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Bromelain is a plant-based molecule with antioxidant, antithrombotic, anticancer, and anti-inflammatory properties. Bromelain has been shown to reduce the release of inflammatory cytokines. This study aimed to determine whether bromelain can prevent ataxia in rats caused by 3-acetylpyridine (3-AP). Thirty-six albino rats were divided into the control, 3-AP, and 3-AP + Brom groups. In the 3-AP + Brom group, bromelain was injected intraperitoneally at 40 mg/kg daily for 30 days. Various techniques such as rotarod, electromyography (EMG), elevated plus maze, IHC, and Sholl analysis were used to evaluate the possible effects of bromelain on cerebellar neurons and glial cells. The results demonstrated significant improvements in most of the 3-AP + Brom, including motor coordination, neuromuscular response, anxiety, oxidative capacity, microgliosis, astrogliosis, cell death, and morphological variables compared to the 3-AP group. The mechanism of action of bromelain in restoring cerebellar ataxia needs further investigation, but it may be a candidate to help restore degeneration in animals with ataxia. [ABSTRACT FROM AUTHOR]

• Individuals with Fanconi anemia have a higher incidence of posterior reversible encephalopathy syndrome (PRES). • Cyclosporine level is not correlated with PRES occurrence. • PRES can present with a nonposterior distribution. • PRES is nonreversible in all cases. Posterior reversible encephalopathy syndrome (PRES) is one of the most common neurologic complications following hematopoietic stem cell transplantation (HSCT). We aimed to evaluate the incidence, clinical, and imaging features of PRES in pediatric patients with Fanconi anemia (FA) following HSCT. This prospective study included all post-HSCT patients with underlying FA disease between 2014 and 2017. Brain computed tomography scan and magnetic resonance imaging (MRI) were performed in all individuals who developed neurologic symptoms. PRES was diagnosed based on clinic-radiological evidence. Follow-up MRI was performed in all patients with PRES within two months. Forty-one patients with FA (28 males; mean age, 8.19 ± 3.25 years) were enrolled. Out of 15 patients with acute neurologic symptoms, PRES was diagnosed in 9 individuals (21.95% of the total cohort). The occurrence of PRES was significantly higher in patients who had a donor with a 1-locus mismatch (P =.02). Donor relation, stem cell source, and graft-versus-host disease grade did not have any significant association with the development of PRES. MRI showed asymmetric vasogenic edema in 5 patients, an overt infarct in 1 patient, and foci of microhemorrhages in 3 patients, 1 of whom developed a hemorrhagic infarct. This patient died shortly, and persistent microhemorrhages were noted in the other 2 patients. Our findings demonstrate a greater risk of developing PRES after HSCT in patients with FA compared with those with other diseases (21.95% versus 1% to 10%), and in contrast to its term, it might be irreversible and has adverse effects on HSCT outcomes. The increased vascular and endothelial fragility in FA may contribute to the higher frequency of PRES in these individuals. [ABSTRACT FROM AUTHOR]

Objective: There is evidence that standard assessment techniques for detecting PAD might be of less diagnostic accuracy in people with type 2 diabetes. The aim of this study was to examine diagnostic performance of Plethysmographic-and-Doppler derived ankle brachial index, toe brachial index, and Pulse volume waveform analysis for detecting PAD in people with T2DM.Methods: In this cross-sectional study 303 patients with T2DM were included in the study. The participants underwent ABI measurement, applying both Plethysmographic and Doppler derived devices, as well as TBI, PVW was also recorded for each patient. Diagnostic performance of each test for detecting PAD, applying ultrasound Doppler scan as the reference standard, was measured. Moreover, the best cut-off point for each method to detect PAD was determined.Results: PVW showed the highest sensitivity (81.8%) for detecting PAD, followed by ABIDOP (72.7%), and ABIPLE (20%). However, all devices showed an excellent specificity for detecting PAD. The optimal cut-off point for diagnosis of PAD was 0.9 for ABIDOP, 1.2 for ABIPLE, and 0.38 for TBI.Conclusion: Within this population of patients with T2DM, TBI less than 0.38 provided the best sensitivity for detection of PAD followed by PVW, ABIDOP≤0.9, and ABIPLE<1.2. [ABSTRACT FROM AUTHOR]

