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).
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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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