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The skew-normal distribution and various generalizations have received much attention in recent years in behalf of their non-normal characteristics, such as heavy right or left tail, which are appeared in many real data sets. So far, many mathematical results have been derived about the skew distributions. Nevertheless, less attention has been paid on the inferential aspects of the proposed distributions. Hence in this paper, we focus on some inferential results of the skew-normal distribution. The amount of Fisher information in the order statistics of a simple random sample is studied and some properties are discussed with respect to variations of skewness parameter. Also, the most informative part of a sample is determined via simulation. The maximum likelihood estimators of skewness parameter are derived based on both complete sample and the most informative part of the sample and their efficiencies are compared. Furthermore, a ranked based sampling scheme is introduced to do inference about the skewness parameter in populations with high right skewness. Finally, a real data set is used to illustrate the results of the paper. [ABSTRACT FROM AUTHOR]

Consider a two-sampling scheme in which an initial sample is first taken from the underlying population and then by assuming a suitable restriction on this sample, some more data points are observed as a new restricted sample. This sampling scheme is used to do inference about the lower quantiles of the underlying distribution. The results are compared with those of simple random sampling in view of mean squared error and Pitman’s measure of closeness criteria for exponential and uniform distributions. It will be shown that the proposed sampling scheme would improve the performance of the point estimators of the lower quantiles of the population. [ABSTRACT FROM PUBLISHER]

A large family of distributions arising from distributions of ordered data is proposed which contains other models studied in the literature. This extension subsume many cases of weighted random variables such as order statistics, records, k-records and many others in variety. Such a distribution can be used for modeling data which are not identical in distribution. Some properties of the theoretical model such as moment, mean deviation, entropy criteria, symmetry and unimodality are derived. The proposed model also studies the problem of parameter estimation and derives maximum likelihood estimators in a weighted gamma distribution. Finally, it will be shown that the proposed model is the best among the previously introduced distributions for modeling a real data set. [ABSTRACT FROM AUTHOR]

Abstract: The effect of temperature and complex dopant composition on oxygen ion conductivity in solid oxide electrolyte fuel cells was investigated by atomistic molecular dynamics simulation. A new electrolyte (Nd2−x Gd x Zr2O7) was selected to study oxygen ion conductivity using three Gd compositions (x = 0.8, 1.0, and 1.2) in a wide range of temperature (T = 1273 K–1873 K). MSD results of cations showed these groups of electrolyte are stable at high operating temperature. The first composition (x = 0.8) had the highest ionic conductivity that was in good agreement with the experimental data. A simple effective model that works with configuration energy of the oxygen crossing plate was applied to explain the observed conductivity trend. The model illustrated the point as well. Increasing Gd concentration decreases existence probability of easy crossing plate. Radial distribution function analysis also confirmed results. Thermal expansion of the electrolyte has a major effect on the selecting of the electrolyte materials; thus, this important factor was also studied. Results showed the first composition had the greatest thermal expansion. [Copyright &y& Elsevier]

In this paper, the situation in which some lower records from a proportional reversed hazard rate model (PRHRM) are lost at the beginning of the experiment is considered. The reconstruction problem of the past lower records based on observed records from a PRHRM is discussed. Several various methods are used to obtain point reconstructors. More details are given for the Fréchet distribution. Three reconstruction intervals are also obtained and compared in the sense of the expected width for the case of Fréchet distribution. A data set representing the annual flood loss is applied to illustrate the proposed procedure in this paper. Eventually, some concluding remarks are presented. [ABSTRACT FROM AUTHOR]

