Application of Mathematical Modeling in Cancer, Blood Clotting Abnormalities and Migraine Headaches Research

Mathematical modeling of biological processes has contributed significantly to improving our understanding of how different biological systems function, how and why different diseases start and develop, and how the diseases can be prevented or treated. In the first part of this dissertation, we use mechanistic modeling together with local and global sensitivity analyses to explore why different patients and/or different cancer types respond differently to retinoic acid (RA), an anticancer drug. Our findings indicate that the efficacy of RA treatment highly depends on intracellular levels of four main RA binding proteins namely, retinoic acid receptor (RAR), cellular retinoic acid binding proteins (CRABP1 and CRABP2) and cytochrome P450 (CYP). These proteins are expressed at different levels in different patients and/or cell types. Our results indicate that CRABP2 and RAR are the most and the least important receptors, respectively, in regulating the response to RA treatment at physiological concentrations (1–10 nM). However, at pharmacological concentrations of RA (0.1–1 μM), CYP and RAR are the most sensitive parameters of the model. These results can help in the development of pharmacological methods to increase the efficacy of the drug. In the second part of this dissertation, we study the positive side effects of RA therapy on blood clotting abnormalities in cancer patients. Although there are several lines of evidence regarding the improvement of hemostatic complications such as thrombosis and disseminated intravascular coagulation (DIC) in cancer patients undergoing RA therapy, the mechanisms underlying this improvement have yet to be understood. We build mechanistic and pharmacokinetics models and use in vitro and pharmacokinetics data from the literature to test the hypothesis that this improvement is due to RA-induced upregulation of thrombomodulin (TM) on the endothelial cells. Our results indicate that treatment with a single daily oral dose of 110 mg/m^2 RA, increases the TM concentration by almost two folds. We then show that this RA-induced TM upregulation reduces the peak thrombin levels and endogenous thrombin potential (ETP) up to 50 and 49%, respectively. Our results demonstrate that progressive reductions in plasma levels of RA, observed in continuous RA therapy with a once-daily oral dose of 110 mg/m^2 RA do not influence TM-mediated decrease in thrombin generation. This observation raises the hypothesis that continuous RA treatment will have more consistent therapeutic effects on coagulation disorders than on cancer. Our results reveal that the upregulation of TM expression on the endothelial cells over the course of RA therapy could significantly contribute to the treatment of coagulation abnormalities in cancer patients. In the last part of this dissertation, we use mechanistic modeling to study sodium homeostasis disturbance in the brain during migraines. Previous animal and human studies have revealed that migraine sufferers have higher levels of cerebrospinal fluid (CSF) and brain tissue sodium than control groups, while the underlying mechanisms of this increase are not known. Under the hypothesis that disturbances in sodium transport mechanisms at the blood-CSF barrier (BCSFB) and/or the blood-brain barrier (BBB) are the underlying cause of the elevated CSF and brain, we develop a mechanistic model of a rat’s brain to compare the significance of the BCSFB and the BBB in controlling CSF and brain tissue sodium levels. Our model consists of the ventricular system, subarachnoid space, brain tissue and blood. We model sodium transport from blood to CSF across the BCSFB, and from blood to brain tissue across the BBB by influx permeability coefficients P_BCSFB and P_BBB, respectively, while sodium movement from CSF into blood across the BCSFB, and from brain tissue to blood across the BBB were modeled by efflux permeability coefficients P_BCSFB^' and P_BBB^', respectively. We then perform a global sensitivity analysis to investigate the sensitivity of the ventricular CSF, subarachnoid CSF and brain tissue sodium levels to pathophysiological variations in P_BCSFB, P_BBB, P_BCSFB^' and P_BBB^'. Our findings indicate that the ventricular CSF sodium concentration is highly influenced by perturbations of P_BCSFB, and to a much lesser extent by perturbations of P_BCSFB^'. Brain tissue and subarachnoid CSF sodium concentrations are more sensitive to pathophysiological variations of P_BBB and P_BBB^' than variations of P_BCSFB and P_BCSFB^' within 30 minutes of the onset of the perturbations. However, P_BCSFB is the most sensitive model parameter, followed by P_BBB and P_BBB^', in controlling brain tissue and subarachnoid CSF sodium levels within 3 hours of the perturbation onset. Our findings suggest that increased influx permeability of the BCSFB to sodium caused by altered homeostasis of the enzymes which transport sodium from blood to CSF is the potential cause of elevated brain sodium levels in migraines

ADAPTIVE NEURO-FUZZY INFERENCE SYSTEM (ANFIS) APPROACH TO EVALUATE THE DEBUTANIZER TOP PRODUCT

Abstract This paper proposed an ANFIS estimator to evaluate the top product from secondary measurements. Real debutanizer column in one of the Iranian refineries has been purchased and the adaptive neuro-fuzzy inference system is trained and validated with real data. According to results, ANFIS can be used with acceptable approximation in replace of costly measurement instruments as gas chromatographs

