Heat and mass transfer in the hyperthermia cancer treatment by magnetic nanoparticles.

In this study, a more precise and cost-effective method is used for studying the drug delivery and distribution of magnetic nanoparticles in fluid hyperthermia cancer treatment, and numerical methods are employed to determine the effect of blood circulation on heat transfer and estimate the success of cancer treatment. A combination of numerical, analytical, and experimental researches is being conducted, which illustrates the essential role of numerical methods in medical and biomedical science. Magnetic NanoParticles' distribution and effects of infusion rate on the treatment are also discussed by considering the real distribution of MNPs. To increase accuracy and reduce costs in the in-vitro section, direct cutting and image processing methods are used instead of MRI. Based on the results of this section, with a tenfold increase in the infusion rate (4 µl/min to 40 µl/min), the penetration depth increases by 1 mm, which represents a nearly 17 percent increase. Concentrations of MNPs also decrease significantly at higher infusion rates. The simulations of heat transfer reveal that maximum temperatures occur at the lowest infusion rate (1.25 µl/min), and blood flow also has a significant effect on heat transfer. With an increase in the infusion rate, necrosis tissue recedes from the tumor center and approaches the border between the tumor and healthy tissue. Results also show that, in lower MNPs' concentrations, higher infusion rates result in better treatment even though minimum infusion rates are suggested to be the best rates to facilitate distribution and treatment.

A Combinational Approach Towards Treatment of Breast Cancer: an Analysis of Noscapine-Loaded Polymeric Nanoparticles and Doxorubicin.

Our aim in this study was to clarify the combination anticancer effect of Noscapine (Nos) loaded in a polymeric nanocarrier with Doxorubicin (Dox) on breast cancer cells. Nanoprecipitation method was used to prepare methoxy polyethylene glycol (mPEG), poly lactic-co-glycolic acid (PLGA) nanoparticles (NPs) containing Nos. Transmission electron microscopy (TEM) and dynamic light scattering (DLS) were used to characterize the prepared Nos NPs. The anticancer activity of Nos NPs alone and in combination with Dox was assessed on 4T1 breast cancer cell line and in mice model. Spherical-shaped Nos NPs were prepared, with size of 101 ± 4.80 nm and zeta potential of - 15.40 ± 1 mV. Fourier transform infrared (FTIR) spectroscopy results demonstrated that Nos chemical structure was kept stable during preparation process. However, differential scanning calorimetric (DSC) thermogram proved that crystalline state of Nos changed to amorphous state in Nos NPs. The entrapment efficacy % (EE%) and drug loading % (DL%) of Nos NPs were about 87.20 ± 3.50% and 12.50 ± 2.30%, respectively. Synergistic anticancer effects of Nos both in free form (in hydrochloride form, Nos HCl) and Nos NPs form with Dox hydrochloride (Dox HCl) were observed on 4T1 cells. Combination of Nos NPs and Dox HCl inhibited tumor growth (68.50%) in mice more efficiently than Nos NPs (55.10%) and Dox HCl (32%) alone. Immunohistochemical (IHC) analysis of the tumor tissues confirmed antiangiogenic effect of Nos NPs. The findings highlighted efficacy of Nos NPs alone and in combination with Dox HCl on breast cancer tumors.

The pivotal role of angiogenesis in a multi-scale modeling of tumor growth exhibiting the avascular and vascular phases.

The mechanisms involved in tumor growth mainly occur at the microenvironment, where the interactions between the intracellular, intercellular and extracellular scales mediate the dynamics of tumor. In this work, we present a multi-scale model of solid tumor dynamics to simulate the avascular and vascular growth as well as tumor-induced angiogenesis. The extracellular and intercellular scales are modeled using partial differential equations and cellular Potts model, respectively. Also, few biochemical and biophysical rules control the dynamics of intracellular level. On the other hand, the growth of melanoma tumors is modeled in an animal in-vivo study to evaluate the simulation. The simulation shows that the model successfully reproduces a completed image of processes involved in tumor growth such as avascular and vascular growth as well as angiogenesis. The model incorporates the phenotypes of cancerous cells including proliferating, quiescent and necrotic cells, as well as endothelial cells during angiogenesis. The results clearly demonstrate the pivotal effect of angiogenesis on the progression of cancerous cells. Also, the model exhibits important events in tumor-induced angiogenesis like anastomosis. Moreover, the computational trend of tumor growth closely follows the observations in the experimental study.

