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1. In search of triple-negative DCIS: tumor-type dependent model of breast cancer
progression from DCIS to the invasive cancer.
Kurbel S.
Tumour Biol. 2012 Dec 4. [Epub ahead of print]
Department of Physiology, Osijek Medical Faculty, J Huttlera 4, 31000, Osijek,
Croatia, sven@jware.hr.
This paper is based on the idea that ductal breast cancer in situ (DCIS) precedes
the invasive breast cancer (invBC), although the triple-negative invBCs almost
lack their DCIS precursor. Reported incidences of breast tumor types in DCIS and
in invasive BCs suggest that probabilities of tumor progression might differ
among tumor types, and these differences can have some impact on our patients.
Reported data from several papers on incidences of the four breast tumor
types-luminal A, luminal B, HER2, and triple negative-are used to compare
tumor-type incidences for DCIS and for the invasive BC. The pooled distributions
differed (? (2)?=?97.05, p?<?0.0001), suggesting a strong selection pressure that
reduces the number of triple-negative DCIS lesions at the time of breast tumor
diagnosis. Reported shares of DCIS in all newly diagnosed breast cancers range in
large screening trials from 9 to 26 %, so in making a population model, three
values are arbitrarily chosen: one DCIS out of ten breast cancers (the 10 %
share), one DCIS out of seven breast cancers (one seventh or the 14.3 % share),
and one out of five (the 20 % share). By using these shares and the pooled data
of tumor-type incidences, values are calculated that would be expected from a
hypothetical population in which types of DCIS and invasive BC are distributed
accordingly to the reported incidences. The model predicts that the shares of
breast cancer tumor types in the modeled population (DCIS plus invasive BCs) are
39 % for luminal A, 20 % for luminal B, 11 % for HER2 positive, and 30 % for the
triple-negative cancers. Some 59 % of all breast tumors are expected to be
hormone receptor positive, and HER2 to be overexpressed in 31 %. Simulated
probabilities of tumor progression were used to calculate the number of tumor
progression t(1/2) that has passed before the time of diagnosis. Calculated
relative t(1/2) durations in the modeled population suggest that the
triple-negative DCIS cases were fastest in tumor progression, three times faster
than the HER2-positive tumors and near twice as fast as luminal A. Luminal A is
the model slower than luminal B DCIS, suggesting that although their progression
depends on estrogen exposure, HER2 overexpression in luminal B tumors adds some
speed in tumor progression. The model results suggest that quick tumor
progression might be the main feature of the triple-negative breast tumors,
leading to seldom triple-negative DCIS at the time of breast cancer diagnosis.
Applying approach of the presented model to the real data from a well-defined
population seems warranted.
PMID: 23208673 [PubMed - as supplied by publisher]
2. Can estrogen receptor overexpression in normal tissues due to previous estrogen
deprivation explain the fulvestrant efficacy in breast cancer therapy?
Kurbel S.
Med Hypotheses. 2012 Dec;79(6):869-71. doi: 10.1016/j.mehy.2012.09.010. Epub 2012
Oct 10.
Department of Physiology, Osijek Medical Faculty, Osijek, Croatia. Electronic
address: sven@jware.hr.
Fulvestrant is a down-regulator of estrogen receptors (ERs) with still evolving
optimal dosage for ER-positive breast cancer patients. The CONFIRM phase III
trial in women with advanced breast cancer proved fulvestrant 500-mg to be
associated with a longer time till progression (TTP) than the 250-mg schedule.
Detailed results suggest that the fulvestrant in both schedules depended on the
previous endocrine therapy. All complete responses and the only significant TTP
difference between the two schedules was found among women previously treated
with tamoxifen (TAM) and not in women after aromatase inhibitors (AIs). Noting
that TAM competes with estrogen binding to ERs is important, so the optimal TAM
dosage produces drug concentrations comparable to concentrations of available ER
ligands. All AIs diminish production of the main ER ligand, so the optimal AI
dosage depends on the overall pool of aromatase molecules in the body. Both
treatments are not directly related to the pool of available ERs in the body.
