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THE EPIGENETIC CHANGES ASSOCIATED WITH ACUTE AND CHRONIC EXPOSURE TO CIGARETTE AND WATERPIPE SMOKE EXTRACTS ON A COLON CANCER CELL LINE
No full textIntroduction
Tobacco smoking is a major public health issue worldwide, and it has been linked to various health risks, including colon cancer. While the link between cigarette smoking and colon cancer is well established, the extent to which waterpipe smoking causes phenotypic and molecular changes in colon cancer requires further investigation. Both cigarette and waterpipe smoking may promote colon cancer development and progression through different mechanisms, including epigenetic modulation, such as DNA methylation. The aim of this study is to identify the phenotypic effects and the underlying epigenetic mechanisms through which cigarette smoke (CSE) and waterpipe smoke (WPE) extracts affect the HCT116 colon cancer cell line.
Methods
MTT assay was initially conducted to determine the inhibitory concentrations leading to 20% and 50% cell cytotoxicity (IC20 and IC50, respectively) for both CSE and WPE. Subsequently, these concentrations were validated using the trypan blue assay. The cell line was then acutely exposed to IC20 and IC50 of CSE and WPE for 24 hours to study the genotoxic, cell cycle, and apoptosis phenotypic effects, using γH2Ax, PI, and annexin/PI staining assays, respectively, acquired by flow cytometry, as well as RNA expression of epithelial to mesenchymal transition (EMT) markers by RT-qPCR. Furthermore, scratch assay was conducted to investigate the effects of acute exposure on the migration process, but only with IC20. In addition, the HCT116 cells were chronically exposed to IC20 of CSE and WPE over 12 weeks followed by migration and EMT analysis. Whole methylome analysis will be conducted to assess alterations in DNA methylation upon acute and chronic exposures.
Results
Exposure to IC50 of CSE and WPE for 24 hours induced statistically significant genotoxic effects and apoptosis in HCT116 cells. However, there were no statistically significant differences in cell cycle and migration assays following acute exposure to both extracts, when compared to control. In the migration assay after chronic exposure, a decrease in the migration ability was observed with WPE, while an increase was observed with CSE. Analysis of EMT markers revealed that acute exposure to IC20 of WPE and CSE resulted in an increase in the mesenchymal markers SNAIL 1 and SNAIL2, along with a slight increase in CK7 epithelial marker. Chronic exposures resulted in a significant slight decrease in the CK7 epithelial marker and SNAIL 1 mesenchymal marker, and an evident increase in the mesenchymal marker Vimentin. Notably, whole Genome-wide DNA methylation analysis is currently in progress and its results are pending.
Conclusion
Our results indicate that CSE and WPE have pro-apoptotic and genotoxic effects on HCT116 cells. These effects are only observed at higher concentrations (IC50) and not at sub-cytotoxic concentrations (IC20). Moreover, both extracts appear to trigger the acquisition of mesenchymal characteristics in the cells. Furthermore, chronic exposure to IC20 of WPE and CSE showed differential effects on cell migration after 24hours.We hope to decipher epigenetically deregulated biological pathways that may underlie this smoking-induced progression
ELECTROSPUN PVC/MOFS-AG NANOCOMPOSITES AS EFFICIENT ANTIBACTERIAL MEMBRANES
No full textIn this study, electrospinning is employed to prepare composite membranes of polyvinylchloride (PVC) embedded with nanocrystals of post-metalated metal organic frameworks (MOFs), UiO-66(COOH)2-Ag, and ZIF-8-Ag. The composites were fully characterized using scanning electron microscopy (SEM), powder X-ray diffraction (PXRD), thermoGravimetric analysis (TGA), porosity analysis, and water contact angle measurement (WCA). The incorporation of the MOFs nanocrystals within the nano-fibrous PVC membranes by electrospinning resulted in the formation of a highly stable MOFs-membrane composite with a larger fiber diameter and greater average pore size compared to PVC. The antibacterial properties of the obtained membranes were investigated as a function of MOF-Ag loading. It showed an improved antibacterial activity (up to 95% inhibition) with the increased MOF-Ag loading when the silver concentration was kept constant which supports a contact-based inhibition. Those findings ensure that such membranes can act as a potential antibacterial air filters due to their nature