The first successful application of preimplantation genetic diagnosis for hearing loss in Iran.

Hearing impairment (HI) caused by mutations in the connexin-26 gene (GJB2) accounts for the majority of cases with inherited, nonsyndromic sensorineural hearing loss. Due to the illegality of the abortion of deaf fetuses in Islamic countries, preimplantation genetic diagnosis (PGD) is a possible solution for afflicted families to have a healthy offspring. This study describes the first use of PGD for GJB2 associated non-syndromic deafness in Iran. GJB2 donor splicing site IVS1+1G>A mutation analysis was performed using Sanger sequencing for a total of 71 Iranian families with at least 1 deaf child diagnosed with non-syndromic deafness. In Vitro Fertilization (IVF) was performed, followed by PGD for a cousin couple with a 50% chance of having an affected child. Bi-allelic pathogenic mutations were found in a total of 12 families (~17 %); of which a couple was a PGD volunteer. The deaf woman in this family was homozygous and her husband was a carrier of the IVS1+1G>A gene mutation. Among 8 biopsied embryos, two healthy embryos were implanted which resulted in a single pregnancy and subsequent birth of a healthy baby boy. This is the first report of a successful application of PGD for hearing loss in Iran. Having a baby with a severe hearing impairment often imposes families with long-term disease burden and heavy therapy costs. Today PGD has provided an opportunity for high-risk individuals to avoid the birth of a deaf child.

Turmeric effect on subcutaneous insulin-induced amyloid mass: an in vivo study.

Protein-derived amyloid structures are associated with a wide variety of pathologies, including neurodegenerative diseases and local amyloidoses. Reports exist on the ability of insulin to form local amyloidoses under specific conditions. In vitro-generated fibrils of insulin have been previously shown to produce amyloid-containing masses upon repetitive subcutaneous injection in mouse. The present study aimed at investigating the effect of insulin fibrils injection in rats, as well as the potential of turmeric in attenuating this process. It was found that subcutaneous amyloid-containing masses could form in rats at a faster rate compared with mice. Upon addition of turmeric to the fibrils, previous to injection, formed masses had a significantly reduced size, as well as less ordered cellular structure. In conclusion, the results of this study show the potential of turmeric in attenuation of local amyloidosis. Furthermore, we suggest that this model could be of use in screening antiamyloid compounds.

Thermal analysis of magnetic nanoparticle in alternating magnetic field on human HCT-116 colon cancer cell line.

PURPOSE: The purpose of this study was to closely investigate the effects of heat dissipation of superparamagnetic nanoparticles on HCT-116 human cancer cell lines cultured under laboratory conditions and also to examine important parameters including size and concentration of nanoparticles, magnetic field frequency, magnetic field intensity, and exposure time. MATERIALS AND METHODS: Conducting experimental tests required special hardware capable of producing an AC magnetic field with various frequencies. The design and construction process for such an experimental set-up is presented here. First, three different Fe3O4 nanoparticle sizes (8, 15 and 20 nm) with different concentrations (d = 10, 20, 40, 80, 160 and 200 µg/ml) were added to cell culture medium and the resulting mixture was exposed to an AC magnetic field with maximum amplitude of 10 kOe for 30 min under three operating frequencies (f = 80, 120 and 180 kHz). The level of intracellular iron was estimated by the ferrozine-based colorimetric assay. Three concentrations including 20, 40 and 80 µg/ml from each of the three nanoparticles sizes were chosen for the study. RESULTS: It was shown that the power dissipation is a function of frequency, time, nanoparticles size and dose. It was also found that the alternating magnetic field with three different frequencies (f = 80, 120 and 180 kHz) and the maximum amplitude of 10 kOe did not have any adverse effect on cell survival. CONCLUSIONS: Our results demonstrate that where thermal dose is equal to 4.5 ± 0.5 °C/30 min from a starting temperature of 37 °C, HCT-116 cell death is initiated when a magnetic nanoparticle electromagnetic field induced.

