SFRP4 promotes autophagy and blunts FSH responsiveness through inhibition of AKT signaling in ovarian granulosa cells.

BACKGROUND: Secreted frizzled-related proteins (SFRPs) comprise a family of WNT signaling antagonists whose roles in the ovary are poorly understood. Sfrp4-null mice were previously found to be hyperfertile due to an enhanced granulosa cell response to gonadotropins, leading to decreased antral follicle atresia and enhanced ovulation rates. The present study aimed to elucidate the mechanisms whereby SFRP4 antagonizes FSH action. METHODS: Primary cultures of granulosa cells from wild-type mice were treated with FSH and/or SFRP4, and effects of treatment on gene expression were evaluated by RT-qPCR and RNAseq. Bioinformatic analyses were conducted to analyse the effects of SFRP4 on the transcriptome, and compare them to those of FSH or a constitutively active mutant of FOXO1. Additional granulosa cell cultures from wild-type or Sfrp4-null mice, some pretreated with pharmacologic inhibitors of specific signaling effectors, were used to examine the effects of FSH and/or SFRP4 on signaling pathways, autophagy and apoptosis by western blotting and TUNEL. RESULTS: Treatment of cultured granulosa cells with recombinant SFRP4 was found to decrease basal and FSH-stimulated mRNA levels of FSH target genes. Unexpectedly, this effect was found to occur neither via a canonical (CTNNB1-dependent) nor non-canonical WNT signaling mechanism, but was found to be GSK3ß-dependent. Rather, SFRP4 was found to antognize AKT activity via a mechanism involving AMPK. This lead to the hypophosphorylation of FOXO1 and a decrease in the expression of a portion of the FSH and FOXO1 transcriptomes. Conversely, FSH-stimulated AMPK, AKT and FOXO1 phosphorylation levels were found to be increased in the granulosa cells of Sfrp4-null mice relative to wild-type controls. SFRP4 treatement of granulosa cells also induced autophagy by signaling via AKT-mTORC1-ULK1, as well as apoptosis. CONCLUSIONS: This study identifies a novel GSK3ß-AMPK-AKT signaling mechanism through which SFPR4 antagonizes FSH action, and further identifies SFRP4 as a novel regulator of granulosa cell autophagy. These findings provide a mechanistic basis for the phenotypic changes previously observed in Sfrp4-null mice, and broaden our understanding of the physiological roles of WNT signaling processes in the ovary.

Cross-cultural adaptation and validation of Leicester Cough Questionnaire in sarcoidosis: the persian version.

BACKGROUND AND AIM: Cough is a common symptom among patients with sarcoidosis, and the Leicester Cough Questionnaire, a cough-specific quality-of-life measure, evaluates the impact of cough across physical, psychological, and social domains in patients with chronic cough. The aim of this study was cross-cultural adaptation and validation of Persian version of Leicester Cough Questionnaire (LCQ) in pulmonary sarcoidosis in Iran. METHODS: Psychometric analyses included translation and back translation of the questionnaire, face validity, content validity, construct validity, criterion-related validity, internal consistency, and test -retest reliability were performed. RESULTS: Twenty-five participants demonstrated no major language barriers or difficulties in completing the questionnaire and adequate face validity of ≥1.5. Twelve experts confirmed the content validity was good (CVR˃0.56, I-CVI≤0.79, S-CVI/Ave˃0.80). Totally, 190 patients were included in the study. The Pearson's coefficients and their significance's (P<0.05) showed an acceptable agreement between the LCQ and the SF-36 questionnaire. The goodness-of-fit of the conceptual model including psychological, physical, and social domains, obtained from EFA, was confirmed throughout the RMSEA of 0.09 (<0.1), NFI of 0.9, NNFI of 0.91, and CFI of 0.92 which all were ≥0.9. The Persian LCQ showed an excellent internal consistency regarding Cronbach's alpha of 0.974 and ICC (95%CI) value of 0.983 (0.977, 0.987). CONCLUSIONS: The psychometric properties showed that the Persian version of LCQ is a valid and reliable measure to evaluate cough-specific quality of life and is a fit-for-purpose measure for use in patients with pulmonary sarcoidosis and the results can guide clinicians in treatment decisions.

