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Although the fields of systems and integrative biology are in full expansion, few teams are involved worldwide into the study of reproductive function from the mathematical modeling viewpoint. This may be due to the fact that the reproductive function is not compulsory for individual organism survival, even if it is for species survival. Alternatively, the complexity of reproductive physiology may be discouraging. Indeed, the hypothalamo-pituitary-gonadal (HPG) axis involves not only several organs and tissues but also intricate time (from the neuronal millisecond timescale to circannual rhythmicity) and space (from molecules to organs) scales. Yet, mathematical modeling, and especially multiscale modeling, can renew our approaches of the molecular, cellular, and physiological processes underlying the control of reproductive functions. In turn, the remarkable dynamic features exhibited by the HPG axis raise intriguing and challenging questions to modelers and applied mathematicians. In this article, we draw a panoramic review of some mathematical models designed in the framework of the female HPG, with a special focus on the gonadal and central control of follicular development. On the gonadal side, the modeling of follicular development calls to the generic formalism of structured cell populations, that allows one to make mechanistic links between the control of cell fate (proliferation, differentiation, or apoptosis) and that of the follicle fate (ovulation or degeneration) or to investigate how the functional interactions between the oocyte and its surrounding cells shape the follicle morphogenesis. On the central, mainly hypothalamic side, models based on dynamical systems with multiple timescales allow one to represent within a single framework both the pulsatile and surge patterns of the neurohormone GnRH. Beyond their interest in basic research investigations, mathematical models can also be at the source of useful tools to study the encoding and decoding of the (neuro-) hormonal signals at play within the HPG axis and detect complex, possibly hidden rhythms, in experimental time series. [ABSTRACT FROM AUTHOR]

We recently reported the synthesis of NOSH-aspirin, a novel hybrid compound capable of releasing both nitric oxide (NO) and hydrogen sulfide (H 2 S). In NOSH-aspirin, the two moieties that release NO and H 2 S are covalently linked at the 1, 2 positions of acetyl salicylic acid, i.e., ortho -NOSH-aspirin. Here we report on the synthesis of meta - and para -NOSH-aspirins. We also made a head-to-head evaluation of the effects of these three positional isomers of NOSH-aspirin on colon cancer cell kinetics and induction of reactive oxygen species, which in recent years has emerged as a key event in causing cancer cell regression. Electron donating/withdrawing groups incorporated about the benzoate moiety significantly affected the potency of these compounds with respect to colon cancer cell growth inhibition. [ABSTRACT FROM AUTHOR]

Abstract: In mammals, the number of ovulations at each ovarian cycle is determined during the terminal phase of follicular development by a tightly controlled follicle selection process. The mechanisms underlying follicle selection take place on different scales and different levels of the gonadotropic axis. These include the endocrine loops between the ovary and the hypothalamic-pituitary complex, the dynamics of follicle populations within the ovary and the dynamics of cell populations within ovarian follicles. A compartmental modelling approach was first designed to describe the cell dynamics in the selected follicle. It laid the basis for a multiscale model formulated with partial differential equations of conservation law type, resulting in the structuring of the follicular cell populations according to cell age and cell maturity. In this model, the selection occurs as a FSH (follicle stimulating hormone)-driven competition between simultaneously developing follicles. The selection output (mono-ovulation, poly-ovulation or anovulation) results from a subtle interplay between the hypothalamus, the pituitary gland and the ovaries, combined with slight differences in the initial conditions or ageing and maturation velocities of the competing follicles. This modelling approach is proposed as a useful complement to experimental studies of follicular development and in turn, the mechanisms of follicle selection raise challenging questions on the mathematical ground. [Copyright &y& Elsevier]

Abstract: In this short work, by combining the total cell evolution curve and the two-compartment model, the evolution of one of the subpopulations is simulated while the system interacts with a proliferating regulatory factor. [Copyright &y& Elsevier]

Abstract: By combining the total cell evolution curve and a two-compartment model interacting with dynamic anti-cancer agents, the evolution of subpopulations has been analytically obtained and investigated in this work. [Copyright &y& Elsevier]

