Publications by authors named "Hamed Ghaffari"

19 Publications

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Automated detection of pneumonia cases using deep transfer learning with paediatric chest X-ray images.

Br J Radiol 2021 May 16;94(1121):20201263. Epub 2021 Apr 16.

Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

Objective: Pneumonia is a lung infection and causes the inflammation of the small air sacs (Alveoli) in one or both lungs. Proper and faster diagnosis of pneumonia at an early stage is imperative for optimal patient care. Currently, chest X-ray is considered as the best imaging modality for diagnosing pneumonia. However, the interpretation of chest X-ray images is challenging. To this end, we aimed to use an automated convolutional neural network-based transfer-learning approach to detect pneumonia in paediatric chest radiographs.

Methods: Herein, an automated convolutional neural network-based transfer-learning approach using four different pre-trained models ( VGG19, DenseNet121, Xception, and ResNet50) was applied to detect pneumonia in children (1-5 years) chest X-ray images. The performance of different proposed models for testing data set was evaluated using five performances metrics, including accuracy, sensitivity/recall, Precision, area under curve, and F1 score.

Results: All proposed models provide accuracy greater than 83.0% for binary classification. The pre-trained DenseNet121 model provides the highest classification performance of automated pneumonia classification with 86.8% accuracy, followed by Xception model with an accuracy of 86.0%. The sensitivity of the proposed models was greater than 91.0%. The Xception and DenseNet121 models achieve the highest classification performance with F1-score greater than 89.0%. The plotted area under curve of receiver operating characteristics of VGG19, Xception, ResNet50, and DenseNet121 models are 0.78, 0.81, 0.81, and 0.86, respectively.

Conclusion: Our data showed that the proposed models achieve a high accuracy for binary classification. Transfer learning was used to accelerate training of the proposed models and resolve the problem associated with insufficient data. We hope that these proposed models can help radiologists for a quick diagnosis of pneumonia at radiology departments. Moreover, our proposed models may be useful to detect other chest-related diseases such as novel Coronavirus 2019.

Advances In Knowledge: Herein, we used transfer learning as a machine learning approach to accelerate training of the proposed models and resolve the problem associated with insufficient data. Our proposed models achieved accuracy greater than 83.0% for binary classification.
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http://dx.doi.org/10.1259/bjr.20201263DOI Listing
May 2021

Analysis of trace elements in human hair through X-ray fluorescence spectroscopy for screening of prostate cancer.

Med J Islam Repub Iran 2020 28;34:86. Epub 2020 Jul 28.

Department of Radiation Oncology, Shohada-e-Tajrish Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.

Use of hair samples to analyze the trace element concentrations is one of the interesting fields among many researchers. X-ray fluorescence (XRF) is considered as one of the most common methods in studying the concentration of elements in tissues and also crystalline materials, using low energy X-ray. In the present study, we aimed to evaluate the concentration of the trace elements in the scalp hair sample through XRF spectroscopy using signal processing techniques as a screening tool for prostate cancer. Hair samples of 22 men (including 11 healthy and 11 patients) were analyzed. All the sample donors were Iranian men. EDXRF method was used for the measurements. Signals were analyzed, and signal features such as mean, root-mean-square (RMS), variance, and standard deviation, skewness, and energy were investigated. The Man-Whitney U test was used to compare the trace element concentrations. The analysis of variance (ANOVA) test was used to identify which extracted feature could help to identify healthy and patient people. P values ≤ 0.05 were considered statistically significant. Statistical analysis was performed using SPSS 16.0 software. The mean±SD age was 67.8±8.7 years in the patient group and 61.4±6.9 years in the healthy group. There were statistically significant differences in the aluminum (Al, P<0.001), silicon (Si, P=0.006), and phosphorus (P, P=0.028) levels between healthy and patient groups. Skewness and variance were found to be relevant in identifying people with cancer, as signal features. The use of EDXRF is a feasible method to study the concentration of elements in the hair sample, and this technique may be effective in prostate cancer screening. Further study with a large sample size will be required to elucidate the efficacy of the present method in prostate cancer screening.
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http://dx.doi.org/10.34171/mjiri.34.86DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711052PMC
July 2020

Molecular imaging in tracking cancer stem cells: A review.