Automated deep learning-based segmentation of COVID-19 lesions from chest computed tomography images

Purpose: The novel coronavirus COVID-19, which spread globally in late December 2019, is a global health crisis. Chest computed tomography (CT) has played a pivotal role in providing useful information for clinicians to detect COVID-19. However, segmenting COVID-19-infected regions from chest CT results is challenging. Therefore, it is desirable to develop an efficient tool for automated segmentation of COVID-19 lesions using chest CT. Hence, we aimed to propose 2D deep-learning algorithms to automatically segment COVID-19-infected regions from chest CT slices and evaluate their performance. Material and methods: Herein, 3 known deep learning networks: U-Net, U-Net++, and Res-Unet, were trained from scratch for automated segmenting of COVID-19 lesions using chest CT images. The dataset consists of 20 labelled COVID-19 chest CT volumes. A total of 2112 images were used. The dataset was split into 80% for training and validation and 20% for testing the proposed models. Segmentation performance was assessed using Dice similarity coefficient, average symmetric surface distance (ASSD), mean absolute error (MAE), sensitivity, specificity, and precision. Results: All proposed models achieved good performance for COVID-19 lesion segmentation. Compared with Res-Unet, the U-Net and U-Net++ models provided better results, with a mean Dice value of 85.0%. Compared with all models, U-Net gained the highest segmentation performance, with 86.0% sensitivity and 2.22 mm ASSD. The U-Net model obtained 1%, 2%, and 0.66 mm improvement over the Res-Unet model in the Dice, sensitivity, and ASSD, respectively. Compared with Res-Unet, U-Net++ achieved 1%, 2%, 0.1 mm, and 0.23 mm improvement in the Dice, sensitivity, ASSD, and MAE, respectively. Conclusions: Our data indicated that the proposed models achieve an average Dice value greater than 84.0%. Two-dimensional deep learning models were able to accurately segment COVID-19 lesions from chest CT images, assisting the radiologists in faster screening and quantification of the lesion regions for further treatment. Nevertheless, further studies will be required to evaluate the clinical performance and robustness of the proposed models for COVID-19 semantic segmentation

UGROŽENE RIBE SVIJETA: Paracobitis rhadinaeus (Regan, 1906) (NEMACHEILIDAE)

Paracobitis rhadinaeus is an endemic Nemacheiline loach in the Sistan basin, southeast Iran. The population is declining probably due to habitat loss or degradation, damming, drought and poaching. Urgent habitat protection with bans on further regulation of the Hamoun wetland and related reservoirs is suggested. Captive breeding of the fish should be initiated.Fishing activities should be forbidden or limited. A detailed study of current population status, biology and ecology of P. rhadinaeus is required.Paracobitis rhadinaeus je endemski vijun iz Sistanskog slijeva na jugoistoku Irana. Populacija je u opadanju najvjerojatnije zbog gubitka i narušavanja staništa, podizanja brana, isušivanja i potapanja zemljišta. Predlaže se hitna zaštita staništa sa zabranom daljnje regulacije slijeva Hamuni njegovih akumulacijskih jezera. Potrebno je potaknuti kontrolirani mrijest ove vrste te zabraniti ili ograničiti ribolov. Nužna je detaljna studija sadašnjeg stanja populacije, biologije i ekologijevrste P. rhadinaeus

A historical literature review on the role of posterior axillary boost field in the axillary lymph node coverage and development of lymphedema following regional nodal irradiation in breast cancer

To elucidate whether (1) a posterior axillary boost (PAB) field is an optimal method to target axillary lymph nodes (LNs); and (2) the addition of a PAB increases the incidence of lymphedema, a systematic review was undertaken. A literature search was performed in the PubMed database. A total of 16 studies were evaluated. There were no randomized studies. Seven articles have investigated dosimetric aspects of a PAB. The remaining 9 articles have determined the effect of a PAB field on the risk of lymphedema. Only 2 of 9 articles have prospectively reported the impact of a PAB on the risk of lymphedema development. There are conflicting reports on the necessity of a PAB. The PAB field provides a good coverage of level I/II axillary LNs because these nodes are usually at a greater depth. The main concern regarding a PAB is that it produces a hot spot in the anterior region of the axilla. Planning studies optimized a traditional PAB field. Prospective studies and the vast majority of retrospective studies have reported the use of a PAB field does not result in increasing the risk of lymphedema development over supraclavicular-only field. The controversies in the incidence of lymphedema suggest that field design may be more important than field arrangement. A key factor regarding the use of a PAB is the depth of axillary LNs. The PAB field should not be used unless there is an absolute indication for its application. Clinicians should weigh lymphedema risk in individual patients against the limited benefit of a PAB, in particular after axillary dissection. The testing of the inclusion of upper arm lymphatics in the regional LN irradiation target volume, and universal methodology measuring lymphedema are all areas for possible future studies