Abstract: Objectives: To investigate epithelial cell turnover alterations, and p53, bcl-2 protein expression during development of early and advanced gastric cancer in a Western population. Methods: We investigated cell apoptosis and proliferation rates, p53 and bcl-2 protein expression in 17 early and 34 advanced gastric carcinomas and in the adjacent non-dysplastic mucosa. Cell proliferation, p53 and bcl-2 expression were detected immunohistochemically using MIB-1, anti-p53 and anti-bcl-2 monoclonal antibodies. Apoptosis was measured by TUNEL. The rate of the positive stained cells (labelling index) was count using image analysis technique. Results: No difference was observed of either apoptotic (10 vs. 11) or proliferation (35 vs. 25) index between early and advanced cancers. However, the apoptotic index was significantly higher in intestinal type advanced tumors. While both apoptotic and proliferation indices were significantly higher in tumors than in the adjacent mucosa, no difference was observed of either apoptotic (2 vs. 2) or proliferation (8 vs. 13) index between the tissues adjacent to early and advanced tumors. p53 protein expression was significantly higher in advanced cancers (7 vs. 5, p =0.001) and in the non-dysplastic tissue adjacent to advanced tumors (3.5 vs. 2, p =0.001). bcl-2 labelling index was significantly higher in the mucosa adjacent to advanced carcinomas (15 vs. 5, p =0.016) but this difference did not reach significance in the tumors (20 vs. 15, p =0.37). Conclusions: Our data indicate similar cell turnover during tumorigenesis of early and advanced cancer. p53 and bcl-2 protein accumulation is more intense in gastric mucosa adjacent to advanced tumors and p53 immunoreactivity peaks in advanced carcinomas. [Copyright &y& Elsevier]

Abstract: Cell kinetic concepts have pervaded radiation therapy since the early part of the 20th century and have been instrumental in the development of modern radiotherapy. In this review, the fundamental radiobiological concepts that have been developed based on cell kinetic knowledge will be revisited and discussed in the context of contemporary radiation therapy. This will include how the proliferation characteristics, variation in sensitivity during the cell cycle and the extent of radiation-induced cell cycle delay translate into a variable time for the expression of damage, how cell kinetics interacts with hypoxia and how the response to fractionated radiation schedules is influenced by cell kinetics in terms of repair, redistribution, reoxygenation and repopulation. The promise of combining radiation with new biologically targeted agents and the potential of non-invasive positron emission tomography imaging of proliferation are areas where cell kinetics will continue to influence radiotherapy practice. [Copyright &y& Elsevier]

Abstract: This paper presents a method for parametric estimation in the class of multitype Bellman–Harris branching processes when the data consist of cell counts collected on several colonies observed at discrete time points. This sampling scheme arises frequently in biology to analyze cell proliferation in tissue culture. We investigate the use of a pseudo-likelihood approach in this context. It is defined from the mean vectors and variance–covariance matrices of the numbers of cells. The proposed estimator is strongly consistent and asymptotically normal as the number of observed colonies goes to infinity. In situations where these two moments have no closed-form expressions their values can be replaced by simulation-based approximations. The resulting simulated pseudo-maximum likelihood estimator is asymptotically equivalent to the pseudo-maximum likelihood estimator as the number of simulation increases. We illustrate the proposed method via two examples, and evaluate its finite sample properties through simulations. [Copyright &y& Elsevier]

