The human adenovirus PI3K-Akt activator E4orf1 is targeted by the tumor suppressor p53.

Human adenoviruses (HAdV) are classified as DNA tumor viruses due to their potential to mediate oncogenic transformation in non-permissive mammalian cells and certain human stem cells. To achieve transformation, the viral early proteins of the E1 and E4 regions must block apoptosis and activate proliferation: the former predominantly through modulating the cellular tumor suppressor p53 and the latter by activating cellular pro-survival and pro-metabolism protein cascades, such as the phosphoinositide 3-kinase (PI3K-Akt) pathway, which is activated by HAdV E4orf1. Focusing on HAdV-C5, we show that E4orf1 is necessary and sufficient to stimulate Akt activation through phosphorylation in H1299 cells, which is not only hindered but repressed during HAdV-C5 infection with a loss of E4orf1 function in p53-positive A549 cells. Contrary to other research, E4orf1 localized not only in the common, cytoplasmic PI3K-Akt-containing compartment, but also in distinct nuclear aggregates. We identified a novel inhibitory mechanism, where p53 selectively targeted E4orf1 to destabilize it, also stalling E4orf1-dependent Akt phosphorylation. Co-IP and immunofluorescence studies showed that p53 and E4orf1 interact, and since p53 is bound by the HAdV-C5 E3 ubiquitin ligase complex, we also identified E4orf1 as a novel factor interacting with E1B-55K and E4orf6 during infection; overexpression of E4orf1 led to less-efficient E3 ubiquitin ligase-mediated proteasomal degradation of p53. We hypothesize that p53 specifically subverts the pro-survival function of E4orf1-mediated PI3K-Akt activation to protect the cell from metabolic hyper-activation or even transformation.IMPORTANCEHuman adenoviruses (HAdV) are nearly ubiquitous pathogens comprising numerous subtypes that infect various tissues and organs. Among many encoded proteins that facilitate viral replication and subversion of host cellular processes, the viral E4orf1 protein has emerged as an intriguing yet under-investigated player in the complex interplay between the virus and its host. Nonetheless, E4orf1 has gained attention as a metabolism activator and oncogenic agent, while recent research is showing that E4orf1 may play a more important role in modulating the cellular pathways such as phosphoinositide 3-kinase-Akt-mTOR. Our study reveals a novel and general impact of E4orf1 on host mechanisms, providing a novel basis for innovative antiviral strategies in future therapeutic settings. Ongoing investigations of the cellular pathways modulated by HAdV are of great interest, particularly since adenovirus-based vectors actually serve as vaccine or gene vectors. HAdV constitute an ideal model system to analyze the underlying molecular principles of virus-induced tumorigenesis.

Additional new species of Xenodidymella from pasture-medicinal plants in Iran.

Xenodidymella species have a wide range of hosts and can be found as pathogens and saprobes. In this study, two new species of Xenodidymella were found from leaf diseases of three pasture-medicinal plants in Ilam Province, in the west of Iran, and proposed here as X. ilamica and X. scandicis spp. nov. These species were identified based on morphological features and phylogenetic analyses of the internal transcribed spacer regions 1 & 2 and 5.8S nrDNA (ITS), partial beta-tubulin gene (tub2), and partial RNA polymerase II second largest subunit (rpb2) gene. The four Xenodidymella strains isolated in this study were delimited into two sister clades, with the two isolates of X. ilamica from the leaf spot of Colchicum speciosum and Ficaria kochii and two isolates of X. scandicis from leaf blight of Scandix pecten-veneris. Morphologically, X. scandicis produces larger, ostiolate or poroid pycnidia in vitro, while pycnidia in the cultures of X. ilamica are non-ostiolate and smaller. Some pycnidia in old cultures of X. scandicis produce a neck, but a distinct neck in X. ilamica has not been observed. Moreover, three plants under study are new hosts for the genus Xenodidymella.

The impact of continuous and intermittent supportive counseling on self-efficacy and continuation of breastfeeding in lactating women affected by COVID-19: a quasi-experimental trial.

