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EXPLORING NEW THERAPEUTIC AVENUES AGAINST HER2-POSITIVE BREAST CANCER
No full textHER2-positive breast cancer (BC) is a challenging disease characterized by poor prognosis, relapses, and aggressive behavior in the tumor. HER2 oncoprotein dimerization with other growth factor receptor family members (EGFR, HER2, HER3, and IGF-1R) is the crucial driver of cancer cell growth. Thus, targeting HER2 and its family members is an effective strategy to tackle this disease. However, currently available treatments face several limitations, mainly acquired resistance and severe side effects. In this study, we explored a novel treatment strategy to target HER2-positive BC using a combination of neratinib (NER) and metformin (MET). We used a panel of HER2-positive BC cell lines in addition to a non-cancerous control. We investigated the effect of NER and MET combination on cell morphology, cell viability, colony formation, cell migration, cell invasion, and cell cycle. Western blotting was used to investigate changes in the protein levels upon treatment. Further, a tissue microarray followed by immunohistochemistry (IHC) was used to identify the presence of drug targets in HER2-positive BC tissue blocks. Our data revealed a significant dose-dependent decrease in HER2-positive BC cell viability after monotreatment with NER and MET (P<0.05) (down to 13.7%±0.43%, 25.49%±2.53%, 26.92%±0.15%, and 29.8%±1.82% in SKBR3, HCC1954, ZR75, and MDA-MB-453, respectively). The combination treatment demonstrated a further reduction in cell viability compared to individual treatments at the same doses, showing mostly a synergistic effect (combination index ≤1). NER and MET combination treatment inhibited colony formation (by ~ 60%), cell migration, and invasion (by ~ 80%) significantly compared to controls and individual treatment (P<0.01). Cell cycle deregulation was also observed upon treatment with NER and MET combination. The underlying mechanisms of action were found to be downregulating the expression patterns of EGFR, HER2, HER3, and IGF-1R proteins, in addition to ERK1/2, p38 MAPK, mTOR, AKT, and c-Jun and other EMT and apoptotic markers. Using a cohort of 55 HER2-positive BC samples, we revealed that HER2 and IGF-1R are co-expressed in most cases.
We also established NER-resistant cell lines from parental SKBR3 and HCC1954; these two cell lines were named SNR and HNR, respectively. The resistant cell lines exhibited significantly elevated levels of EGFR, HER2, HER3, and IGF-1R. Interestingly, treatment with NER combined with MET re-sensitized the resistant cell lines to NER treatment.
Finally, the effect of NER and MET on angiogenesis was investigated using the chorioallantoic membrane (CAM) of the chicken embryo as a model. Our findings revealed that NER and MET combination inhibit the angiogenesis of the CAM compared to controls by significantly reducing vessel percentage area and average vessel length (P<0.05).
Our findings introduce a promising new combination treatment strategy against HER2-positive BC using NER and MET. This approach offers a fresh perspective by targeting multiple key proteins, including IGF-1R, and reducing tumor angiogenesis. Future directions include exploring the therapeutic potential of combining MET with other HER2-targeted agents and validating predictive biomarkers of response in in-vivo and patient-derived models
Near-complete Middle Eastern genomes refine autozygosity and enhance disease-causing and population-specific variant discovery
No full textAdvances in long-read sequencing have enabled routine complete assembly of human genomes, but much remains to be done to represent broader populations and show impact on disease-gene discovery. Here, we report highly accurate, near-complete and phased genomes from six Middle Eastern (ME) family trios (n = 18) with neurodevelopmental conditions, representing ancestries from Sudan, Jordan, Syria, Qatar and Afghanistan. These genomes revealed 42.2 Mb of new sequence (13.8% impacting known genes), 75 new HLA/KIR alleles and strong signals of inbreeding, with ROH covering up to one-third of chromosomes 6 and 12 in one individual. Using assembly-based variant calling, we identified 23 de novo and recessive variants as strong candidates for causing previously unresolved symptoms in the probands. The ME genomes revealed unique variation relative to existing references, showing enhanced mappability and variant calling. These results underscore the value of de novo assembly for disease variant discovery and the need for sampled ME-specific references to better characterize population-relevant variation.This work was supported by Qatar Foundation and the Ministry of Finance, Qatar. This study was funded in part by Qatar National Research Fund (QNRF awards ARG01-0426-230012, PPM1-1122-150008 and NPRP10-1219-160035) as well as Sidra internal funds. E.E.E. is an investigator of the Howard Hughes Medical Institute and is supported by US National Institutes of Health (NIH) grant R01MH101221
ELECTRIC VEHICLE CHARGING STRATEGIES AND THEIR INTEGRATION IMPACT ON ACTIVE DISTRIBUTION NETWORK