Efficacy and safety of a proposed omalizumab biosimilar compared to the reference product in the management of uncontrolled moderate-to-severe allergic asthma: a multicenter, phase III, randomized, double-blind, equivalency clinical trial.

Background and aims: Allergic asthma has a considerable burden on the quality of life. A significant portion of moderate-to-severe allergic asthma patients need omalizumab, an anti-immunoglobulin-E monoclonal antibody, as an add-on therapy. In this phase III clinical trial P043 (Zerafil®, CinnaGen, Iran) efficacy, safety, and immunogenicity were compared with Xolair® (the originator omalizumab). The primary outcome was the rate of protocol-defined asthma exacerbations. Methods: Exacerbation rates, Asthma Control Test (ACT) results, spirometry measurements, immunogenicity, and safety were evaluated. Each subject received either medication with a dose ranging from 150 to 375 mg based on pre-treatment serum total IgE level (IU/mL) and body weight (kg) every two or four weeks for a duration of 28 weeks. Results: Exacerbation rates were 0.150 (CI: 0.079-0.220) in the P043 group, and 0.190 (CI: 0.110-0.270) in the omalizumab group (per-protocol). The least squares mean differences of predicted Forced Expiratory Volume in the First second (FEV1) were -2.51% (CI: -7.17-2.15, P=0.29) and -3.87% (CI: -8.79-1.04, P=0.12), pre- and post-bronchodilator use. The mean ± SD of ACT scores at the screening and the last visit were 10.62 ± 2.93 and 20.93 ± 4.26 in P043 and 11.09 ± 2.75 and 20.46 ± 5.11 in the omalizumab group. A total of 288 adverse events were reported for the 256 enrolled participants. Among all, "dyspnea" and "headache" were the most reported ones. The overall incidence of adverse events (P=0.62) and serious adverse events (P=0.07) had no significant differences between the two groups. None of the samples were positive for anti-drug antibodies. Conclusion: P043 was equivalent to omalizumab in the management of asthma in reduction of exacerbations. There was no significant difference in other efficacy and safety parameters. Clinical trial registration: www.clinicaltrials.gov (NCT05813470) and www.IRCT.ir (IRCT20150303021315N20).

Evaluation of the Tracheal Stenosis Effects on Airway Resistance and Work of Breathing Using Computational Fluid Dynamics.

Background: Bronchoscopy is one of the most accurate procedures to diagnose airway stenosis which is an invasive procedure. However, a quick and noninvasive estimation of the percent area of obstruction (%AO) of the lumen is helpful in decision-making before performing a bronchoscopy procedure. We hypothesized that there is a relationship between %AO and tracheal resistance against fluid flow. Materials and Methods: By measuring airway resistance, %AO could be estimated before the procedure. Using computational fluid dynamics (CFD), this study simulates the fluid flow through trachea models with web-liked stenosis using CFD. A cylindrical segment was inserted into the trachea to represent cross-sectional areas corresponding to 20%, 40%, 60%, and 80% AO. The fluid flow and pressure distribution in these models were studied. Our CFD simulations revealed that the tracheal resistance is exponentially increased by %AO. Results: The results showed a 130% and 55% increase in lung airway resistance and resistive work of breathing for an 80% AO, respectively. Moreover, a curve-fitted relationship was obtained to estimate %AO based on the measured airway resistance by body plethysmography or forced oscillation technique. Conclusion: This pre-estimation is very useful in diagnostic evaluation and treatment planning in patients with tracheal stenosis.

Impact of Using Educational Multimedia on Knowledge, Skill, and Reduction of Medical Error Following Bronchoscopy.