Nd2- xHo xZr2O7 is an ionic conductor for solid oxide fuel cell electrolytes. Temperature and dopant composition are two main factors that affect ionic conductivity of these groups of materials. Accordingly, Nd2- xHo xZr2O7 was studied in a wide range of temperature, 1,173-1,873 K, and dopant composition, x = 0.0-2.0, by molecular dynamics simulation. Arrhenius plots of ionic conductivity in region of low temperature declared that the maximum occurred at composition x = 0.6 (H6). Surprisingly, it was observed that complexity of dopant improved ionic conductivity of the electrolyte. Moreover, radial distribution function confirmed this result. Two types of anions were observed in the electrolyte, which were dynamic oxygen ions (DOIs) and static oxygen ions (SOIs). Mean square displacement (MSD) of DOIs was higher than SOIs and enhanced oxygen ionic conductivity. Migration barrier of Nd2- xHo xZr2O7 varied from 0.68 to 1.22 eV that was in the range of a good solid oxide electrolyte. Nd1.2Gd0.8Zr2O7 (G8) and Y0.2Zr0.9O2.1 (Y2) were simulated and their results of simulations were compared with H6. Order of ionic conductivity at low temperatures was H6 > Y2 > G8. Another important factor of electrolyte is thermal expansion. Thermal expansion of Nd2- xHo xZr2O7 was around a constant value in the studied temperature range. [ABSTRACT FROM AUTHOR]

Objective: Brain tumors are mostly developing tumors with low survival rate worldwide. Among different types of brain tumors, high grade gliomas are not curable while low grade gliomas are well differentiated tumors with better prognosis. Meningiomas are various sets of brain tumors arising from the meninges. Genistein has been recently introduced with anti-proliferative and anti-angiogenic potent effects in a variety of tumors. In this study the effects of Genistein on the proliferation rate and viability of meningioma, low grade and high grade glioma tumor cells was assessed. Materials and Methods: Brain tumor tissues obtained from patients diagnosed with different types of brain tumors were washed with PBS, cut into small pieces, digested with Collagenase type 1 and cultured in the tissue culture flask containing DMEM and 10% FBS. In passage 3 of culture, cells were treated with different concentrations of Genistein (0, 0.01, 1/250, 1/500 and 0.001 M) for 72 hours and then IC 50 was evaluated with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay. Expression of Fas was determined using quantitative Real-Time PCR before and after treatment with Genistein. Results: Tumor cells have plastic adherent ability with mesenchymal like appearance and the ability to be cultured to 10 passages. High grade and low grade gliomas showed approximately 2-fold decrease in viability after treatment with Genistein (p value<0.05). Meningioma cells also showed 1.4-fold vitality decrease post treatment. Expression of Fas transcripts showed statistically significant higher expression in high grade glioma and meningioma samples after Genistein treatment compared to untreated cells (p value<0.05). Conclusion: Results of this study have important implications for the application of Genistein in different types of brain tumors as a therapeutic intervention in future [ABSTRACT FROM AUTHOR]

Objective: Adipose derived stem cells (ASCs) are detected in the tumor microenvironment and have immunomodulatory effects on both innate and adaptive immune responses. ASC-mediated immunesuppression is mainly induced through the secretion of soluble molecules such as IDO1, IDO2, MICA, MICB, NO, PGE2 and HLAG5. To evaluate the mRNA expression of IDO1, IDO2, MICA & MICB in adipose derived stem cells isolated from breast cancer patients and compare them to those of normal breast tissues. Materials and Methods: ASCs were isolated from 20 breast cancer patients and 10 normal breast adipose tissues obtained by cosmetic mamoplasty using collagenase digestion. The specified genes were assessed by q-RT- PCR method. Results: IDO1 gene expression in ASC cells from breast cancer patients was 2.3 fold more than that of ASCs from normal breasts. mRNA expression of the other genes including IDO2, MICA and MICB, was respectively 2.9 fold, 1.2 fold and 1.9 fold more than those of ASCs from normal breasts. However there was no significant difference between the expression of the indicated genes in ASCs of breast cancer patients and those of normal individuals. Conclusion: In the current study, the mRNA expression of IDO1, IDO2, MICA and MICB had no significant difference between breast cancer and normal breast tissue. This could be because of the relatively small number of samples in each group; therefore further studies on larger number of samples are needed to shed more light on this issue [ABSTRACT FROM AUTHOR]

