Extracting Mutual Interaction Rules Using Fuzzy Structured Agent-based Model of Tumor-Immune System Interactions.

BACKGROUND: There are many studies to investigate the effects of each interacting component of tumor-immune system interactions. In all these studies, the distinct effect of each component was investigated. As the interaction of tumor-immune system has feedback and is complex, the alternation of each component may affect other components indirectly. OBJECTIVE: Because of the complexities of tumor-immune system interactions, it is important to determine the mutual behavior of such components. We need a careful observation to extract these mutual interactions. Achieving these observations using experiments is costly and time-consuming. MATERIAL AND METHODS: In this experimental and based on mathematical modeling study, to achieve these observations, we presented a fuzzy structured agent-based model of tumor-immune system interactions. In this study, we consider the confronting of the effector cells of the adaptive immune system in the presence of the cytokines of interleukin-2 (IL-2) and transforming growth factor-beta (TGF-ß) as a fuzzy structured model. Using the experimental data of murine models of B16F10 cell line of melanoma cancer cells, we optimized the parameters of the model. RESULTS: Using the output of this model, we determined the rules which could occur. As we optimized the parameters of the model using escape state of the tumor and then the rules which we obtained, are the rules of tumor escape. CONCLUSION: The results showed that using fuzzy structured agent-based model, we are able to show different output of the tumor-immune system interactions, which are caused by the stochastic behavior of each cell. But different output of the model just follow the predetermined behavior, and using this behavior, we can achieve the rules of interactions.

MicroRNAs and exosomes: key players in HIV pathogenesis.

OBJECTIVES: HIV infection is well known to cause impairment of the human immune system, and until recently was a leading cause of death. It has been shown that T lymphocytes are the main targets of HIV. The virus inactivates T lymphocytes by interfering with a wide range of cellular and molecular targets, leading to suppression of the immune system. The objective of this review is to investigate to what extent microRNAs (miRNAs) are involved in HIV pathogenesis. METHODS: The scientific literature (Pubmed and Google scholar) for the period 1988-2019 was searched. RESULTS: Mounting evidence has revealed that miRNAs are involved in viral replication and immune response, whether by direct targeting of viral transcripts or through indirect modulation of virus-related host pathways. In addition, exosomes have been found to act as nanoscale carriers involved in HIV pathogenesis. These nanovehicles target their cargos (i.e. DNA, RNA, viral proteins and miRNAs) leading to alteration of the behaviour of recipient cells. CONCLUSIONS: miRNAs and exosomes are important players in HIV pathogenesis. Additionally, there are potential diagnostic applications of miRNAs as biomarkers in HIV infection.

Assessment of Computer Regulation Thermography (CRT) as a Complemetrary Diagnostic tool for Breast Cancer Patient.

BACKGROUND: Breast cancer is the most common type of cancer in women demanding accurate diagnosis to take remedial measures to treat. OBJECTIVE: Comparing the diagnostic capability of the computer regulation thermography (CRT), as a novel and safe diagnostic procedure, with common methods including sonography, mammography and clinical examinations for diagnosing breast cancer in suspicious patients against pathology as the gold standard. MATERIAL AND METHODS: In this prospective clinical trial study, out of 97 referred patients, 44 meeting the inclusion criteria were selected. The selected patients were subjected to mammography, sonography, CRT and clinical examinations. Then, the patients showing suspicious symptoms of breast cancer underwent pathological examinations. RESULTS: CRT indicated a higher specificity compared to mammography and sonography (78.9% vs. 71.4% and 47.0%, respectively). However, CRT sensitivity was lower than those of mammography, sonography and clinical examination (52% vs. 70.6%, 82.4% and 84.0%). Furthermore, CRT accuracy was lower than mammography, sonography and clinical examination (63.6% vs. 70.9%, 64.7% and 88.6%). While CRT positive prediction value (PPV) was higher than those of mammography and sonography, it was lower than that of clinical examination (76.5% vs. 75%, 60.9% and 95.5%). The negative prediction value (NPV) of CRT was less than all other modalities (55.5% vs. 66.7%, 72.7% and 81.8% for the clinical examination, mammography and sonography, respectively). CONCLUSION: Although CRT with a lower sensitivity and higher specificity, cannot be recommended to be used as a definitive diagnostic tool for breast cancer patients, it can be used as a complementary method with other methods to increase the diagnostic accuracy of suspicious patients.