BACKGROUND: Promoting exclusive breastfeeding can have a great effect in reducing the complications and mortality rate of mother and child. OBJECTIVE: The study aimed to compare the effects of continuous and intermittent supportive counselling on the self-efficacy and continuity of breastfeeding among Lactating mothers with COVID-19. METHODS: The study was a semi-experimental research method and was conducted on 73 mothers with COVID-19 who were hospitalized in Ayatollah Mousavi Hospital in Zanjan, Iran from May 2021 to April 2022. In the continuous counselling group, counselling was provided daily for 14 days, while in the intermittent counselling group, counselling was provided once a week for four weeks. Breastfeeding continuity was assessed based on the World Health Organization's classification, and breastfeeding self-efficacy was measured using Dennis' standard breastfeeding self-efficacy questionnaire (BSE) up to four months after delivery. The data were analyzed using chi-square tests, independent t-tests, paired t-tests, analysis of variance with repeated measures, and survival analysis (Kaplan-Meier) with a 95% confidence level. RESULTS: The survival analysis revealed that the cessation of exclusive breastfeeding occurred in 17 cases within the continuous counselling group and in 22 cases within the intermittent counselling group. The rates of continuation for exclusive breastfeeding were 52.8% and 40.5% in the continuous and intermittent counselling group respectively. However, no statistically significant differences were observed in the continuation of breastfeeding and the trend of changes in the mean scores of breastfeeding self-efficacies between the continuous and intermittent counselling groups. Furthermore, comparing the change in breastfeeding self-efficacy scores between the one-month and four-month follow-ups within the continuous counselling group, a statistically significant increase was observed. CONCLUSION: The results indicated no difference in the effectiveness of continuous and intermittent counseling methods in improving breastfeeding continuity in women with COVID-19. Further research is needed to explore the long-term effects of different counseling approaches on breastfeeding outcomes during crises. TRIAL REGISTRATION: The study was registered on the Iranian Registry of Clinical Trials website on 29/06/2021 with the registration code IRCT20150731023423N19. It can be accessed via this link: https://irct.behdasht.gov.ir/user/trial/55391/view .

Household financial burden associated with out-of-pocket payments for healthcare in Iran: insights from a cross-sectional survey.

BACKGROUND: One of the key functions and ultimate goals of health systems is to provide financial protection for individuals when using health services. This study sought to evaluate the level of financial protection and its inequality among individuals covered by the Social Security Organization (SSO) health insurance between September and December 2023 in Iran. METHODS: We collected data on 1691 households in five provinces using multistage sampling to examine the prevalence of catastrophic healthcare expenditure (CHE) at four different thresholds (10%, 20%, 30%, and 40%) of the household's capacity to pay (CTP). Additionally, we explored the prevalence of impoverishment due to health costs and assessed socioeconomic-related inequality in OOP payments for healthcare using the concentration index and concentration curve. To measure equity in out-of-pocket (OOP) payments for healthcare, we utilized the Kakwani progressivity index (KPI). Furthermore, we employed multiple logistic regression to identify the main factors contributing to households experiencing CHE. FINDINGS: The study revealed that households in our sample allocated approximately 11% of their budgets to healthcare services. The prevalence of CHE at the thresholds of 10%, 20%, 30%, and 40% was found to be 47.1%, 30.1%, 20.1%, and 15.7%, respectively. Additionally, we observed that about 7.9% of the households experienced impoverishment due to health costs. Multiple logistic regression analysis indicated that the age of the head of the household, place of residence, socioeconomic status, utilization of dental services, utilization of medicine, and province of residence were the main factors influencing CHE. Furthermore, the study demonstrated that while wealthy households spend more money on healthcare, poorer households spend a larger proportion of their total income to healthcare costs. The KPI showed that households with lower total expenditures had higher OOP payments relative to their CTP. CONCLUSION: The study findings underscore the need for targeted interventions to improve financial protection in healthcare and mitigate inequalities among individuals covered by SSO. It is recommended that these interventions prioritize the expansion of coverage for dental services and medication expenses, particularly for lower socioeconomic status household.

Comparison of psychological reactions, fear of negative evaluation and mood-emotional alexithymia in successful and unsuccessful people in addiction recovery: a survey of Baluchestan in Iran.

