Characterization of a xenograft model for anti-CD19 CAR T cell studies

Purpose Chimeric antigen receptor (CAR) T cell development for B cell malignancies treatment has triggered a paradigm shift in oncology. The development of anti-CD19 CAR T cells relies primarily on a panel of cell line-derived xenograft models, including Raji cells; however, the behavior of this model is under debate. We attempted to characterize this lymphoma model and propose outcome measures for CAR T cell studies Methods Raji cell line was inoculated into NOG mice via intra-venous (IV), intra-peritoneal (IP), and subcutaneous (SC) routes with different inoculum sizes, and consequent clinical and histopathological outcomes were assessed. Results Inoculum sizes of 105–106 resulted in a complete take rate. The mice with IV and SC-inoculated Raji cells presented the shortest and longest survival among lymphoma-bearing mice, respectively (P < 0.01). The IP group had the highest number of both infiltrated organs (P < 0.05; compared to SC) and involvement of lymphatic sites (P < 0.05; compared to IV). The number of lymphoma lesions on the liver was higher in the IV compared to IP (P < 0.001) and SC (P < 0.05). Conclusion We demonstrate that the Raji cell line inoculation route could determine the xenograft model system behavior in terms of survival, tumor burden, and dissemination pattern and gives the model the specific features suitable for testing the specific hypothesis in CAR T cell therapy. We also conclude outcome measures for CAR T cell studies that do not require imaging techniques (AU)

Characterization of a xenograft model for anti-CD19 CAR T cell studies.

PURPOSE: Chimeric antigen receptor (CAR) T cell development for B cell malignancies treatment has triggered a paradigm shift in oncology. The development of anti-CD19 CAR T cells relies primarily on a panel of cell line-derived xenograft models, including Raji cells; however, the behavior of this model is under debate. We attempted to characterize this lymphoma model and propose outcome measures for CAR T cell studies METHODS: Raji cell line was inoculated into NOG mice via intra-venous (IV), intra-peritoneal (IP), and subcutaneous (SC) routes with different inoculum sizes, and consequent clinical and histopathological outcomes were assessed. RESULTS: Inoculum sizes of 105-106 resulted in a complete take rate. The mice with IV and SC-inoculated Raji cells presented the shortest and longest survival among lymphoma-bearing mice, respectively (P < 0.01). The IP group had the highest number of both infiltrated organs (P < 0.05; compared to SC) and involvement of lymphatic sites (P < 0.05; compared to IV). The number of lymphoma lesions on the liver was higher in the IV compared to IP (P < 0.001) and SC (P < 0.05). CONCLUSION: We demonstrate that the Raji cell line inoculation route could determine the xenograft model system behavior in terms of survival, tumor burden, and dissemination pattern and gives the model the specific features suitable for testing the specific hypothesis in CAR T cell therapy. We also conclude outcome measures for CAR T cell studies that do not require imaging techniques.

Molecular modelling of the antiviral action of Resveratrol derivatives against the activity of two novel SARS CoV-2 and 2019-nCoV receptors.

The pandemic threat of COVID-19 causes serious concern for people and world organizations. The effect of Coronavirus disease on the lifestyle and economic status of humans is undeniable, and all of the researchers (biologists, pharmacists, physicians, and chemists) can help decrease its destructive effects. The molecular docking approach can provide a fast prediction of the positive influence the targets on the COVID-19 outbreak. In this work, we choose resveratrol (RV) derivatives (22 cases) and two newly released coordinate structures for COVID-19 as receptors [Papain-like Protease of SARS CoV-2 (PBD ID: 6W9C) and 2019-nCoV RNA-dependent RNA Polymerase (PBD ID: 6M71)]. The results show that conformational isomerism is significant and useful parameter for docking results. A wide spectrum of interactions such as Van der Waals, conventional hydrogen bond, Pi-donor hydrogen bond, Pi-Cation, Pi-sigma, Pi-Pi stacked, Amide-Pi stacked and Pi-Alkyl is detected via docking of RV derivatives and COVID-19 receptors. The potential inhibition effect of RV-13 (-184.99 kj/mol), and RV-12 (-173.76 kj/mol) is achieved at maximum value for 6W9C and 6M71, respectively.

Varicocelectomy with primary gubernaculum veins closure: A randomised clinical trial.