Monte Carlo Simulation of Electron Beams produced by LIAC Intraoperative Radiation Therapy Accelerator.

Background: One of the main problems of dedicated IORT accelerators is to determine dosimetric characteristics of the electron beams. Monte Carlo simulation of IORT accelerator head and produced beam will be useful to improve the accuracy of beam dosimetry. Materials and Methods: Liac accelerator head was modeled using the BEAMnrcMonte Carlo simulation system. Phase-space files were generated at the bottom of the applicators. These phase-space files were used as an input source in DOSXYZnrc and BEAMDP codes for dose calculation and analysis of the characteristic of the electron beams in all applicators and energies. Results: The results of Monte Carlo calculations are in very close agreement with the measurements. There is a decrease in the peak of the initial spectrum when electrons come from the end of accelerator wave guide to the end of applicator. By decreasing the applicator diameter, the mean energy of electron beam decreased. Using applicators and increasing their size, X-ray contamination will increase. The percentage of X-ray contamination increases by applicator diameter. This is related to the increase of the mean energy of electron beams. Conclusion: Application of PMMA collimator leads to, although well below accepted level, the production of bremsstrahlung. The results of this study showed that special design of LIAC head accompanying by PMMA collimator system cause to produce an electron beam with an individual dosimetric characteristic making it a useful tool for intraoperative radiotherapy purposes.

Imaging techniques: new avenues in cancer gene and cell therapy.

Cancer is one of the world's most concerning health problems and poses many challenges in the range of approaches associated with the treatment of cancer. Current understanding of this disease brings to the fore a number of novel therapies that can be useful in the treatment of cancer. Among them, gene and cell therapies have emerged as novel and effective approaches. One of the most important challenges for cancer gene and cell therapies is correct monitoring of the modified genes and cells. In fact, visual tracking of therapeutic cells, immune cells, stem cells and genetic vectors that contain therapeutic genes and the various drugs is important in cancer therapy. Similarly, molecular imaging, such as nanosystems, fluorescence, bioluminescence, positron emission tomography, single photon-emission computed tomography and magnetic resonance imaging, have also been found to be powerful tools in monitoring cancer patients who have received therapeutic cell and gene therapies or drug therapies. In this review, we focus on these therapies and their molecular imaging techniques in treating and monitoring the progress of the therapies on various types of cancer.

Molecular imaging and cancer gene therapy.

Gene therapy is known as one of the most advanced approaches for therapeutic prospects ranging from tackling genetic diseases to combating cancer. In this approach, different viral and nonviral vector systems such as retrovirus, lentivirus, plasmid and transposon have been designed and employed. These vector systems are designed to target different therapeutic genes in various tissues and cells such as tumor cells. Therefore, detection of the vectors containing therapeutic genes and monitoring of response to the treatment are the main issues that are commonly faced by researchers. Imaging techniques have been critical in guiding physicians in the more accurate and precise diagnosis and monitoring of cancer patients in different phases of malignancies. Imaging techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT) are non-invasive and powerful tools for monitoring of the distribution of transgene expression over time and assessing patients who have received therapeutic genes. Here, we discuss most recent advances in cancer gene therapy and molecular approaches as well as imaging techniques that are utilized to detect cancer gene therapeutics and to monitor the patients' response to these therapies worldwide, particularly in Iranian Academic Medical Centers and Hospitals.Cancer Gene Therapy advance online publication, 18 November 2016; doi:10.1038/cgt.2016.62.

Circulating microRNA: a new candidate for diagnostic biomarker in neuroblastoma.