Objective: Epithelial-mesenchymal transition (EMT) is an important mechanism in tumor progression and metastasis. In addition to the uncontrolled epithelial proliferation and angiogenesis, the role of this mechanism in solid tumors such as breast cancer is also important for cancer progression and metastasis. The role of cytokines such as TGF-β and SDF-1 in triggering the EMT mechanism is previously demonstrated. In contrast to the SDF- 1 with angiogenic roles, the chemokine IP-10 has been documented with anti-angiogenic activities but there is no research which shows the effect of IP-10 on EMT. Thus, in this study we investigated the effect of IP-10 overexpression on EMT mechanism in tumor cells. Besides, because of the key role of tumor microenvironment on tumor progression and the importance of ASCs, we also investigated the effect of these cells on the EMT mechanism. Materials and Methods: ASCs were isolated from 6 breast cancer patients and 6 normal individuals and then cultured. MDA-MB-468 breast cancer cell line was transfected by IP-10 plasmid through electroporation. Transfected cell line was co-cultured with ASCs using transwell system. After 4 days, proteins were extracted and the expressions of MMP9 and MMP13 were defined by western blotting. Results: Results of western blot for MMP9 and MMP13 protein expressions showed that the expression of both proteins were downregulated in IP-10 transfected MDAMB- 468 cells compared to the untransfected cells. Presence of ASCs causes the upregulation of MMP9 in MDA-MB468 cell line. Conclusion: Based on the results of this study, IP-10 may downregulate the EMT markers in MDA-MB-468 cancer cell line. No different was found between the ASCs from different sources but the presence of ASCs in tumor microenvironment can lead to the up-regulation of EMT markers. Accordingly, IP-10 may use as an antitumor therapeutic agent to suppress tumor progression and metastasis [ABSTRACT FROM AUTHOR]

Objective: Despite advances in surgical and adjuvant radiation therapy and chemotherapy strategies, malignant gliomas continue to be associated with poor prognosis in patients. To address suitable strategies, scientists pay close attention to factors that cause angiogenesis. Angiogenesis is a possible target in the treatment of human gliomas. Genistein has been previously introduced as an anti-angiogenic agent for different cancers. To evaluate the effect of Genistein on the angiogenic cascade, we investigated the expression of hepatocyte growth factor (HGF) transcripts in mesenchymal stem cell like cells from high grade and low grade brain tumors before and after treatment with Genistein. Materials and Methods: Brain tumor obtained from patient diagnoses with GBM and low grade glioma in sterile condition, wash with PBS, cut in to small pieces, digested with collagenase type I and culture in tissue culture flask contain MDEM 10% FBS. As cells arise to passage 3, they were treated with Genistein and then the HGF gene expression was determined by QRT-PCR in treated and untreated cells. Results: Genistein has a significant effect on both types of tumors after cells expose to compound compared to untreated cells. According to the results, Genistein has a remarkable effect on downregulating HGF transcripts where it showed 13×106- and 2-fold lower expression than untreated cells in high grade and low grade glioma cells, respectively. Conclusion: Our research showed that Genistein has a significant effect on downregulation of HGF. Consequently, Genistein have some important advantages for treatment of invasive brain tumors, however more investment cannot be ignore to make a suitable decision about effect of this compound on brain tumors [ABSTRACT FROM AUTHOR]

Objective: WEE1 Kinase is associated with controlling the cell cycle progression through G2/M check point. Inhibition of this Kinase has been shown to induce apoptosis in a variety of cancerous cells by skipping the repair mechanisms. In majority of cancer cells, the G1/S check point is damaged due to p53 mutations. So inhibition of this Kinase seems to be a justified approach for induction of DNA damage mediated apoptosis with normal p53 positive cells being excluded. In this study the effect of WEE1 shRNA mediated suppression was evaluated in a cell line from Non small cell lung cancer, considering the reported high profile of WEE1 expression in NSCLC. Materials and Methods: WEE1 gene was silenced using the specific shRNA in QU-DB cell line. Transfection efficacy was examined by flowcytometery based on GFP expression. 48 hours post-transfection, the fixed DNA content and permealized cells was stained with Propodium Iodide and evaluated by flowcytometery. WEE1 protein expression was also assessed by Western Blotting. Results: Analysis of Cell Cycle by flowcytometry and after PI staining showed that the majority of treated cells were within the M phase of cell cycle 48h post treatment. On the other hand, Analysis of protein content in treated cells and the control group by Western blotting was indicative of successful WEE1 suppression. Conclusion: The significant progression through Mphase is suggestive of the prominent role of WEE1 in G2/M regulation. We concerned WEE1 suppression might be a good candidate to fight against NSCLC. Inhibition of cell cycle checkpoint regulators has also been exploited to improve the efficacy of stem cell and iPSCs production. Therefore, this Kinase would be a suggestion for further studies in this field [ABSTRACT FROM AUTHOR]

