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Onset, progression and cardiovascular outcome of chronic kidney disease (CKD) are influenced by the concomitant sterile inflammation. The pro-inflammatory cytokine family interleukin (IL)-1 is crucial in CKD with the key alarmin IL-1α playing an additional role as an adhesion molecule that facilitates immune cell tissue infiltration and consequently inflammation. Here, we investigate calcium ion and reactive oxygen species (ROS)-dependent regulation of different aspects of IL-1α-mediated inflammation. We show that human CKD monocytes exhibit altered purinergic calcium ion signatures. Monocyte IL-1α release was reduced when inhibiting P2X7, and to a lesser extent P2X4, two ATP-receptors that were found upregulated compared to monocytes from healthy people. In murine CKD models, deleting P2X7 (P2X7 -/- ) abolished IL-1α release but increased IL-1α surface presentation by bone marrow derived macrophages and impaired immune cell infiltration of the kidney without protecting kidney function. In contrast, immune cell infiltration into injured wild type and P2X7 -/- hearts was comparable in a myocardial infarction model, independent of previous kidney injury. Both the chimeric mouse line harboring P2X7 -/- immune cells in wild type recipient mice, and the inversely designed chimeric line showed less acute inflammation. However, only the chimera harboring P2X7 -/- immune cells showed a striking resistance against injury-induced cardiac remodeling. Mechanistically, ROS measurements reveal P2X7-induced mitochondrial ROS as an essential factor for IL-1α release by monocytes. Our studies uncover a dual role of P2X7 in regulating IL-1α biogenesis with consequences for inflammation and inflammation-induced deleterious cardiac remodeling that may determine clinical outcomes in CKD therapies., (Copyright © 2024 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Cryoprotective agents play a critical role in minimizing cell damage caused by ice formation during cryopreservation. However, high concentrations of CPAs are toxic to cells and tissues. Required concentrations of CPAs can be reduced by utilizing higher cooling and warming rates, but insight into the thermophysical properties of biological solutions in the vitrification method is necessary for the development of cryopreservation protocols. Most studies on thermophysical properties under ultra-rapid cooling conditions have been qualitatively based on visualization. Differential scanning calorimetry methods are ideal for studying the behavior of biomaterials in various freezing conditions quantitatively and accurately, though previous studies have been predominantly restricted to slower cooling rates. Here, we developed an ultra-rapid cooling method for DSC that can achieve minimal cooling rates exceeding 2000 °C/min. We investigated the thermophysical vitrification behavior of ternary solutions of phosphate buffer saline (1X), dimethyl sulfoxide or glycerol and ice blocking polymers (X-1000 or Z-1000). We quantified the impact of solute concentration on ice crystal formation during rapid cooling. Our findings support the expectation that increasing the solute concentration reduces the amount of ice formation, including devitrification. Devitrification increases from 0 % to 40 % (v/v) Me 2 SO and then reduces significantly. The relative amounts of devitrification to the total ice formation are 0 %, 60 %, 0 % in 20 %, 40 %, 60 % (v/v) Me 2 SO, and 2 %, 48 %, 49 % in 20 %, 40 %, 60 % (v/v) glycerol, respectively. The results suggest that at low concentrations, such as below 20 % (v/v) for Me 2 SO or glycerol, increasing the warming rate after ultra-rapid freezing is not essential to eliminate devitrification. Furthermore, ice blocking polymers do not reduce ice formation substantially and cannot eliminate devitrification under ultra-rapid cooling conditions. In conclusion, our results provide insights into the impact of solute concentration on ice formation and devitrification during rapid cooling, which can be practical for optimizing cryopreservation protocols., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

β-propiolactone (BPL) is an alkylating agent used for inactivation of biological samples such as vaccines. Due to its known carcinogenic properties, complete hydrolysis of BPL is essential, and the detection of trace amounts is crucial. In this study a novel High-Performance Liquid Chromatography-Ultraviolet (HPLC-UV) method was developed. Rhodamine B hydrazide (RBH) was synthesized and utilized as a derivatizing reagent to react with BPL. The reaction was optimized in a weak acidic solution, resulting in a high yield. The separation of the RBH-derivatized BPL was achieved on a C8 column and detected by a UV detector at a wavelength of 560 nm. The method's validation demonstrated a high linearity (r2 > 0.99) over a concentration range of 0.5-50 µg/mL, with detection and quantification limits of 0.17 µg/mL and 0.5 µg/mL, respectively. The average recovery of samples was 85.20 % with a relative standard deviation (RSD) of 1.75 %. This method was successfully applied for BPL residue analysis in inactivated COVID-19 vaccines. This novel derivatization method offers a promising solution for monitoring BPL residues in the vaccine production process for quality control purposes and compliance with regulatory standards., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Purpose: In the present study, biodegradable poly (3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) nanoparticles (NPs) containing insulin were loaded in sodium alginate/jeffamine (ALG/jeff) hydrogel for prolonged delivery of insulin. The main aim of this work was to fabricate an efficient insulin delivery system to improve patient adherence by decreasing the repetition of injections., Methods: Swelling and morphological properties and crosslinking efficiency of ALG/jeff hydrogel were assessed. The composite hydrogel was prepared by adding PHBV NPs to ALG/jeff hydrogel concurrently with crosslinking process. The morphology and loading capacity of composite hydrogel were analyzed., Results: Circular dichroism measurement demonstrated that insulin remains stable following fabrication process. The release profile exhibited 54.6 % insulin release from composite hydrogel within 31 days with minor initial burst release equated to nanoparticles and hydrogels. MTT cell viability analysis was performed by applying L-929 cell line and no cytotoxic effect was observed., Conclusions: Favorable results clearly introduced fabricated composite hydrogel as an excellent candidate for drug delivery systems and also paves the route for prolonged delivery systems of other proteins., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

A novel, dual-faced, and hierarchical type of Janus hybrid structures (JHSs) was assembled through an in situ growing of lipase@cobalt phosphate sheets on the laccase@copper phosphate sponge-like structures. The chemical and structural information of prepared JHSs was investigated by Scanning electron microscopy-energy dispersive X-ray analysis (SEM-EDX), Fourier Transform Infrared Spectroscopy (FTIR), and X-ray diffraction analysis (XRD). The catalytic activity, storage stability, and reusability of JHSs were then investigated. The SEM-EDX analysis clearly confirmed the asymmetric morphology of the fabricated JHSs with two distinct metal distributions. Under optimized synthesis conditions, the prepared JHSs showed 97.8 % and 100 % of laccase and lipase activity, respectively. Compared to the free biocatalysts, the immobilization resulted in ~ a 2-fold increase in laccase and lipase stability at temperatures of >40 °C. The fabricated JHSs maintained 61 % and 90 % of their original laccase and lipase activity upon 12 successive repetition cycles. Up to 80 % of Reactive Blue-19 (RB-19), an anthraquinone-based vinyl sulphone dye, was removed after 5 h treatment with the prepared JHSs (50 % higher than the free forms of laccase and lipase). The dye removal data fitted very well on the pseudo-second-order kinetic model with a rate constant of 0.8 g mg -1  h -1 . Following the bioremoval process, bacterial toxicity also decreased by about 70 %. Therefore, the prepared JHSs provide a facile and sustainable approach for the decolorization, biotransformation, and detoxification of RB-19 by integrating enzymatic oxidation and hydrolysis., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Somayeh Mojtabavi reports financial support was provided by Tehran University of Medical Sciences. Somayeh Mojtabavi reports a relationship with Tehran University of Medical Sciences that includes: funding grants., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Herlyn-Werner-Wunderlich (HWW) syndrome is a rare anomaly of the female urogenital tract characterized by the combination of uterine didelphys, obstructed hemivagina, and ipsilateral renal anomalies. The exact incidence of the syndrome remains unknown, but it has been reported to be 1 per 2000 to 1 per 28,000 women. It is believed that the triad is a mesonephric duct-induced paramesonephric duct anomaly. In majority of the cases with complete hemivaginal obstruction, the pathology is diagnosed after menarche due to retained menstrual flow. While the common clinical presentations are dysmenorrhea, pelvic pain, intermenstrual bleeding, and pelvic mass, it can also manifest itself with unusual gastrointestinal and urinary tract symptoms. We present a case of HWW syndrome with gastrointestinal symptoms like worsening constipation and abdominal fullness. The unusual clinical presentation of this syndrome makes diagnosis more challenging. To solve such medical puzzles and prevent complications, detailed history-taking and radiological guidance are critical., (© 2023 The Authors. Published by Elsevier Inc. on behalf of University of Washington.)