Neuroblastoma (NB) is known as a pediatric neoplasm that is associated with variable histopathological features. The use of biomarkers contributes to the monitoring and treatment of various malignancies such as NB. The identification of novel biomarkers such as (epi)genetic biomarkers and microRNAs (miRNAs) in NB has led to better treatments of NB. Among them, miRNAs have emerged as powerful tools in diagnosis, prognosis and therapeutic biomarkers for patients with NB. Circulating biomarkers such as circulating miRNAs present in body fluids (for example, plasma, serum and urine) provided an interesting field of study in NB treatment. The miRNAs have central roles in different pathogenic events in various malignancies such as NB. Hence, these molecules can be a suitable candidate for monitoring and treating NB patients. Here, we summarize some miRNAs as potential prognosis, diagnosis and therapeutic biomarkers in NB.

Mesenchymal stem cell: a new horizon in cancer gene therapy.

Cancer is one of the main problems in public health worldwide. Despite rapid advances in the diagnosis and treatment of cancer, the efficacy of current treatment strategies is still limited. There are promising new results in animal models whereby mesenchymal stem cells (MSCs) can be used as vehicles for targeted therapies. The use of MSCs as therapeutic biological vehicles in cell therapy has several advantages, including immune-silence, tumor tropism, easy and rapid isolation, ex vivo expansion, multilineage differentiation and the capacity to deliver a number of therapeutic agents. Some studies have shown that the microenvironment of the tumor provides a preferential niche for homing and survival of MSCs. Here, we have highlighted various applications of MSCs in cancer gene therapy.

PiggyBac as a novel vector in cancer gene therapy: current perspective.

Selection of suitable delivery system is one of the crucial aspects in gene therapy that determines the efficiency of gene therapy. The past two decades have witnessed extensive efforts for finding safe and efficient vectors to overcome the limitations of viral vectors. The utilization of DNA transposon-based vectors for gene therapy has emerged as a promising non-viral alternative. DNA 'cut-and-paste' is one of the main mechanisms of genome engineering by transposon elements. However, the lack of an efficient transposition system has limited the utilization of transposon vectors in mice and mammalian systems. PiggyBac (PB) is known as a highly efficient DNA transposon originally isolated from Trichoplusia ni as an alternative to Sleeping Beauty (SB). It has been shown that PB can be functional in various species including mammalian systems. This vector could overcome some limitations of other vectors in cancer gene therapy. Some advantages of PB include the capacity for integration into the genome and providing a stable expression, capacity to harbor 10 and 9.1 kb of foreign DNA into the host genome, without a significant reduction in their transposition activity and display non-overlapping targeting preferences. However, to advance PB to clinical applications, some obstacles still require to be overcome to improve its safety and efficiency. Hence, it seems that this vector could open new horizons in gene and cancer therapy.

Estimation of ideal ratios of methionine and threonine to lysine in starting broiler chicks using response surface methodology.

In a dose-response study, dietary levels of standardized ileal digestible methionine (dMet), lysine (dLys), and threonine (dThr) were optimized by response surface methodology (RSM) using a central composite rotatable design in starting broiler chicks that were feed-deprived 2 d posthatch. In total, 60 floor pens of 6 birds each were assigned to 15 diets of central composite rotatable design containing 5 levels of dMet (0.42-0.58%), dLys (0.88-1.32%), and dThr (0.53-0.87%) from 3 to 16 d of age. Experimental levels of dMet, dLys, and dThr significantly affected bird performance. The second-order models for BW gain and feed conversion ratio (FCR) were generated. The response surface analysis showed significant quadratic models for BW gain and FCR. The crossproduct of amino acids was significant for FCR but not significant for BW gain. Canonical analyses on BW gain and FCR models showed that the maximum BW gain at the stationary point may be obtained with 0.54, 1.12, and 0.78% of dMet, dLys, and dThr in the diet, respectively, and the minimum FCR at the stationary point may be obtained with 0.53, 1.13, and 0.75% of dMet, dLys, and dThr in diet, respectively. Estimated ideal ratios of dMet and dThr to dLys were 48 and 70% for BW gain and 47 and 66% for FCR. Canonical analysis revealed the most important amino acids in the models of BW gain and FCR were Lys and Thr, respectively.

Modeling of crossbred cattle growth, comparison between cubic and piecewise random regression models.

