Search results for: city renewal strategy

Authors: Nazym Zhumabayeva, Aleksandr Mezin, Alexandra Knysheva

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Women's underrepresentation in STEM is critical, worsened by ineffective engagement in educational practices. UNICEF Kazakhstan and GameLab KBTU's collaborative initiatives aim to enhance female STEM participation by fostering an inclusive environment. Learning from LEVEL UP's 2023 program, which featured a hackathon, the 2024 strategy pivots towards non-competitive gamification. Although the data from last year's project showed higher than average student engagement, observations and in-depth interviews with participants showed that the format was stressful for the girls, making them focus on points rather than on other values. This study presents a gamified educational system, DPG Lab, aimed at incentivizing young women's participation in STEM through the development of digital public goods (DPGs). By prioritizing collaborative gamification elements, the project seeks to create an inclusive learning environment that increases engagement and interest in STEM among young women. The DPG Lab aims to find a solution to minimize competition and support collaboration. The project is designed to motivate female participants towards the development of digital solutions through an introduction to the concept of DPGs. It consists of a short online course, a simulation videogame, and a real-time online quest with an offline finale at the KBTU campus. The online course offers short video lectures on open-source development and DPG standards. The game facilitates the practical application of theoretical knowledge, enriching the learning experience. Learners can also participate in a quest that encourages participants to develop DPG ideas in teams by choosing missions throughout the quest path. At the offline quest finale, the participants will meet in person to exchange experiences and accomplishments without engaging in comparative assessments: the quest ensures that each team’s trajectory is distinct by design. This marks a shift from competitive hackathons to a collaborative format, recognizing the unique contributions and achievements of each participant. The pilot batch of students is scheduled to commence in April 2024, with the finale anticipated in June. It is projected that this group will comprise 50 female high-school students from various regions across Kazakhstan. Expected outcomes include increased engagement and interest in STEM fields among young female participants, positive emotional and psychological impact through an emphasis on collaborative learning environments, and improved understanding and skills in DPG development. GameLab KBTU intends to undertake a hypothesis evaluation, employing a methodology similar to that utilized in the preceding LEVEL UP project. This approach will encompass the compilation of quantitative metrics (conversion funnels, test results, and surveys) and qualitative data from in-depth interviews and observational studies. For comparative analysis, a select group of participants from the previous year's project will be recruited to engage in the DPG Lab. By developing and implementing a gamified framework that emphasizes inclusion, engagement, and collaboration, the study seeks to provide practical knowledge about effective gamification strategies for promoting gender diversity in STEM. The expected outcomes of this initiative can contribute to the broader discussion on gamification in education and gender equality in STEM by offering a replicable and scalable model for similar interventions around the world.

Keywords: collaborative learning, competitive learning, digital public goods, educational gamification, emerging regions, STEM, underprivileged groups

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Authors: Mohamed Sameer Mughal, Andrew D. Ross, Damian J. Fearon