Due to high mortality rates, typhoid fever still is one of the major health problems in the world, particularly in developing countries. The lack of highly specific and sensitive diagnostic tests and the great resemblance of typhoid fever symptoms to other diseases made the false-negative diagnosis a major challenge in typhoid fever management. Hence, we decided to design a Surface Plasmon Resonance (SPR) based biosensor for specific detection of Salmonella typhi through DNA hybridization. The results showed that the 10 nM of the synthetic target sequence, as well as 1 nM of PCR product, were the lowest feasible detected concentrations by the designed biosensor. This genosensor was also found to significantly distinguish the complementary sequence with the accuracy of one base mismatch sequence. The surface of the chip can be regenerated with NaOH solution and used for consecutive diagnosis. Therefore, the function of the designed biosensor indicates its high potential for Salmonella typhi detection practice., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Photodynamic therapy (PDT) is a light-based anti-neoplastic therapeutic approach. Growing evidence indicates that combining conventional anti-cancer therapies with PDT can be a promising approach to treat malignancies. Herein, we aimed to investigate anti-cancer effects of the combination treatment of zinc phthalocyanine (ZnPc)-PDT with tamoxifen (TA) on MDA-MB-231 cells (as a triple-negative breast cancer (TNBC) cell line). For this purpose, we investigated the cytotoxicity of TA and ZnPc-PDT on MDA-MB-231 cells performing the MTT assay. The effect of TA and ZnPc-PDT on the apoptosis of MDA-MB-231 cells was studied using Annexin V/PI and DAPI staining. The wound-healing assay, and colony formation assay were performed to study the effect of TA and ZnPc-PDT on the migration, and clonogenicity of MDA-MB-231 cells, respectively. The qRT-PCR was done to study the gene expression of caspase-8, caspase-9, caspase-3, ZEB1, ROCK1, SNAIL1, CD133, CD44, SOX2, and ABCG2 (ATP-binding cassette sub-family G member 2). Based on our results, monotherapies with TA and ZnPc-PDT can remarkably increase cell cytotoxicity effects, stimulate apoptosis via downregulating Bcl-2 and upregulating caspase-3 and caspase-9, inhibit migration via downregulating SNAIL1 and ZEB1, and suppress clonogenicity via downregulating SOX2 and CD44 in MDA-MB-231 cells. Besides, these monotherapies can downregulate the expression of ABCG2 in MDA-MB-231 cells. Nevertheless, the combination treatment can potentiate the above-mentioned anti-cancer effects compared to monotherapy with TA. Of interest, the combined treatment of TA with ZnPc-PDT can synergically increase cell cytotoxicity effects on MDA-MB-231 cells. In fact, synergistic effects were estimated by calculation of Combination Index (CI); that synergistic outcomes were observed in all groups. Also, this combination treatment can significantly upregulate the caspase-8 gene expression and downregulate ROCK1 and CD133 gene expression in MDA-MB-231 cells. Overall, our results show that ZnPc-PDT can more sensitize the MDA-MB-231 cells to TA treatment. Based on our knowledge and experiment, the synergistic effects of ZnPc-PDT and TA deserve further evaluation in cancer research., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Despite significant improvements in terms of the predictive ability of Quantitative Computed Tomography based Finite Element (QCT-FE) models in estimating femoral strength (fracture load and stiffness), no substantial clinical adoption of this method has taken place to date. Narrowing the wide variability of FE results by standardizing the methodology and validation protocols, as well as reducing the uncertainties in the FEA process have been proposed as routes towards improved reliability. The aim of this study was to: First, validate a QCT-FE model of proximal femoral stiffness in multiple stance load cases, and second, using a parametric approach, determine the influence of select experimental and modeling parameters on the predictive ability of our model. Ten fresh frozen human femoral samples were tested in neutral stance, 15° adducted and 15° abducted load cases. Voxel-based linear-elastic QCT-FE models of the samples were generated to predict the models' stiffness values in all load cases. The base FE models were validated against the experimental results using linear regression. Thirty six deviated models were created using the minimum and maximum values of experiment-based "plausible range" for 18 parameters in 4 categories of embedding, loading, material, and segmentation. The predictive ability of the models were compared in terms of the coefficient of determination (R 2 ) of the linear regression between the measured and predicted stiffness values in all load cases. Our model was capable of capturing 90% of the variation in the experimental stiffness of the samples in neutral stance position (R 2 = 0.9, concordance correlation coefficient (CCC) = 0.93, percent root mean squared error (RMSE%) = 8.4%, slope and intercept not significantly different from unity and zero, respectively). Embedding and loading categories strongly affected the predictive ability of the models with an average percent difference in R 2 of 4.36% ± 2.77 and 2.96% ± 1.69 for the stance-neutral load case, respectively. The performance of the models were significantly different in adducted and abducted load cases with their R 2 dropping to 71% and 70%, respectively. Similarly, off-axes load cases were affected by the parameters differently compared to the neutral load case, with the loading parameter category imposing more than 10% difference on their R 2 , larger than all other categories. We also showed that automatically selecting the best performing plausible value for each parameter and each sample would result in a perfectly linear correlation (R 2 > 0.99) between the "tuned" model's predicted stiffness and experimental results. Based on our results, high sensitivity of the model performance to experimental parameters requires extra diligence in modeling the embedding geometry and the loading angles since these sources of uncertainty could dwarf the effects of material modeling and image processing parameters. The results of this study could help in improving the robustness of the QCT-FE models of proximal femur by limiting the uncertainties in the experimental and modeling steps., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Given the limited sensitivity of screening methods and the lack of effective therapeutic interventions for malignant brain tumors such as glioblastoma multiforme (also known as GBM), diagnostic and therapeutic procedures for these tumors are rarely performed on a routine basis. Nanostructures with great selectivity, including silica-based nanovehicles, metallic nanostructures, lipid nanoparticles, quantum dots, and polymeric nanoparticles, have been demonstrated to have excellent potential for passing the BBB efficiently. Based on tumor-derived cells, surface modification, encapsulation of contrast agent, bio composition, and functionalities by appropriate coating materials can all be used to take advantage of the photodynamic, magnetic, and optical capabilities of nanostructures. As a result, nanotechnology has revolutionized the detection, screening, as well as treatment of malignancies and brain tumors. In recent years, nanostructures with biomimetic activities have been designed for uptake by tumors in deep cancer regions, with the goal of monitoring and treating the disease. Also, nanostructures are exceptional nano-vehicles for delivering therapeutic agents to their targeted areas due to their special physicochemical properties, which include nanosized dimensions, larger surface area, specific geometrical characteristics, and the capabilities to encompass various substances within their inner parts or on their exterior surface. This paper describes the current developments of several nanostructures such as dendrimers, liposomes, carbon dots, carbon nanotubes, micelles, and metallic nanoparticles for efficient detection of GBM as well as drug delivery in GBM treatment. The importance of metallic nanoparticle-based radiosensitization, as well as immunotherapy, as good ways to fight metastasis and GBM growth, will also be discussed., (Copyright © 2022. Published by Elsevier B.V.)

