Post-transcriptional regulation of BIRC5/survivin expression and induction of apoptosis in breast cancer cells by tristetraprolin.

Inhibition of apoptosis is one of the hallmarks of cancer and is a target of various therapeutic interventions. BIRC5 is an inhibitor of apoptosis that is aberrantly expressed in cancer leading to sustained growth of tumours. Post-transcriptional control mechanisms involving RNA-binding proteins and AU-rich elements (AREs) are fundamental to many cellular processes and changes in the expression or function of these proteins can promote an aberrant and pathological phenotype. BIRC5 mRNA has an ARE in its 3' UTR making it a candidate for regulation by the RNA binding proteins tristetraprolin (TTP) and HuR (ELAVL1). In this study, we investigated the binding of TTP and HuR by RNA-immunoprecipitation assays and found that these proteins were associated with BIRC5 mRNA to varying extents. Consequently, BIRC5 expression decreased when TTP was overexpressed and apoptosis was induced. In the absence of TTP, BIRC5 mRNA was stabilized, protein expression increased and the number of apoptotic cells declined. As an ARE-mRNA stabilizing protein, recombinant HuR led to upregulation of BIRC5 expression, whereas HuR silencing was concomitant with downregulation of BIRC5 mRNA and protein and increased cell death. Survival analyses demonstrated that increased TTP and low BIRC5 expression predicted an overall better prognosis compared to dysregulated TTP and high BIRC5. Thus, the results present a novel target of ARE-mediated post-transcriptional regulation.

Extent of exposure to scented candles and prevalence of respiratory and non-respiratory symptoms amongst young university students.

BACKGROUND: Incense burning such as scented candles are commonly used in Arabian Gulf regions as it is thought to produce relaxing effects on people's mood. This study is conducted to examine the prevalence of scented candles' usage, extent of exposure and its effects on individuals' health based on symptoms prevalence in young university students. MATERIAL AND METHOD: A cross-sectional study was conducted on university students from different regions in Saudi Arabia. Data was collected in March 2020 using an online questionnaire survey adapted from The European Community Respiratory Health Survey-II (ECRHS-II). Inclusion criterion for recruitment was students with non-smoking status. Descriptive statistics were used to report demographic data on the extent of exposure to scented candles (in terms of frequency and duration) and the presence of symptoms. Multiple logistic regression analysis was used to assess the relationship between scented candles exposure and respiratory and other health-related problems. RESULTS: The prevalence of scented candles usage was 65.7% (472/718) among the respondents. However, its pervasiveness was significantly higher in females than in male respondents (74.9% vs. 28.4%; p = 0.0001). Among the scented candle users, 34.8% of the respondents used the scented candles more than 4 times a month and 40.2% of the respondents lit the scented candles for 20-40 min. A total of 117 (24.8%) respondents reported health-related problem and the top three health problems were headache 72 (15.2%), shortness of breath 42 (8.9%) and cough 37 (7.8%). The scented candle usage 5-6 times a week showed significantly lower wheezing (OR = 0.10, 95%CI 0.02-0.54, p = 0.008). The duration of more than 60 min of scented candle exposure showed higher occurrence of headache 1.42 times (95% CI = 0.68-2.96), sneezing 1.29 times (95% CI = 0.42-4.00) and wheezing 1.23 times (95% CI = 0.48-3.13), though the association was not significant. CONCLUSION: The results show that scented candle usage is more prevalent among female university students in Saudi Arabia. The common health-related problems associated with scented candle exposure were headache, shortness of breath and coughing.

Changes in the patterns of respiratory support and incidence of bronchopulmonary dysplasia; a single center experience.