Infection with Helicobacter pylori may predispose to atherosclerosis: role of inflammation and thickening of intima-media of carotid arteries
Get PDFAtherosclerosis is a major instigator of cardiovascular disease (CVD) and a main cause of global morbidity and mortality. The high prevalence of CVD calls for urgent attention to possible preventive measures in order to curb its incidence. Traditional risk factors of atherosclerosis, like age, smoking, diabetes mellitus, dyslipidemia, hypertension and chronic inflammation, are under extensive investigation. However, these only account for around 50% of the etiology of atherosclerosis, mandating a search for different or overlooked risk factors. In this regard, chronic infections, by Helicobacter pylori for instance, are a primary candidate. H. pylori colonizes the gut and contributes to several gastrointestinal diseases, but, recently, the potential involvement of this bacterium in extra-gastric diseases including CVD has been under the spotlight. Indeed, H. pylori infection appears to stimulate foam cell formation as well as chronic immune responses that could upregulate key inflammatory mediators including cytokines, C-reactive protein, and lipoproteins. These factors are involved in the thickening of intima-media of carotid arteries (CIMT), a hallmark of atherosclerosis. Interestingly, H. pylori infection was found to increase (CIMT), which along with other evidence, could implicate H. pylori in the pathogenesis of atherosclerosis. Nevertheless, the involvement of H. pylori in CVD and atherosclerosis remains controversial as several studies report no connection between H. pylori and atherosclerosis. This review examines and critically discusses the evidence that argues for a potential role of this bacterium in atherogenesis. However, additional basic and clinical research studies are warranted to convincingly establish the association between H. pylori and atherosclerosis. Copyright © 2023 Aramouni, Assaf, Azar, Jabbour, Shaito, Sahebkar, Eid, Rizzo and Eid
Lebanese Intelligence Community Restructuring Project: Exploring a Smarter and Modernized Joint Operating Policy
No full textAmid a global trend of performance optimization focusing on public institutions, fueled by shortened budget financing and increased execution fiascos, Intelligence Communities near and far are undergoing restructuring, designed according to their respective countries’ specificities, in the aim of preserving their supreme interests.
This paper examines the Lebanese Intelligence apparatus through the lens of its policies for multidirectional coordination. This paper describes how this model is far from being functional, especially following a significant turning point in Lebanon’s recent history, taking into account the Beirut Port explosion and the persistent economic crisis. It is for this reason that the study analyzes how the interests of the politico-sectarian elites influence the communication flow between the four main operators in this arena, as well as the appointments of Intelligence personnel to key positions. The paper concludes that the existing operating model jeopardizes Lebanese National Security and inflate public budget expenses in the long term. Therefore, a reform proposal is suggested, and the different positions of stakeholders are presented. In this context, the study argues that a centralization reform policy is the most appropriate and equitable solution, despite the challenges of the complex politico-sectarian system. The paper proposes adopting the US Intelligence Community's operating model, which features one fusion cell harmonizing and compiling all other cells’ outcomes.