Immune checkpoints are vital molecules that regulate T-cell function by activation or inhibition. Among the immune checkpoint molecules, the B7-family proteins are significantly involved in the immune escape of tumor cells. By binding to inhibitory receptors, they can suppress T-cell-mediated immunity. B7-family proteins are found at various stages of tumor microenvironment formation and promote tumorigenesis and tumor progression. B7-H6 (encoded by gene NCR3LG1) is a prominent member of the family. It has unique immunogenic properties and is involved in natural killer (NK) cell immunosurveillance by binding to the NKp30 receptor. High B7-H6 expression in certain tumor types and shortage of or low expression in healthy cells - except in cases of inflammatory or microbial stimulation - have made the protein an attractive target of research activities in recent years. The avoidance of NK-mediated B7-H6 detection is a mechanism through which tumor cells escape immune surveillance. The stimulation of tumorigenesis occurs by suppressing caspase cascade initiation and anti-apoptosis activity stimulation via the STAT3 pathway. The B7-H6-NKp30 complex on the tumor membrane activates the NK cells and releases both tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ). B7-H6 is highly expressed in a wide range of tumor cells, including glioma, hematologic malignant tumors, and breast cancer cells. Clinical examination of cancer patients indicated that the expression of B7-H6 is related to distant metastasis status and permits postoperative prognosis. Because of its unique properties, B7-H6 has a high potential be utilized as a biological marker for cancer diagnosis and prognosis, as well as a target for novel treatment options., (Copyright © 2022. Published by Elsevier Inc.)

The main goal of bariatric surgery (BS) in patients with morbid obesity is reducing body mass and fat mass (FM). However, body mass loss is systematically accompanied by a decline in fat-free mass (FFM). We aimed to examine the time-course effect of BS on FFM and body FFM percentage (FFM%) in individuals with morbid obesity by conducting a systematic review and meta-analysis of controlled adult human trials. We searched PubMed, Scopus, Embase, Institute for Scientific Information Web of Science, and Cochrane databases within the period from October 2002 to May 2021, with no restriction in the English language, to find studies assessing the effect of BS on FFM and FFM% in patients with morbid obesity. A meta-analysis of 122 studies carried out on data of 10,758 patients with morbid obesity after BS showed that BS was associated with a substantial decrease in FFM at 1 (-3.47 kg [95% confidence interval [CI]: -3.88, -3.07]), 3 (-5.59 kg [95% CI: -6.01, -5.17], 6 (-6.61 kg [95% CI: -7.25, -5.98]), and 12 (-8.34 kg [95% CI: -9.04, -7.63]) months after the surgery; however, the FFM% increased at 3 (6.51% [95% CI: 5.00, 8.02]), 6 (8.56% [95% CI: 6.81, 10.31], and 12 (11.29% [95% CI: 8.94, 13.64]) months after the surgery. BS was associated with sustained declines in FFM and increases in FFM% from 1-12 months with no indication of plateau phase postoperatively. These findings emphasize that postbariatric care should focus more on FFM loss during the first year after surgery., (Copyright © 2022. Published by Elsevier Inc.)

Background: Breast cancer (BC) has been known as the most common type of cancer worldwide and resulted in death among women. BC is usually resistant to standard therapies that are significant problems in managing BC patients. miR-200c belongs to the miRNA family, which is considered as a tumor suppressor with reduced expression levels in various kinds of cancer like BC. Increased expression of miR-200c has been reported as a potent inhibitor of drug resistance and tumor advancement. The purpose of this paper is to examine the outcome of miR-200c restoring on enhancing the BC cells' sensitivity to Doxorubicin through downregulating the MDR1 expression., Methods: Initially, MDA-MB-231 cells were transfected with miR-200c to perform functional analyses. After that, MTT assay was performed to investigate the viability of the cell. Finally, qRT-PCR was used to assess gene expression., Results: According to the results, the miR-200c expression was downregulated in BC cells compared to control. Moreover, the cell viability was reduced in transfected cells via regulation in gene expression associated with apoptosis. Furthermore, miR-200c could increase the BC cells' sensitivity to Doxorubicin by reducing the MDR1 gene expression., Conclusion: Hence, this study's findings recommend that miR-200c can consider as a method of therapy for the treatment of BC., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Objective: To investigate the impact of harmonization on the performance of CT, PET, and fused PET/CT radiomic features toward the prediction of mutations status, for epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene (KRAS) genes in non-small cell lung cancer (NSCLC) patients., Methods: Radiomic features were extracted from tumors delineated on CT, PET, and wavelet fused PET/CT images obtained from 136 histologically proven NSCLC patients. Univariate and multivariate predictive models were developed using radiomic features before and after ComBat harmonization to predict EGFR and KRAS mutation statuses. Multivariate models were built using minimum redundancy maximum relevance feature selection and random forest classifier. We utilized 70/30% splitting patient datasets for training/testing, respectively, and repeated the procedure 10 times. The area under the receiver operator characteristic curve (AUC), accuracy, sensitivity, and specificity were used to assess model performance. The performance of the models (univariate and multivariate), before and after ComBat harmonization was compared using statistical analyses., Results: While the performance of most features in univariate modeling was significantly improved for EGFR prediction, most features did not show any significant difference in performance after harmonization in KRAS prediction. Average AUCs of all multivariate predictive models for both EGFR and KRAS were significantly improved (q-value < 0.05) following ComBat harmonization. The mean ranges of AUCs increased following harmonization from 0.87-0.90 to 0.92-0.94 for EGFR, and from 0.85-0.90 to 0.91-0.94 for KRAS. The highest performance was achieved by harmonized F&#95;R0.66&#95;W0.75 model with AUC of 0.94, and 0.93 for EGFR and KRAS, respectively., Conclusion: Our results demonstrated that regarding univariate modelling, while ComBat harmonization had generally a better impact on features for EGFR compared to KRAS status prediction, its effect is feature-dependent. Hence, no systematic effect was observed. Regarding the multivariate models, ComBat harmonization significantly improved the performance of all radiomics models toward more successful prediction of EGFR and KRAS mutation statuses in lung cancer patients. Thus, by eliminating the batch effect in multi-centric radiomic feature sets, harmonization is a promising tool for developing robust and reproducible radiomics using vast and variant datasets., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