The aim of this study was to examine psychological responses, fear of negative evaluation, and mood-related alexithymia in individuals in addiction recovery who have succeeded versus those who have not. This study employed a causal-comparative design. The research focused on all individuals who sought treatment for addiction at clinics within a specific district in Zahedan city, Iran. Out of the group, 100 individuals were chosen (50 who successfully stopped their addiction and 50 who were unsuccessful in their attempts to quit) through convenience sampling. Data were gathered using the depression, Anxiety, and Stress Scale (DASS-21), Lori's fear of negative evaluation scale, and Toronto's mood-emotional alexithymia scale. Data were examined through both descriptive statistics and multivariate analysis of variance. Based on the results, successful and unsuccessful individuals in addiction recovery showed varying levels of depression, stress, fear of negative evaluation, and having no fear of negative evaluation (p < .01). In simpler terms, unsuccessful individuals in addiction recovery scored higher in depression, stress, fear of negative evaluation, inability feeling emotions, inability to express feelings compared to successful individuals. But successful individuals in addiction recovery obtained higher mean scores than unsuccessful individuals in addiction recovery on having no fear of negative evaluation. According to the findings psychological reactions, fear of negative evaluation and mood-emotional alexithymia play a significant role in addiction treatment and can be helpful in addiction recovery in unsuccessful people in addiction recovery. It is feasible to enhance the effectiveness of addiction recovery by implementing interventions that target the reduction of depression, stress, fear of negative evaluation, and alexithymia.

Insights adjusting for non-adherence in randomized clinical trials: a reanalysis of an adjuvant trial of tamoxifen duration in early breast cancer.

BACKGROUND: Several randomized clinical trials provide evidence of the survival benefit of extended adjuvant tamoxifen in women with estrogen receptor (ER)-positive early breast cancer (BC). However, non-adherence may lead to underestimate treatment effects using intention to treat (ITT) methods. We reanalyzed a randomized trial using contemporary statistical methods adjusting for non-adherence. METHODS: The TAM01 study was a phase 3 trial including women with early BC, who had completed 2-3 years of adjuvant tamoxifen between 1986 and 1995. Participants were randomly assigned to continue tamoxifen up to 10 years or to discontinue the treatment at randomization. Invasive disease-free survival (iDFS) and overall survival (OS) were estimated using marginal structural models (MSM) and rank preserving structural failure time model (RPSFTM). RESULTS: Of 3830 patients enrolled, 2485 were randomized to extended tamoxifen, and 1345 to treatment discontinuation. The 10-year non-adherence rate in the extended group was 27.2%. Among women with ER-positive BC (n = 2402), extended tamoxifen was associated with a 45% and 21% relative improvement in iDFS by MSM and RPSFTM, respectively (Hazard Ratio (HR), 0.55; 95% Confidence Interval (CI), 0.48-0.64 and HR, 0.79; 95%CI, 0.67-0.95, respectively), a considerable greater benefit than in the ITT analysis (HR, 0.90; 95%CI, 0.81-0.99). The OS reanalysis revealed a substantial benefit of extended tamoxifen (MSM: HR, 0.70; 95%CI, 0.59-0.83; RPSFTM: HR, 0.85; 95%CI, 0.67-1.04), compared to the ITT analyses (HR, 0.94; 95%CI, 0.84-1.07). CONCLUSION: This analysis emphasizes both the importance of adherence to hormonotherapy in hormone-receptor positive early BC and the usefulness of more complex statistical analyses.

Synthesis and evaluation of 99mTc-labeled 1-(2-Pyridyl)piperazine derivatives as radioligands for 5HT7 receptors.

Glioblastoma multiform (GBM) is one of the most aggressive tumors of the central nervous system in humans. GBM overexpresses serotonin-7 receptors (5-HT7Rs); hence, this study aims to develop 5-HT7R targeted radiotracers. Aryl piperazine derivatives can act as ligands for 5-HT7R. Therefore, compounds 6 and 7 as 1-(3-nitropyridin-2-yl)piperazine derivatives were synthesized and radiolabeled with 99mTcN2+ core. Radiolabeled 6 and 7 (99mTcN-[6] and 99mTcN-[7]) were prepared with high radiochemical purity (RCP > 96%). They displayed high affinity toward U-87 MG cell line 5-HT7R. The calculated Ki for 99mTcN-[7] was lower than that of 99mTcN-[6] (14.85 ± 0.32 vs 22.57 ± 0.73 nM) which indicates the higher affinity of 99mTcN-[7] toward 5-HT7R. A molecular docking study also confirmed the binding of these radiotracers to 5-HT7R. The biodistribution study in normal mice revealed that 99mTcN-[7] has the highest brain accumulation at 30 min post-injection (0.54 ± 0.12 %ID/g) while the uptake of 99mTcN-[6] is much lower (0.14 ± 0.02 %ID/g). The biodistribution study in the xenograft model confirms that the radiotracers recognize the tumor site. 99mTcN-[6], and 99mTcN-[7] showed the highest tumor uptake at 1-hour post-injection (5.44 ± 0.58 vs 4.94 ± 1.65 %ID/g) and tumor-to-muscle ratios were (4.61 vs. 5.61). The injection of pimozide blocks the receptors and significantly reduces the tumor-to-muscle ratios at 1-hour post-injection to 0.81 and 0.31, respectively. In correlation with in vitro study, 99mTcN-[6] and 99mTcN-[7] visualize the tumor site in U-87 MG glioma xenografted nude mice and display the tumor-to-muscle ratios of 7.05 and 6.03.