Med J Islam Repub Iran 2020 3;34:90. Epub 2020 Aug 3.

Department of Radiologic Sciences and Medical Physics, School of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran.

Cancer stem cells (CSCs) have critical roles in tumor development, progression, and recurrence. They are responsible for current cancer treatment failure and remain questionable for the design and development of new therapeutic strategies. With this issue, medical imaging provides several clues for finding biological mechanisms and strategies to treat CSCs. This review aims to summarize current molecular imaging approaches for detecting CSCs. In addition, some promising issues for CSCs finding and explaining biological mechanisms have been addressed. Among the molecular imaging approaches, modalities including Magnetic resonance imaging (MRI) and positron emission tomography (PET) have the greatest roles and several new approaches such as optical imaging are in progress.
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http://dx.doi.org/10.34171/mjiri.34.90DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7711048PMC
August 2020

Letter to the editor on: F. Campostrini et al. Association between acute histopathological changes of rectal walls and late radiation proctitis following radiotherapy for prostate cancer.

Strahlenther Onkol 2021 04 9;197(4):353-354. Epub 2020 Dec 9.

Department of Medical Physics, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.

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http://dx.doi.org/10.1007/s00066-020-01719-4DOI Listing
April 2021

Assessment of background radiation levels in the southeast of Iran.

Med J Islam Repub Iran 2020 1;34:56. Epub 2020 Jun 1.

Department of Medical Physics & Biomedical Engineering, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran.

Measuring background radiation (BR) is highly important from different perspectives, especially from that of human health. This study was conducted to measure BR in the southeast of Iran. BR was measured in Hormozgan and Sistan-Bluchestan provinces using portable Environmental Radiation Meter Type 6- 80 detector. The average value was used to calculate the absorbed dose rate and indoor annual effective dose (AED) from BR. In addition, excess lifetime cancer risk (ELCR) was evaluated. The results showed that the maximum and minimum absorbed dose rates were 71.9 and 34.2 nGy.h-1 in Abomoosa and Minab in Hormozgan province and 90.0 and 47.8 nGy.h-1 in Zahedan and Chabahar in Sistan-Bluchestan province, respectively. Data indicated that these areas had a lower BR level compared with the worldwide level. The ELCR from indoor AED was larger compared with the worldwide average of 0.29 × 10-3. This study provided a reference for designing and developing specific regional surveys associated with the measurement of natural BR in the southeast of Iran.
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http://dx.doi.org/10.34171/mjiri.34.56DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7481852PMC
June 2020

In regard to Cuccia et al.: impact of hydrogel peri-rectal spacer insertion on prostate gland intra-fraction motion during 1.5 T MR-guided stereotactic body radiotherapy.

Radiat Oncol 2020 Aug 17;15(1):199. Epub 2020 Aug 17.

Department of Medical Physics, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.

We read the article entitled "Impact of hydrogel peri-rectal spacer insertion on prostate gland intra-fraction motion during 1.5 T MR-guided stereotactic body radiotherapy" with great interest. In that study, the author reported that there is a statistically significant difference in the rotational antero-posterior shifts between the spacer and the non-spacer groups. Also, there was no statistically significant difference between the groups in terms of translational shifts. However, there are some points about the study. In this letter, we aimed to clarify these points.
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http://dx.doi.org/10.1186/s13014-020-01642-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433034PMC
August 2020

Effectiveness of rectal displacement devices in managing prostate motion: a systematic review.

Strahlenther Onkol 2021 Feb 22;197(2):97-115. Epub 2020 May 22.

Department of Medical Physics, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.

Purpose: To determine whether rectal displacement devices (RDDs) have a prostate-stabilizing effect during prostate external beam radiotherapy (EBRT).

Methods: A systematic literature search using the PubMed database from January 1, 2000 to December 30th, 2019 was conducted. The effect of RDDs on inter- and intra-fractional prostate displacements was extracted.