No full textThe increasing sales of Electric Vehicles (EVs) presents both opportunities and significant challenges for active distribution networks (ADN). Challenges include increased peak demand, voltage drop and power quality issues. Therefore, it is necessary to understand how EV integration impacts the distribution network and propose a controlled charging scheme; active management of resources and real-time status is crucial for sustainable EV integration. This dissertation focuses on EV charging strategies and their integration impact on ADN . Furthermore, the dissertation investigates the impact of EVs on the voltage profile, transformers and feeder overloading caused by uncontrolled and controlled charging strategies. The impact assessment of EV integration is carried out based on various factors such as the percentage of EV penetration, different ratings of EV chargers, charging time, different networks (IEEE standard and integration actual network) and different methods of EV modelling. The impact assessment of EVs is investigated through load flow analysis using Power Factory and MATLAB Softwares. The impact of uncontrolled EV charging causes the voltage drop and overloading of transformers and feeders. Moreover, the impact of uncontrolled EV charging can be mitigated by proposing unique reward charging schemes and network reconfiguration. Furthermore, the power distribution networks can integrate renewable sources to mitigate voltage drops and support both active and reactive power demands. In addition, advanced sensors, metering, communication networks, and advanced network management are needed to coordinate different renewable sources. Coordinating active DG sources can support the distribution network in managing voltage rise and drop issues through the Centralized Supervisory Voltage Controller Scheme (CSVC). Lastly, the proposed method to evaluate the hosting capacity for EVs (HCEVs) in the distribution network is carried out for the integration of EVs and proper utilization of grid resources
Factors Associated with Physical Activity Among People with Multiple Sclerosis in Jordan: Which Clinical Characteristics are Important?
No full textBackgroundPhysical activity (PA) enhances mental and physical functioning of people with multiple sclerosis (PwMS). Yet, PwMS often do not engage in sufficient PA in the Middle East region.ObjectiveTo explore PA-associated factors according to The International Classification of Functioning, Disability and Health (ICF) framework among PwMS in Jordan.MethodsA cross-sectional study was conducted on 97 PwMS. PA levels were measured using The International Physical Activity Questionnaire (IPAQ). Potential associated factors with PA were determined using the ICF framework. Multiple linear regression was used to identify the factors that explain IPAQ's total score.ResultsThe Mean age of the participants was 36.09 years (SD = 10.9), 71.7% females. IPAQ was negatively associated with disease severity, history of falling, fatigue, family social support, and participation in social activities (P < 0.05). Anxiety levels and participation in instrumental activities of daily living were positively associated with IPAQ (P < 0.05).ConclusionsThe study suggests that factors contributing to PA levels in PwMS in the Middle East are multifactorial. A comprehensive rehabilitation plan that addresses those factors is essential to enhance PA levels in this population. Further research is needed to understand the clinical, personal, and cultural factors associated with PA among PwMS in the Middle East
Unveiling the nexus: The tumor microenvironment as a strategic frontier in viral cancers
No full textViral infections are a significant factor in the etiology of various cancers, with the tumor microenvironment (TME) playing a crucial role in disease progression. This review delves into the complex interactions between viruses and the TME, highlighting how these interactions shape the course of viral cancers. We explore the distinct roles of immune cells, including T-cells, B-cells, macrophages, and dendritic cells, within the TME and their influence on cancer progression. The review also examines how viral oncoproteins manipulate the TME to promote immune evasion and tumor survival. Unraveling these mechanisms highlights the emerging paradigm of targeting the TME as a novel approach to cancer treatment. Our analysis provides insights into the dynamic interplay between viruses and the TME, offering a roadmap for innovative treatments that leverage the unique characteristics of viral cancers.Open access funding was provided by Qatar National Library
THE ROLE OF HUMAN RIGHTS MECHANISMS IN IMPROVING HUMAN RIGHTS SITUATIONS OF THE STATE OF QATAR
No full textThis study provides a theoretically informed analysis of the human rights situation in the State of Qatar by using both secondary and interview data as main sources of evidence. Moreover, two different theories were used to understand the progress that Qatar has made in advancing the human rights agenda: the theory of diffusion and adoption of international human rights norms, and the theory of cultural relativism. By integrating these two theories in the research, this study has provided a novel interpretation of the human rights situation in Qatar, which the current academic literature is lacking. By applying the theory of cultural relativism, the research found that many of the tensions that exist between Qatar and the UN human rights mechanisms and international human rights organizations arise from the reading of human rights, that seek to both respect the international obligation of the state and commit to the cultural and religious norms that define the Qatari society. In this regard, the Western human rights organizations have failed to consider that human rights in Qatar are to be interpreted through Sharia lenses, thus such organizations are not paying adequate attention to the local culture and norms. In seeking to critically explore the role of UN human rights mechanisms and international NGOs in the context of promoting human rights in Qatar, the research uncovered that both the UN mechanisms and the international NGOs have a crucial role to play in the promotion of human rights in the state of Qatar. The cooperation with the different UN human rights mechanisms provided the much-needed technical and legal expertise to support Qatar in promoting and enhancing the human rights situation. In assessing the challenges that Qatar has faced in adopting the recommendations from the human rights mechanism, the research uncovered that there had been substantial resistance among Qatari policymakers to implement the recommendations conflicting with the Sharia law principles and cultural norms and values. Societal attitudes were also found to be a barrier preventing the state of Qatar from embracing a progressive human rights agenda, while the NGOs are burning their bridges with the Qatari government by overly criticizing the country