Numerical analysis of surface hydrogeological water budget to estimate unconfined aquifers recharge.

Under changing climate, groundwater resources are the main drivers of socioeconomic development and ecosystem sustainability. This study assessed the contribution of two adjacent watersheds, Muse Street (MS) and West Wood (WW), with low and high urban development, to the Memphis aquifer recharge process in central Jackson, Tennessee, USA. The numerical MODFLOW model was created using data from 2017 to 2019 and calibrated using reported water budget components derived from in-situ data. The calibrated MODFLOW model was then used to investigate the impact of high and low urban developments on the recharge rate. The hydraulic parameters and recharge rates were optimized by adjusting the groundwater level based on the observed water level using PEST. The stochastic modeling was also carried out using the Latin Hypercube approach to reduce the uncertainty. The calibration results were satisfactory, with RMSE of 0.124 and 0.63 obtained in the WW and MS watersheds, respectively, indicating accurate estimation of the input parameters, precisely the hydrodynamic coefficients. The study results indicate that, per unit area, the MS watershed contributes 119% more to recharge and 186% more to riverbed leakage compared to the WW watershed. However, regarding total recharge and riverbed leakage, the WW watershed contributed more than the MS watershed. The results of this study have enhanced the knowledge of the impact of urbanization on hydrology and the recharge process in watersheds with diverse land uses.

Epigenetic mechanisms of lung carcinogenesis involve differentially methylated CpG sites beyond those associated with smoking.

Smoking-related epigenetic changes have been linked to lung cancer, but the contribution of epigenetic alterations unrelated to smoking remains unclear. We sought for a sparse set of CpG sites predicting lung cancer and explored the role of smoking in these associations. We analysed CpGs in relation to lung cancer in participants from two nested case-control studies, using (LASSO)-penalised regression. We accounted for the effects of smoking using known smoking-related CpGs, and through conditional-independence network. We identified 29 CpGs (8 smoking-related, 21 smoking-unrelated) associated with lung cancer. Models additionally adjusted for Comprehensive Smoking Index-(CSI) selected 1 smoking-related and 49 smoking-unrelated CpGs. Selected CpGs yielded excellent discriminatory performances, outperforming information provided by CSI only. Of the 8 selected smoking-related CpGs, two captured lung cancer-relevant effects of smoking that were missed by CSI. Further, the 50 CpGs identified in the CSI-adjusted model complementarily explained lung cancer risk. These markers may provide further insight into lung cancer carcinogenesis and help improving early identification of high-risk patients.

Multicenter evaluation of breast cancer patients' satisfaction and experience with oncology telemedicine visits during the COVID-19 pandemic.

INTRODUCTION: During the COVID-19 pandemic, teleconsultation was implemented in clinical practice to limit patient exposure to COVID-19 while monitoring their treatment and follow-up. We sought to examine the satisfaction of patients with breast cancer (BC) who underwent teleconsultations during this period. METHODS: Eighteen centres in France and Italy invited patients with BC who had at least one teleconsultation during the first wave of the COVID-19 pandemic to participate in a web-based survey that evaluated their satisfaction (EORTC OUT-PATSAT 35 and Telemedicine Satisfaction Questionnaire [TSQ] scores) with teleconsultation. RESULTS: Among the 1299 participants eligible for this analysis, 53% of participants were undergoing standard post-treatment follow-up while 22 and 17% were currently receiving active anticancer therapy for metastatic and localised cancers, respectively. The mean satisfaction scores were 77.4 and 73.3 for the EORTC OUT-PATSAT 35 and TSQ scores, respectively. In all, 52.6% of participants had low/no anxiety. Multivariable analysis showed that the EORTC OUT-PATSAT 35 score correlated to age, anxiety score and teleconsultation modality. The TSQ score correlated to disease status and anxiety score. CONCLUSION: Patients with BC were satisfied with oncology teleconsultations during the COVID-19 pandemic. Teleconsultation may be an acceptable alternative follow-up modality in specific circumstances.