Background: Laryngeal cancer is a common head and neck cancer. Surgical treatment can impair patients' voice and swallowing function, making definitive radiotherapy a viable alternative for locally advanced cases., Methods: To compare the outcomes of definitive versus adjuvant radiotherapy in patients with primary locally advanced laryngeal cancer, we retrospectively evaluated consecutive patients treated from 2007 to 2020. We assessed and compared the median and 3-year overall survival (OS), disease-free survival (DFS), distant metastasis control (DMC), and local recurrence-free survival (LRC) in all patients and in T4 patients exclusively., Results: One hundred patients were studied, including definitive (N = 64) and adjuvant (N = 36) radiotherapy. The median follow-up was 29 months. Overall, the median OS in the definitive vs. adjuvant group was 100 months (95%CI = 46.5-153.5) vs. not reached, respectively (log-rank P = 0.506). The median DFS in the definitive vs. adjuvant group was 20 months (95%CI = 7.7-32.3) vs. not reached, respectively (log-rank P = 0.148). Three-year OS and DFS rates in all patients were 64% (95%CI: 48-78) vs. 75% (95%CI: 55-95) and 43% (95%CI:29-57) vs. 61% (95%CI: 41-81) in the definitive vs. adjuvant groups, respectively. Among T4 patients, the median OS in the definitive RT group vs. adjuvant group was not reached vs. 48 (95%CI = 0-105.3), respectively (log-rank P = 0.788). The median DFS in the definitive RT group vs. adjuvant group was 12 months (95%CI = 9.34-14.65) vs. 36 months (95%CI = 4.4-67.5), respectively (log-rank P = 0.868). Three-year OS and DFS rates were 71% (95%CI: 42-100) vs. 75% (95%CI: 50-100) and 40% (95%CI:21-79) vs. 56% (95%CI: 25-87) in the definitive vs. adjuvant groups, respectively., Conclusions: Our analysis suggests that definitive radiotherapy in laryngeal cancer does not lead to a poorer outcome than total laryngectomy followed by adjuvant radiotherapy. In T4 patients, our findings should reassure clinicians and patients about the viability of definitive radiotherapy as a treatment approach., Competing Interests: Declarations. Ethics approval and consent to participate: Ethics code: IR.TUMS.IKHC.REC.1399.102. Consent for publication: Availability of data and materials: Competing interests: The authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Sinonasal malignancies are a rare group of head and neck cancers. We aimed to report the oncological outcomes based on histological types in patients who underwent radiotherapy., Materials and Methods: In this single-institution study, we retrospectively retrieved and analyzed data of patients with sinonasal carcinomas who underwent radiotherapy during 2011-2016 as part of their treatment. The 3-year rate of local, regional, and distant recurrences, and overall survival were evaluated according to the histological type., Results: A total of 28 patients were evaluated in this study, the majority of whom were male (60%). Squamous cell carcinoma (SCC), adenoid cystic carcinoma (ACC), and adenocarcinoma (ADC) were found in 15 patients (53.5%), 8 (28.5%), and 5 (18%), respectively. The highest rates of local and regional recurrences were observed in ACC and SCC, respectively. Distant recurrences were numerically more common in ADC. The 3-year OS was 48%, 50%, and 73% in SCC, ADC, and ACC, respectively., Conclusion: Different histopathologies of sinonasal cancer seem to have different patterns of failure, and this may be considered in the treatment approach.

