have worked with the online Physics Test,
performed by gender
3. Concluding Remarks
1. The online Physics Test is a good tool that engages our students in
challenging learning experiences. The students can test their knowledge without
the direct supervision of the teacher and improve their final grade. We give
them the opportunity to save the online Physics Test on their computers and
work with it at home or in campus. The online Physics Test asks a good
understanding of the content of the Physics course and also of other
bibliographic items. Using the provided material the students will be well
prepared for the seminars and exams.
2. We notice an improvement in the understanding of the chapters of
Physics that we teach and also an increasing in the number of students who use
the online Physics Test and who want to improve their final grade with this elearning tool. We also point out that the male students have a greater confidence
to use the test than the female students. The majority of students successfully
have improved their final grade on average over two semesters. For determining
what problems the remaining percentage of students faced we have to discuss
with them and to work more together or to propose them to work more in
groups with their colleagues.
97
3. From our analysis, we aim at deriving what a better online Physics Test
could be and how we can improve it. As a conclusion, very important for
improving the learning process has been to bring the pieces together, the Virtual
Physics Laboratory, the Physics Course and seminars and the Virtual Physics
Test designated for the first and second semester at our faculty. Having these elearning tools our students are able to access a well structured material, evaluate
information, solve problems, interprets formulae, work in teams, discuss and
make progresses.
4. Our strategy to integrate the physics simulations, the Virtual Physics
Lab and the online Physics Test in the Physics curriculum has contributed to our
success to attract more students to use these tools and to improve their results in
Physics learning, and obtain a better grade at the exams.
5. As a future project we intend to increase the number of questions of the
online Physics Test for testing the students performance.
REFERENCES
Escalada L.T., Grabhorn R., Zollman D.A., Application of Interactive Digital Video in a
Physics Classroom, Journal of Educational Multimedia and Hypermedia, 5, 1,
73-97 (1996).
Radinschi I., Scripcariu L., Ciobanu B., Frunz M. D., Online Quizzes, an Application
of PHP-Triad and MySQL. Romanian Journal of Physics, 53(1-2), 423-427
(2008).
Murariu G., Toma D., A Note about the Simulation Programs for Heat and Molecular
Physics Laboratory. xxx.lanl.gov physics/0505053.
Murariu G.,, Interactive Computer Simulations of Electrokinetic Physics Phenomena.
xxx.lanl.gov physics/0609215
Radinschi I., Frunz M.D., Ciobanu B.nline Virtual Model for Testing the Knowledge,
In IATED, Eds., Proceedings of International Technology, Education and
Development Conference INTED 2007, March 7-9; Valencia, Spain, 2007, pp.
42-47.
Radinschi I., Damoc C., Cehan A., Cehan V., Computer Simulations of Physics
Phenomena Using Flash. 5th International Conference on Hands-on Science
Formal and Informal Science Education, October 13-17, 2008, Espao Cincia,
Olinda-Recife, Brazil, Edited by Manuel Filipe Pereira da Cunha Martins Costa
(Universidade do Minho), Jos Benito Vazquez Dorro (Universidade de Vigo),
Antnio Carlos Pavo (Espao Cincia), Mikiya Muramatsu (Universidade de
So Paulo), 2008, pp. 147-151; Radinschi I., Damoc C., Cehan A., Cehan V.,
The Role of Computer simulations in Teaching-learning Process. In Research,
Reflections and Innovations in Integrating ICT in Education, pp. 1450 1454,
Zurbaran 1, 2a Planta, Oficina 1, 06002 Budajoz, Spain, BA-224-2009 (Book
contains a compilation of paper presented at the V International Conference on
Multimedia and Information & Communication Technologies in Education mICTE2009, Lisbon, Portugal); Radinschi I., Damoc C., Aignatoaie B., Cehan V.,
Improving the e-Learning of Engineering Physics with the Aid of Adobe Flash,
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