High levels of soil salinity can cause substantial decline in growth and productivity of crops worldwide, thus representing a major threat to global agriculture. In recent years, engineered nanoparticles (NPs) have been deemed as a promising alternative in combating abiotic stress factors, such as salinity. In this context, the present study was designed to explore the potential of cerium oxide nanoparticles (CeO 2 NPs) in alleviating salt stress in grapevine (Vitis vinifera L. cv. Flame Seedless) cuttings. Specifically, the interaction between CeO 2 NPs (25, 50 and 100 mg L -1 ) and salinity (25 and 75 mM NaCl) was evaluated by assaying an array of agronomic, physiological, analytical and biochemical parameters. Treatments with CeO 2 NPs, in general, alleviated the adverse impacts of salt stress (75 mM NaCl) significantly improving relevant agronomic traits of grapevine. CeO 2 NPs significantly ameliorated chlorophyll damage under high levels of salinity. Furthermore, the presence of CeO 2 NPs attenuated salinity-induced damages in grapevine as indicated by lower levels of proline, MDA and EL; however, H 2 O 2 content was not ameliorated by the presence of CeO 2 NPs under salt stress. Additionally, salinity caused substantial increases in enzymatic activities of GP, APX and SOD, compared with control plants. Similar to stress conditions, all concentrations of CeO 2 NPs triggered APX activity, while the highest concentration of CeO 2 NPs significantly increased GP activity. However, CeO 2 NPs did not significantly modify SOD activity. Considering mineral nutrient profile, salinity increased Na and Cl content as well as Na/K ratio, while it decreased K, P and Ca contents. Nevertheless, the presence of CeO 2 NPs did not lead to significant alterations in Na, K and P content of salt-stressed plants. Taken together, current findings suggest that CeO 2 NPs could be employed as promising salt-stress alleviating agents in grapevine., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Gastric cancer (GC) is one of the leading causes of cancer-related death worldwide, due to poor prognosis and treatment failure; demanding new diagnostic and therapeutic targets. Therefore, in the present study, the methylation and expression status of ZNF677, as a promising tumor suppressor, were investigated in GC. Gene Expression Omnibus (GEO) datasets were used to initially evaluate ZNF677 expression and methylation in GC samples. Confirmation was performed on fifty internal samples, including gastric tumors and adjacent normal specimens, using q-MSP and q-PCR methods. Further validations were done using The Cancer Genome Atlas (TCGA) data on human cancers. The obtained results in silico and experimentally illustrated that ZNF677 is significantly hypermethylated and downregulated through gastric tumorigenesis. ZNF677 methylation levels were also correlated with perineural invasion (p = 0.0382) in internal samples. Furthermore, Spearman's correlation analysis showed that ZNF677 methylation is negatively (r = -0.4614, p < 0.0001) correlated with its mRNA expression levels. ROC curve analysis also illustrated the high diagnostic value of ZNF677 methylation for early detection of GC (AUC = 0.8592). Gene set enrichment analysis further revealed that ZNF677 participates in the regulation of cellular processes such as cell proliferation in GC. Moreover, in addition to hypermethylation in other malignancies, including breast, lung, and colorectal cancers, ZNF677 was hypermethylated in precancerous gastric tissues with intestinal metaplasia, indicating its methylation as a driver event through tumorigenesis. Taken together, our results suggest ZNF677 as a potential tumor suppressor gene, which could be considered as a diagnostic and therapeutic target for GC., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Mitogen-activated protein kinase (MAPK) signal transduction, as a highly conserved signaling pathway, is reported to be involved in various biological events, including metabolic reprogramming, cell proliferation, survival, and differentiation. Mutations in key molecules involved in MAPK/ERK signaling and dysregulation of this pathway are very common events in various human malignancies, which make the MAPK signaling a crucial signaling pathway participating in the regulation of glucose uptake by malignant cells and tumorigenesis. MicroRNAs (miRNAs), as small non-coding RNAs, are critical regulators of gene expression that play key roles in cancer initiation and progression. On the other hand, these small RNAs mutually regulate the MAPK signaling which is often overexpressed in the case of cancer progression; suggesting that crosstalk between miRNAs and this signaling pathway plays a pivotal role in the development of human cancers. Some miRNAs such as miR-20b, miR-34c-3p, miR-152, miR-181a, and miR-302b through inhibiting MAPK signaling, and miR-193a-3p, miR-330-3p, and miR-592 by activating this signaling pathway, play imperative roles in tumorigenesis. Therefore, in this review, we aimed to focus on the interplay between miRNAs and MAPK signaling in the various steps of tumorigenesis, including metabolic regulation, cell proliferation, apoptosis, metastasis, angiogenesis, and drug resistance., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: The utility of adjuvant chemotherapy (AC) after neoadjuvant therapy and curative intent surgery for clinical stage IIIA (cIIIA) non-small cell lung cancer (NSCLC) is not defined. We sought to evaluate the contribution of AC to overall survival (OS) in patients with cIIIA NSCLC who underwent neoadjuvant therapy followed by curative intent surgical resection., Methods: The National Cancer Database was queried from 2010 to 2016 for patients with cIIIA NSCLC who underwent curative intent surgical resection after neoadjuvant therapy. Patients were grouped by receipt of AC, and OS was calculated using the Kaplan-Meier method. The association between mortality and AC was evaluated using Cox regression. Ninety-day landmark and propensity score-matched analyses were performed to address bias associated with early postoperative morbidity and mortality., Results: Of 3847 patients who met the inclusion criteria, 780 received AC (20.2%). In the unadjusted cohort there was no difference in 5-year OS between the AC and no AC groups (42.8% vs 43.9%, P = .105). Cox regression demonstrated a decreased risk of mortality in pN > 0 patients receiving AC (hazard ratio, 0.79; 95% confidence interval, 0.68-0.92; P < .003), whereas no difference was seen in node-negative patients (hazard ratio, 0.95; 95% confidence interval, 0.78-1.17; P = .64). In the propensity score-matched groups OS was significantly increased in pN > 0 patients who received AC (5-year OS: 42.4% vs 37%, P < .01), whereas no survival benefit was seen in those who were pN0., Conclusions: For patients with completely resected cIIIA NSCLC after neoadjuvant therapy, AC is associated with an increase in OS for patients with residual pathologic lymph node involvement., (Copyright © 2021 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Methadone and buprenorphine can affect the psychological symptoms and cognitive functioning of substance users. This study aimed to compare psychological symptoms and neuropsychological functioning in methadone maintenance patients (MMP), buprenorphine maintenance patients (BMP), current opioid users, and healthy subjects. One hundred and twenty participants (30 in each group) matched for age, sex, and education completed the Symptom Checklist-90-Revised (SCL-90-R) and a battery of neuropsychological tests including the Wisconsin Card Sorting Test (WCST), Wechsler Memory Scale (WMS-IV), and Stroop Color-Word Test (SCWT) assessing executive functioning, working memory, and attention, respectively. Overall, opioid users showed more severe psychological symptoms compared to healthy subjects. MMP and BMP had intermediate scores in SCL-90-R subscales; however, BMP had fewer severe symptoms compared to the MMP group. In terms of cognitive functioning, healthy subjects and current users demonstrated the best and the worst performance, respectively. Also, BMP outperforms MMP on executive functions and attention. However, the MMP had a better performance in WMS (visual memory). Patients receiving maintenance treatment had fewer psychological symptoms and better cognitive performance compared to opioid users. BMP had a better profile in all psychological symptoms and better performance in executive functions and selective attention compared to the MMP suggesting buprenorphine may be a better choice for the treatment of opioid-dependent patients., (Copyright © 2021 Elsevier B.V. All rights reserved.)

We performed a meta-analysis to provide quantitative estimates of fat mass (FM) and fat-free mass (FFM) changes in patients following bariatric surgery over 1 year. A systematic search of PubMed, SCOPUS and Web of Science databases was conducted; the pooled weighted mean difference (WMD) and 95% confidence intervals (CI) were calculated using a random-effects model. Thirty-four studies including Roux en-Y gastric bypass (RYGB), sleeve gastrectomy (SG) biliopancreatic diversion (BPD) and gastric banding (GB) were analyzed. RYGB decreased in body FM (-28.99 kg [31.21, -26.77]) or FM% (-12.73% [-15.14, -10.32]) or FFM (-9.97 kg [-10.93, -9.03]), which were greater than SG and GB. Moreover, the FFM% in RYGB group (11.72% [7.33, 16.11]) was more than SG (5.7% [4.44, 6.95]) and GB (8.1% [6.15, 10.05]) groups. Bariatric surgeries, especially RYGB, might be effective for a decrease in FM and maintenance of FFM in patients with morbid obesity in over 1 year., Competing Interests: Conflict of interest None., (Copyright © 2020. Published by Elsevier Ltd.)