Abstract: The division tracking dye, carboxyfluorescin diacetate succinimidyl ester (CFSE) is currently the most informative labeling technique for characterizing the division history of cells in the immune system. Gett and Hodgkin (Nat. Immunol. 1 (2000) 239–244) have proposed to normalize CFSE data by the 2-fold expansion that is associated with each division, and have argued that the mean of the normalized data increases linearly with time, t, with a slope reflecting the division rate p. We develop a number of mathematical models for the clonal expansion of quiescent cells after stimulation and show, within the context of these models, under which conditions this approach is valid. We compare three means of the distribution of cells over the CFSE profile at time t: the mean, , the mean of the normalized distribution, , and the mean of the normalized distribution excluding nondivided cells, . In the simplest models, which deal with homogeneous populations of cells with constant division and death rates, the normalized frequency distribution of the cells over the respective division numbers is a Poisson distribution with mean , where p is the division rate. The fact that in the data these distributions seem Gaussian is therefore insufficient to establish that the times at which cells are recruited into the first division have a Gaussian variation because the Poisson distribution approaches the Gaussian distribution for large pt. Excluding nondivided cells complicates the data analysis because , and only approaches a slope p after an initial transient. In models where the first division of the quiescent cells takes longer than later divisions, all three means have an initial transient before they approach an asymptotic regime, which is the expected and . Such a transient markedly complicates the data analysis. After the same initial transients, the normalized cell numbers tend to decrease at a rate , where d is the death rate. Nonlinear parameter fitting of CFSE data obtained from Gett and Hodgkin to ordinary differential equation (ODE) models with first-order terms for cell proliferation and death gave poor fits to the data. The Smith–Martin model with an explicit time delay for the deterministic phase of the cell cycle performed much better. Nevertheless, the insights gained from analysis of the ODEs proved useful as we showed by generating virtual CFSE data with a simulation model, where cell cycle times were drawn from various distributions, and then computing the various mean division numbers. [Copyright &y& Elsevier]

Purpose: Tumor cell repopulation is still considered to be a major cause of failure in radiotherapy. In this study, we investigated the influence of cell kinetic parameters on the outcome of patients treated in a randomized trial of accelerated fractionation, with or without mitomycin C, vs. conventional fractionation.Methods and Materials: Sixty-two patients were studied using administration of bromodeoxyuridine (BrdUrd), and cell kinetic parameters were measured using flow cytometry. The patients were treated with either 70 Gy for 7 weeks or 55.3 Gy for 17 continuous days (V-CHART) with or without 20 mg/m2 mitomycin C on day 5.Results: The potential doubling time (Tpot) and labeling index (LI) failed to provide any prognostic information with regard to local control or survival. However, the duration of the S phase (Ts) revealed patients whose tumors had a long Ts had significantly worse local control (p = 0.028) and survival (p = 0.034) irrespective of treatment. A similar trend was evident within the different treatment arms particularly associated with overall survival.Conclusions: The Ts values of head-and-neck squamous cell cancers provided prognostic information that predicted clinical outcome irrespective of treatment schedule in this study. This neglected parameter of the Tpot method might provide information related to redistribution of cells during fractionated radiotherapy. [Copyright &y& Elsevier]

Influence of hydroxyurea (HU) on the antitumor effect of irinotecan hydrochloride (CPT-11) was investigated in ICR male mice transplanted with sarcoma 180 cells (S-180). A single dose of CPT-11 (100 mg/kg) was injected at various times after a single dose of HU (300 mg/kg). The relative tumor weight varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The higher antitumor effect of CPT-11 was observed when DNA synthesis of S-180 cells increased (20 hr), and the lower effect was observed when the DNA synthesis decreased (0 hr). The loss of body weight also varied significantly depending on the timing of CPT-11 injection after HU injection (P < 0.01). The toxicity of CPT-11 was higher when the inhibitory effect of HU on DNA synthesis of bone marrow cells was stronger (15 hr), and the lower toxicity was observed when the inhibitory effect was not observed (0 hr). The plasma SN-38 concentration at 2 hr after CPT-11 injection was higher at 20 hr after HU injection than at 0 hr after HU injection. The difference in plasma esterase activity between 0 hr and 20 hr after HU injection was regarded as the mechanism underlying the dosing time-dependent difference of the SN-38 concentration. These experiments suggest that HU can produce a different phase of cell cycle between tumor cells and normal cells. This leads to increase the antitumor effect of CPT-11 without increasing the adverse effect of the drug. It is essential to consider the dosing time in the two-drug combination therapy. [Copyright &y& Elsevier]

We here report a case of squamous cell carcinoma of the lung, with an unusually fast tumor growth rate, so fast that its early detection was impossible even with two sequential chest roentgenograms taken only 36 days apart. Literature related to the concept of cell growth kinetics was reviewed, and the tumor volume doubling time that characterizes any measurable tumor was calculated for our case accordingly, based on the single lesion found on the plain chest film, with the best possible estimation of its volume. We concluded that, to the best of our knowledge, a squamous cell carcinoma of the lung that grew so fast (with a tumor doubling time less than 7.5 days) has not yet been reported to date; neither has a bronchogenic carcinoma of any cell type been reported with such a presentation. Given that a patient aged 81 belonged to a group usually with slower growth in tumor cell kinetics, the behavior of his tumor was indeed uncommon. [Copyright &y& Elsevier]