Results: From 356 articles identified via the PubMed database and hand search, 21 articles were included in the systematic review. There was no randomized study. Twelve studies evaluated the role of the endorectal balloon (ERB) in managing prostate motion. Four studies reported the effect of hydrogel spacer on prostate motion. Four studies examined the effect of the rectal retractor (RR) on intra-fractional prostate motion, and only one study assessed the impact of ProSpare (Nottinghamshire, UK) in reducing prostate motion.

Conclusion: Using an ERB significantly reduces intra-fractional prostate motion. This prostate-stabilizing effect of the ERB can translate into reduced planning target volume (PTV) margins and additional rectal dose sparing. Even with an ERB in place, inter-fractional prostate displacements are seen. As a consequence, ERB application does not obviate daily verification; however, this is not a crucial topic because pretreatment imaging is always done nowadays. As compared with ERB, the hydrogel spacer significantly reduces rectal dose and toxicity without influencing prostate immobilization. The RR can increase prostate and rectal inter- and intra-fractional stability without a clear influence on the reduction of rectal toxicity. Finally, it is unclear whether ProSpare is a suitable device reducing prostate motion. Further study will be required to clarify whether the prostate-stabilizing effects of the ERB and RR can result in a safe reduction of PTV margins and further sparing of organs at risks, especially the rectum.
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http://dx.doi.org/10.1007/s00066-020-01633-9DOI Listing
February 2021

Letter to the editor regarding "Rectal spacing, prostate coverage, and periprocedural outcomes after hydrogel spacer injection during low-dose-rate brachytherapy implantation".

Brachytherapy 2020 Jul - Aug;19(4):554-555. Epub 2020 May 11.

Department of Radiology, Faculty of Para-Medicine, Hormozgan University of Medical Sciences, Bandar-Abbas, Iran.

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http://dx.doi.org/10.1016/j.brachy.2020.04.003DOI Listing
November 2020

Linac-based radiotherapy for epicondylitis humeri.

EXCLI J 2020 4;19:296-300. Epub 2020 Mar 4.

Department of Medical Physics, Faculty of Medicine, Ardabil University of Medical Sciences, Ardabil, Iran.

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http://dx.doi.org/10.17179/excli2020-1069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174575PMC
March 2020

Re: Placement of SpaceOAR hydrogel spacer for prostate cancer patients treated with iodine-125 low-dose-rate brachytherapy.

Authors:
Hamed Ghaffari

Int J Urol 2020 05 5;27(5):473. Epub 2020 Mar 5.

Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.1111/iju.14209DOI Listing
May 2020

Regulation of CSF and Brain Tissue Sodium Levels by the Blood-CSF and Blood-Brain Barriers During Migraine.

Front Comput Neurosci 2020 4;14. Epub 2020 Feb 4.

Neuroscience, Huntington Medical Research Institutes, Pasadena, CA, United States.

Cerebrospinal fluid (CSF) and brain tissue sodium levels increase during migraine. However, little is known regarding the underlying mechanisms of sodium homeostasis disturbance in the brain during the onset and propagation of migraine. Exploring the cause of sodium dysregulation in the brain is important, since correction of the altered sodium homeostasis could potentially treat migraine. 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 tissue sodium levels during migraines, we developed a mechanistic, differential equation model of a rat's brain to compare the significance of the BCSFB and the BBB in controlling CSF and brain tissue sodium levels. The model includes the ventricular system, subarachnoid space, brain tissue and blood. Sodium transport from blood to CSF across the BCSFB, and from blood to brain tissue across the BBB were modeled by influx permeability coefficients and , 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 and , respectively. We then performed a global sensitivity analysis to investigate the sensitivity of the ventricular CSF, subarachnoid CSF and brain tissue sodium concentrations to pathophysiological variations in , , and . Our results show that the ventricular CSF sodium concentration is highly influenced by perturbations of , and to a much lesser extent by perturbations of . Brain tissue and subarachnoid CSF sodium concentrations are more sensitive to pathophysiological variations of and than variations of and within 30 min of the onset of the perturbations. However, is the most sensitive model parameter, followed by and , in controlling brain tissue and subarachnoid CSF sodium levels within 3 h of the perturbation onset.
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http://dx.doi.org/10.3389/fncom.2020.00004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010722PMC
February 2020

Application of rectal retractor for postprostatectomy salvage radiotherapy of prostate cancer: A case report and literature review.