DYNAMIC ALGORITHM FOR TIP SELECTION IN MULTI-AGENT BLOCKCHAIN ENVIRONMENTS: OPTIMIZATION AND ANALYSIS
No full textThe rise of decentralized technologies has brought forward novel challenges in maintaining fairness, efficiency, and scalability in distributed ledger protocols. The Internet of Things Applications (IOTA), a Directed Acyclic Graph (DAG)-based structure, offers an alternative to traditional blockchain systems by enabling scalable and feeless transactions, particularly suited for the Internet of Things (IoT). However, ensuring fairness and addressing issues such as orphaned transactions and lazy behavior in such a decentralized network remain significant challenges. This dissertation introduces a novel Partially Observable Markov Decision Process (POMDP)-based Tip Selection Algorithm (TSA) aimed at optimizing fairness in the IOTA Tangle. Unlike existing algorithms, the proposed method reduces orphaned transactions to as low as 0.003% in medium-activity networks and 0.013% in high-activity networks, significantly outperforming other TSAs. POMDP-based TSA also avoids lazy tip selection with 0.000% lazy tips in low to medium network loads, ensuring fairness in tip selection even under network congestion. Through extensive simulation experiments, the performance of the proposed algorithm is compared to other established TSAs, including Random, Unweighted, Weighted, Hybrid-1, Hybrid-2, G-IOTA, and E-IOTA, across various network conditions. Results indicate that the POMDP-based TSA confirms up to 107 transactions at optimal arrivate rate (lambda values), outperforming the next best-performing algorithm (Weighted TSA, confirming 25 transactions) by 328% in efficiency. The algorithm maintains its robust performance even in high-throughput scenarios, demonstrating both scalability and adaptability. These findings contribute to the ongoing development of DAG-based distributed ledger systems by offering a scalable and secure TSA. The proposed algorithm's novel approach to handling orphaned and lazy transactions offers significant improvements over state-of-the-art TSAs, making it a robust solution for IoT-based decentralized applications
The role of THEQA, as a government-led trustmark, in developing consumers’ trust in local e-commerce websites
No full textThe purpose of this study is to explore how THEQA, a government-led trustmark program in the State of Qatar, provides local vendors with mechanisms to establish online trust. This is the first study to explore a government-led local trustmark, and the only one that studies THEQA from the local online vendor’s perspective. The research used semi-structured interviews with both THEQA representatives and online vendors. A research model was established based on the conducted interviews. Both quantitative and thematic content analysis were used. Results show that THEQA trustmark establishes online trust in local e-commerce vendors through four mechanisms: initial-trust related mechanisms, reputation-related mechanism, website-quality related mechanisms, and security-related mechanisms. The study provides managers and decision-makers with trust-building and risk-reduction mechanisms to reinforce trust in e-commerce through e-government initiatives. This study is limited by its small sample size. Further, THEQA trustmark is a newly developed program and still in the growing stage
Sleep patterns in autistic children and adolescents and their caregivers during the COVID-19 pandemic lockdown: A systematic review
No full textBackgroundSleep patterns significantly influence health and wellbeing, with disturbances to sleep quality and duration, and increased sleep disorders commonly affecting autistic people. The COVID-19 pandemic lockdown altered daily routines for almost all people, impacting their sleep patterns. AimThis study aimed to systematically review studies on sleep patterns among autistic children, adolescents, and their caregivers during the COVID-19 lockdown. MethodsIn April 2023, six databases (PubMed, Embase, Web of Science, Scopus, ProQuest Central, and CINAHL) were searched for quantitative and qualitative studies. Data from eligible studies were extracted and analyzed through narrative synthesis. ResultsThirty-four studies were included, with thirty-one focusing on autistic children and adolescents and three on caregivers. Autistic males and mothers were the predominant demographic groups in the studies. The findings regarding sleep quality, duration, and disorders were inconsistent; some studies reported improvements, while others noted worsening sleep or no changes. The most common negative impacts in autistic children and adolescents were decreased sleep quality and an increase in sleep disorders. All caregiver studies indicated significant declines in sleep quality and duration. ConclusionThe COVID-19 lockdown adversely affected sleep patterns in many autistic children, adolescents, and their caregivers. To address these challenges during extreme circumstances such as lockdowns, strategies are needed to maintain or improve sleep quality and reduce the risk of negative sleep patterns in these populations