Here proposed interpretation is that estrogen deprivation due to years of
endocrine breast cancer therapy increases ER expression in breast cancer cells
and in other healthy estrogen target tissues. The breast cancer exposure to
fulvestrant depends on the presence of all ERs in the body. Only when this
overall pool is sufficiently saturated with fulvestrant, we can expect to achieve
some breast cancer response due to down-regulation of ER in cancer tissue. The
CONFIRM data suggest that among patients switching from TAM to fulvestrant, only
the 500-mg schedule could down-regulate the moderately enlarged total body ER
pool and thus induce breast cancer regression. In patients switching from
previous AI treatments, both 250 and 500-mg schedules were unable to prolong the
TTP, suggesting that in both doses, fulvestrant showed no efficacy since the
overall ER pool was more enlarged after AIs. Fulvestrant might be more effective
before TAM and AIs, in the first line endocrine therapy of metastatic breast
cancer, since an unaltered ER pool in normal tissues is expected in this setting.
Copyright © 2012 Elsevier Ltd. All rights reserved.
PMID: 23062772 [PubMed - in process]
3. A phase plane graph based model of the ovulatory cycle lacking the "positive
feedback" phenomenon.
Kurbel S.
Theor Biol Med Model. 2012 Aug 7;9:35. doi: 10.1186/1742-4682-9-35.
Dept, of Physiology, Osijek Medical Faculty, J Huttlera 4, Osijek, 31000,
Croatia. sven@jware.hr.
ABSTRACT: When hormones during the ovulatory cycle are shown in phase plane
graphs, reported FSH and estrogen values form a specific pattern that resembles
the leaning "&" symbol, while LH and progesterone (Pg) values form a "boomerang"
shape. Graphs in this paper were made using data reported by Stricker et al.
[Clin Chem Lab Med 2006;44:883-887]. These patterns were used to construct a
simplistic model of the ovulatory cycle without the conventional "positive
feedback" phenomenon. The model is based on few well-established
relations:hypothalamic GnRH secretion is increased under estrogen exposure during
two weeks that start before the ovulatory surge and lasts till lutheolysis.the
pituitary GnRH receptors are so prone to downregulation through ligand binding
that this must be important for their function.in several estrogen target tissue
progesterone receptor (PgR) expression depends on previous estrogen binding to
functional estrogen receptors (ER), while Pg binding to the expressed PgRs
reduces both ER and PgR expression.Some key features of the presented model are
here listed:High GnRH secretion induced by the recovered estrogen exposure starts
in the late follicular phase and lasts till lutheolysis. The LH and FSH surges
start due to combination of accumulated pituitary GnRH receptors and increased
GnRH secretion. The surges quickly end due to partial downregulation of the
pituitary GnRH receptors (64% reduction of the follicular phase pituitary GnRH
receptors is needed to explain the reported LH drop after the surge). A strong
increase in the lutheal Pg blood level, despite modest decline in LH levels, is
explained as delayed expression of pituitary PgRs. Postponed pituitary PgRs
expression enforces a negative feedback loop between Pg levels and LH secretions
not before the mid lutheal phase.Lutheolysis is explained as a consequence of Pg
binding to hypothalamic and pituitary PgRs that reduces local ER expression. When
hypothalamic sensitivity to estrogen is diminished due to lack of local ERs,
hypothalamus switches back to the low GnRH secretion rate, leading to low
secretion of gonadotropins and to lutheolysis. During low GnRH secretion rates,
previously downregulated pituitary GnRH receptors recover to normal levels and
thus allow the next cycle.Possible implications of the presented model on several
topics related to reproductive physiology are shortly discussed with some
evolutionary aspects including the emergence of menopause.
PMCID: PMC3479218
PMID: 22870942 [PubMed - in process]
4.Breast cancer survival and immunohistochemical similarities between primary and
metastatic sites, as a surrogate marker for the cancer self-seeding.
Kurbel S, Dmitrovic B, Tomas I, Kristek J, Bozac M.
Int J Biol Markers. 2012 Jul 19;27(2):e167-8. doi: 10.5301/JBM.2012.9313.