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Background: The fast-paced changing landscape of UK Higher Education Institution (HEIs) is poised by changes and challenges affecting Middle Managers (MM) in their job roles. MM contribute to the success of HEIs by balancing the equilibrium and pass organization strategies from senior staff towards operationalization directives to junior staff. However, this study showcased from the data analyzed during the semi structured interviews; MM job role is becoming more complex due to changes and challenges creating colossal pressures and workloads in day-to-day working. Current development programmes provisions by Human Resources (HR) departments in such HEIs are not feasible, applicable, and matching the true essence and requirements of MM who suggest that programmes offered by HR are too generic to suit their precise needs and require tailor made espousal to work effectively in their pertinent job roles. Methodologies: This study aims to capture demands of MM Development Needs (DN) by means of a conceptual model as conclusive part of the research that is divided into 2 phases. Phase 1 initiated by carrying out 2 pilot interviews with a retired Emeritus status professor and HR programmes development coordinator. Key themes from the pilot and literature review subsidized into formulation of 22 set of questions (Kvale and Brinkmann) in form of interviewing questionnaire during qualitative data collection. Data strategy and collection consisted of purposeful sampling of 12 semi structured interviews (n=12) lasting approximately an hour for all participants. The MM interviewed were at faculty and departmental levels which included; deans (n=2), head of departments (n=4), subject leaders (n=2), and lastly programme leaders (n=4). Participants recruitment was carried out via emails and snowballing technique. The interviews data was transcribed (verbatim) and managed using Computer Assisted Qualitative Data Analysis using Nvivo ver.11 software. Data was meticulously analyzed using Miles and Huberman inductive approach of positivistic style grounded theory, whereby key themes and categories emerged from the rich data collected. The data was precisely coded and classified into case studies (Robert Yin); with a main case study, sub cases (4 classes of MM) and embedded cases (12 individual MMs). Major Findings: An interim conceptual model emerged from analyzing the data with main concepts that included; key performance indicators (KPI’s), HEI effectiveness and outlook, practices, processes and procedures, support mechanisms, student events, rules, regulations and policies, career progression, reporting/accountability, changes and challenges, and lastly skills and attributes. Conclusion: Dynamic elements affecting MM includes; increase in government pressures, student numbers, irrelevant development programmes, bureaucratic structures, transparency and accountability, organization policies, skills sets… can only be confronted by employing structured development programmes originated by HR that are not provided generically. Future Work: Stage 2 (Quantitative method) of the study plans to validate the interim conceptual model externally through fully completed online survey questionnaire (Bram Oppenheim) from external HEIs (n=150). The total sample targeted is 1500 MM. Author contribution focuses on enhancing management theory and narrow the gap between by HR and MM development programme provision.

Keywords: development needs (DN), higher education institutions (HEIs), human resources (HR), middle managers (MM)

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Authors: Lan Cheng, Harry Qin, Yang Wang

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Background: COVID-19 has induced the largest digital learning experiment in history. There is also emerging research evidence that students have paid a high cost of learning loss from virtual learning. University-wide survey results demonstrate that digital learning remains difficult for students who struggle with learning challenges, isolation, or a lack of resources. Large-scale efforts are therefore increasingly utilized for digital education. To better prepare students in higher education for this grand scientific and technological transformation, STEM education has been prioritized and promoted as a strategic imperative in the ongoing curriculum reform essential for unfinished learning needs and whole-person development. Building upon five key elements identified in the STEM education literature: Problem-based Learning, Community and Belonging, Technology Skills, Personalization of Learning, Connection to the External Community, this case study explores the potential of pedagogical innovation that integrates computational and experimental methodologies to support, enrich, and navigate STEM education. Objectives: The goal of this case study is to create a high-fidelity prototype design for STEM education with knowledge transfer technology that contains a Cooperative Multi-Agent System (CMAS), which has the objectives of (1) conduct assessment to reveal a virtual learning mechanism and establish strategies to facilitate scientific learning engagement, accessibility, and connection within and beyond university setting, (2) explore and validate an interactional co-creation approach embedded in project-based learning activities under the STEM learning context, which is being transformed by both digital technology and student behavior change,(3) formulate and implement the STEM-oriented campaign to guide learning network mapping, mitigate the loss of learning, enhance the learning experience, scale-up inclusive participation. Methods: This study applied a case study strategy and a methodology informed by Social Network Analysis Theory within a cross-disciplinary communication paradigm (students, peers, educators). Knowledge transfer technology is introduced to address learning challenges and to increase the efficiency of Reinforcement Learning (RL) algorithms. A co-creation learning framework was identified and investigated in a context-specific way with a learning analytic tool designed in this study. Findings: The result shows that (1) CMAS-empowered learning support reduced students’ confusion, difficulties, and gaps during problem-solving scenarios while increasing learner capacity empowerment, (2) The co-creation learning phenomenon have examined through the lens of the campaign and reveals that an interactive virtual learning environment fosters students to navigate scientific challenge independently and collaboratively, (3) The deliverables brought from the STEM educational campaign provide a methodological framework both within the context of the curriculum design and external community engagement application. Conclusion: This study brings a holistic and coherent pedagogy to cultivates students’ interest in STEM and develop them a knowledge base to integrate and apply knowledge across different STEM disciplines. Through the co-designing and cross-disciplinary educational content and campaign promotion, findings suggest factors to empower evidence-based learning practice while also piloting and tracking the impact of the scholastic value of co-creation under the dynamic learning environment. The data nested under the knowledge transfer technology situates learners’ scientific journey and could pave the way for theoretical advancement and broader scientific enervators within larger datasets, projects, and communities.