BACKGROUND: With the advances in neonatal intensive care, the survival rate of extremely preterm infants is increasing. However, bronchopulmonary dysplasia (BPD) remains a major cause of morbidity among infants in this group. This study examined the changes in respiratory support modalities, specifically heated humidified high-flow nasal cannula (HHHFNC), and their association with BPD incidence among preterm infants born at < 29 weeks of gestation. METHOD: This population-based retrospective cohort study included infants born at < 29 weeks of gestation between 2016 and 2020. Data regarding the use and duration of respiratory support modalities were obtained, including mechanical ventilation, continuous positive airway pressure, HHHFNC, and low-flow oxygen therapy. Additionally, the incidence of BPD was determined in the included infants. Trend analysis for each respiratory support modality and BPD incidence rate was performed to define the temporal changes associated with changes in BPD rates. In addition, a logistic regression model was developed to identify the association between BPD and severity grade using HHHFNC. RESULTS: Three Hundred and sixteen infants were included in this study. The use and duration of HHHFNC therapy increased during the study period. Throughout the study period, the overall incidence of BPD was 49%, with no significant trends. The BPD rate was significantly higher in the infants who received HHHFNC than in those who did not (52% vs. 39%, P = 0.03). Analysis of BPD severity grades showed that both grade 1 BPD (34% vs. 21%, P = 0.03) and grade 2 BPD (12% vs. 1%, P < 0.01) were significantly more common among infants who received HHHFNC than among those who did not. In contrast, the incidence of grade 3 BPD was lower in infants who received HHFNC (6% vs. 17%, P < 0.01). The duration in days of HHHFNC was found to significantly predict BPD incidence (OR 1.04 [95%CI: 1.01-1.06], P < 0.01) after adjusting for confounding variables. CONCLUSION: The use of HHHFNC in extremely preterm infants born at < 29 weeks of gestation is increasing. There was a significant association between the duration of HHHFNC therapy and the development of BPD in extremely preterm infants born at < 29 weeks of gestation.

Elevated level of creatine phosphokinase in newborn: Clinical significance and association with congenital muscle diseases.

OBJECTIVES: To establish the normal Creatine phosphokinase (CPK) range in newborns of all 3 modes of delivery and prove that high CPK level in neonates is not specific a indicator for muscular pathology. METHODS: This is a prospective cohort study that is conducted in King Abdulaziz Medical City and King Abdullah Specialized Children Hospital in Riyadh and included 504 term neonates who were born between March 2021 and August 2021. Two hundred and fifty three were males and 251 were females. Data and consents were managed and collected using 2 coordinators. RESULTS: Duration of the second stage of labor, age on the first CPK test and fetal gestational age were significantly correlated with CPK values (r=0.197, r=-0.234, r=0.274, respectively). The normal ranges for each delivery type were 334 U/L-2667U/L in normal spontaneous vaginal delivery, 265U/L-1182U/L in elective cesarean section, and 223U/L-3082 U/L in emergency cesarean section. CONCLUSION: The CPK was elevated in all neonates in all 3 modes of deliveries. An elevated levels of CPK in neonates is not a specific indicator for any congenital muscular pathology.

The effects of non-pharmaceutical interventions on SARS-CoV-2 transmission in different socioeconomic populations in Kuwait: a modeling study.

BACKGROUND: Aggressive non-pharmaceutical interventions (NPIs) may reduce transmission of SARS-CoV-2. The extent to which these interventions are successful in stopping the spread have not been characterized in countries with distinct socioeconomic groups. We compared the effects of a partial lockdown on disease transmission among Kuwaitis (P1) and non-Kuwaitis (P2) living in Kuwait. METHODS: We fit a modified metapopulation SEIR transmission model to reported cases stratified by two groups to estimate the impact of a partial lockdown on the effective reproduction number ([Formula: see text]). We estimated the basic reproduction number ([Formula: see text]) for the transmission in each group and simulated the potential trajectories of an outbreak from the first recorded case of community transmission until 12 days after the partial lockdown. We estimated [Formula: see text] values of both groups before and after the partial curfew, simulated the effect of these values on the epidemic curves and explored a range of cross-transmission scenarios. RESULTS: We estimate [Formula: see text] at 1·08 (95% CI: 1·00-1·26) for P1 and 2·36 (2·03-2·71) for P2. On March 22nd, [Formula: see text] for P1 and P2 are estimated at 1·19 (1·04-1·34) and 1·75 (1·26-2·11) respectively. After the partial curfew had taken effect, [Formula: see text] for P1 dropped modestly to 1·05 (0·82-1·26) but almost doubled for P2 to 2·89 (2·30-3·70). Our simulated epidemic trajectories show that the partial curfew measure greatly reduced and delayed the height of the peak in P1, yet significantly elevated and hastened the peak in P2. Modest cross-transmission between P1 and P2 greatly elevated the height of the peak in P1 and brought it forward in time closer to the peak of P2. CONCLUSION: Our results indicate and quantify how the same lockdown intervention can accentuate disease transmission in some subpopulations while potentially controlling it in others. Any such control may further become compromised in the presence of cross-transmission between subpopulations. Future interventions and policies need to be sensitive to socioeconomic and health disparities.