L-asparaginase is an enzyme capable of hydrolyzing the asparagine to aspartic acid and ammonia. L-asparaginase is widely used in the treatment of acute lymphoblastic leukemia (ALL) and other cancers. Here, for the first time, the effects of a novel yeast L-asparaginase from Yarrowia lipolytica were studied on human lung (A549) and breast cancer (MCF7) cell lines as the solid cancer cell lines in terms of cell growth and metastasis inhibition. Functional analysis showed the L-asparagine deprivation mediated anti-proliferation effects by apoptosis induction and changes in the expression of target genes involved in apoptosis and migration pathways. The qRT-PCR analysis showed the higher expression levels of pro-apoptosis genes, including Bax, P53, caspase 3, caspase 8, and down-regulation of Bcl-2 anti-apoptotic gene in treated cells. On the other hand, there was no increase in ROS production in the treated cells. However, L-asparaginase treatment was able to significantly induce autophagy activation in A549 cells. Besides, wound healing assay showed that L-asparaginase could considerably inhibit the migration of A549 and MCF7 cells. Taken together, our results suggested that Yarrowia lipolytica L-asparaginase might be considered for enzyme therapy against breast and lung cancers., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Progression of resistance to chemotherapy in breast cancer (BC) has been recognized as a main factor in decreasing the survival of patients with this malignancy. Recent investigations have described the involvement of immune checkpoint molecules in the progress of drug resistance in breast carcinoma patients. In the present study, the molecular participation of immune checkpoint factors in chemoresistance of BC both in-vitro and in-vivo is reviewed. Numerous immune checkpoints such as PD-1/PD-L1, CTLA-4, B7-H3, B7-H4, B7-1, and B7-2 have been specified as positive regulators of resistance to various drug types in BC. In several molecular pathways of drug resistance in BC, immune checkpoints affect the chemoresistance of this cancer in a drug- and cell-type-dependent manner. In addition, immune checkpoints promote chemoresistance in response to particular drugs in specific BC cell lines. Furthermore, several the immune checkpoint molecules have not been evaluated in the field of the chemoresistance in breast malignancy either in-vitro or in-vivo. Overall, investigations have indicated that targeting immune checkpoint molecules may be considered as a novel method to improve existing anti-BC treatments., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Combination treatment based on gene and chemotherapy is a promising strategy for effective cancer treatment due to the limited therapeutic efficacy of anticancer drugs. Dual functional polymeric micelles (PMs) have been emerged as potent nanocarriers for combinational cancer therapy. In the present study, the potential of tri-layer PMs loaded with anti-nuclear factor-κB (NF-κB) siRNA and 4-(N)-stearoyl gemcitabine (GemC18) has been investigated for cancer treatment. PMs with different core hydrophobicity were prepared by using poly(ε-caprolactone), polyethyleneimine and polyethylene glycol (PCL-PEI-PEG) copolymers and evaluated. The results revealed that GemC18-loaded PMs were significantly more cytotoxic than free drug on breast and pancreatic cancer cells. However, the cytotoxicity of drug loaded micelles was decreased by increasing the micellar core hydrophobicity because of decreasing drug release rate. Moreover, siRNA loaded PMs could considerably inhibit NF-κB expression. PMs loaded with both GemC18 and siRNA exhibited higher capability to induce apoptosis and inhibit migration of both cells. PMs with the most hydrophobic core indicated higher tumor accumulation efficiency via in-vivo imaging study. In conclusion, the prepared PMs hold a promise as an attractive dual functional delivery system for an effective cancer therapy., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Antioxidants are essential in preventing the formation and suppressing the activities of reactive nitrogen and oxygen species. The aim of this study was to review the role of antioxidants in cancer development or prevention. Antioxidants are believed to prevent and treat various types of malignancies. Currently, natural antioxidant compounds have been generally consumed to prevent and treat cancers. Certainly, phenolic compounds extracted from medicinal plants have opened a new prospect with respect to the prevention and treatment of cancers due to having antioxidant characteristics. However, some recently published studies have revealed that antioxidant compounds do not indicate absolute anti-tumor properties. Some antioxidants are helpful in cancer initiation and progression. Taken together, antioxidants demonstrate a two-faced nature toward cancer. However, it is required to conduct further cell culture and in vivo studies to confirm the exact role of antioxidants and then use them for efficient cancer treatments., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Aims: Gastric cancer (GC) remains one of the deadliest malignancies worldwide due to its poor prognosis. DNA methylation changes, as an early event during tumor progression, constitute attractive markers for cancer diagnostics. In the current study, CD40 DNA methylation was investigated in GC as a novel epigenetic biomarker., Main Methods: We first analyzed DNA methylation microarrays from the Gene Expression Omnibus database on GC samples to evaluate the potential diagnostic value of CD40 methylation. Moreover, using q-MSP, in a set of internal samples including GC primary tumors and adjacent normal specimens, CD40 DNA methylation levels were determined. The Cancer Genome Atlas (TCGA) data on GC was also analyzed for further validation., Key Findings: Our results illustrated significant CD40 hypermethylation in GC samples compared to normal specimens which was significantly correlated with the clinical stage of malignancy. Besides, the high accuracy of CD40 methylation as a diagnostic biomarker in GC was confirmed using the ROC curve analysis with an AUC value of 0.9089. Also, gene set enrichment analysis showed that CD40 is mainly involved in biological processes regulating immune response activation in GC. Further analysis of other prevalent cancer entities in TCGA showed that CD40 hypermethylation is a common event during tumor progression and could be considered as a potential biomarker for the detection of breast, colorectal, and prostate cancers as well., Significance: The finding of this study suggests that CD40 methylation as a potential pan biomarker could be a valuable target for liquid biopsy application of human cancers., Competing Interests: Declaration of competing interest The authors declare that there are no conflicts of interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Early diagnosis of Prostate cancer (PCa) plays a vital role in successful treatment increasing the survival rate of patients. Prostate Specific Membrane Antigen (PSMA) is over-expressed in almost all types of PCa. The goal of present study is to introduce new 99m Tc-labeled peptides as a PSMA inhibitor for specific detection of PCa at early stages. Based on published PSMA-targeting compounds, a set of peptides bearing the well-known Glu-Urea-Lys pharmacophore and new non-urea containing pharmacophore were designed and assessed by in silico docking studies. The selected peptides were synthesized and radiolabeled with 99m Tc. The in-vitro tests (log P, stability in normal saline and fresh human plasma, and affinity toward PSMA-positive LNCaP cell line) and in-vivo characterizations of radiopeptides (biodistribution and Single Photon Emission Computed Tomography-Computed Tomography (SPECT-CT) imaging in normal and tumour-bearing mice) were performed. The peptides 1-3 containing Glu-Urea-Lys and Glu-GABA-Asp as pharmacophores were efficiently interacted with crystal structure of PSMA and showed the highest binding energies range from -8 to -11.2 kcal/mol. Regarding the saturation binding test, 99m Tc-labeled peptide 1 had the highest binding affinity (K d  = 13.58 nM) to PSMA-positive cells. SPECT-CT imaging and biodistribution studies showed high kidneys and tumour uptake 1 h post-injection of radiopeptide 1 and 2 (%ID/g tumour = 3.62 ± 0.78 and 1.8 ± 0.32, respectively). 99m Tc-peptide 1 (Glu-urea-Lys-Gly-Ala-Asp-Naphthylalanine-HYNIC- 99m Tc) exhibited the highest binding affinity, high radiochemical purity, the most stability and high specific accumulation in prostate tumour lesions. 99m Tc-peptide 1 being of comparable efficacy and pharmacokinetic properties with the well-known PET tracer ( 68 Ga-PSMA-11) seems to be applied as a promising SPECT imaging agent to early diagnose of PCa and consequently increase survival rate of patients., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

With respect to the main role of amyloid-β (Aβ) plaques as one of the pathological hallmarks in the brain of Alzheimer's patients, the development of new imaging probes for targeted detection of Aβ plaques has attracted considerable interests. In this study, a novel cyclopentadienyl tricarbonyl Technetium-99 m ( 99m Tc) agent with peptide scaffold, 99m Tc-Cp-GABA-D-(FPLIAIMA)-NH 2 , for binding to the Aβ plaques was designed and successfully synthesized using the Fmoc solid-phase peptide synthesis method. This radiopeptide revealed a good affinity for Aβ42 aggregations (K d  = 20 µM) in binding affinity study and this result was confirmed by binding to Aβ plaques in brain sections of human Alzheimer's disease (AD) and rat models using in vitro autoradiography, fluorescent staining, and planar scintigraphy. Biodistribution studies of radiopeptide in AD and normal rats demonstrated a moderate initial brain uptake about 0.38 and 0.35% (ID/g) 2 min post-injection, respectively. Whereas, AD rats showed a notable retention time in the brain (0.23% ID/g at 30 min) in comparison with fast clearance in normal rat brains. Normal rats following treatment with cyclosporine A as a p-glycoprotein inhibitor showed a significant increase in the radiopeptide brain accumulation compared to non-treated ones. There was a good correlation between data gathered from single-photon emission computed tomography/computed tomography (SPECT/CT) imaging and biodistribution studies. Therefore, these findings showed that this novel radiopeptide could be a potential SPECT imaging agent for early detection of Aβ plaques in the brain of patients with AD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Inc. All rights reserved.)