Cylindrical agar gel with fluid flow subjected to an alternating magnetic field during hyperthermia.

PURPOSE: In magnetic fluid hyperthermia (MFH), nanoparticles are injected into diseased tissue and subjected to an alternating high frequency magnetic field. The process triggers sufficient heat to destroy the cancerous cells. One of the challenging problems during MFH is blood flow in tissue. In real conditions the heat which is transferred by blood flow should be considered in the analysis of MFH. METHODS: In this study, heat transfer was investigated in an agar gel phantom containing fluid flow. Fe3O4 as a nano-fluid was injected into the centre of a gel cylinder which was filled with another gel cylinder and subjected to an alternating magnetic field of 7.3 kA/m and a frequency of 50 kHz for 3600 s. The temperature was measured at three points in the gel. Temperature distributions regarding the time at these three points were experimentally measured. Moreover, the specific absorption rate (SAR) function was calculated with a temperature function. RESULTS: The SAR function was a key asset in the hyperthermia and was obtained on the condition that the fluid flowed through the gel. Finally, a finite element analysis (FEA) was performed to verify the SAR function. The results revealed that there was good agreement between the measured temperature and the one obtained from FEA. In addition, the effects of fluid flow and accuracy of function obtained for heat production in the gel were presented. CONCLUSION: It is believed that the proposed model has the potential ability to get close to reality in this type of investigation. The proposed function has implications for use in further modelling studies as a heat generation source.

Injection of insulin amyloid fibrils in the hippocampus of male Wistar rats: report on memory impairment and formation of amyloid plaques.

Amyloid fibrils result from a particular type of protein aggregation, and have been linked with various disorders, including neurodegenerative ones. In the case of Alzheimer's disease, amyloid beta (abeta) fibrils are detected in patients' brain, in the amyloid plaques. These fibrils can be produced in vitro, and their injection into animals' brains generates an animal model of Alzheimer's disease. Based on the structural similarity of amyloid fibrils that are formed from different proteins, we hypothesized that injecting insulin amyloid fibrils into rats' brains could result in amyloid plaque formation. Fourteen male Wistar rats were divided into control and experimental groups (n = 7). The experimental group was bilaterally injected with insulin amyloid in the hippocampus. Seven days after injection, a shuttle box test was performed and the experimental group's memory was found to be impaired. Histological investigation of these rats' brain showed the formation of amyloid plaques in the hippocampus. A limited test has provided preliminary evidence for the stability of these plaques up to 35 days. Further complementary studies are required to fully validate the proposed procedure, which is simple and relatively low cost, and could be suggested as an alternative to models generated with abeta fibrils.

In-vivo trachea regeneration: fabrication of a tissue-engineered trachea in nude mice using the body as a natural bioreactor.

PURPOSE: To investigate the outcomes of implanting rat decellularized trachea scaffold (DTS) between the paravertebral muscles of nude mice using the body as a bioreactor for total graft recellularization. METHODS: The tracheas of four rats were aseptically resected and decellularized. To assess the efficiency of the decellularization procedure, all decellularized scaffolds and native control tissues were evaluated with scanning electron microscopy (SEM), DAPI staining, DNA quantification, biomechanical analyses and hydroxyproline measurement. They were then implanted between the paravertebral muscles of four nude mice. The biopsies were precisely evaluated at 1, 3, 6 and 12 months postoperatively for tracheal cartilage and soft tissue recellularization by staining for TTF1, CD34, S100 and leukocyte common antibody. RESULTS: Hematoxylin and eosin (H&E) staining, SEM and the tensile test confirmed the preservation of the tissue structure and the biophysical and biochemical properties of the DTS. The present study clearly demonstrated that the hydroxyproline content of the DTS was similar to that of the native tissue. On the other hand, in biopsy samples obtained after 12 months, histological evaluation showed superior organization and cell seeding in both the cartilage and connective tissues. CONCLUSION: This study demonstrated the feasibility of using a natural bioreactor for recellularizing DTS; this may have the potential to facilitate homologous transplantation for repairing segmental trachea defects.

A Review: Biomechanical Aspects of the Fallopian Tube Relevant to its Function in Fertility.