Transformer neural networks have revolutionized natural language processing by effectively addressing the vanishing gradient problem. This study focuses on applying Transformer models to time-series forecasting and customizing them for a simultaneous multistep-ahead prediction model in surrogate model predictive control (MPC). The proposed method showcases improved control performance and computational efficiency compared to LSTM-based MPC and one-step-ahead prediction models using both LSTM and Transformer networks. The study introduces three key contributions: (1) a new MPC system based on a Transformer time-series architecture, (2) a training method enabling multistep-ahead prediction for time-series machine learning models, and (3) validation of the enhanced time performance of multistep-ahead Transformer MPC compared to one-step-ahead LSTM networks. Case studies demonstrate a significant fifteen-fold improvement in computational speed compared to one-step-ahead LSTM, although this improvement may vary depending on MPC factors like the lookback window and prediction horizon. • Transformer and LSTM models compared in Model Predictive Control. • New multistep Transformer architecture proposed for MPC. • Transformer MPC outperforms LSTM-based MPC with 15x speedup. • Practical implementation on fluidized-bed gold ore roaster. [ABSTRACT FROM AUTHOR]

Abstract: Aim: PR81 is a monoclonal antibody that binds with high affinity to MUC1 antigen that is over expressed in 80% of breast cancers. In this study, we developed a method for indirect labeling of PR81 with lutetium-177 and performed all preclinical qualifications in production of a biologic agent for radioimmunotherapy of breast cancer. Materials and Methods: The radiochemical purity and in vitro stability of 177Lu labeled PR81 was determined by instant thin layer chromatography. The immunoreactivity and cell toxicity of the complex were tested on MCF7 cell line. The biodistribution and scintigraphy studies were performed in BALB/c mice with breast tumor. Results: The radiochemical purity was 91.2±3.8% after 2 h. The in vitro stabilities in phosphate buffer and human blood serum were 83.1±3.4% and 76.2±3.6% at 96 h, respectively. The immunoreactivity of the complex was 83.4±2.4%. The cell toxicity study showed that the complex inhibited 85.2±3.4% growth of MCF7 cells at a concentration of 2500 ng/ml after 96 h. The biodistribution and scintigraphy studies showed the accumulation of the complex at the site of tumors with high sensitivity and specificity. Conclusion: The results showed that one may consider 177Lu-DOTA–PR81 as a potential radiopharmaceutical for therapy of human breast cancer, which needs further investigations. [Copyright &y& Elsevier]

Abstract: Technetium-99m complex of hexamethyl-propylene-amineoxime (HMPAO) is used as an efficient agent to label liposomes. For this, 99mTc-HMPAO is incubated with preformed liposomes that contain glutathione (GSH). Effect of GSH and lipid concentration on labeling efficiency, as well as the effect of lipid composition on in vitro stability of labeled liposomes, was investigated in the present study. d,l-HMPAO was synthesized and kits including d,l-HMPAO and SnCl2·2H2O were optimized at 0.5 mg HMPAO, 5.0 μg SnCl2·2H2O and pH 7, and lyophilized. DSPC/CHOL (molar ratio 2:1) liposomes encapsulating GSH were labeled with 99mTc-HMPAO prepared kits. Increase of GSH concentration in hydration buffer from 5 to 200 mM during liposome preparation resulted in a broad labeling efficiency of liposomes ranging from 4.16% to 69.81%. An initial approximate concentration of 100 mM GSH in the hydration buffer seems to be appropriate for a good labeling efficiency. At the optimum concentration of GSH, change of the total initial lipid concentration from 10 to 70 mM did not produce a remarkable difference in labeling efficiency. Study of the effect of lipid composition on the stability of liposomes showed that all three kinds of labeled liposomes composed of DSPC/CHOL, DPPC/CHOL and DMPC/CHOL (molar ratio 2:1) had good in vitro stability in human plasma at 37°C for 48 h; however, employing DSPC resulted in the most stable ones. [Copyright &y& Elsevier]