Clinical and functional significance of tumor/stromal ATR expression in breast cancer patients.

BACKGROUND: Most breast cancer-associated fibroblasts (CAFs) are active and important cancer-promoting cells, with significant impact on patient prognosis. Therefore, we investigated here the role of the protein kinase ATR in breast stromal fibroblasts in the prognosis of locally advanced breast cancer patients. METHODS: We have used immunohistochemistry to assess the level of ATR in breast cancer tissues and their adjacent normal tissues. Immunoblotting as well as quantitative RT-PCR were utilized to show the role of breast cancer cells and IL-6 as well as AUF-1 in downregulating ATR in breast stromal fibroblasts. Engineered human breast tissue model was also used to show that ATR-deficient breast stromal fibroblasts enhance the growth of breast cancer cells. RESULTS: We have shown that the protein kinase ATR is downregulated in cancer cells and their neighboring CAFs in breast cancer tissues as compared to their respective adjacent normal tissues. The implication of cancer cells in ATR knockdown in CAFs has been proven in vitro by showing that breast cancer cells downregulate ATR in breast fibroblasts in an IL-6/STAT3-dependent manner and via AUF-1. In another cohort of 103 tumors from locally advanced breast cancer patients, we have shown that absence or reduced ATR expression in tumoral cells and their adjacent stromal fibroblasts is correlated with poor overall survival as well as disease-free survival. Furthermore, ATR expression in CAFs was inversely correlated with tumor recurrence and progression. CONCLUSION: ATR downregulation in breast CAFs is frequent, procarcinogenic, and correlated with poor patient survival.

Reduction of severe intraventricular hemorrhage, a tertiary single-center experience: incidence trends, associated risk factors, and hospital policy.

OBJECTIVES: To determine the incidence, trends, maternal and neonatal risk factors of severe intraventricular hemorrhage (IVH) among infants born 24-32 weeks and/or < 1500 g, and to evaluate the impact of changing of hospital policies and unit clinical practice on the IVH incidence. STUDY DESIGN: Retrospective chart review of preterm infants with a gestational age (GA) of 24-326 weeks and/or weight of < 1500 g born at King Abdulaziz Medical City-Riyadh (KAMC-R), Saudi Arabia, from 2016 to 2018. Multivariate logistic regression model was constructed to determine the probability of developing severe IVH and identify associations with maternal and neonatal risk factors. RESULTS: Among 640 infants, the overall incidence of severe IVH was 6.4% (41 infants), and its rate decreased significantly, from 9.4% in 2016 to 4.5% and 5% in 2017 and 2018 (p = 0.044). Multivariate analysis revealed that caesarian section delivery decreased the risk of severe IVH in GA group 24-27 weeks (p = 0.045). Furthermore use of inotropes (p = 0.0004) and surfactant (p = 0.0003) increased the risk of severe IVH. Despite increasing use of inotropes (p = 0.024), surfactant therapy (p = 0.034), and need for delivery room intubation (p = 0.015), there was a significant reduction in the incidence of severe IVH following the change in unit clinical practice and hospital policy (p = 0.007). CONCLUSION: Cesarean section was associated with decreased all grades of IVH and severe IVH, while use of inotropes was associated with increased severe IVH. The changes in hospital and unit policy were correlated with decreased IVH during the study period.