PMID: 22653743 [PubMed - in process]
5. Donnan effect on chloride ion distribution as a determinant of body fluid
composition that allows action potentials to spread via fast sodium channels.
Kurbel S.
Theor Biol Med Model. 2011 May 30;8:16. doi: 10.1186/1742-4682-8-16.
Dept, of Physiology, Osijek Medical Faculty, Osijek, Croatia. sven@jware.hr
Proteins in any solution with a pH value that differs from their isoelectric
point exert both an electric Donnan effect (DE) and colloid osmotic pressure.
While the former alters the distribution of ions, the latter forces water
diffusion. In cells with highly Cl--permeable membranes, the resting potential is
more dependent on the cytoplasmic pH value, which alters the Donnan effect of
cell proteins, than on the current action of Na/K pumps. Any weak (positive or
negative) electric disturbances of their resting potential are quickly corrected
by chloride shifts.In many excitable cells, the spreading of action potentials is
mediated through fast, voltage-gated sodium channels. Tissue cells share similar
concentrations of cytoplasmic proteins and almost the same exposure to the
interstitial fluid (IF) chloride concentration. The consequence is that similar
intra- and extra-cellular chloride concentrations make these cells share the same
Nernst value for Cl-.Further extrapolation indicates that cells with the same
chloride Nernst value and high chloride permeability should have similar resting
membrane potentials, more negative than -80 mV. Fast sodium channels require
potassium levels >20 times higher inside the cell than around it, while the
concentration of Cl- ions needs to be >20 times higher outside the cell.When
osmotic forces, electroneutrality and other ions are all taken into account, the
overall osmolarity needs to be near 280 to 300 mosm/L to reach the required
resting potential in excitable cells. High plasma protein concentrations keep the
IF chloride concentration stable, which is important in keeping the resting
membrane potential similar in all chloride-permeable cells. Probable consequences
of this concept for neuron excitability, erythrocyte membrane permeability and
several features of circulation design are briefly discussed.
PMCID: PMC3118367
PMID: 21624136 [PubMed - indexed for MEDLINE]
6. Arterial hypertension due to fructose ingestion: model based on intermittent
osmotic fluid trapping in the small bowel.
Kurbel S.
Theor Biol Med Model. 2010 Jun 25;7:27. doi: 10.1186/1742-4682-7-27.
Osijek Medical Faculty, Department of Physiology, J Huttlera 4, 31000 Osijek,
Croatia. sven@jware.hr
Based on recently reported data that fructose ingestion is linked to arterial
hypertension, a model of regulatory loops involving the colon role in maintenance
of fluid and sodium homeostasis is proposed.In normal digestion of hyperosmolar
fluids, also in cases of postprandial hypotension and in patients having the
"dumping" syndrome after gastric surgery, any hyperosmolar intestinal content is
diluted by water taken from circulation and being trapped in the bowel until
reabsorption. High fructose corn sirup (HFCS) soft drinks are among common
hyperosmolar drinks. Fructose is slowly absorbed through passive carrier-mediated
facilitated diffusion, along the entire small bowel, thus preventing absorption
of the trapped water for several hours.Here presented interpretation is that
ingestion of hyperosmolar HFCS drinks due to a transient fluid shift into the
small bowel increases renin secretion and sympathetic activity, leading to rise
in ADH and aldosterone secretions. Their actions spare water and sodium in the
large bowel and kidneys. Alteration of colon absorption due to hormone exposure
depends on cell renewal and takes days to develop, so the momentary capacity of
sodium absorption in the colon depends on the average aldosterone and ADH
exposure during few previous days. This inertia in modulation of the colon
function can make an individual that often takes HFCS drinks prone to sodium
retention, until a new balance is reached with an expanded ECF pool and arterial
hypertension. In individuals with impaired fructose absorption, even a higher
risk of arterial hypertension can be expected.
PMCID: PMC2904277
PMID: 20579372 [PubMed - indexed for MEDLINE]
7. Characteristics of dietary sugars compared with their roles in body metabolism.
Kristek B, Kurbel S, Banjari I.