During the last years, enzyme-based biosensors have gained much more attention among the researchers and have had great success in the determination of different biological macromolecules. Nanomaterials with intrinsic enzyme-mimic activity are widely used in biomedicine as artificial enzymes. Here, we report glucose oxidase-mimic activity of nanolayered manganese-calcium (Mn-Ca) oxide nanoparticles (NL-MnCaO 2 ). In this work, NL-MnCaO 2 nanoparticles were synthesized and characterized using different techniques including transmission electron microscopy (TEM), scanning electron microscopy (SEM), fourier-transform infrared spectroscopy (FTIR) and powder X-ray diffraction (XRD). Also, the ability of these compounds for the glucose and hydrogen peroxide (H 2 O 2 ) determination was investigated. A non-enzymatic strategy for the colorimetric detection of glucose and H 2 O 2 was reported which can be utilized not only for the rapid detection and analysis of glucose by the naked eye but also the quantitative assay of glucose by spectrophotometry. The in situ generated H 2 O 2 and gluconic acid (GA) from the oxidation of glucose through the glucose oxidase-mimicking activity of NL-MnCaO 2 was detected using a colorimetric method. Also, the results confirmed the application of these compounds for the detection of glucose in human serum samples with a detection limit (LOD) of 6.12 × 10 -6  M. The results showed that NL-MnCaO 2 can be used as an alternative for the natural enzymes and act as a simple, sensitive and enzyme-free biosensor for the detection of glucose in real samples. The proposed strategy shows some advantages including sensitivity, short detection time and low detection limit., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Context: The fatigue is reported as the most common and annoying symptom in patients with cancer, timely diagnosis, and treatment can significantly influence the treatment and rehabilitation. It is crucial to have an appropriate tool to accurately assess fatigue status., Objectives: Our purpose was to assess psychometric properties of the Persian versions of fatigue scale by Original Scales from the viewpoint of children with cancer (Child Fatigue Scale [CFS]-24 h), their parents (Parent Fatigue Scale [PFS]-24 h), and staff (Staff Fatigue Scale FSF-24 h)., Methods: Convenience sampling of the participants was conducted 100, including children with cancer within the age range of 7-12 years, their parents, and caregivers in medical staff. Test-retest reliability and internal consistency were evaluated using intraclass correlation (ICC) and Cronbach's alpha coefficient. Dimensionality was determined by factor analysis. The patients' fatigue was also assessed through visual analog scale-fatigue (VAS-F)., Results: Test-retest (ICC CFS = 0.71, ICC PSF = 0.82, and ICC SFS = 0.78) was acceptable with a high level of internal consistency (α CFS = 0.80, α PFS = 0.83, and α SFS = 0.84). Factor analysis identified three, five, and two components for the CFS, PFS, and Staff Fatigue Scale (SFS), respectively. There was moderate correlation between CFS and VAS-F., Conclusions: Results of the current study indicated that CFS in children with cancer, PFS in their parents, and SFS in medical staff were valid and reliable instruments to assess fatigue from the viewpoint of children with cancer along with their parents and medical staff., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Ann & Joshua Medical Publishing Co. Ltd.)

Somatostatin receptor-targeted radionuclide therapy has become an effective treatment in patients with neuroendocrine tumors. Recently, investigations on the development of antagonistic peptides are increasing with possible superior biological properties as opposed to the agonists. Herein, we have reported the development of a new somatostatin receptor peptide ligand labeled with 177 Lu to achieve a therapeutic ligand for tumor treatment. The interactions of selected and drown ligands using Avogadro software were docked on somatostatin receptor by Dink algorithm. The best docked peptide-chelator conjugate (DOTA-p-Cl-Phe-Cyclo(d-Cys-l-BzThi-d-Aph-Lys-Thr-Cys)-d-Tyr-NH 2 ) (DOTA-Peptide 2) was synthesized using the Fmoc solid-phase method. DOTA-Peptide 2 was radiolabeled with the 177 Lu Trichloride ( 177 LuCl 3 ) solution at 95 °C for 30 min and radiochemical purity (RCP) of 177 Lu-DOTA-Peptide 2 solution was monitored by radio-HPLC and radio-TLC procedures. The new radiolabeled peptide was evaluated for stability, receptor binding, internalization, biodistribution and single-photon emission computed tomography (SPECT) imaging using C6 glioma cells and C6 tumor-bearing rats. DOTA-Peptide 2 was obtained with 98% purity and efficiently labeled with 177 Lu (RCP > 99%). 177 Lu-DOTA-Peptide 2 showed a high value of stability in acetate buffer (91.4% at 312 h) and human plasma (>97% at 24 h). Radioconjugate exhibited low internalization (<5%) and high affinity for somatostatin receptors (K d  = 12.06 nM, B max  = 0.20 pmol/10 6 cells) using saturation binding assay. Effective tumor uptake of 7.3% ID/g (percentage of injected dose per gram of tumor) at 4 h post-injection and fast clearance of radiopeptide from blood and other organs led to a high tumor-to-normal organ ratios. SPECT/CT imaging clearly showed the activity localization in tumor. The favorable antagonistic properties of 177 Lu-DOTA-Peptide 2 on the somatostatin receptors can make it a suitable candidate for peptide receptor radionuclide therapy (PRRT). In the future study, the therapeutic application of this radiopeptide will be evaluated., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Drug-associated adverse events cause approximately 30 billion dollars a year of added health care expense, along with negative health outcomes including patient death. This constitutes a major public health concern. The US Food and Drug Administration (FDA) requires drug labeling to include potential adverse effects for each newly developed drug product. With the advancement in incidence of adverse drug events (ADEs) and potential adverse drug events, published studies have mainly concluded potential ADEs from labeling documents obtained from the FDA's preapproval clinical trials, and very few analyzed their research work based on reported ADEs after widespread use of a drug to animal subjects. The aforesaid procedure of deriving practice based on information from preapproval labeling may misrepresent or deprecate the incidence and prevalence of specific ADEs. In this study, we make the most of the recently disseminated ADE data by the FDA for animal drugs and devices used in animals to address this public and welfare concern. For this purpose, we implemented 5 different methods (Pearson distance, Spearman distance, cosine distance, Yule distance, and Euclidean distance) to determine the most efficient and robust approach to properly discover highly associated ADEs from the reported data and accurately exclude noise-induced reported events, while maintaining a high level of correlation precision. Our comparative analysis of ADEs based on an artificial intelligence (AI) approach for the 5 robust similarity methods revealed high ADE associations for 2 drugs used in dogs and cats. In addition, the described distance methods systematically analyzed and compared ADEs from the drug labeling sections with a specific emphasis on analyzing serious ADEs. Our finding showed that the cosine method significantly outperformed all the other methods by correctly detecting and validating ADEs based on the comparative similarity association analysis compared with ADEs reported by preapproval clinical trials, premarket testing, or postapproval complication experience of FDA-approved animal drugs., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Structure activity correlation revealed that the quinoxaline ring is a satisfactory backbone for anticancer activity and a specific functional group at position 1 and 2 can improve the activity. In this basis, besides quinoxaline, imidazoles as potential anticancer agents were used as a supplementary agents for cancer treatment. In this paper, a new series of N-alkyl-2, 4-diphenylimidazo [1, 2-a] quinoxalin-1-amine derivatives were synthesized in a simple and efficient step. The products are fully characterized by 1H NMR, 13 C NMR, FT-IR, HRMS, and CHN elemental analysis. Several starting materials with different functionalities have been used for the synthesis of the final products with high isolated yields. The biological activities of the synthesized compounds were evaluated in kinase inhibition and cytotoxic activity in several cancerous cell lines. All compounds (6) were evaluated for inhibition of the cell proliferation using 4 cancerous cell lines. Five of the more active compounds were studied for determination of IC50 %. Compounds 6(32-34) showed good activity on some of cancerous cell lines. The results showed that compound 6-32 has the highest biological activity (IC 50 % 9.77 for K562 cell line). An IC 50 % value of 15.84 µM was observed for 6-34. Furthermore 6-34 exhibited inhibition of ABL1 and c-Src kinases with an IC50% value of 5.25 µM and 3.94 µM respectively. Docking simulation was performed to position active synthesized compounds 6-32, 6-33, and 6-34 over the ABL1 active site in two different wild-type (DFG-in and DFG-out motif conformer) and T315I mutant to determine the probable binding orientation, conformation and mode of interaction. According to docking study, the docked location in wild type forms is similar and can be found near the P-loop region while in the case of T315I mutant form, the compounds have a distinct docked location which is close to the αC helix and activation loop. Also, it concluded the role of R 1 substituent on phenyl ring produced higher interaction energy. Additionally, the detailed inter-molecular energy and types of non-bonding interaction of these compounds over the wild-type and mutant form of ABL1., (Copyright © 2019. Published by Elsevier Inc.)