Humans are potentially exposed to nano(micro)plastics, however their interaction with tissues and cells in humans remains largely unknown. This premise is particularly notable with nano-sized plastic particulates, a potentially most pernicious form of plastic pollution. In this study, even in a hypothetical scenario in terms of dose (1, 3, 6 and 10 mg/kg-day) and exposure time (five weeks), the potential endocrine disturbances with particular reference to reproductive toxicity of polystyrene nanoplastics (PS NPs, average size = 38.92 nm) was studied in male rats considering biomarkers of semen quality, changes in hormonal milieu and molecular signatures of endocrine disruption. Sperm DNA integrity and its chromatin structure were also analyzed. There observed significant inverse associations between exposure to PS NPs and serum concentrations of testosterone, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). Tissue and cell impairments were also noticed even at the lowest tested dosage, though the severity of lesions followed a clear dose-response pattern. DNA damage as well as alterations in sperm morphology and viability were evident, again proportionally with the amount of exposure dosage. RT-qPCR data were in accordance with the results of physio-histological alterations and fluorescence imaging, as significant down-regulation of PLZF , DAZL , FSH and LH gene expressions were noticed in the testis of exposed animals, suggesting that exposure interferes with spermatogenesis and also with HPT-axis. However, among those with highest exposure dosage, expressions of FSH and LH were significantly increased. ABP modulation further revealed evidence of a nonlinear dose response. The association between PS NPs exposure and GnRH was indeed in an unexpected positive direction, though these end-points were less sensitive at higher doses. Although additional evidence is warranted, the present work provides new insights into the possible risks of plastic nanoparticles exposure in humans, especially since the problem is growing and will persist for a long time. Image 1 • Rats were orally exposed to virgin and fluorescently labeled polystyrene nanoplastics. • Early warning signs of reproductive toxicity in rats from the ingestion of PS. • A significant down-regulation of PLZF , DAZL , FSH and LH gene expressions were found. • Endocrine disturbance was ascribed to NPs bioaccumulation and histological lesion. [ABSTRACT FROM AUTHOR]

Continuous welded rail (CWR) tracks have particular advantages over common tracks with jointed rails such as increased ride comfort, reduced noise and vibration and decreased maintenance costs due to the removal of joints in rail connections. Alternatively, some complications associated with CWR tracks, for instance increased lateral forces, are the main reason of track buckling and its subsequent lateral deformation. These problems are usually more severe in curved tracks. In order to overcome the large lateral forces caused by temperature deviations of CWR tracks which results in railway vehicle instability, the ballasted track lateral resistance should be improved. Among the various methods proposed in this area, no specific study has been carried out on the effect of geogrid reinforcement on ballasted track lateral resistance. Thus, the present research was allocated to investigating the effect of geogrid on the lateral resistances of both single tie and track panel via laboratory and field tests. In this regard, at the first stage, the ballast layer was reinforced with various number of geogrid layers, the effect of which was investigated by conducting the single tie push test (STPT) in the lab environment to assess the optimum number of geogrid layers and their installation levels along the ballast layer thickness. Afterwards, a test track was executed in the field including various sections which were reinforced in the same way as the lab tests. Consequently, many STPTs and track panel displacement tests (TPDTs) were accomplished. As a result, the STPTs in the lab and field confirmed more than 31% and 42% increase in single tie lateral resistance for ballast layers reinforced respectively with one and two geogrid layers, while these values were reached to 29% and 40% in the case of TPDT. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: In the present study, Herceptin was labeled with lutetium-177 via DOTA, and the necessary preclinical quality control tests (in vitro and in vivo) were performed to evaluate its use as a radioimmunotherapy agent. Material and Methods: Herceptin was conjugated to DOTA as a chelator in three different conjugation buffers (ammonium acetate, carbonate and HEPES buffer); each of the resulting conjugates was compared with respect to in vitro characteristics such as number of chelates per antibody, incorporated activity, immunoreactivity and in vitro stability in PBS buffer and blood serum. The biodistribution study and gamma camera imaging were performed in mice bearing breast tumors. To assess the therapeutic effects of 177Lu-Herceptin, cytotoxicity was investigated for 7 days in a SKBr3 breast cancer cell line. Results: Carbonate buffer was the best conjugation buffer (number of chelates per antibody: 6; incorporated activity: 81%; immunoreactivity: 87%; buffer stability: 86%; serum stability: 81%, after 4 days). The efficient tumor uptake observed in the biodistribution studies was consistent with the gamma camera image results. At a concentration of 4 μg ml−1, 177Lu-Herceptin (surviving cells: 5±0.6% of the total cells) of the total cells corresponded to an approximately eightfold increase in cytotoxicity in comparison to unmodified Herceptin (surviving cells: 43±3.9%). Conclusion: The new complex described herein could be considered for further evaluation in animals and potentially in humans as a radiopharmaceutical for use in the radioimmunotherapy of breast cancer. These results may be important for patients who cannot tolerate the therapeutic dosage of Herceptin currently used because of heart problems. [Copyright &y& Elsevier]

Abstract: Aim: Trastuzumab is a monoclonal antibody that is used in treating breast cancer. We labeled this monoclonal antibody with lutetium-177 and performed in vitro quality control tests as a first step in the production of a new radiopharmaceutical. Material and Methods: Trastuzumab was labeled with lutetium-177 using DOTA as chelator. Radiochemical purity and stability in buffer and human blood serum were determined using thin layer chromatography. Immunoreactivity and toxicity of the complex were tested on MCF7 breast cancer cell line. Results: The radiochemical purity of the complex was 96±0.9%. The stabilities in phosphate buffer and in human blood serum at 96 h postpreparation were 93±1.2% and 85±3.5%, respectively. The immunoreactivity of the complex was 89±1.4%. At a concentration of 1 nM, the complex killed 70±3% of MCF7 cells. At 1.9 nM, 90±5% of the cells were killed. Conclusions: The results showed that the new complex could be considered for further evaluation in animals and possibly in humans as a new radiopharmaceutical for use in radioimmunotherapy against breast cancer. [Copyright &y& Elsevier]