Clin Case Rep 2019 Nov 27;7(11):2102-2107. Epub 2019 Sep 27.

Department of Medical Physics School of Medicine Iran University of Medical Sciences Tehran Iran.

Using a rectal retractor (RR) during salvage radiotherapy after radical prostatectomy is a promising approach for reducing dose to the rectum. The patient well tolerated the daily RR insertion. This area of research encourages researchers for a comprehensive evaluation of the role of the RR in postprostatectomy radiotherapy.
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http://dx.doi.org/10.1002/ccr3.2430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6878068PMC
November 2019

Optimization of prostate brachytherapy techniques with polyethylene glycol-based hydrogel spacers: A systematic review.

Brachytherapy 2020 Jan - Feb;19(1):13-23. Epub 2019 Sep 18.

Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran. Electronic address:

Purpose: The objective of this overview was to critically evaluate the effect of polyethylene glycol (PEG)-based hydrogel spacers during prostate brachytherapy with regard to dosimetric and clinical benefits, as well as procedure-related toxicity.

Methods And Materials: A systematic search in the PubMed database was performed.

Results: A total of 12 studies, involving 615 patients with PEG hydrogel injection, were included. Overall, patients well tolerated the implantation of PEG hydrogel spacers with an excellent safety profile. However, although there were some procedure-related complications, rates of these complications were very rare. Toxicities related to the spacer were limited to Grade 1 rectal discomfort and pain (9/615 patients), Grade 2 rectal ulceration (1 in 615 patients), perineal abscess (1 in 615 patients), and bacterial prostatitis (2/615 patients) according to Common Terminology Criteria for Adverse Events v4.0 grading scheme. The application of PEG hydrogel spacers significantly reduced radiation doses to the rectum during prostate brachytherapy in the different setting. Although there was no prospective randomized clinical trial, retrospective studies showed that reducing rectal doses by the implantation of PEG hydrogel may result in an improvement in rectal toxicity.

Conclusions: The insertion of hydrogel spacers is safe, resulting in a significant decrease in rectal doses. This may lead to a reduction in rectal or gastrointestinal toxicity. Prospective randomized clinical trials are warranted to confirm the clinical impact of rectal dosimetric improvements.
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http://dx.doi.org/10.1016/j.brachy.2019.08.009DOI Listing
September 2020

Reject analysis in digital radiography: A local study on radiographers and students' attitude in Iran.

Med J Islam Repub Iran 2019 29;33:49. Epub 2019 May 29.

Department of Radiologic Sciences and Medical Physics, Faculty of Allied Medicine, Kerman University of Medical Sciences, Kerman, Iran.

Reject analysis is as a quality indicator and critical tool for dose and image quality optimization in radiology departments. By reducing image rejection rate (RR), radiation dose to patients can be reduced effectively, yielding increased total cost-effectiveness. The aims of this study were to assess the rate of image rejection at 2 direct digital radiography (DR) departments to find the sources of rejection and to observe how radiology students and radiographers deal with image rejection. Two radiology departments were surveyed during a 3-month period for all imaging procedures. Type of examination, numbers, and reasons for digital image rejection were obtained by systems and questionnaire. A predefined questionnaire, including 13 causes for rejection, was filled by radiographers and students. Out of the 14 022 acquired images, 1116 were rejected, yielding an overall RR of 8%. Highest RRs were found for examination of cervical spine and lumbosacral. Positioning errors and improper patient preparation were the main reasons for digital image rejection. The image RR was small, but there is a need for optimizing radiographic practice, and enhancing radiographer's knowledge may enhance the performance.
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http://dx.doi.org/10.34171/mjiri.33.49DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6708103PMC
May 2019

Is there a role for hydrogel spacer in post-prostatectomy radiotherapy setting?

Authors:
Hamed Ghaffari

Radiol Med 2019 10 4;124(10):1062-1063. Epub 2019 Jul 4.

Department of Medical Physics, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.

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http://dx.doi.org/10.1007/s11547-019-01054-4DOI Listing
October 2019

Fiducial markers in prostate cancer image-guided radiotherapy.