The fallopian tube (FT) plays a crucial role in the reproductive process by providing an ideal biomechanical and biochemical environment for fertilization and early embryo development. Despite its importance, the biomechanical functions of the FT that originate from its morphological aspects, and ultrastructural aspects, as well as the mechanical properties of FT, have not been studied nor used sufficiently, which limits the understanding of fertilization, mechanotrasduction, and mechanobiology during embryo development, as well as the replication of the FT in laboratory settings for infertility treatments. This paper reviews and revives valuable information on human FT reported in medical literature in the past five decades relevant to the biomechanical aspects of FT. In this review, we summarized the current state of knowledge concerning the morphological, ultrastructural aspects, and mechanical properties of the human FT. We also investigate the potential arising from a thorough consideration of the biomechanical functions and exploring often neglected mechanical aspects. Our investigation encompasses both macroscopic measurements (such as length, diameter, and thickness) and microscopic measurements (including the height of epithelial cells, the percentage of ciliated cells, cilia structure, and ciliary beat frequency). Our primary focus has been on healthy women of reproductive age. We have examined various measurement techniques, encompassing conventional metrology, 2D histological data as well as new spatial measurement techniques such as micro-CT.

Connection between MiR-490 and CCND1 and GSK3ß genes play an effective role in Wnt signaling pathway in colorectal cancer.

The Wnt signaling pathway is identified as one of the main disrupted pathways in Colorectal cancer (CRC). Results from studies focusing on this route will aid greatly in the detection and treatment of CRC. MicroRNAs (MiRs), particularly MiR-490, has emerged as key regulator of gene expression in biological pathways, making it an attractive research target. This is notably true for the Wnt signaling pathway, which is usually disordered in CRC tissues. This study aimed to evaluate the expression level of MiR-490 isomiRs and determine some of its key target genes involved in Wnt signaling pathway in CRC tissues and cell lines, based on experimental and bioinformatics analysis. Elevated expression of GSK3ß and CCND1 indicate that the progression of CRC tumor is associated with the inhibitory effect of MiR-490 isomiRs on the Wnt/ß-catenin signaling pathway. This finding was supported by the observation of a positive connection between the expression pattern of miR-490-3p and 5p, and CCND1 and GSK3ß in CRC. The valuable results of this study provide a means of identifying biomarkers with the potential to either inhibit or activate CRC cellular pathways.

Human unrestricted somatic stem cell administration fails to protect nude mice from cisplatin-induced acute kidney injury.

BACKGROUND: Kidney failure is a debilitating disorder with limited treatment options. The kidney-protective effects of stem cells have been vastly investigated and promising results have been achieved with various sources of stem cells. However, in spite of beneficial effects on other disease models, the renoprotective potential of human cord blood-derived unrestricted somatic stem cells (USSC) has not been examined so far. METHODS: In the present study, acute kidney failure was induced in female nude mice and the effect of USSC transplantation on kidney function and structure was assessed. Furthermore, the expression of some cytokine genes was examined by real-time PCR. Homing of the transplanted cells into kidneys was assessed by flow cytometry, immunohistochemistry, and real-time PCR. RESULTS: USSC-conditioned medium did not attenuate the in vitro nephrotoxic effects of cisplatin. Transplantation of USSC to nude mice did not protect kidney function and was associated with worsened kidney structural damage. USSC transplantation was also associated with a decline in the renal expression of VEGF-A gene. In spite of these effects, the transplanted cells could not be detected in the kidneys by any of the exploited methods and they were mainly entrapped in the lungs. CONCLUSION: These data indicate that USSC are not suitable for cell therapy in the setting of acute kidney injury. Also, this study shows that these stem cells are able to affect damaged kidneys even if they are not homed there.

Testicular histopathology in rats co-exposed to heat and psychological stressors.