Understanding occupational heat exposure in the United States and proposing a quantifying stress index.

PURPOSE: Millions of workers exposed to the outdoor environment are extremely susceptible to extreme heat. Although several articles analyzed heat-related illnesses, injuries, fatalities at the country level, few investigated regional and state statistics especially for OSHA Region 4 and the state of Alabama, U.S, which we explored in this study. METHODS: We studied the number of heat-days over 90 °F (32.2 °C) heat-index within our study area, analyzed heat-related injury and illnesses to calculate their incidence rate during 2015 to 2019, observed the nature of such incidents, their monthly occurrence, and incidence trend over average air temperature. We conducted a comparative analysis of heat-related fatalities between construction and all industries. The existing heat regulations by OSHA and some state agencies have also been summarized. RESULTS: We observed the highest mean, maximum heat-days and injury-illness rate in the south and southeast part of Region 4; increase in incidence rate from 0.03 in 2017 to 0.28 per 10,000 employees in 2018 for the contiguous U.S; highest injury-illness rate (HIR) in OSHA Region 1, 4 and 6; highest HIR in Lee, Montgomery, Mobile and Madison counties of Alabama; 34.7% (construction) and 31.3% (all industries) of all cases experiencing nonclassifiable heat-light effects; high fatalities in construction industry with a trend of 1 death/5 years; increased mortality in all occupations with 1 death/2.4 years. We also proposed a Heat-Stress Index (HSI) as a routine heat-stress measure on jobsite. CONCLUSION: The findings from this research and the proposed index can help in understanding heat-related risk at a regional level and implementing workplace interventions.

Agnostic Cys34-albumin adductomics and DNA methylation: Implication of N-acetylcysteine in lung carcinogenesis years before diagnosis.

Although smoking and oxidative stress are known contributors to lung carcinogenesis, their mechanisms of action remain poorly understood. To shed light into these mechanisms, we applied a novel approach using Cys34-adductomics in a lung cancer nested case-control study (n = 212). Adductomics profiles were integrated with DNA-methylation data at established smoking-related CpG sites measured in the same individuals. Our analysis identified 42 Cys34-albumin adducts, of which 2 were significantly differentially abundant in cases and controls: adduct of N-acetylcysteine (NAC, p = 4.15 × 10-3 ) and of cysteinyl-glycine (p = 7.89 × 10-3 ). Blood levels of the former were found associated to the methylation levels at 11 smoking-related CpG sites. We detect, for the first time in prospective blood samples, and irrespective of time to diagnosis, decreased levels of NAC adduct in lung cancer cases. Altogether, our results highlight the potential role of these adducts in the oxidative stress response contributing to lung carcinogenesis years before diagnosis.

Spectrofluorometric Method Development and Validation for the Determination of Curcumin in Nanoliposomes and Plasma.

In this paper, we have reported a rapid, simple, sensitive, straightforward, and validated method for the concentration determination of curcumin (CUR) in nanoliposomes and plasma using the spectrofluorimetry. For both nanoliposomal formulation and plasma, methanol was used as a solvent to extract the CUR. The excitation and emission wavelengths were set at 423 nm and 527 nm, respectively. The method validation was performed based on International Council for Harmonization (ICH) guidelines, Q2, in which parameters; such as, linearity, precision, accuracy and etc., were determined. The results showed that the calibration curve was linear for CUR concentrations of 0.05 to 0.5 µg /mL with a correlation coefficient of 0.9996. The limit of detection (LOD) and limit of quantification (LOQ) were 0.03 and 0.10 µg/mL, respectively. Liposomal CUR (15 mg/kg) was injected intravenously to mice, and at certain time intervals (1, 3, 6, and 24 h), blood samples were collected. The samples were extracted by methanol and CUR concentrations were detected using a fluorescence spectrophotometer. Results indicated the rate of liposomal formulation decline was slower than free CUR. The results of this study indicated that the validation method based on fluorimetry which was developed here is reliable for the detection of CUR in liposomal formulations and plasma.