Background Objectives: Semaphorins were initially characterized as axon guidance factors but were subsequently implicated in the regulation of immune responses, angiogenesis, organ formation and a variety of other physiological and developmental functions. Various semaphorins enhance or inhibit tumour progression through different mechanisms. The objective of this study was to assess the expression of various semaphorins and vascular endothelial growth factor (VEGF) gene transcripts as well as the serum level of Sema3A in individuals with laryngeal squamous cell carcinoma (LSCC)., Methods: Tissue expression of Sema3A, Sema3C, Sema4D, Sema6D and VEGF was determined in both tumour tissues and tissues around the tumour from 30 individuals with pathologically confirmed LSCC using quantitative real-time PCR. Furthermore, the serum level of Sema3A in these individuals was assessed using enzyme-linked immunosorbent assay., Results: Sema3C gene transcript showed a significant increase (P=0.001), while Sema4D was observed with a significant decrease in tumour samples compared to non-tumoural tissues (P≤0.01). The expression of the Sema3C gene was found to be associated with the stage of LSCC tumour as it was statistically significant for tumours with stage IV (P<0.01). The serum level of Sema3A was not found to be significant between cases and controls., Interpretation Conclusions: Increased expression of Sema3C but decreased expression of Sema4D in tumour tissue of LSCC may introduce these two growth factors as crucial mediators orchestrating tumour growth in individuals with LSCC. This result could open a new vision for the treatment of this malignancy., (Copyright © 2023 Copyright: © 2023 Indian Journal of Medical Research.)

Background: Due to their ability to recruit immune cells to kill tumor cells directly, bispecific T cell engager antibodies (BiTE) hold great potential in T cell redirecting therapies. BiTE is able to activate T cells through CD3 and target them to tumor-expressed antigens. However, there are many components in the tumor microenvironment (TME) such as mesenchymal stem cells (MSCs) that may interfere with BiTE function. Herein, we designed an anti-PDL1-BiTE that targets programmed death ligand 1 (PDL1) and CD3 and investigated its effect on PDL1pos cancer cells in the presence or absence of adipose-derived MSCs (ASCs)., Method: Our anti-PDL1-BiTE comprises of VL and VH chains of anti-CD3 monoclonal antibody (mAb) linked to the VL and VH chains of anti-PDL1 mAb, which simultaneously bind to the CD3 ε subunit on T cells and PDL1 on tumor cells. Flow cytometry was employed to assess the strength of binding of anti-PDL1-BiTE to tumor cells and T cells. Cytotoxicity, proliferation, and activation of peripheral blood lymphocyte (PBLs) were evaluated by CFSE assay and flow cytometry after using anti-PDL1-BiTE in the presence or absence of ASCs and their conditioned media (C.M.)., Results: Anti-PDL1-BiTE had the ability to induce selective lysis of PDL1pos U251-MG cancer cells while PDL1neg cells were not affected. Also, anti-PDL1-BiTE significantly stimulated peripheral blood lymphocyte (PBL) proliferation and CD69 expression. ASCs/C.M. did not show a significant effect on the biological activity of anti-PDL1-BiTE., Conclusion: Overall, anti-PDL1-BiTE selectively depletes PDL1pos cells and represents a new immunotherapeutic approach. It would increase the accumulation of T cells and can improve the prognosis of PDL1pos cancers in spite of the immunomodulatory effects of ASCs and C.M., Competing Interests: The authors declare that they have no competing interests., (Copyright © 2023 Leila Moeinzadeh et al.)