To evaluate the effect of microsurgical inguinal varicocelectomy with testicular delivery on semen parameters. A total of 416 patients, diagnosed with grade III varicocele, were randomised into two groups. One group underwent microsurgical inguinal varicocelectomy without testicular delivery. For the other group, testicular delivery and ligation of gubernacular and all collateral veins were performed. A semen analysis was performed before and 6 months after the procedure. Mean age of the patients in the case and control groups was 27.3 ± 6.1 years and 25.9 ± 4.6 years respectively (p = .1). The total number of recurrence after 6 months in the conventional and testicular delivery groups was 13 (6.5%) and 3 (1.5%) (p < .05). No case of hydrocele formation was observed in any of the groups. All sperm parameters were improved 6 months after the surgery in both groups. But comparing the mean improved difference between the two groups revealed a significant difference in improvement in sperm motility for patients who had undergone varicocelectomy with testicular delivery (p = .05). Microsurgical inguinal varicocelectomy is a safe and efficient technique with a minimum chance of post-operative complications and recurrence and also may have role in improvement of sperm motility compared with conventional techniques.

ESR response of CFQ-Gd2O3 dosimeters to a mixed neutron-gamma field: Monte Carlo simulation.

Clear fused quartz (CFQ) may be considered a suitable material for electron and gamma dose measurements using electron spin resonance (ESR) technique. Research has been ongoing to optimize the neutron capture therapy (NCT) mechanism and its effects in cancer treatment. Neutron sources of the mixed neutron-gamma field are a challenge for this treatment method. A reliable dosimetric measurement and treatment should be able to determine various components of this mixed field. In this study, the ESR response of cylindrical and spherical shells of CFQ dosimeters, filled with Gd2O3, when exposed to a thermal neutron beam, has been investigated using Monte Carlo simulation. In order to maximize the ESR response, the dimensions of the outer and inner parts of the samples have been chosen as variables, and the amount of energy deposited in the samples has been determined. The optimum size of the samples has been determined, and the capability of discriminating gamma and neutron dose in a mixed neutron-gamma field regarding the CFQ-Gd2O3 dosimeter has also been widely studied.

Cardiovascular and single-unit responses to L-glutamate injection into the posterior insular cortex in rat.

The insular cortex in rat is a longitudinal strip that runs along the rostral half of the rhinal fissure. The previous studies showed connections between the posterior insular cortex (PIC) and some major cardiovascular centers. Based on the stimulation site, electrical or chemical stimulation of the PIC induced an increase or a decrease in blood pressure (BP) and heart rate (HR). There is no report of simultaneous cardiovascular and single-unit recording microinjection of Glut in the PIC. In this study, L-glutamate was microinjected into the PIC of urethane anesthetized rats and arterial pressure, HR and single-unit responses were recorded simultaneously. Also the response of the neurons to baroreceptor activation was explored. Glut produced five types of long oscillatory, pressor, depressor, bradycardic and tachycardic cardiovascular responses, with no association between pressure and HR responses. We also observed five single-unit responses, consisting of short excitatory, long oscillatory, excitatory, inhibitory and mixed responses. There was an association between oscillation in BP and in single-unit response. There were some differences between the two sides especially for single-unit responses. In conclusion, there were five types of cardiovascular and five types of single-unit responses, to Glut microinjection into PIC, from which three types were correlated. The left side of the PIC is involved more in the cardiovascular functions. These data along with the fact that most recorded neurons responded to baroreceptor activation, might imply the presence of feedback systems in the PIC, producing irregularity in BP and HR.

Application of Isfarzeh seed (Plantago ovate L.) mucilage as a fat mimetic in mayonnaise.

In present study, application of Isfarzeh seed (Plantago ovate L.) mucilage as fat replacer was studied in mayonnaise formulation. Fat was partially substituted by mucilage gels (2 and 3 % suspensions) at levels of 30, 40 and 50 % which were referred to as FM2-30 % (2 % gel and 30 % substitution level), FM2-40 %, FM2-50 %, FM3-30 %, FM3-40 %, and FM3-50 % formulations, respectively and the full fat (Ff) mayonnaise with 78 % oil was used as control. Physicochemical, texture and sensory analysis of Ff and Low fat (Lf) treatments were evaluated. Results indicated that Lf samples had considerably lower energy content compared with control, but higher water content than their Ff counterpart. In view of texture, FM3-30 % showed similar textural characteristics as those of control. Both Ff and Lf samples exhibited thixotropic and shear thinning behavior through rheological studies and all samples followed the power law model except FM3-40 % and FM3-50 %. Sensory evaluation demonstrated that all of mayonnaise samples, containing 3 % mucilage, were more acceptable. It was concluded that Isfarzeh seed mucilage can be used as a suitable fat replacer in mayonnaise formulation.