Two analyses, cubic and piecewise random regression, were conducted to model growth of crossbred cattle from birth to about two years of age, investigating the ability of a piecewise procedure to fit growth traits without the complications of the cubic model. During a four-year period (1994-1997) of the Australian "Southern Crossbreeding Project", mature Hereford cows (N = 581) were mated to 97 sires of Angus, Belgian Blue, Hereford, Jersey, Limousin, South Devon, and Wagyu breeds, resulting in 1141 steers and heifers born over four years. Data included 13 (for steers) and eight (for heifers) live body weight measurements, made approximately every 50 days from birth until slaughter. The mixed model included fixed effects of sex, sire breed, age (linear, quadratic and cubic), and their interactions between sex and sire breed with age. Random effects were sire, dam, management (birth location, year, post-weaning groups), and permanent environmental effects and for each of these when possible, their interactions with linear, quadratic and cubic growth. In both models, body weights of all breeds increased over pre-weaning period, held fairly steady (slightly flattening) over the dry season then increased again towards the end of the feedlot period. The number of estimated parameters for the cubic model was 22 while for the piecewise model it was 32. It was concluded that the piecewise model was very similar to the cubic model in the fit to the data; with the piecewise model being marginally better. The piecewise model seems to fit the data better at the end of the growth period.

Joint analysis of beef growth and carcass quality traits through calculation of co-variance components and correlations.

A joint growth-carcass model using random regression was used to estimate the (co)variance components of beef cattle body weights and carcass quality traits and correlations between them. During a four-year period (1994-1997) of the Australian "southern crossbreeding project", mature Hereford cows (N = 581) were mated to 97 sires of Jersey, Wagyu, Angus, Hereford, South Devon, Limousin, and Belgian Blue breeds, resulting in 1141 calves. Data included 13 (for steers) and 8 (for heifers) body weight measurements approximately every 50 days from birth until slaughter and four carcass quality traits: hot standard carcass weight, rump fat depth, rib eye muscle area, and intramuscular fat content. The mixed model included fixed effects of sex, sire breed, age (linear, quadratic and cubic), and their interactions between sex and sire breed with age. Random effects were sire, dam, management (birth location, year, post-weaning groups), and permanent environmental effects, and their interactions with linear, quadratic and cubic growth, when possible. Phenotypic, sire and dam correlations between body weights and hot standard carcass weight and rib eye muscle area were positive and moderate to high from birth to feedlot period. Management variation accounted for the largest proportion of total variation in both growth and carcass traits. Management correlations between carcass traits were high, except between rump fat depth and intramuscular fat (r = 0.26). Management correlations between body weight and carcass traits during the pre-weaning period were positive except for intramuscular fat. The correlations were low from birth to weaning, then increased dramatically and were high during the feedlot period.

Prediction model of a joint analysis of beef growth and carcass quality traits.

A joint growth-carcass analysis was conducted to develop equations for predicting carcass quality traits associated with variation in growth path of crossbred cattle. During a four-year period (1994-1997) of the Australian "Southern Crossbreeding Project", mature Hereford cows (r = 581) were mated to 97 sires of Jersey, Wagyu, Angus, Hereford, South Devon, Limousin, and Belgian Blue breeds, resulting in 1141 calves. Data included body weight measurements of steers and heifers from birth until slaughter and four carcass quality traits: hot standard carcass weight, rump fat depth, rib eye muscle area, and intramuscular fat content. The model provides nine outputs: median and mean of carcass quality traits, predicted means, and lower and upper confidence intervals, as well as predicted intervals of carcass quality traits (95%) and economic values for domestic market and export markets. Input to the model consists of sex, sire breeds, age (in days)-weight (kg) pairs and slaughter age (500 days for heifer and 700 days for steers). The prediction model is able to accommodate different sexes across seven sire breeds and various management groups at any slaughter age. Its strength lies in its simplicity and flexibility, desirable to accommodate producers with different management schemes. In general, fat depth and intramuscular fat were found to be more affected by differences in growth rate than hot carcass weight and eye muscle area. Also, export market value was more sensitive to growth rate modifications than domestic market value. This model provides a tool by which the producer can estimate the impact of management decisions.