Objectives: The present study aimed to investigate the effect of co-exposure to heat and psychological stressors on testicular tissue as one of the major male reproductive organs in rats. Methods: Forty adult male Wistar rats were divided into four groups of 10 animals each. The first group was exposed to heat stress (Temperature Humidity Index: 57.75 ± 3), the second group was exposed to three psychological stressors including strobe light ultrasonic sound, and tilting cage, and the third group was co-exposed to both heat and psychological stress daily. The order of exposure to various psychological stressors was randomized. Following the last day of the 40 -day exposure, the rats were euthanized and their testicular tissues were fixed in Bouin's solution. Moreover, a tissue processor, a microtome as well as hematoxylin, and eosin staining were used for tissue preparation. Results: The co-exposure to psychological and heat stress can cause negative testis histopathological changes including spermatid retention, degeneration of round spermatids and spermatocytes, degeneration and depletion of elongated Spermatid, Sertoli cell status, tubular degeneration/atrophy, Leydig cell atrophy, tubular dilatation, re-tubular dilation, and sclerosis status in a number of rats. Moreover, the histopathological changes were higher in the group exposed to heat stress compared with those exposed to psychological stress. Conclusions: Although exposure to either stressor alone can affect testicular tissue as part of the reproductive system, co-exposure to both stressors may result in an increased risk of adverse effects on testicular tissue.

Inhibition of IRE1 RNase activity modulates tumor cell progression and enhances the response to chemotherapy in colorectal cancer.

Drug resistance is one of the clinical challenges that limits the effectiveness of chemotherapy. Recent reports suggest that the unfolded protein response (UPR) and endoplasmic reticulum stress-adaptation signalling pathway, along with increased activation of its inositol-requiring enzyme 1α (IRE1α) arm, may be contributors to the pathogenesis of colorectal cancer (CRC). Here, we aimed to target the IRE1α/XBP1 pathway in order to sensitise CRC cells to the effects of chemotherapy. The CT26 colorectal cell line was treated with tunicamycin, and then was exposed to different concentrations of 5-fluorouracil (5-FU), either alone and/or in combination with the IRE1α inhibitor, 4µ8C. An MTT assay, flow cytometry and RT-PCR were performed to determine cell growth, apoptosis and IRE1α activity, respectively. In vivo BALB/c syngeneic colorectal mice received chemotherapeutic drugs. Treatment responses, tumour sizes and cytotoxicity were assessed via a range of pathological tests. 4µ8C was found to inhibit the growth of CRC, at a concentration of 10 µg/ml, without detectable cytotoxic effects and also significantly enhanced the cytotoxic potential of 5-FU, in CRC cells. In vivo experiments revealed that 4µ8C, at a concentration of 50 µM/kg prevented tumour growth without any cytotoxic or metastatic effects. Interestingly, the combination of 4µ8C with 5-FU remarkably enhanced drug responses, up to 40-60% and also lead to significantly greater inhibition of tumour growth, in comparison to monotherapy, in CRC mice. Targeting the IRE1α/XBP1 axis of the UPR could enhance the effectiveness of chemotherapy in both in vitro and in vivo models of CRC.

Unraveling complex relationships between COVID-19 risk factors using machine learning based models for predicting mortality of hospitalized patients and identification of high-risk group: a large retrospective study.

Background: At the end of 2019, the coronavirus disease 2019 (COVID-19) pandemic increased the hospital burden of COVID-19 caused by the SARS-Cov-2 and became the most significant health challenge for nations worldwide. The severity and high mortality of COVID-19 have been correlated with various demographic characteristics and clinical manifestations. Prediction of mortality rate, identification of risk factors, and classification of patients played a crucial role in managing COVID-19 patients. Our purpose was to develop machine learning (ML)-based models for the prediction of mortality and severity among patients with COVID-19. Identifying the most important predictors and unraveling their relationships by classification of patients to the low-, moderate- and high-risk groups might guide prioritizing treatment decisions and a better understanding of interactions between factors. A detailed evaluation of patient data is believed to be important since COVID-19 resurgence is underway in many countries. Results: The findings of this study revealed that the ML-based statistically inspired modification of the partial least square (SIMPLS) method could predict the in-hospital mortality among COVID-19 patients. The prediction model was developed using 19 predictors including clinical variables, comorbidities, and blood markers with moderate predictability (Q2 = 0.24) to separate survivors and non-survivors. Oxygen saturation level, loss of consciousness, and chronic kidney disease (CKD) were the top mortality predictors. Correlation analysis showed different correlation patterns among predictors for each non-survivor and survivor cohort separately. The main prediction model was verified using other ML-based analyses with a high area under the curve (AUC) (0.81-0.93) and specificity (0.94-0.99). The obtained data revealed that the mortality prediction model can be different for males and females with diverse predictors. Patients were classified into four clusters of mortality risk and identified the patients at the highest risk of mortality, which accentuated the most significant predictors correlating with mortality. Conclusion: An ML model for predicting mortality among hospitalized COVID-19 patients was developed considering the interactions between factors that may reduce the complexity of clinical decision-making processes. The most predictive factors related to patient mortality were identified by assessing and classifying patients into different groups based on their sex and mortality risk (low-, moderate-, and high-risk groups).