Influence of magnetic field on the electric breakdown in penning ion source.

A cold-cathode penning-type ion source has been developed in our laboratory to study the electric breakdown in this type of sources. The breakdown voltage was measured as a function of axial magnetic field, in the range of 440-600 G, and anode length, in steps of 14, 20, and 24 mm. The measurement was performed with stainless steel cathodes in argon gas at pressure of 4 × 10(-2) mbar. Furthermore, a model was developed to explain the breakdown voltage data. In the construction of the model, the first Townsend coefficient was not directly used to avoid difficulties originating from the non-uniformity of the electric field. The empirical parameters of the model were obtained using the experimental data. The equation γ = c × (E(z)/N)(n), expressing the effective secondary emission coefficient in terms of reduced electric field, which was needed in the modeling process, was inspired from previous works. The parameters c and n were then calculated from the empirical parameters of the model. The n parameter turned out to be 0.59, which differs from the value reported by other authors merely by 1.6%. Three values, 0.010, 0.013, and 0.017 corresponding to the three anodes were obtained for the c parameter. These numbers are in good agreement with 0.01, which has been reported in the previous works. It was also found that the value of n has a decisive impact on the breakdown voltage curve in the high breakdown voltage region.

A retrospective 7-years study of aluminum phosphide poisoning in Tehran: opportunities for prevention.

The objective of this study was to survey aluminum phosphide (AIP) poisoning in a referral poisoning hospital in Tehran servicing an estimation of 10,000,000 populations. Records of all patients admitted and hospitalized during a period of 7 years from January 2000 to January 2007 were collected and analyzed according to gender, age, cause of intoxication, amount of AIP consumed, route of exposure, time between exposure and onset of treatment, signs and symptoms of intoxication at admission, therapeutic intervention, laboratory tests, and outcome. During the studied years, 471 patients were admitted to the hospital with AIP poisoning; 50% of them were men. The overall case fatality ratio was 31%. The mean age was 27.1 years, and most of the patients were between 20 and 40 years old. Self-poisoning was observed in 93% of cases. The average ingested dose was 5.1 g, and most of the patients (73%) consumed 1-3 tablets of AIP. A wide range of symptoms and signs was seen on admission, but the most common one was cardiovascular manifestations (78.12%). The majority (65%) of patients were from Tehran. Poisoning in spring and winter (34% and 24%, respectively) was more common than other seasons. Gastric decontamination with potassium permanganate, and administration of calcium gluconate, magnesium sulfate, sodium bicarbonate, and charcoal were considered for most of the patients. Mean arterial blood pH was 7.23 and bicarbonate concentration was 12.7 mEq/L. One-hundred percent of patients with blood pH <7 died and 100% of patients with blood pH >or= 7.35 survived. Electrocardiogram (EKG) abnormalities were noted in 65.6% of cases. There was a significant difference between survival and non-survival according to pH, HCO(3) concentration, and EKG abnormality. Even without an increase in resources, there appears to be significant opportunities for reducing mortality by better medical management and further restrictions on the AIP tablets usage. Arterial blood pH seems to be a prognostic factor for the outcome of AIP-poisoned patients.

ESR response of bulk samples of clear fused quartz (CFQ) material to high doses from 10 MeV electrons: its possible application for radiation processing and medical sterilization.

Clear fuse quartz (CFQ) could be a good candidate for dose measurements in the radiation processing of food material and in the sterilization of disposable medical and pharmaceutical products. In this study, bulk samples of CFQ materials were exposed to 10 MeV electrons at doses between 5-15 and 25-35 kGy; the dose ranges normally used for processing and sterilization. After irradiation, the samples were subjected to electron spin resonance analysis to test the intensity of their signal against the applied doses. The reproducibility of dose curve of the material to 10 MeV electrons was also studied, in which the dosed samples were annealed at 800 degrees C for 20 min and reused for further dose curve reproducibility investigation. The dose response curves of the reused samples showed a good linearity between the absorbed dose and the ESR intensity of the signals. They also indicated that the ESR intensity in the dose response curve, in both dose ranges, decreased by approximately 37% for the first reuse process and approximately 41% for the second reuse process of the samples in comparison to the first measurement. The thermal fading of the cylindrical samples of the CFQ, at room temperature, showed a sharp decay of approximately 20% over a period of 15 days, after which the decay-rate was negligible for a measured period of 60 days.