Gene therapy of hematological disorders: current challenges.

Recent advances in genetic engineering technology and stem cell biology have spurred great interest in developing gene therapies for hereditary, as well as acquired hematological disorders. Currently, hematopoietic stem cell transplantation is used to cure disorders such as hemoglobinopathies and primary immunodeficiencies; however, this method is limited by the availability of immune-matched donors. Using autologous cells coupled with genome editing bypasses this limitation and therefore became the focus of many research groups aiming to develop efficient and safe genomic modification. Hence, gene therapy research has witnessed a noticeable growth in recent years with numerous successful achievements; however, several challenges have to be overcome before gene therapy becomes widely available for patients. In this review, I discuss tools used in gene therapy for hematological disorders, choices of target cells, and delivery vehicles with emphasis on current hurdles and attempts to solve them, and present examples of successful clinical trials to give a glimpse of current progress.

An atypical pulmonary fibrosis is associated with co-inheritance of mutations in the calcium binding protein genes S100A3 and S100A13.

BACKGROUND: Pulmonary fibrosis is one of the leading indications for lung transplantation. The disease, which is of unknown aetiology, can be progressive, resulting in distortion of the extracellular matrix (ECM), inflammation, fibrosis and eventual death. METHODS: 13 patients born to consanguineous parents from two unrelated families presenting with interstitial lung disease were clinically investigated. Nine patients developed respiratory failure and subsequently died. Molecular genetic investigations were performed on patients' whole blood or archived tissues, and cell biological investigations were performed on patient-derived fibroblasts. RESULTS: The combination of a unique pattern of early-onset lung fibrosis (at 12-15 years old) with distinctive radiological findings, including 1) traction bronchiectasis, 2) intralobular septal thickening, 3) shrinkage of the secondary pulmonary lobules mainly around the bronchovascular bundles and 4) early type 2 respiratory failure (elevated blood carbon dioxide levels), represents a novel clinical subtype of familial pulmonary fibrosis. Molecular genetic investigation of families revealed a hypomorphic variant in S100A3 and a novel truncating mutation in S100A13, both segregating with the disease in an autosomal recessive manner. Family members that were either heterozygous carriers or wild-type normal for both variants were unaffected. Analysis of patient-derived fibroblasts demonstrated significantly reduced S100A3 and S100A13 expression. Further analysis demonstrated aberrant intracellular calcium homeostasis, mitochondrial dysregulation and differential expression of ECM components. CONCLUSION: Our data demonstrate that digenic inheritance of mutations in S100A3 and S100A13 underlie the pathophysiology of pulmonary fibrosis associated with a significant reduction of both proteins, which suggests a calcium-dependent therapeutic approach for management of the disease.

Differences in Stability, Activity and Mutation Effects Between Human and Mouse Leucine-Rich Repeat Kinase 2.

Mutations in the Leucine-rich repeat kinase 2 (LRRK2) gene have been implicated in the pathogenesis of Parkinson's disease (PD). Identification of PD-associated LRRK2 mutations has led to the development of novel animal models, primarily in mice. However, the characteristics of human LRRK2 and mouse Lrrk2 protein have not previously been directly compared. Here we show that proteins from different species have different biochemical properties, with the mouse protein being more stable but having significantly lower kinase activity compared to the human orthologue. In examining the effects of PD-associated mutations and risk factors on protein function, we found that conserved substitutions such as G2019S affect human and mouse LRRK2 proteins similarly, but variation around position 2385, which is not fully conserved between humans and mice, induces divergent in vitro behavior. Overall our results indicate that structural differences between human and mouse LRRK2 are likely responsible for the different properties we have observed for these two species of LRRK2 protein. These results have implications for disease modelling of LRRK2 mutations in mice and on the testing of pharmacological therapies in animals.