The influence of dietary fiber on plasma glucagon and enteroglucagon (EG) and on ileal crypt cell production rate (CCPR) was assessed in the rat. A fiber-free semisynthetic diet and diets containing insoluble cellulose, Na-carboxymethylcellulose (CMC), guar gum, pectin, gum arabic, methylcelbubose (MC), and hydroxypropylmethylcellubose (HPMC) at 10 g/100 g were fed for 14 d. Animals given soluble polysaccharides had plasma EG levels significantly higher than animals given insoluble cellulose, but only those fed the most viscous gums showed evidence of increased mucosal cell proliferation in the distal ileum. It was concluded that viscous nonfermentable polysaccharide gums stimulate the release of EG in the rat by slowing the absorption of nutrient, whereas the nonviscous polysaccharide gum arabic, or its breakdown products, probably directly stimulate mucosal endocrine cells. The failure of gum arabic to stimulate CCPR despite increased plasma EG indicated that EG alone is not a sufficient stimulus for increased mucosal cell proliferation. [ABSTRACT FROM AUTHOR]

Pancreatic cancer has poor survival rates and largely ineffective therapies. Aspirin is the prototypical anti-cancer agent but its long-term use is associated with significant side effects. NOSH-aspirin belongs to a new class of anti-inflammatory agents that were designed to be safer alternatives by releasing nitric oxide and hydrogen sulfide. In this study we evaluated the effects of NOSH-aspirin against pancreatic cancer using cell lines and a xenograft mouse model. NOSH-aspirin inhibited growth of MIA PaCa-2 and BxPC-3 pancreatic cancer cells with IC 50 s of 47 ± 5, and 57 ± 4 nM, respectively, while it did not inhibit growth of a normal pancreatic epithelial cell line at these concentrations. NOSH-aspirin inhibited cell proliferation, caused G 0 /G 1 phase cycle arrest, leading to increased apoptosis. Treated cells displayed increases in reactive oxygen species (ROS) and caspase-3 activity. In MIA PaCa-2 cell xenografts, NOSH-aspirin significantly reduced tumor growth and tumor mass. Growth inhibition was due to reduced proliferation (decreased PCNA expression) and induction of apoptosis (increased TUNEL positive cells). Expressions of ROS, iNOS, and mutated p53 were increased; while that of NF-κB and FoxM1 that were high in vehicle-treated xenografts were significantly inhibited by NOSH-aspirin. Taken together, these molecular events and signaling pathways contribute to NOSH-aspirin mediated growth inhibition and apoptotic death of pancreatic cancer cells in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The ongoing extension of usage for lithium-ion cells and packs in both stationary and mobile applications necessitates a steeply increasing need for comprehensive tools and models to diagnose and prognose cell performance. Among those, a simple mechanistic framework using electrode half-cell data has gained a lot of attention due to its ability to synthesize the terminal voltage of battery cells based on the individual electrode potentials. Although proven valid in the quantification of cell degradation, path dependence of aging and cell-to-cell variations, the application of the model framework has been restricted so far mostly to voltage profiles recorded at low C-rates. For use in battery management systems, this limitation should preferably be overcome to enable on-board diagnostics from medium to high rates and at any temperature. For this reason, this study aims at an advanced exploration of the cell's kinetics and how it can be compensated within the mechanistic framework. This was done by investigating two previously proposed parameters, the ohmic resistance increase and the rate degradation factor. This study indicates that both parameters follow a well-defined Arrhenius dependency allowing to map the voltage behaviour of the underlying half-cell to the measured full cell data at different rates and temperatures. • Different C-rates were emulated from half-cell data from each electrode. • Different temperatures were emulated from room temperature data. • Kinetic parameters followed an Arrhenius behaviour with temperature. [ABSTRACT FROM AUTHOR]