Adv Physiol Educ. 2010 Jun;34(2):111-4. doi: 10.1152/advan.00029.2010.
Osijek Medical Faculty, Croatia.
PMID: 20522907 [PubMed - indexed for MEDLINE]
8. Model of pulmonary fluid traffic homeostasis based on respiratory cycle pressure,
bidirectional bronchiolo-pulmonar shunting and water evaporation.
Kurbel S, Kurbel B, Gulam D, Spajić B.
Med Hypotheses. 2010 Jun;74(6):993-9. doi: 10.1016/j.mehy.2010.01.018. Epub 2010
Feb 12.
Department of Physiology, Osijek Medical Faculty, Osijek, Croatia. sven@jware.hr
The main puzzle of the pulmonary circulation is how the alveolar spaces remain
dry over a wide range of pulmonary vascular pressures and blood flows. Although
normal hydrostatic pressure in pulmonary capillaries is probably always below 10
mmHg, well bellow plasma colloid pressure of 25 mmHg, most textbooks state that
some fluid filtration through capillary walls does occur, while the increased
lymph drainage prevents alveolar fluid accumulation. The lack of a measurable
pressure drop along pulmonary capillaries makes the classic description of
Starling forces unsuitable to the low pressure, low resistance pulmonary
circulation. Here presented model of pulmonary fluid traffic describes lungs as a
matrix of small vascular units, each consisting of alveoli whose capillaries are
anastomotically linked to the bronchiolar capillaries perfused by a single
bronchiolar arteriole. It proposes that filtration and absorption in pulmonary
and in bronchiolar capillaries happen as alternating periods of low and of
increased perfusion pressures. The model is based on three levels of filtration
control: short filtration phases due to respiratory cycle of the whole lung are
modulated by bidirectional bronchiolo-pulmonar shunting independently in each
small vascular unit, while fluid evaporation from alveolar groups further tunes
local filtration. These mechanisms are used to describe a self-sustaining
regulator that allows optimal fluid traffic in different settings. The proposed
concept is used to describe development of pulmonary edema in several clinical
entities (exercise in wet or dry climate, left heart failure, people who rapidly
move to high altitudes, acute cyanide and carbon monoxide poisoning, large
pulmonary embolisms).
.
PMID: 20153588 [PubMed - indexed for MEDLINE]
9. Do Thebesian veins and arterioluminal vessels protect against myocardial edema
occurrence?
Kurbel S, Marić S, Gros M.
Med Hypotheses. 2009 Jul;73(1):38-9. doi: 10.1016/j.mehy.2009.01.042. Epub 2009
Mar 4.
Dept. of Physiology, Osijek Medical Faculty, J Huttlera 4, 31000 Osijek, Croatia.
sven@jware.hr
Thebesian veins, arteriosinusoidal and arterioluminal vessels drain blood from
heart muscle into the chambers. Thebesian veins are reported common in atria and
right ventricle, but scarce in the left ventricle. Since the left ventricle may
be less prone to edema due to its intermittent cycle of perfusion, it is here
proposed that Thebesian veins prevent myocardial edema. This is in concordance
with reports that Thebesian veins are common at the ventricle apex and at
papillary muscles base, regions prone to edema due to distance to the coronary
sinus. Thebesian veins can act as local reducers of venous hydrostatic pressure
that correct small differences in fluid filtration and maintain contractility. By
analogy, arterioluminal and arteriosinusoidal vessels might act as regulators of
local arteriolar pressure. All these vessels reduce capillary fluid filtration in
otherwise healthy tissue surrounding ischemic lesions in coronary patients and
other situations that lead to edema.
PMID: 19264425 [PubMed - indexed for MEDLINE]
10. Complexity of human circulation design: tips for students.
Kurbel S, Gros M, Maric S.
Adv Physiol Educ. 2009 Jun;33(2):130-1. doi: 10.1152/advan.90217.2008.
Department of Physiology, Osijek Medical Faculty, Croatia. sven@jware.hr
PMID: 19509399 [PubMed - indexed for MEDLINE]
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