Octreotide (OCT) is a therapeutic peptide which is administered for the treatment of acromegaly. The purpose of this study was to design a new polyethylene glycol (PEG)-conjugated nanoparticle (PEG-NP) to overcome the short half-life and poor stability of OCT. The developed PEG-NPs were compared with non-PEGylated NPs with respect to their size, morphological characteristics, loading efficiency, release profile, and macrophage uptake. The OCT-loaded NPs and PEG-NPs were prepared by ionic complexion of chitosan (Cs) with either heparin (Hp) or PEGylated heparin (PEG-Hp). The chemical structure of PEG-Hp was confirmed by IR and proton nuclear magnetic resonance. Morphological analyses by scanning electron microscopy showed that NPs and PEG-NPs have a uniform shape. Dynamic laser scattering measurements indicated that hydrodynamic diameter of NPs and PEG-NPs were 222.5 ± 10.0 nm and 334.9 ± 6.7 nm, respectively. NPs and PEG-NPs had a positive zeta potential of about 32.5 ± 1.1 mv and 20.6 ± 2.4 mv, respectively. Entrapment efficiency was 61.4 ± 1.0% and 55.7 ± 2.4% for NPs and PEG-NPs, respectively. Compared with the NPs, the PEG-NPs exhibited a slower release profile. Subsequently, fluorescein isothiocyanate-labeled chitosanCs was synthesized and used to evaluate the stealth characteristic of PEG-NPs. In vitro macrophage uptake of fluorescently labeled NPs was measured by flow cytometry., (Copyright © 2019 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Chitosan as a biopolymer is an attractive vehicle for biomedical applications due to its unique characteristics. In order to improve chitosan's physicochemical features, chemical modification has been carried out to make it more suitable for such approaches. The aim of this study was to prepare and evaluate thiolated chitosan-lauric acid as a new chitosan derivative for biomedical use. Lauric acid was introduced to chitosan via stable amide bond between carboxylic acid group of fatty acid and the amine in the chitosan and thiolation was carried out using thioglycolic acid. Resulted polymers were characterized by FTIR, 1 H NMR and TGA. Moreover, cell viability assessment of new derivative was performed using MTT method. FTIR and 1 H NMR results showed that both substitution reactions were successfully completed. Furthermore, new synthesized polymer had no significant cytotoxicity against normal gingiva human cells (HGF1-PI 1).These findings confirm that this new derivative can be introduced as a suitable polymer for biomedical purposes such as mucosal drug delivery., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Tyrosinase enzyme plays a crucial role in melanin biosynthesis and enzymatic browning process of vegetables and fruits. Hence, tyrosinase inhibitors are important in the fields of medicine, cosmetics and agriculture. In this study, novel N-(2-morpholinoethyl)cinnamamide derivatives bearing different substituents on phenyl ring were designed, synthesized and evaluated for their tyrosinase diphenolase inhibitory activity. The compounds were found to be better tyrosinase inhibitors (IC 50 s were in micro molar range) than cinnamic acid. (E)-3-(3-chlorophenyl)-N-(2-morpholinoethyl)acrylamide (B6) exhibited the highest inhibition with IC 50 value of 15.2 ± 0.6 μM which was comparable to that of kojic acid. The inhibition kinetic analysis of B6 indicated that the compound was a mixed-type tyrosinase inhibitor. In silico ADME prediction indicated that B6 might show more skin penetration than kojic acid. Molecular docking analysis confirmed that the active inhibitors well accommodated in the mushroom tyrosinase active site and it was also revealed that B6 formed the most stable drug-receptor complex with the target protein. Therefore, cinnamamide B6 could be introduced as a potent tyrosinase inhibitor that might be a promising lead in cosmetics, medicine and food industry., (Copyright © 2019 Elsevier B.V. All rights reserved.)

We previously showed that folate liposomes of 5FU made from Dipalmitoylphosphatidylcholine (DPPC) induced cell death in HT-29 and HeLa cells more potently than bulk 5FU. Also, a primary 5FU liposomal formulation with phosphatidyl choline (PC) exhibited higher cytotoxicity in murine colon cancer cells. In the present study, optimization of 5FU PC liposome, mechanism of cell death induction in human cancer cell lines and its safety along with other assays have been employed for targeted PC liposomes of 5FU. Liposomes were prepared using thin layer method and optimization of preparation was assessed using central composite design (CCD) of response surface methodology (RSM). Folic acid (FA) was employed as the targeting ligand. Morphology of 5FU loaded liposomes and changes in their thermal behavior were assessed by transmission electron microscopy (TEM) and differential scanning calorimetry (DSC), respectively. In vitro cytotoxicity was explored using MTT assay in HT-29, Caco-2, HeLa and MCF-7 cell lines. Cytotoxicity mechanism of the targeted delivery system was searched through the evaluation of reactive oxygen species (ROS) overproduction, mitochondrial membrane potential (∆Ψ m ), the release of cytochrome c, the activity of caspase 3/7 and apoptosis and necrosis rate. Liposomes were spherical in shape and 5FU was successfully encapsulated into liposomes rather in an amorphous state. Our interesting results showed that in HT-29 cells targeted liposomes triggered the mitochondrial apoptotic pathway by decreasing the mitochondrial membrane potential, releasing of cytochrome c and promoting the substantial activity of caspase 3/7. In HeLa cells, however, targeted liposomes particularly activated necrosis pathway through the overproduction of ROS. Folate-liposomal 5FU showed significantly higher antitumor efficiency compared to free drug. The results of this study offer new prospects for cancer therapy with reducing systemic drug exposure and associated toxicities., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Dissolution enhancement of poorly water soluble drugs is a major challenge in pharmaceutical industry. The aim of this study is to fabricate curcumin nanoparticles by antisolvent crystallization in the presence of PVP-K30 or HPMC with various concentrations as a stabilizer. The effect of high pressure homogenization on properties of curcumin particles is also investigated in this study. The antisolvent crystallization method followed by freeze drying (CRS-FD) and also antisolvent crystallization and high pressure homogenization followed by freeze drying (HPH-FD) were employed to modify curcumin particles. Physical mixtures of the drug and additives were also prepared for comparison purposes. The solid state analysis (DSC, XRPD and FT-IR studies), particle size measurement, morphological analysis, saturation solubility and dissolution behavior of the samples were investigated. The curcumin crystallized without using stabilizer produced polymorph 2 curcumin with lower crystallinity and higher solubility. The samples obtained in the presence of stabilizers showed higher solubility compared to its physical mixtures counterpart. It was found that the stabilizers used in the current study were capable of inhibiting the crystal growth of particles during crystallization. High pressure homogenizer method generated smaller particles compared to those samples that were not subjected to high pressure homogenizer (for example, 2748 nm for 5% PVP CRS-FD sample and 706 nm for 5% PVP HPH-FD sample). Particles obtained via HPH showed better solubility and dissolution rate compared to those samples that HPH was not employed (for example, the saturated solubility of 25% PVP CRS-FD sample was near 2 μg/ml while this amount was approximately 4.3 μg/ml for 25% HPH-FD sample. The effect of high pressure homogenization on dissolution rate is more pronounced for samples with lower stabilizer ratio. The samples prepared with high pressure homogenizer using 50% PVP showed 25-fold higher solubility compared to untreated curcumin. Generally, it can be concluded that the method of preparation, selection of suitable stabilizer and concentration of stabilizer play a critical role on particle size and dissolution rate of curcumin., (Copyright © 2018 Elsevier B.V. All rights reserved.)