According to strong evidence, diabetes mellitus increases the risk of cognitive impairment. Mesenchymal stem cells have been shown to be potential therapeutic agents for neurological disorders. In the current study, we aimed to examine the effects of Wharton's jelly-derived mesenchymal stem cell-conditioned medium (WJMSC-CM) on learning and memory, oxidative stress, apoptosis, and histological changes in the hippocampus of diabetic rats. Randomly, 35 male Sprague Dawley rats weighing 260-300 g were allocated into five groups: control, diabetes, and three diabetic groups treated with insulin, WJMSC-CM, and DMEM. The injections of insulin (3 U/day, S.C.) and WJMSC-CM (10 mg/week, I.P.) were done for 60 days. The Morris water maze and open field were used to measure cognition and anxiety-like behaviors. Colorimetric assays were used to determine hippocampus glutathione (GSH), malondialdehyde (MDA) levels, and antioxidant enzyme activity. The histopathological evaluation of the hippocampus was performed by Nissl staining. The expression levels of Bax, Bcl-2, BDNF, and TNF- α were detected by real-time polymerase chain reaction (RT-PCR). According to our findings, WJMSC-CM significantly reduced and increased blood glucose and insulin levels, respectively. Enhanced cognition and improved anxiety-like behavior were also found in WJMSC-CM-treated diabetic rats. In addition, WJMSC-CM treatment reduced oxidative stress by lowering MDA and elevating GSH and antioxidant enzyme activity. Reduced TNF- α and enhanced Bcl-2 gene expression levels and elevated neuronal and nonneuronal (astrocytes and oligodendrocytes) cells were detected in the hippocampus of WJMSC-CM-treated diabetic rats. In conclusion, WJMSC-CM alleviated diabetes-related cognitive impairment by reducing oxidative stress, neuroinflammation, and apoptosis in diabetic rats., Competing Interests: The authors declare no competing financial interests., (Copyright © 2023 Zohre Aghaei et al.)

Purpose: To identify efficacy, complication, and pathologic response of high-dose-rate endorectal brachytherapy (HDR-BRT) boost in neo-adjuvant chemoradiotherapy (nCRT) of locally advanced rectal cancer., Material and Methods: Forty-four patients who met eligibility criteria were included in this non-randomized comparative study. Control group was recruited retrospectively. nCRT (50.40 Gy/28 fr. plus capecitabine 825 mg/m 2 twice daily) was administered to both groups before surgery. In the case group, HDR-BRT (8 Gy/2 fr.) was supplemented after chemoradiation. Surgery was done 6-8 weeks after completion of neo-adjuvant therapy. Pathologic complete response (pCR) was the study's primary endpoint., Results: From 44 patients in the case and control groups, pCR was 11 (50%) and 8 (36.4%), respectively ( p = 0.27). According to Ryan's grading system, tumor regression grade (TRG) TRG1, TRG2, and TRG3 were 16 (72.7%), 2 (9.1%), and 4 (18.2%) in the case, and 10 (45.5%), 7 (31.8%), and 5 (22.7%) in the control group ( p = 0.118). T down-staging was found in 19 (86.4%) and 13 (59.1%) patients in the case and control groups, respectively. No grade > 2 toxicity was identified in both the groups. Organ preservation was achieved in 42.8% and 15.3% in the case and control arm ( p = 0.192). In the case group, 8-year overall survival (OS) and disease-free survival (DFS) were 89% (95% CI: 73-100%) and 78% (95% CI: 58-98%), respectively. Our study did not reach median OS and median DFS., Conclusions: Treatment schedule was well-tolerated, and neo-adjuvant HDR-BRT could achieve better T down-staging as a boost comparing with nCRT, without significant complication. However, the optimal dose and fractions in the context of HDR-BRT boost needs further studies., Competing Interests: The authors report no conflict of interest., (Copyright © 2023 Termedia.)

Introduction: The effect of the functional group of the cation on SO2 acidic gas absorption by some designed amino acid ionic liquids (AAILs) was studied. Methods: An isolated pair of glycinate anion and pristine imidazolium-based cation, as well as decorated cation functionalized by hydroxyl (OH), amine (NH 2 ), carboxylic acid (COOH), methoxy (OCH 3 ), and acetate (CH 3 COO) groups, were structurally optimized by density functional theory (DFT) using split-valence triple-zeta Pople basis set. Results and Discussion: The binding and Gibbs free energy (ΔG int ) values of SO 2 absorption show the AAIL functionalized by the COOH group is the most thermodynamically favorable green solvent and this functional group experiences the closest distance between anion and captured SO 2 and vice versa in the case of cation … SO 2 which may be the main reason for being the best absorbent; in addition, the highest net charge-transfer amount of SO 2 is observed. Comparing the non-covalent interaction of the systems demonstrates that the strongest hydrogen bond between captured gas and anion, as well as π-hole, and van der Waals (vdW) interaction play critical roles in gas absorption; besides, the COOH functional group decreases the steric effect while the CH 3 COO functional group significantly increases steric effect after absorption that declines the hydrogen bond., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Siami, Razmkhah and Moosavi.)