Hyper pure quartz as a promising material for retrospective and radiation processing dosimetry using ESR technique.

Samples of highly purified naturally occurring silicon dioxide (SiO(2)) commercially named clear fused quartz (CFQ), both in bulk and in powder form were exposed to 4 and 8 MeV electrons from a linear accelerator (radiotherapy unit) at doses between 0.5 and 60 Gy (minimum and maximum attainable dose, respectively). After irradiation, the samples were subjected to electron spin resonance (ESR) analysis readout to test their use as a mean of measuring absorbed doses in the samples. A good linearity between the absorbed dose (from 2 Gy up to the maximum dose applied of 60 Gy) and the ESR intensity of the samples was observed while a poor linearity at low doses (between the absorbed dose from 0.5 to 10 Gy and the ESR intensity) is seen. The background intensity in the case of the powder was higher than for the cylindrical samples and the ESR intensity was also lower in the former case, which gave rise to a dose curve response with a lower slope for the powders. No energy dependence was apparent for electrons of 4 and 8 MeV energy. The thermal fading of CFQ at room temperature showed a relatively sharp decay of approximately 30% over a period of 10 days after which the decay rate was negligible for a measured period of 80 days. The results in this study plus the previous work done (gamma irradiation of the samples) by the authors suggest that the materials could, by using the ESR technique, be a suitable candidate for alternative dose measurements in radiation processing and retrospective dosimetry.

Oxidative stress in operating room personnel: occupational exposure to anesthetic gases.

Health professionals exposed to anesthetic gases are at higher risk of reproductive, neurological, hematological, immunological, hepatic and renal system diseases. We investigated if oxidative stress induced by chronic exposure to anesthetic gases has any association with this matter. Plasma lipid peroxidation, total antioxidant capacity and total thiol molecule levels were measured in 66 operating room staff in comparison with 66 controls. The exposed group had a significantly higher level of lipid peroxidation with decreased thiol groups compared to control subjects. Total antioxidant capacity of the body was no different among exposed and not exposed subjects. Increased lipid peroxidation in the blood of exposed subjects warns that oxygen free radicals have increased in the body and thus might attack cells, which, in the long-term, results in multi-organ damage. The remaining blood total antioxidant capacity at normal values is promising and means that other non-thiol antioxidants, such as uric acid, transferrin, ceruloplasmin, albumin, and vitamin antioxidants, such as alpha-tocopherol and ascorbic acid, have been stimulated to maintain the total anti-oxidant power of the body at normal state.

Induction of oxidative stress and acetylcholinesterase inhibition in organophosphorous pesticide manufacturing workers.

Oxidative stress status and acetylcholinesterase (AChE) activity were studied in blood samples obtained from 45 organophosphorous (OP)-formulating pesticide workers with a minimum work history of 1 year in the age range of 23-55. Controls were age-matched workers of a food-making factory. They were evaluated for oxidative stress markers, including thiobarbituric acid-reactive substances (TBARS) indicator of lipid peroxidation (LPO), ferric-reducing ability of plasma (FRAP) indicator of total anti-oxidant capacity, total thiol (SH) groups and gamma glutamyl transpeptidase (GGT) levels in blood and AChE activity in erythrocytes. The results show marked inhibition of AChE activity, increased TBARS, decreased FRAP and decreased thiol group levels in workers. The reduction in activity of AChE correlated well with increased TBARS and decreased FRAP in OP formulators. It is concluded that OP-formulating workers are exposed to more oxidative stress. The measurement of erythrocyte AChE activity in pesticide workers who formulate OPs can be a good monitoring factor and is recommended to be performed in a regular manner.

Selenium deficiency and hypothyroidism: a new etiology in the differential diagnosis of hypothyroidism in children.

Three female children presented with different clinical symptoms that could be related to impaired thyroid function. They underwent an accurate pediatric-endocrinologic diagnosis. Laboratory tests revealed no pathological findings, except latent hypothyroidism and selenium deficiency. Hypothyroidism was diagnosed by elevated basal TSH and by a pathological i.v.-TRH-stimulation test. After treating the children with sodium selenite orally for 4 wk, their metabolism had returned to normal and we saw a marked improvement of all clinical symptoms. For the first time, we have been able to describe hypothyroidism caused exclusively by selenium deficiency, the pathophysiology of which may be expressed as a malfunction of human 5'-deiodinases.