Keywords: co-creation, cross-disciplinary, knowledge transfer, STEM education, social network analysis

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Authors: H. M. El-Askary, S. A. Abd El-Mawla, M. Allali, M. M. El-Hattab, M. El-Raey, A. M. Farahat, M. Kafatos, S. Nickovic, S. K. Park, A. K. Prasad, C. Rakovski, W. Sprigg, D. Struppa, A. Vukovic

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A clear distinction between weather and climate is a necessity because while they are closely related, there are still important differences. Climate change is identified when we compute the statistics of the observed changes in weather over space and time. In this work we will show how the changing climate contribute to the frequency, magnitude and extent of different extreme events using a multi sensor approach with some synergistic modeling activities. We are exploring satellite observations of dust over North Africa, Gulf Region and the Indo Gangetic basin as well as dust versus anthropogenic pollution events over the Delta region in Egypt and Seoul through remote sensing and utilize the behavior of the dust and haze on the aerosol optical properties. Dust impact on the retreat of the glaciers in the Himalayas is also presented. In this study we also focus on the identification and monitoring of a massive dust plume that blew off the western coast of Africa towards the Atlantic on October 8th, 2012 right before the development of Hurricane Sandy. There is evidence that dust aerosols played a non-trivial role in the cyclogenesis process of Sandy. Moreover, a special dust event "An American Haboob" in Arizona is discussed as it was predicted hours in advance because of the great improvement we have in numerical, land–atmosphere modeling, computing power and remote sensing of dust events. Therefore we performed a full numerical simulation to that event using the coupled atmospheric-dust model NMME–DREAM after generating a mask of the potentially dust productive regions using land cover and vegetation data obtained from satellites. Climate change also contributes to the deterioration of different marine habitats. In that regard we are also presenting some work dealing with change detection analysis of Marine Habitats over the city of Hurghada, Red Sea, Egypt. The motivation for this work came from the fact that coral reefs at Hurghada have undergone significant decline. They are damaged, displaced, polluted, stepped on, and blasted off, in addition to the effects of climate change on the reefs. One of the most pressing issues affecting reef health is mass coral bleaching that result from an interaction between human activities and climatic changes. Over another location, namely California, we have observed that it exhibits highly-variable amounts of precipitation across many timescales, from the hourly to the climate timescale. Frequently, heavy precipitation occurs, causing damage to property and life (floods, landslides, etc.). These extreme events, variability, and the lack of good, medium to long-range predictability of precipitation are already a challenge to those who manage wetlands, coastal infrastructure, agriculture and fresh water supply. Adding on to the current challenges for long-range planning is climate change issue. It is known that La Niña and El Niño affect precipitation patterns, which in turn are entwined with global climate patterns. We have studied ENSO impact on precipitation variability over different climate divisions in California. On the other hand the Nile Delta has experienced lately an increase in the underground water table as well as water logging, bogging and soil salinization. Those impacts would pose a major threat to the Delta region inheritance and existing communities. There has been an undergoing effort to address those vulnerabilities by looking into many adaptation strategies.