Finally, this paper highlights three different policy options, each with a comprehensive feasibility study in order to be adopted by policymakers in that regards. The paper concludes with recommendations for future research and acknowledging limitations of the current study
Lewis Structures and the Bonding Classification of End-on Bridging Dinitrogen Transition Metal Complexes
No full textThe activation of dinitrogen by coordination to transition metal ions is a widely used and promising approach to the utilization of Earth’s most abundant nitrogen source for chemical synthesis. End-on bridging N2 complexes (μ-η1:η1-N2) are key species in nitrogen fixation chemistry, but a lack of consensus on the seemingly simple task of assigning a Lewis structure for such complexes has prevented application of valence electron counting and other tools for understanding and predicting reactivity trends. The Lewis structures of bridging N2 complexes have traditionally been determined by comparing the experimentally observed NN distance to the bond lengths of free N2, diazene, and hydrazine. We introduce an alternative approach here and argue that the Lewis structure should be assigned based on the total π-bond order in the MNNM core (number of π-bonds), which derives from the character (bonding or antibonding) and occupancy of the delocalized π-symmetry molecular orbitals (π-MOs) in MNNM. To illustrate this approach, the complexes cis,cis-[(iPr4PONOP)MCl2]2(μ-N2) (M = W, Re, and Os) are examined in detail. Each complex is shown to have a different number of nitrogen-nitrogen and metal-nitrogen π-bonds, indicated as, respectively: W≡N-N≡W, Re═N═N═Re, and Os-N≡N-Os. It follows that each of these Lewis structures represents a distinct class of complexes (diazanyl, diazenyl, and dinitrogen, respectively), in which the μ-N2 ligand has a different electron donor number (total of 8e-, 6e-, or 4e-, respectively). We show how this classification can greatly aid in understanding and predicting the properties and reactivity patterns of μ-N2 complexes. © 2023 The Authors. Published by American Chemical Society
Predicting Major Adverse Cardiovascular Events Following Carotid Endarterectomy Using Machine Learning
Get PDFBACKGROUND: Carotid endarterectomy (CEA) is a major vascular operation for stroke prevention that carries significant perioperative risks; however, outcome prediction tools remain limited. The authors developed machine learning algorithms to predict outcomes following CEA. METHODS AND RESULTS: The National Surgical Quality Improvement Program targeted vascular database was used to identify patients who underwent CEA between 2011 and 2021. Input features included 36 preoperative demographic/clinical vari-ables. The primary outcome was 30-day major adverse cardiovascular events (composite of stroke, myocardial infarction, or death). The data were split into training (70%) and test (30%) sets. Using 10-fold cross-validation, 6 machine learning models were trained using preoperative features. The primary metric for evaluating model performance was area under the receiver operating characteristic curve. Model robustness was evaluated with calibration plot and Brier score. Overall, 38 853 patients underwent CEA during the study period. Thirty-day major adverse cardiovascular events occurred in 1683 (4.3%) patients. The best performing prediction model was XGBoost, achieving an area under the receiver operating characteristic curve of 0.91 (95% CI, 0.90–0.92). In comparison, logistic regression had an area under the receiver operating characteristic curve of 0.62 (95% CI, 0.60–0.64), and existing tools in the literature demonstrate area under the receiver operating characteristic curve values ranging from 0.58 to 0.74. The calibration plot showed good agreement between predicted and observed event probabilities with a Brier score of 0.02. The strongest predictive feature in our algorithm was carotid symptom status. CONCLUSIONS: The machine learning models accurately predicted 30-day outcomes following CEA using preoperative data and performed better than existing tools. They have potential for important utility in guiding risk-mitigation strategies to improve outcomes for patients being considered for CEA. © 2023 The Authors
Inflammasomes as biomarkers and therapeutic targets in traumatic brain injury and related-neurodegenerative diseases: A comprehensive overview
Get PDFGiven the ambiguity surrounding traumatic brain injury (TBI) pathophysiology and the lack of any Food and Drug Administration (FDA)-approved neurotherapeutic drugs, there is an increasing need to better understand the mechanisms of TBI. Recently, the roles of inflammasomes have been highlighted as both potential therapeutic targets and diagnostic markers in different neurodegenerative disorders. Indeed, inflammasome activation plays a pivotal function in the central nervous system (CNS) response to many neurological conditions, as well as to several neurodegenerative disorders, specifically, TBI. This comprehensive review summarizes and critically discusses the mechanisms that govern the activation and assembly of inflammasome complexes and the major methods used to study inflammasome activation in TBI and its implication for other neurodegenerative disorders. Also, we will review how inflammasome activation is critical in CNS homeostasis and pathogenesis, and how it can impact chronic TBI sequalae and increase the risk of developing neurodegenerative diseases. Additionally, we discuss the recent updates on inflammasome-related biomarkers and the potential to utilize inflammasomes as putative therapeutic targets that hold the potential to better diagnose and treat subjects with TBI. © 2022 Elsevier Lt