Med J Islam Repub Iran 2019 11;33:15. Epub 2019 Mar 11.

Department of Medical Physics, Roshana Radiotherapy Cancer Center, Tehran, Iran.

Image-guided radiotherapy (IGRT) is recommended to reduce the risk of geometrical miss when modern radiotherapy technologies with high grades of conformity are used. The purpose of this study was to evaluate the efficacy of fiducial markers (FMs) for electronic portal imaging in prostate cancer radiotherapy in term of evaluating the complications associated with FMs implantation, quantifying inter-fraction prostate motion, and determination of optimal planning target volume (PTV) margins. In this single institution, prospective, consecutive study, 27 patients underwent implantation of three-gold seed FMs into the prostate gland before prostate radiotherapy. Prior to computed tomography planning, all patients were asked to report any complication associated with FMs implantation that have experienced to date. Daily pre-treatment electronic portal images were captured, and prostate position errors were corrected if they were greater than 2 mm along three translational directions. Optimal PTV expansions were computed using van Herk formula [PTV-margin= 2.5Σ + 0.7σ]. FMs implantation was successful with an acceptable toxicity profile in all patients. Without IGRT, margins of 5.4 mm, 5.8 mm and 5.5 mm, in vertical, longitudinal and lateral directions, respectively, are needed for a 95% confidence level of complete clinical target volume (CTV) coverage in each treatment session. The PTV margins of 3.0 mm, 3.3 mm and 4.0 mm in corresponding directions were calculated when FMs based electronic portal imaging was applied. FMs based electronic portal imaging is an effective tool for prostate cancer IGRT.
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http://dx.doi.org/10.34171/mjiri.33.15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6504932PMC
March 2019

Rectal retractor application during image-guided dose-escalated prostate radiotherapy.

Strahlenther Onkol 2019 Oct 1;195(10):923-933. Epub 2019 Mar 1.

Department of Biostatistics, School of Public Health, Iran University of Medical Sciences, Tehran, Iran.

Purpose: To investigate efficacy of a rectal retractor (RR) on rectal dose during image-guided dose-escalated prostate three-dimensional conformal radiotherapy (3DCRT).

Patients And Methods: In all, 21 patients with localized prostate cancer were treated with a RR for 3DCRT in 40 × 2 Gy. Patient underwent two scans for radiotherapy planning, without and with RR. RR was used for the first half of the treatment sessions. Two plans were created for each patient to compare the effect of RR on rectal doses. PTW-31014 Pinpoint chamber embedded within RR was used for in vivo dosimetry in 6 of 21 patients. The patient tolerance and acute rectal toxicity were surveyed during radiotherapy using Common Terminology Criteria for Adverse Events (CTCAE) v.4.0.

Results: Patients tolerated the RR well during 20 fractions with mild degree of anal irritation. Using a RR significantly reduced the rectal wall (RW), anterior RW and posterior RW dose-volume parameters. The average RW D was 29.4 and 43.0 Gy for plans with and without RR, respectively. The mean discrepancy between the measured dose and planned dose was -3.8% (±4.9%). Grade 1 diarrhea, rectal urgency and proctitis occurred in 4, 2 and 3 cases, respectively. There were no grade ≥2 acute rectal toxicities during the treatment.

Conclusion: Rectal retraction resulted in a significant reduction of rectal doses with a safe toxicity profile, which may reduce rectal toxicity. Dosimeter inserted into the RR providing a practical method for in vivo dosimetric verification. Further prospective clinical studies will be necessary to demonstrate the clinical advantage of RR.
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http://dx.doi.org/10.1007/s00066-019-01445-6DOI Listing
October 2019

Analysis of the role of thrombomodulin in all-trans retinoic acid treatment of coagulation disorders in cancer patients.

Theor Biol Med Model 2019 02 14;16(1). Epub 2019 Feb 14.

Department of Mechanical Engineering, University of California Santa Barbara, Santa Barbara, CA, 93106, USA.