Keywords: remote sensing, modeling, long range transport, dust storms, North Africa, Gulf Region, India, California, climate extremes, sea level rise, coral reefs

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Authors: Chau So Ling

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I.INTRODUCTION: Educators have always been interested in exploring factors that contribute to students’ academic success. It is beyond question that language, as a medium of instruction, will affect student learning. This paper tries to investigate whether language is a crucial factor in determining students’ achievement in their studies. II. BACKGROUND AND SIGNIFICANCE OF STUDY: The issue of using English as a medium of instruction in Hong Kong is a special topic because Hong Kong is a post-colonial and international city which a British colony. In such a specific language environment, researchers in the education field have always been interested in investigating students’ language proficiency and its relation to academic achievement and other related educational indicators such as motivation to learn, self-esteem, learning effectiveness, self-efficacy, etc. Along this line of thought, this study specifically focused on business education. III. METHODOLOGY: The methodology in this study involved two sequential stages, namely, a focus group interview and a data analysis. The whole study was directed towards both qualitative and quantitative aspects. The subjects of the study were divided into two groups. For the first group participating in the interview, a total of ten high school students were invited. They studied Business Studies, and their English standard was varied. The theme of the discussion was “Does English affect your learning and examination results of Business Studies?” The students were facilitated to discuss the extent to which English standard affected their learning of Business subjects and requested to rate the correlation between English and performance of Business Studies on a five-point scale. The second stage of the study involved another group of students. They were high school graduates who had taken the public examination for entering universities. A database containing their public examination results for different subjects has been obtained for the purpose of statistical analysis. Hypotheses were tested and evidence was obtained from the focus group interview to triangulate the findings. V. MAJOR FINDINGS AND CONCLUSION: By sharing of personal experience, the discussion of focus group interviews indicated that higher English standards could help the students achieve better learning and examination performance. In order to end the interview, the students were asked to indicate the correlation between English proficiency and performance of Business Studies on a five-point scale. With point one meant least correlated, ninety percent of the students gave point four for the correlation. The preliminary results illustrated that English plays an important role in students’ learning of Business Studies, or at least this was what the students perceived, which set the hypotheses for the study. After conducting the focus group interview, further evidence had to be gathered to support the hypotheses. The data analysis part tried to find out the relationship by correlating the students’ public examination results of Business Studies and levels of English standard. The results indicated a positive correlation between their English standard and Business Studies examination performance. In order to highlight the importance of the English language to the study of Business Studies, the correlation between the public examination results of other non-business subjects was also tested. Statistical results showed that language does play a role in affecting students’ performance in studying Business subjects than the other subjects. The explanation includes the dynamic subject nature, examination format and study requirements, the specialist language used, etc. Unlike Science and Geography, students in their learning process might find it more difficult to relate business concepts or terminologies to their own experience, and there are not many obvious physical or practical activities or visual aids to serve as evidence or experiments. It is well-researched in Hong Kong that English proficiency is a determinant of academic success. Other research studies verified such a notion. For example, research revealed that the more enriched the language experience, the better the cognitive performance in conceptual tasks. The ability to perform this kind of task is particularly important to students taking Business subjects. Another research was carried out in the UK, which was geared towards identifying and analyzing the reasons for underachievement across a cohort of GCSE students taking Business Studies. Results showed that weak language ability was the main barrier to raising students’ performance levels. It seemed that the interview result was successfully triangulated with data findings. Although education failure cannot be restricted to linguistic failure and language is just one of the variables to play in determining academic achievement, it is generally accepted that language does affect students’ academic performance. It is just a matter of extent. This paper provides recommendations for business educators on students’ language training and sheds light on more research possibilities in this area.

Keywords: academic performance, language, learning, medium of instruction

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Authors: P. C. Kutschera, Elena C. Tesoro, Mary Grace Talamera-Sandico, Jose Maria G. Pelayo III