Background: Achieving procedural skills is one of the pillars of health higher education which is in line with the social responsibility of medical education. Since it is not possible to encounter important cases in bronchoscopy during the training course, the common cases that the students encounter in their future work environment were prepared as an educational video. Therefore, the purpose of this study was to find out the impact of using bronchoscopy educational video intervention on medical assistants' knowledge, skill, and medical error comparing it with the traditional method at Dr. Masih Daneshvari Hospital. Materials and Methods: In this experimental study, two groups were randomly assigned: the experimental and the control. Each one consists of 15 participants. The first group used mannequins (traditional method) and the second used multimedia as the experimental group. Both groups were evaluated by pre and post-tests. Multiple choices (MCQs) were given to evaluate the knowledge and a checklist for skills. A comparison of the impact of intervention before and after education in both groups was statistically analyzed using the independent t-test. Results: There were statistically significant differences between the experimental group and the control group at a significance level of 0.042 for the skill. An average increase of 3 points was observed in the experiment group, while the control group increased by 1.4 points. No significant difference was seen for knowledge. The number of patients with pneumothorax was also decreased. Conclusion: Results showed that the multimedia training method effectively promotes the assistants' skills and reduces medical errors following bronchoscopy Administration. It is recommended to use educational videos (multimedia) to improve assistants' skills. It is suggested to apply the new model of education rather than sticking to the traditional one.

Investigating the Coronavirus Disease 2019 Process and its Related Occurrences during the Treatment Course.

Background: The disease process involves the occurrences happening during the disease and treatment course for the patient. Investigating this process is a significant and necessary issue for all diseases, including coronavirus disease 2019 (COVID-19). Materials and Methods: Using the information of 4372 patients with COVID-19 referring to Dr. Masih Daneshvari Hospital in Tehran during the COVID-19 epidemic, being hospitalized, cared for, and home quarantined due to having mild symptoms, the COVID-19 process and its related occurrences were investigated during the treatment course. Results: In the COVID-19 course, considering the disease severity, the likelihood of hospitalization in the general ward or the intensive care unit (ICU) ward, the likelihood of isolation or home quarantine, and the likelihood of occurrences such as recovery or death at the end of the disease course were taken into consideration. Based on the results of this study, the likelihood of hospitalization in the general ward, the ICU ward, and isolation or home quarantine was determined to be approximately 49.54%, 14.73%, and 35.73%, respectively. Also, for patients hospitalized in the general ward, the ICU ward, and isolated or home quarantined, the likelihood of recovery was estimated at approximately 64.79%, 10.82%, and 96.31%, respectively, and the likelihood of death was also estimated at about 35.21%, 89.18%, and 3.69% respectively. Conclusion: Investigating the COVID-19 process and estimating the likelihood of incidence of its related occurrences during the treatment course both create an accurate prognosis and provide the possibility of achieving an efficient treatment for these patients.

Trends in Epidemiology and Outcome of Small Cell Lung Cancer over 10 Years at Tertiary Cancer Care Center in Iran.

Background: Lung cancer is the leading cause of cancer death. Among different lung cancer histopathologies, small cell lung cancer (SCLC) has been known to be the most aggressive and lethal nature. This study analyzed the epidemiological characteristics, outcomes, and trends of SCLC at a tertiary cancer care center in Iran. Materials and Methods: Retrospectively collected demographic characteristics and survival outcome data on histologically proven SCLC patients during 2009-2019 at the National Research Institute of Tuberculosis and Lung Disease (NRITLD) were reviewed. Results: In a study of 334 SCLC patients, there were more male patients than female, with a ratio of 2.5 to 1, and the mean age at diagnosis was 58.36 years. While gender distribution and smoking status among women remained consistent over the study period, there was a significant increase in male smokers (P<0.001). Female patients were diagnosed at younger age and had a significantly lower proportion of smokers compared to males (P<0.016). The mean and median overall survival were 10.9 and 8.2 months, with one-, two-, and three-year survival rates of 21%, 10%, and 3% respectively. Younger patients and females had significantly higher survival rates. In both uni/multivariate analyses, only age < 58 years and female gender were significantly associated with longer survival. Conclusion: The relatively unchanged trend of SCLC in our series suggests that further research on prevention strategies especially smoking cessation, early detection, and new treatment options is urgently required.