Health-related quality of life in patients with β-thalassemia: Data from the phase 3 BELIEVE trial of luspatercept
Get PDFBackground: Patients with transfusion-dependent (TD) β-thalassemia require long-term red blood cell transfusions (RBCTs) that lead to iron overload, impacting health-related quality of life (HRQoL). Methods: The impact of luspatercept, a first-in-class erythroid maturation agent, versus placebo on HRQoL of patients with TD β-thalassemia was evaluated in the phase 3 BELIEVE trial. HRQoL was assessed at baseline and every 12 weeks using the 36-item Short Form Health Survey (SF-36) and Transfusion-dependent Quality of Life questionnaire (TranQol). Mean change in HRQoL was evaluated from baseline to week 48 for patients receiving luspatercept + best supportive care (BSC) and placebo + BSC and between luspatercept responders and non-responders. Results: Through week 48, for both groups, mean scores on SF-36 and TranQol domains were stable over time and did not have a clinically meaningful change. At week 48, more patients who achieved clinical response (≥50% reduction in RBCT burden over 24 weeks) in the luspatercept + BSC group had improvement in SF-36 Physical Function compared with placebo + BSC (27.1% vs. 11.5%; p =.019). Conclusions: Luspatercept + BSC reduced transfusion burden while maintaining patients' HRQoL. HRQoL domain improvements from baseline through 48 weeks were also enhanced for luspatercept responders. © 2023 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd
Between life & death: Political economy of breast cancer care for refugee populations in Lebanon
Get PDFRefugees and displaced groups have been shown to face increased risk of developing advanced cancer stages. This has been shown to be evident in Lebanon, whereby refugees are detected at later stages when compared to the Lebanese population. Lebanon is one of the biggest host (per capita) of refugees worldwide, and suffers from difficult political situation, compounded by an economic crisis, the COVID-19 pandemic and a blast which hit the capital Beirut in 2020. The main determinants of poor health outcomes among migrant populations in Lebanon include a fragmented and inequitable healthcare system and legal constraints to healthcare accessibility. The health care system is largely privatised with multiple health systems operating simultaneously for different nationalities. The current multi-crisis situation has exacerbated the fragility of the health system and its ability to cope with increasing needs. On the other hand, legal constraints for refugees to obtain residency in Lebanon has also contributed to insufficient access to health care and poor health outcomes among this population. Health system reforms, improved emergency preparedness and response measures, and an ease on legal and political restrictions for the refugee populations in Lebanon are considered key policy recommendations to ensure refugees right to health in Lebanon. © 2022 Elsevier Lt
Rb deficiency, neuronal survival and neurodegeneration: In search of the perfect mouse model
Get PDFThree decades following the introduction of the first Rb knockout (KO) mouse model, the role of this critical protein in regulating brain development during embryogenesis and beyond remains a major scientific interest. Rb is a tumor suppressor gene known as the master regulator of the G1/S checkpoint and control of cell cycle progression in stem and progenitor cells, but also their differentiated progeny. Here, we review the recent literature about the various Rb conditional Knockout (cKO) and inducible Knockout (iKO) models studied thus far, highlighting how findings should always be interpreted in light of the model and context under inquiry especially when studying the role of Rb in neuronal survival. There is indeed evidence of age-specific, cell type-specific and region-specific effects following Rb KO in the embryonic and the adult mouse brain. In terms of modeling neurodegenerative processes in human diseases, we discuss cell cycle re-entry (CCE) as a candidate mechanism underlying the increased vulnerability of Rb-deficient neurons to cell death. Notably, mouse models may limit the extent to which CCE due to Rb inactivation can mimic the pathological course of these disorders, such as Alzheimer's disease. These remarks ought to be considered in future research when studying the consequences of Rb inactivation on neuronal generation and survival in rodents and their corresponding clinical significance in humans. © 2023 The Author