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Second generation military Filipino Amerasians comprise a formidable contemporary segment of the estimated 250,000-plus biracial Amerasians in the Philippines today. Overall, they are a stigmatized and socioeconomically marginalized diaspora, historically; they were abandoned or estranged by U.S. military personnel fathers assigned during the century-long Colonial, Post-World War II and Cold War Era of permanent military basing (1898-1992). Indeed, U.S. military personnel remain stationed in smaller numbers in the Philippines today. This inquiry is an outgrowth of two recent small sample studies. The first surfaced the impact of the U.S. military prostitution system on formation of the ‘Derivative Amerasian Family Construct’ on first generation Amerasians; a second, qualitative case study suggested the continued effect of the prostitution systems' destructive impetuous on second generation Amerasians. The intent of this current qualitative, multiple-case study was to actively seek out second generation sex industry toilers. The purpose was to focus further on this human phenomenon in the post-basing and post-military prostitution system eras. As background, the former military prostitution apparatus has transformed into a modern dynamic of rampant sex tourism and prostitution nationwide. This is characterized by hotel and resorts offering unrestricted carnal access, urban and provincial brothels (casas), discos, bars and pickup clubs, massage parlors, local barrio karaoke bars and street prostitution. A small case study sample (N = 4) of female and male second generation Amerasians were selected. Sample formation employed a non-probability ‘snowball’ technique drawing respondents from the notorious Angeles, Metro Manila, Olongapo City ‘AMO Amerasian Triangle’ where most former U.S. military installations were sited and modern sex tourism thrives. A six-month study and analysis of in-depth interviews of female and male sex laborers, their families and peers revealed a litany of disturbing, and troublesome experiences. Results showed profiles of debilitating human poverty, history of family disorganization, stigmatization, social marginalization and the ghost of the military prostitution system and its harmful legacy on Amerasian family units. Emerging were testimonials of wayward young people ensnared in a maelstrom of deep economic deprivation, familial dysfunction, psychological desperation and societal indifference. The paper recommends that more study is needed and implications of unstudied psychosocial and socioeconomic experiences of distressed younger generations of military Amerasians require specific research. Heretofore apathetic or disengaged U.S. institutions need to confront the issue and formulate activist and solution-oriented social welfare, human services and immigration easement policies and alternatives. These institutions specifically include academic and social science research agencies, corporate foundations, the U.S. Congress, and Departments of State, Defense and Health and Human Services, and Homeland Security (i.e. Citizen and Immigration Services) It is them who continue to endorse a laissez-faire policy of non-involvement over the entire Filipino Amerasian question. Such apathy, the paper concludes, relegates this consequential but neglected blood progeny to the status of humiliating destitution and exploitation. Amerasians; thus, remain entrapped in their former colonial, and neo-colonial habitat. Ironically, they are unwitting victims of a U.S. American homeland that fancies itself geo-politically as a strong and strategic military treaty ally of the Philippines in the Western Pacific.

Keywords: Asian Americans, diaspora, Filipino Amerasians, military prostitution, stigmatization