Does timing in ICSI cycle affect oocyte quality and reproductive outcomes? A prospective study.

PURPOSE: To evaluate the association of time intervals between various steps of the intracytoplasmic sperm injection (ICSI) cycle with oocyte quality and reproductive outcomes. METHODS: We conducted a prospective study among patients undergoing ICSI cycles in an academic hospital between May 2017 and January 2019. The time intervals between the various steps of cycles were recorded. The ICSI cycles were categorized according to the different time intervals; human chorionic gonadotropin (hCG) injection to oocyte pick up (hCG-OPU) (≤ 36 h and > 36 h), OPU-denudation (≤ 2 h and > 2 h), and denudation-ICSI (≤ 2 h and > 2 h). The main outcome measures were oocyte dysmorphisms, fertilization, cleavage, biochemical, and clinical pregnancy rates. RESULTS: A total of 613 ICSI cycles using fresh autologous oocytes were included in this study. After adjusting for confounders, the hCG-OPU interval was associated with the presence of cytoplasmic granulation, inclusion body, and also the total number of morphologically abnormal premature oocytes in the cycle (P = 0.02, P = 0.04, P = 0.008, respectively). OPU-denudation interval was associated with cytoplasmic granulation and extended perivitelline space of the oocytes (P = 0.006 and P = 0.03, respectively). The denudation-ICSI interval was only associated with cytoplasmic granulation (P = 0.01). However, hCG-OPU, OPU-denudation, and denudation-ICSI intervals were not significantly associated with fertilization, cleavage, biochemical, and clinical pregnancy rates. CONCLUSIONS: All the studied time intervals between various steps of ICSI procedure could affect oocyte quality, but the oocyte dysmorphisms were mainly associated with hCG-OPU interval. However, the time intervals were not associated with fertilization, cleavage, and pregnancy outcomes.

Correction to: Does timing in ICSI cycle affect oocyte quality and reproductive outcomes? A prospective study.

In the original article published, the values given in the variables are incorrect.

Candidate antigenic epitopes for vaccination and diagnosis strategies of Toxoplasma gondii infection: A review.

Toxoplasmosis caused by an obligatory intracellular protozoan parasite of Toxoplasma gondii threats a wide spectrum of human and animal hosts. It has been shown that the intensity of the disease in humans depends on the host's immune responses. Immunological investigations on whole protein molecules of T. gondii have shown that these antigens are not fully responsible for the immune response, which leads to a decrease in specificity and affinity of the antigen (epitope)-antibody (paratope) binding. Currently, epitopes have shown promising entities to stimulate B, T, cytotoxic T lymphocyte, and NK cells resulting in enhancement of protective immunity against toxoplasmosis patients. Thus, the accurate designing, prediction, and conducting of antigenic epitopes of T. gondii (with linear and/or spatial structures (can augment our understanding about development of new serological diagnostic kits and vaccines. The current review provides an update on the latest advances of current epitopes described against toxoplasmosis including B cell/T cell epitopes, antigen types, parasite strains, epitope sequences, assay settings (in vitro and/or in vivo), and target strategy. Present results disclosed that the designing of effective multiepitopes of T. gondii by in silico modeling and immunoinformatics tools can strengthen our knowledge about triggering of epitope-based vaccine/diagnosis strategies in future perspectives.

RITA induces apoptosis in p53-null K562 leukemia cells by inhibiting STAT5, Akt, and NF-κB signaling pathways.