Background: Clinical studies have shown that all-trans retinoic acid (RA), which is often used in treatment of cancer patients, improves hemostatic parameters and bleeding complications such as disseminated intravascular coagulation (DIC). However, the mechanisms underlying this improvement have yet to be elucidated. In vitro studies have reported that RA upregulates thrombomodulin (TM) expression on the endothelial cell surface. The objective of this study was to investigate how and to what extent the TM concentration changes after RA treatment in cancer patients, and how this variation influences the blood coagulation cascade.

Results: In this study, we introduced an ordinary differential equation (ODE) model of gene expression for the RA-induced upregulation of TM concentration. Coupling the gene expression model with a two-compartment pharmacokinetic model of RA, we obtained the time-dependent changes in TM and thrombomodulin-mRNA (TMR) concentrations following oral administration of RA. Our results indicated that the TM concentration reached its peak level almost 14 h after taking a single oral dose (110 [Formula: see text]) of RA. Continuous treatment with RA resulted in oscillatory expression of TM on the endothelial cell surface. We then coupled the gene expression model with a mechanistic model of the coagulation cascade, and showed that the elevated levels of TM over the course of RA therapy with a single daily oral dose (110 [Formula: see text]) of RA, reduced the peak thrombin levels and endogenous thrombin potential (ETP) up to 50 and 49%, respectively. We showed that progressive reductions in plasma levels of RA, observed in continuous RA therapy with a once-daily oral dose (110 [Formula: see text]) of RA, did not affect TM-mediated reduction of thrombin generation significantly. This finding prompts the hypothesis that continuous RA treatment has more consistent therapeutic effects on coagulation disorders than on cancer.

Conclusions: Our results indicate that the oscillatory upregulation of TM expression on the endothelial cells over the course of RA therapy could potentially contribute to the treatment of coagulation abnormalities in cancer patients. Further studies on the impacts of RA therapy on the procoagulant activity of cancer cells are needed to better elucidate the mechanisms by which RA therapy improves hemostatic abnormalities in cancer.
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http://dx.doi.org/10.1186/s12976-019-0099-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6376718PMC
February 2019

Identification of influential proteins in the classical retinoic acid signaling pathway.

Theor Biol Med Model 2018 10 16;15(1):16. Epub 2018 Oct 16.

Department of Mechanical Engineering, University of California Santa Barbara, Santa Barbara, CA, 93106, USA.

Background: In the classical pathway of retinoic acid (RA) mediated gene transcription, RA binds to a nuclear hormone receptor dimer composed of retinoic acid receptor (RAR) and retinoid X receptor (RXR), to induce the expression of its downstream target genes. In addition to nuclear receptors, there are other intracellular RA binding proteins such as cellular retinoic acid binding proteins (CRABP1 and CRABP2) and cytochrome P450 (CYP) enzymes, whose contributions to the RA signaling pathway have not been fully understood. The objective of this study was to compare the significance of various RA binding receptors, i.e. CRABP1, CRABP2, CYP and RAR in the RA signaling pathway. In this regard, we developed a mathematical model of the RA pathway, which is one of the few models, if not the only one, that includes all main intracellular RA binding receptors. We then performed a global sensitivity analysis (GSA) to investigate the contribution of the RA receptors to RA-induced mRNA production, when the cells were treated with a wide range of RA levels, from physiological to pharmacological concentrations.

Results: Our results show that CRABP2 and RAR are the most and the least important proteins, respectively, in controlling the model performance at physiological concentrations of RA (1-10 nM). However, at higher concentrations of RA, CYP and RAR are the most sensitive parameters of the system. Furthermore, we found that depending on the concentrations of all RA binding proteins, the rate of metabolism of RA can either change or remain constant following RA therapy. The cellular levels of CRABP1 are more important than that of CRABP2 in controlling RA metabolite formation at pharmacological conditions (RA = 0.1-1 μM). Finally, our results indicate a significant negative correlation between total mRNA production and total RA metabolite formation at pharmacological levels of RA.

Conclusions: Our simulations indicate that the significance of the RA binding proteins in the RA pathway of gene expression strongly depends on intracellular concentration of RA. This study not only can explain why various cell types respond to RA therapy differently, but also can potentially help develop pharmacological methods to increase the efficacy of the drug.
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http://dx.doi.org/10.1186/s12976-018-0088-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6190658PMC
October 2018