Background: Suppression of p53 is an important mechanism in Epstein-Barr virus associate-tumors and described as EBNA1-USP7 which is a key axis in p53 suppression. Thus, in this study, we aimed to evaluate the function of EBNA1 on the expression of p53-inhibiting genes including HDAC-1, MDM2, MDM4, Sirt-3 , and PSMD10 and the influence of USP7 inhibition using GNE-6776 on p53 at protein/mRNA level., Methods: The electroporation method was used to transfect the BL28 cell line with EBNA1 . Cells with stable EBNA1 expression were selected by Hygromycin B treatment. The expression of seven genes, including PSMD10, HDAC-1, USP7, MDM2, P53, Sirt-3 , and MDM4 , was evaluated using a real-time PCR assay. For evaluating the effects of USP7 inhibition, the cells were treated with GNE-6776; after 24 hours and 4 days, the cells were collected and again expression of interest genes was evaluated., Results: MDM2 (P=0.028), MDM4 (P=0.028), USP7 (P=0.028), and HDAC1 (P=0.015) all showed significantly higher expression in EBNA1 -harboring cells compared to control plasmid transfected cells, while p53 mRNA expression was only marginally downregulated in EBNA1 harboring cells (P=0.685). Four-day after treatment, none of the studied genes was significantly changed. Also, in the first 24-hour after treatment, mRNA expression of p53 was downregulated (P=0.685), but after 4 days it was upregulated (P=0.7) insignificantly., Conclusion: It seems that EBNA1 could strongly upregulate p53-inhibiting genes including HDAC1, MDM2, MDM4 , and USP7 . Moreover, it appears that the effects of USP7 suppression on p53 at protein/mRNA level depend on the cell nature; however, further research is needed., Competing Interests: The authors declare no conflict of interest.

Background: Shilajit has been widely used remedy for treating a numerous of illness such as bone defects in Iran traditional folk medicine since hundreds of years ago. The aim of the present study was to explore the effect of Shilajit on the osteogenic differentiation of human adipose-derived mesenchymal stem cells (ASCs) in two- (2D) and three-dimensional (3D) cultures., Materials and Methods: ASCs were seeded in 3D 1% alginate (Alg) hydrogel with or without Shilajit (500 µg/mL) and compared with 2D cultures. Then, characterization was done using electron microscopy (SEM)/energy-dispersive X-ray spectroscopy (EDX), alkaline phosphatase (ALP) activity, alizarin red staining and Raman confocal microscopy., Results: Adding Shilajit had no impact on the Alg scaffold degradability. In the 3D hydrogel and in the presence of osteogenic medium (OM), Shilajit acted as enhancer to increase ALP activity and also showed osteoinductive property in the absence of OM compared to the 2D matched groups at all time points (days 7 and 21 both P = 0.0006, for 14 days P = 0.0006 and P = 0.002, respectively). In addition, calcium deposition was significantly increased in the cultures exposed to Shilajit compared to 2D matched groups on days 14 (P < 0.0001) and 21 (P = 0.0003 and P = 0.003, respectively). In both 3D and 2D conditions, Shilajit induced osteogenic differentiation, but Shilajit/Alg combination starts osteogenic differentiation in a short period of time., Conclusion: As Shilajit accelerates the differentiation of ASCs into the osteoblasts, without changing the physical properties of the Alg hydrogel, this combination may pave the way for more promising remedies considering bone defects., (© 2022. The Author(s).)