The purpose of this study was to prepare transferrin (Tf) targeted liposomal 5-Fluorouracil (5FU) to improve the safety and efficacy of the drug. Liposomes were prepared using thin layer method. Morphology of liposomes was characterized by transmission electron microscopy (TEM) and their particle size was also determined. The in vitro cytotoxicity was investigated via MTT assay on HT-29 (as cancer cell) and fibroblast (as normal cell). Moreover, cytotoxicity mechanism of targeted liposomes was determined through the production of reactive oxygen species (ROS), mitochondrial membrane potential (∆Ψ m ) and release of cytochrome c. Results showed that encapsulation efficiency (EE%) was 58.66±0.58 and average size of liposomes was 107nm. Also, nano-particles were spherical as shown by TEM. MTT assay on HT-29 cells revealed the higher cytotoxic activity of targeted liposomes in comparison to free drug and non-targeted liposome. In contrast, comparing with cancer cells, targeted liposomes had no cytotoxic effect on normal cells. In addition, targeted liposomes induced apoptosis through activation of mitochondrial apoptosis pathways, as evidenced by decreased mitochondrial membrane potential and release of cytochrome c. Results of the study indicated that targeted liposomes would provide a potential strategy to treat colon cancer by inducing apoptosis via mitochondria signaling pathway with reducing dose of the drug and resulting fewer side-effects., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Metastatic cancer is responsible for 90% of deaths in world. Usage of nano-carriers improve the delivery and efficacy of chemotherapeutic agents. Recent studies suggest that decoration of the surface of nano-carriers with various targeting agents may further improve their overall therapeutic efficacy. Using specified peptides in targeted drug delivery is a key point in recent researches. In this study, tumor metastasis targeting (TMT) homing peptide was applied as a targeting group to improve specific drug delivery to tumor cells. TMT peptide is conjugated to poly ethylene glycol-poly caprolactone (PEG-PCL) micellar nanoparticles as carriers for targeted delivery of cabazitaxel to metastatic breast cancer cells. Synthesis of PEG-PCL copolymer was performed by amidation reaction between carboxylic acid group of PEG and amine group of PCL. Nanomicelles were prepared via solvent evaporation method. TMT peptide was covalently conjugated onto nanomicelles through the amine group of PEG. TMT-PEG-PCL nanoparticles were analyzed by Fourier transform infrared spectroscopy (FTIR), scanning electron microscope (SEM), dynamic light scattering (DLS), gel permeation chromatography (GPC) and nuclear magnetic resonance (NMR). Toxicity and cellular uptake of nanomicelles were investigated by in vitro cytotoxicity assays and confocal scanning microscopy in MCF-7 (non-metastatic breast cancer cells) and MDA-MB-231 (metastatic breast cancer cells). The final nanomicelles had about 110nm mean size and encapsulation efficiency of 82.5%. Treatment of metastatic breast cancer cells with targeted nanomicelles significantly increased the necrosis rate to 65%, compared to 33% in non-targeted nanomicelles and 8% in control group. The MDA-MB-231 cells treated with targeted nanomicelles exhibited a strong increase in the fluorescence intensity of coumarin in comparison to the cells treated with non-targeted nanomicelles (p<0.001). It could be concluded that the present carrier has the potential to be considered in treatment of metastatic breast cancer cells., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Formulation of a nanoparticulate Fingolimod delivery system based on biodegradable poly(3-hydroxybutyrate-co-3-hydroxyvalerate) was optimized according to artificial neural networks (ANNs). Concentration of poly(3-hydroxybutyrate-co-3-hydroxyvalerate), PVA and amount of Fingolimod is considered as the input value, and the particle size, polydispersity index, loading capacity, and entrapment efficacy as output data in experimental design study. In vitro release study was carried out for best formulation according to statistical analysis. ANNs are employed to generate the best model to determine the relationships between various values. In order to specify the model with the best accuracy and proficiency for the in vitro release, a multilayer percepteron with different training algorithm has been examined. Three training model formulations including Levenberg-Marquardt (LM), gradient descent, and Bayesian regularization were employed for training the ANN models. It is demonstrated that the predictive ability of each training algorithm is in the order of LM > gradient descent > Bayesian regularization. Also, optimum formulation was achieved by LM training function with 15 hidden layers and 20 neurons. The transfer function of the hidden layer for this formulation and the output layer were tansig and purlin, respectively. Also, the optimization process was developed by minimizing the error among the predicted and observed values of training algorithm (about 0.0341)., (Copyright © 2016 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Herein we reported the structure and several properties of a new biosurfactants produced by Corynebacterium xerosis strain NS5. This strain was capable of producing a novel lipopeptide biosurfactant that we have named coryxin. The biosurfactant structure was characterized by using Fourier transform infrared spectroscopy (FTIR), Nuclear magnetic resonance spectroscopy (NMR), and Liquid chromatography-mass spectrometry (LC-MS). It contained a hydrophobic moiety of 3-hydroxydecanoic acid and a peptide part predicted as a sequence of seven amino acids including Asn-Arg-Asn-Gln-Pro-Asn-Ser. Coryxin lowered the surface tension of water to 31.4 mN/m, with a critical micelle concentration of 25mg/l. It was a strong emulsifier with an emulsification index of 61% against n-hexane. Coryxin showed antibacterial activity against test organisms belonging to Gram-positive and Gram-negative bacteria and disrupted preformed biofilms of Staphylococcus aureus (82.5%), Streptococcus mutans (80%), Escherichia coli (66%) and Pseudomonas aeruginosa (30%). In conclusion, microbial surfactant from C. xerosis exhibited inhibitory and disruptive activities against biofilm formation that could be of use in biofilm-related menace., (Copyright © 2015 Elsevier B.V. All rights reserved.)

miR-145, a tumor suppressor micro RNA (miRNA), is down regulated in cancer and can be introduced as a therapeutic agent in various cancers including breast cancer. In this study, miR-145 plasmid was transfected to MCF-7 cells using chitosan polyplex nanoparticles. The vector was prepared according to an optimized fabricating method determined by response surface analysis and D-optimal design. Effects of chitosan molecular weight (Mw) and polymer amine to DNA phosphate ratio (N/P) as the variables were investigated on size, zeta potential, stability, and transfection efficiency of the polyplex nanoparticles. The results indicated that there is an interaction between effects of Mw and N/P ratio on the size of nanoparticles. Gel retardation assay demonstrated that the stability of the complexes in serum and preparation medium during storage time depends on the formulation variables. Statistical analysis affirmed that in spite of particle size, the variables of N/P ratio, time of incubation, and zeta potential affect the gene transfection. In conclusion, by selecting the perfect formulation prepared through an optimized method, it is possible to achieve a high transfection efficacy for miR-145 as an anticancer biological macromolecule., (Copyright © 2015 Elsevier B.V. All rights reserved.)

A simple and inexpensive methodology was used to develop a new method in order to inspect the DNA damage due to dopamine and some ionic metals. In addition, the inhibitory and repair effects of some antioxidant such as glutathione and ascorbic acid were studied and compared with each other using electrochemical impedance spectroscopy (EIS) and differential pulse voltammetry (DPV). In this work a pencil graphite electrode (PGE) was modified with multiwall carbon nanotubes (MWCNTs) and chitosan (CHIT), then it was decorated with a ds-DNA (ds-DNA/CHIT-MWCNTs/PGE). Due to interaction of ds-DNA and the damaging agents (dopamine+metallic ions), electrochemical and spectroscopy properties of ds-DNA at the surface of the modified electrode was changed, and these changes are followed with EIS and DPV methods. Our study showed that dopamine, Cu(II) and Fe(III) alone could not destroy DNA, but dopamine + Cu(II) and dopamine + Fe(III) can damage DNA. In addition, the ability of dopamine-Cu(II) was greater than dopamine-Fe(III). Moreover, some antioxidant such as glutathione and ascorbic acid can overcome and/or minimize the influence of these damaging interactions., (Copyright © 2015 Elsevier B.V. All rights reserved.)