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Authors: Hosein Maghsoudi

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Rheumatois arthritis (RA) is progressive inflammatory autoimmune diseases that primarily affect the joints, characterized by synovial hyperplasia and inflammatory cell infiltration, deformed and painful joints, which can lead tissue destruction, functional disability systemic complications, and early dead and socioeconomic costs. The cause of rheumatoid arthritis is unknown, but genetic and environmental factors are contributory and the prognosis is guarded. However, advances in understanding the pathogenesis of the disease have fostered the development of new therapeutics, with improved outcomes. The current treatment strategy, which reflects this progress, is to initiate aggressive therapy soon after diagnosis and to escalate the therapy, guided by an assessment of disease activity, in pursuit of clinical remission. The pathobiology of RA is multifaceted and involves T cells, B cells, fibroblast-like synoviocyte (FLSc) and the complex interaction of many pro-inflammatory cytokine. Novel biologic agents that target tumor necrosis or interlukin (IL)-1 and Il-6, in addition T- and B-cells inhibitors, have resulted in favorable clinical outcomes in patients with RA. Despite this, at least 30% of RA patients are résistance to available therapies, suggesting novel mediators should be identified that can target other disease-specific pathway or cell lineage. Among the inflammatory cell population that might participated in RA pathogenesis, FLSc are crucial in initiaing and driving RA in concert of cartilage and bone by secreting metalloproteinase (MMPs) into the synovial fluid and by direct invasion into extracellular matrix (ECM), further exacerbating joint damage. Invasion of fibroblast-like synoviocytes (FLSc) is critical in the pathogenesis of rheumatoid-arthritis. The metalloproteinase (MMPs) and activator of Toll-like receptor 4 (TLR4)/nuclear factor- κB pthway play a critical role in RA-FLS invasion induced by lipopolysaccharide (LPS). The present study aimed to explore the anti-invasion activity of Glycyrrhizic Acid as a pharmacologically safe phytochemical agent with potent anti-inflammatory properties on IL-1beta and TNF-alpha signalling pathways in Bovine fibroblast-like synoviocyte ex- vitro, on LPS-stimulated bovine FLS migration and invasion as well as MMP expression and explored the upstream signal transduction. Results showed that Glycyrrhizic Acid suppressed LPS-stimulated bovine FLS migration and invasion by inhibition MMP-9 expression and activity. In addition our results revealed that Glycyrrhizic Acid inhibited the transcriptional activity of MMP-9 by suppression the nbinding activity of NF- κB in the MMP-9 promoter pathway. The extract of licorice (Glycyrrhiza glabra L.) has been widely used for many centuries in the traditional Chinese medicine as native anti-allergic agent. Glycyrrhizin (GL), a triterpenoidsaponin, extracted from the roots of licorice is the most effective compound for inflammation and allergic diseases in human body. The biological and pharmacological studies revealed that GL possesses many pharmacological effects, such as anti-inflammatory, anti-viral and liver protective effects, and the biological effects, such as induction of cytokines (interferon-γ and IL-12), chemokines as well as extrathymic T and anti-type 2 T cells. GL is known in the traditional Chinese medicine for its anti-inflammatory effect, which is originally described by Finney in 1959. The mechanism of the GL-induced anti-inflammatory effect is based on different pathways of the GL-induced selective inhibition of the prostaglandin E2 production, the CK-II- mediated activation of both GL-binding lipoxygenas (gbLOX; 17) and PLA2, an anti-thrombin action of GL and production of the reactive oxygen species (ROS; GL exerts liver protection properties by inhibiting PLA2 or by the hydroxyl radical trapping action, leading to the lowering of serum alanine and aspartate transaminase levels. The present study was undertaken to examine the possible mechanism of anti-inflammatory properties GL on IL-1beta and TNF-alpha signalling pathways in bovine fibroblast-like synoviocyte ex-vivo, on LPS-stimulated bovine FLS migration and invasion as well as MMP expression and explored the upstream signal transduction. Our results clearly showed that treatment of bovine fibroblast-like synoviocyte with GL suppressed LPS-induced cell migration and invasion. Furthermore, it revealed that GL inhibited the transcription activity of MMP-9 by suppressing the binding activity of NF-κB in the MM-9 promoter. MMP-9 is an important ECM-degrading enzyme and overexpression of MMPs in important of RA-FLSs. LPS can stimulate bovine FLS to secret MMPs, and this induction is regulated at the transcription and translational levels. In this study, LPS treatment of bovine FLS caused an increase in MMP-2 and MMP-9 levels. The increase in MMP-9 expression and secretion was inhibited by ex- vitro. Furthermore, these effects were mimicked by MMP-9 siRNA. These result therefore indicate the the inhibition of LPS-induced bovine FLS invasion by GL occurs primarily by inhibiting MMP-9 expression and activity. Next we analyzed the functional significance of NF-κB transcription of MMP-9 activation in Bovine FLSs. Results from EMSA showed that GL suppressed LPS-induced NF-κB binding to the MMP-9 promotor, as NF-κB regulates transcriptional activation of multiple inflammatory cytokines, we predicted that GL might target NF-κB to suppress MMP-9 transcription by LPS. Myeloid differentiation-factor 88 (MyD88) and TIR-domain containing adaptor protein (TIRAP) are critical proteins in the LPS-induced NF-κB and apoptotic signaling pathways, GL inhibited the expression of TLR4 and MYD88. These results demonstrated that GL suppress LPS-induced MMP-9 expression through the inhibition of the induced TLR4/NFκB signaling pathway. Taken together, our results provide evidence that GL exerts anti-inflammatory effects by inhibition LPS-induced bovine FLSs migration and invasion, and the mechanisms may involve the suppression of TLR4/NFκB –mediated MMP-9 expression. Although further work is needed to clarify the complicated mechanism of GL-induced anti-invasion of bovine FLSs, GL might be used as a further anti-invasion drug with therapeutic efficacy in the treatment of immune-mediated inflammatory disease such as RA.