Describing variation in carcass quality traits of crossbred cattle.

In order to investigate variation in carcass quality traits, during a four-year period, mature Hereford cows (637) were mated to 97 sires from seven breeds (Jersey, Wagyu, Angus, Hereford, South Devon, Limousin and Belgian Blue), resulting in 1144 calves. Carcass production traits (carcass weight = HCWt, fat depth = P8, eye muscle area = EMA, intramuscular fat = IMF) were obtained from these cattle that constitute the Australia's Southern Crossbreeding Project. Data were analysed using multi-variate sire model containing fixed effects of sex, sire breed, slaughter age nested within sexes. Random effects were sire, dam, management (location-year-post-weaning groups) and environmental effects. HCWt of South Devon, Belgian Blue, Limousin and unexpectedly, Angus were the heaviest on the average. Hereford calves were intermediate and Jersey and Wagyu were lighter on the average than others. Carcasses of the Belgian Blue and Limousin had low P8 and IMF, carcasses of Hereford and South Devon were intermediate and Angus, Jersey and Wagyu had high P8 and IMF. Management group effects were greatest especially for EMA and IMF. The sire variation was about 6, 6, 4 and 2% of total variation for HCWt, P8, EMA and IMF. Heritability ranged from 0.20 to 0.37 (carcass weight). The genetic correlation between the two fat depots was not as high (0.18) as expected. Results from this study suggest that strategies to increase genetic potential for HCWt would increase the genetic potential for EMA but may reduce marbling and tend to slightly increase P8. All phenotypic correlations were positive, although not large.

Describing variation in rump P8 fat depth of crossbred cattle from birth to slaughter.

A Principal Component Analysis (PCA) was conducted on the matrix of correlations among P8 fat measures at seven different ages for steers and heifers. The P8 fat measures were collected from 1143 steers and heifer calves that were born to Hereford (h) dams inseminated with semen from seven different sire breeds: Angus, Belgian Blue, Hereford, Jersey, Limousin, South Devon and Wagyu, over a 4-year period (1994 to 1997). The first two principal components explained 61 and 57% of the total phenotypic variation in fatness for steers and heifers, respectively. The first component was positively correlated to all measures and was interpreted as a measure of overall fatness. The second component was positively correlated to fatness approximately pre-weaning and negatively correlated thereafter and thus was interpreted as maturity type but could be a function of milk supply. When estimated from a sire model, the heritability estimates were high for the first component (0.59 and 0.67 for steers and heifers, respectively) but low for the second component (0.05 and 0.19). The results demonstrate the value of combining information across multiple measurements to build accuracy, even when relatively crude methods are used.

Response of male buffalo calves to different levels of energy and protein in finishing diets.

A factorial experiment with completely randomised design was conducted, using 27 heads of 15 month buffalo male calves with initial live weight of 287 +/- 15 kg. The animals were individually housed and randomly allocated into 9 treatment groups of three animals each. Three levels of energy (E1, E2, E3) with three levels of crude protein (P1, P2, P3) were formulated to provide 90, 100 and 110% requirement equivalents for 900 g, expected body weight gain of steers derived from NRC beef cattle requirements (1976). Live weight changes were obtained by direct weighing of the animals every month and ended by slaughtering the calves for carcass index measurements. Results indicated that Dry Matter Intake (DMI) was not significantly different between treatments. Average Daily Gain (ADG) ranged from 503 to 951 g/animal that was significantly varied among the diets (p < 0.05). The significantly higher daily gain was obtained (p < 0.05) when animals received medium energy diets that was similar to 100% beef cattle steer requirements. In addition the feed conversion ratio was significantly lower, when the animals received medium energy diets (p < 0.05). The dressing yield as well as the meat % age was not affected by the type of the diet, but abdominal fat was significantly higher in medium energy diets (p < 0.05). It can be concluded that the optimum fattening performance of 15 month old buffalo male calves may be obtained by providing around 10.42 MJ/kg of dietary metabolisable energy and about 10.22% of crude protein.