Evaluation of unrestricted somatic stem cells as a feeder layer to support undifferentiated embryonic stem cells.

The use of unrestricted somatic stem cells (USSCs) holds great promise for future clinical applications. Conventionally, mouse embryonic fibroblasts (MEFs) or other animal-based feeder layers are used to support embryonic stem cell (ESC) growth; the use of such feeder cells increases the risk of retroviral and other pathogenic infection in clinical trials. Implementation of a human-based feeder layer, such as hUSSCs that are isolated from human sources, lowers such risks. Isolated cord blood USSCs derived from various donors were used as a novel, supportive feeder layer for growth of C4mES cells (Royan C4 ESCs). Complete cellular characterization using immunocytochemical and flow cytometric methods were performed on murine ESCs (mESCs) and hUSSCs. mESCs cultured on hUSSCs showed similar cellular morphology and presented the same cell markers of undifferentiated mESC as would have been observed in mESCs grown on MEFs. Our data revealed these cells had negative expression of Stat3, Sox2, and Fgf4 genes while showing positive expression for Pou5f1, Nanog, Rex1, Brachyury, Lif, Lifr, Tert, B2m, and Bmp4 genes. Moreover, mESCs cultured on hUSSCs exhibited proven differentiation potential to germ cell layers showing normal karyotype. The major advantage of hUSSCs is their ability to be continuously cultured for at least 50 passages. We have also found that hUSSCs have the potential to provide ESC support from the early moments of isolation. Further study of hUSSC as a novel human feeder layer may lead to their incorporation into clinical methods, making them a vital part of the application of human ESCs in clinical cell therapy.

Feasibility and safety of transglottic bronchoscopy in mechanically ventilated sheep.

PURPOSE: Although bronchoscopy can be safely performed through endotracheal tube in most intubated critically ill patients, sometimes it could lead to complications such as hypoxia and high airway pressures. Theoretically, transglottic bronchoscopy (TGB) does not interfere with mechanical ventilation and could avoid these complications. In a two-period crossover study, we compared this technique with trans-endotracheal tube bronchoscopy (TEB) in normal anesthetized sheep. METHODS: In five sheep, we did TGB first. The bronchoscope was introduced through the nasal nares and passed into the trachea via space between endotracheal tube and vocal folds. Heart rate, V(T), P(peak), and O(2) saturation were recorded. One week later, we did TEB. In another five sheep, we did TEB first and TGB later. RESULTS: P(peak) increased and V(T) and O(2) saturation decreased during TEB (53.2 ± 5.7 vs. 27.6 ± 0.6, P = 0.002; 210 ± 32 vs. 285 ± 26, P = 0.002; 94.3 ± 1.3 vs. 97.5% ± 0.5, P = 0.041, respectively), but not during TGB. The only statistically significant abnormal finding during TGB was a mild tachycardia (96.7 ± 5.7 vs. 94.7 ± 5.5, P = 0.034). CONCLUSION: Although TGB is time consuming and less convenient than TEB, it has minimal interference with mechanical ventilation. Expertise with this technique could be useful in patients with anticipated significant hypoxia and high airway pressures during bronchoscopy.

Micro-scale probing of the Rat's oviduct detects its viscoelastic property needed for creating a biologically relevant substrate for In-Vitro- Fertilization.