Abstract: Human epithelial mucin, MUC1, is commonly overexpressed in adenocarcinoma that includes more than 80% of breast cancers. The PR81 is a murine anti-MUC1 monoclonal antibody (MAb) that was prepared against the human breast cancer. We developed an indirect method for labeling of this antibody with 99mTc in order to use the new preparation in immunoscintigraphy studies of BALB/c mice bearing breast tumors. The 99mTc–PR81 complex was prepared using the HYNIC as a chelator and tricine as a coligand. The labeling efficiency determined by instant thin-layer chromatography (ITLC) was 89.2%±4.7%, and radiocolloides measured by cellulose nitrate electrophoresis were 3.4%±0.9%. The in vitro stability of labeled product was determined at room temperature by ITLC and in human serum by gel filtration chromatography — 88.3%±4.6% and 79.8%±5.7% over 24 h, respectively. The integrity of labeled MAb was checked by means of sodium dodecyl sulfate polyacrylamide gel electrophoresis, and no significant fragmentation was seen. The results of cell binding studies showed that both labeled and unlabeled PR81 were able to compete for binding to MCF 7 cells. Biodistribution studies performed in female BALB/c mice with breast tumor xenografts at 4, 16 and 24 h after the 99mTc-HYNIC-PR81 injection demonstrated a specific localization of the compound at the site of tumors and minimum accumulation in non target organs. The tumor imaging was performed in BALB/c mice with breast xenograft tumors at 4, 8, 12, 16, 20, 24, 28, 32 and 36 h after the complex injection. The tumors were visualized with high sensitivity after 8 h. The findings showed that the new radiopharmaceutical is a promising candidate for radioimmunoscintigraphy of the human breast cancer. [Copyright &y& Elsevier]

Abstract: In this study, we labeled trastuzumab with 177Lu to synthesize a new radiopharmaceutical for therapy of breast cancer and at the first stage investigated its therapeutic effects on SKBr3 and MCF7 breast cancer cell lines. Trastuzumab-177Lu showed very good in-vitro characteristics such as high radiochemical purity (91±0.9%), good stability in PBS buffer (86±2.3%) and blood serum (81±2.7%) up to 96h, appropriate immunoreactivity (85.4±1.1%) and high cytotoxicity in HER2 expression cells. 5 fold increase in toxicity of trastuzumab-177Lu was observed when compared with unlabeled trastuzumab on SKBr3 cells. [ABSTRACT FROM AUTHOR]

Background and Aims: Colon cancer is the second leading cause of death due to cancer worldwide. Elevated expression of IGF-IR is a frequent genetic abnormality seen in this malignancy. The aim of the study was to examine the anti-growth effects elicited by a decrease in the protein level of IGF-IR by RNA interference (RNAi) in SW480 cells. Methods: A plasmid-based polymerase III promoter system was used to deliver and express short interfering RNA (siRNA) targeting IGF-IR to reduce its expression in SW480 cells. The expression of IGF-1R protein was detected by Western blot. We assessed the effects of IGF-IR silencing on cancer cell growth by a growth curve. Results: We prepared a type of IGF-IR short hairpin RNA (shRNA) expression vector that could efficiently inhibit the expression of IGF-IR in SW480 cells. At 48 h after transfection, the expression inhibition rate was 92 ± 2% at mRNA level detected by RT-PCR analysis. Western blotting detected a similar inhibition of IGF-IR protein levels in cells transfected with pkD-shRNA-IGF-IR-V2. Downregulation of IGF-IR resulted in significant inhibition of cancer cell growth in vitro. The cell growth inhibition rates at 24, 48, and 72 h after pkD-shRNA-IGF-IR-V2 transfection were 32.06, 47.61, and 35.36%, respectively. Conclusions: Our data show that decreasing the IGF-IR protein level in SW480 cells by RNAi could significantly inhibit tumor growth in vitro, implying the therapeutic potential of RNAi on the treatment of colon cancer by targeting overexpression oncogenes such as IGF-IR. IGF-IR may be a potential therapeutic target for human colon cancer. [Copyright &y& Elsevier]