Targeting oncogenic signaling pathways by small molecules has emerged as a potential treatment strategy for cancer. reactivation of p53 and induction of tumor cell apoptosis (RITA) is a promising anticancer small molecule that reactivates p53 and induces exclusive apoptosis in tumor cells. Less well appreciated was the possible effect of small molecule RITA on p53-null leukemia cells. In this study, we demonstrated that RITA has potent antileukemic properties against p53-null chronic myeloid leukemia (CML)-derived K562 cells. RITA triggered apoptosis through caspase-9 and caspase-3 activation and poly (ADP-ribose) polymerase cleavage. RITA decreased STAT5 tyrosine phosphorylation, although it did not inhibit phosphorylation of the direct BCR-ABL substrate CrkL. Real-time PCR analysis showed that RITA downregulates antiapoptotic STAT5 target genes Bcl-xL and MCL-1. The downregulation of nuclear factor-κB (NF-κB), as evidenced by inhibition of IκB-α phosphorylation and its degradation, was associated with inhibition of Akt phosphorylation in RITA-treated cells. Furthermore, consistent with the decrease of mRNA levels, protein levels of the nuclear factor-κB-regulated antiapoptotic (cIAP1, XIAP, and Bcl-2) and proliferative (c-Myc) genes were downregulated by RITA in K562 cells. In conclusion, the ability of RITA to inhibit prosurvival signaling pathways in CML cells suggests a potential application of RITA in CML therapeutic protocols.

Allostatic load and subsequent all-cause mortality: which biological markers drive the relationship? Findings from a UK birth cohort.

The concept of allostatic load (AL) refers to the idea of a global physiological 'wear and tear' resulting from the adaptation to the environment through the stress response systems over the life span. The link between socioeconomic position (SEP) and mortality has now been established, and there is evidence that AL may capture the link between SEP and mortality. In order to quantitatively assess the role of AL on mortality, we use data from the 1958 British birth cohort including eleven year mortality in 8,113 adults. Specifically, we interrogate the hypothesis of a cumulative biological risk (allostatic load) reflecting 4 physiological systems potentially predicting future risk of death (N = 132). AL was defined using 14 biomarkers assayed in blood from a biosample collected at 44 years of age. Cox proportional hazard regression analysis revealed that higher allostatic load at 44 years old was a significant predictor of mortality 11 years later [HR = 3.56 (2.3 to 5.53)]. We found that this relationship was not solely related to early-life SEP, adverse childhood experiences and young adulthood health status, behaviours and SEP [HR = 2.57 (1.59 to 4.15)]. Regarding the ability of each physiological system and biomarkers to predict future death, our results suggest that the cumulative measure was advantageous compared to evaluating each physiological system sub-score and biomarker separately. Our findings add some evidence of a biological embodiment in response to stress which ultimately affects mortality.

Design and development of vitamin C-encapsulated proliposome with improved in-vitro and ex-vivo antioxidant efficacy.

Vitamin C, as an antioxidant additive in pharmaceutical and food products, is susceptible to environmental conditions, and new design strategies are needed to enhance its stability. The aim of this study is to prepare vitamin C proliposome using film deposition on the carrier by applying different factors, and optimise the characteristics of the obtained powder using the design expert® software. The optimised formulation demonstrated acceptable flowability with 20% vitamin C loading. This formulation released about 90% vitamin C within 2 h and showed higher (1.7-fold) in-vitro antioxidant activity. Ex-vivo antioxidant activity was 1.9 and 1.6 times higher in brain and liver cells, respectively. A 27% reduction in malondialdehyde (MDA) level of liver cell was obtained comparing free vitamin C. Therefore, this study results suggest that the vitamin C-encapsulated proliposome powder might be an appropriate carrier for oral drug delivery of vitamin C with better antioxidant efficacy.

Intradepartment scientific collaboration in Journal of Research in Medical Sciences: A co-authorship study.

BACKGROUND: This study aimed to use social network analysis (SNA) indicators and clique analysis to investigate collaboration between different departments and research centers in Journal of Research in Medical Sciences (JRMS) in 2012-2016. MATERIALS AND METHODS: The study was a scientometric study using micro- and macro-indicators of SNA to investigate the performance of departments and research centers in JRMS. The population consisted of 1073 articles published in JRMS in 2012-2016. Ravar Matrix, UCINET, and VOSviewer software were used for data analysis. RESULTS: According to the productivity and triple centrality indicators, "Department of Epidemiology and Biostatistics," "Department of Pathology," and Department of "Internal Medicine" allocated the first three ranks. Analyzing the cliques of co-authorship network for departments and research centers showed that this network consists of 19 cliques with at least 7 members in each clique. Furthermore, only 30 nodes (8.90% of all nodes in the network) had the presence in minimum clique size of at least 7. CONCLUSION: Given the importance and position of scientific collaboration in medical research and its effect on other performance indicators such as efficiency, effectiveness, and number of citations, it is necessary for policy-makers to propose new strategies for improving scientific collaboration.