Techniques used in assisted reproductive technology such as In-Vitro- Fertilization (IVF) process, often only replicate the biomechanical environment for embryo. Despite its importance, the biomechanics of the Oviduct tissue that is usually called Fallopian Tube in Human, the natural site of fertilization, has not been replicated nor sufficiently studied. This work studies the time-independent and time-dependent biomechanics of the oviduct tissue by realizing a viscoelastic model that accurately fit on the experimental indentation data collected on the mucosal epithelial lining of the oviduct tissue of rats. Nano-scale experiments with varying indentation rates ranging from 0.3 to 8 µms were conducted using atomic force microscopy (AFM) resulting in instantaneous elastic modulus ranging from 0.86 MPa to 6.46 MPa correspondingly. This result showed strong time dependency of the mechanical properties of the oviduct. An improved viscoelastic equation based on the fractional viscoelastic model was proposed. This modified relation successfully captured all the experimental data found at different rates (R2 > 0.8). Using the proposed model, the pure elasticity of the oviduct (i.e., about 317.2 kPa) and the viscoelastic parameters were found.

Down-regulation of immune checkpoints by doxorubicin and carboplatin-containing neoadjuvant regimens in a murine breast cancer model.

OBJECTIVES: Immune checkpoint expression on tumor-infiltrating lymphocytes (TILs) has a correlation with the outcome of neoadjuvant chemotherapy (NAC) in breast cancer. However, the reciprocal effect of these regimens on the quality and quantity of immune checkpoints has hitherto not been addressed. We aimed to evaluate the impact of three NAC regimens on TILs and immune checkpoints in a murine triple-negative breast cancer model. MATERIALS AND METHODS: Syngeneic model of locally-advanced breast cancer was established in immunocompetent mice using a 4T1 cell line. Tumor-bearing animals were treated with human-equivalent dosages of doxorubicin, paclitaxel, paclitaxel and carboplatin combination, and placebo. Infiltration of CD3+, CD8+, and FoxP3+ cells into the tumor was assessed by immunohistochemistry. Expression of immune checkpoints, including PD-1, CTLA-4, and TIM-3, was evaluated by real-time PCR. RESULTS: Doxorubicin led to a significant (P<0.01) increase in the percentage of the stromal infiltrating CD3+ and CD8+ lymphocytes. Doxorubicin also suppressed significantly (P<0.05) the relative expression of PD-1 compared with the placebo. PD-1 expression was significantly (P<0.05) lower in the group treated with paclitaxel and carboplatin combination as compared with the placebo. The relative expression of TIM-3 was significantly (P<0.05) suppressed in doxorubicin-treated mice in comparison with other interventions. CONCLUSION: Our findings hypothesize that NAC with doxorubicin may potentiate antitumor immunity not merely by recruitment of TILs, but via down-regulation of PD-1 and TIM-3 checkpoints. Carboplatin-containing NAC may suppress PD-1 as well.

Effect of Co-exposure to Heat and Psychological Stressors on Sperm DNA and Semen Parameters.

The present study aims to investigate the effects of co-exposure to heat and psychological stress on sperm DNA and semen parameters among male rats. The study was conducted on 40 healthy adult male Wistar rats. The rats were randomly categorized into four groups of same size consisting of a control group, a heat stress, psychological and co-exposure groups. The heat stress group was exposed to a temperature of 36 °C at 20% relative humidity. The psychological stress exposure group was subjected to three stressors including exposure to strobe light, noise and tilting cage. According the results,the co-exposure group had lower mean sperm parameters including sperm count (17.22 ± 4.22 106/ml), motility (42.63 ± 12.95 %), viability (48.50 ± 23.25 %), normal morphology (56 ± 7.5%), progressive motility (11.61 ± 7.81%), non-progressive motility (31.18 ± 7.77%), curvilinear velocity (24.11 ± 3.81 µm/s) and straight-line velocity (3.2 ± 1.4 µm/s) when compared with those of the other groups (P = 0.001). Mean sperm immobility (57.36 ± 12.95%) and non-progressive motility (37.93 ± 11.15%) in the co-exposure group was higher compared to the other groups (P = 0.001 and P = 0.333, respectively). Assessment of damage to sperm DNA revealed that the heat exposure group had a higher percentage of sperm DNA damage (9.44 ± 6.80 %) compared to others (P = 0.185). In case of all of exposure scenario, the chance that the semen quality decreased compared to the control group has been increased. In general the combined stress had a greater significant effect on sperm parameters compared to other exposure groups, except for DNA damage.