Keywords: glycyrrhizic acid, bovine fibroblast-like synoviocyte, tlr4/nf-κb, metalloproteinase-9

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Authors: Ziyad S. Haidar

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Background: Saliva plays a major role in maintaining oral and dental health (consequently, general health and well-being). Where it normally bathes the oral cavity and acts as a clearing agent. This becomes more apparent when the amount and quality of salivare significantly reduced due to medications, salivary gland neoplasms, disorders such as Sjögren’s syndrome, and especially ionizing radiation therapy for tumors of the head and neck, the fifth most common malignancy worldwide, during which the salivary glands are included within the radiation field or zone. Clinically, patients affected by salivary gland dysfunction often opt to terminate their radiotherapy course prematurely because they become malnourished and experience a significant decrease in their quality of life. Accordingly, the development of an alternative treatment to restore or regenerate damaged salivary gland tissue is eagerly awaited. Likewise, the formulation of a radioprotection modality and early damage prevention strategy is also highly desirable. Objectives: To assess the pre-clinical radio-protective effect as well as the reparative/regenerative potential of layer-by-layer self-assembled lipid-polymer-based core-shell nanocapsules designed and fine-tuned in this experimental work for the sequential (ordered) release of dual cytokines, following a single local administration (direct injection) into a murine sub-mandibular salivary gland model of irradiation. Methods: The formulated core-shell nanocapsules were characterized by physical-chemical-mechanically pre-/post-loading with the drugs (in solution and powder formats), followed by optimizing the pharmaco-kinetic profile. Then, nanosuspensions were administered directly into the salivary glands, 24hrs pre-irradiation (PBS, un-loaded nanocapsules, and individual and combined vehicle-free cytokines were injected into the control glands for an in-depth comparative analysis). External irradiation at an elevated dose of 18Gy (revised from our previous 15Gy model) was exposed to the head-and-neck region of C57BL/6 mice. Salivary flow rate (un-stimulated) and salivary protein content/excretion were regularly assessed using an enzyme-linked immunosorbent assay (3-month period). Histological and histomorphometric evaluation and apoptosis/proliferation analysis followed by local versus systemic bio-distribution and immuno-histochemical assays were then performed on all harvested major organs (at the distinct experimental end-points). Results: Monodisperse, stable, and cytocompatible nanocapsules capable of maintaining the bioactivity of the encapsulant within the different compartments with the core and shell and with controlled/customizable pharmaco-kinetics, resulted, as is illustrated in the graphical abstract (Figure) below. The experimental animals demonstrated a significant increase in salivary flow rates when compared to the controls. Herein, salivary protein content was comparable to the pre-irradiation (baseline) level. Histomorphometry further confirmed the biocompatibility and localization of the nanocapsules, in vivo, into the site of injection. Acinar cells showed fewer vacuoles and nuclear aberration in the experimental group, while the amount of mucin was higher in controls. Overall, fewer apoptotic activities were detected by a Terminal deoxynucleotidyl Transferase (TdT) dUTP Nick-End Labeling (TUNEL) assay and proliferative rates were similar to the controls, suggesting an interesting reparative and regenerative potential of irradiation-damaged/-dysfunctional salivary glands. The Figure below exemplifies some of these findings. Conclusions: Biocompatible, reproducible, and customizable self-assembling layer-by-layer core-shell delivery system is formulated and presented. Our findings suggest that localized sequential bioactive delivery of dual cytokines (in specific dose and order) can prevent irradiation-induced damage via reducing apoptosis and also has the potential to promote in situ proliferation of salivary gland cells; maxSALIVA is scalable (Good Manufacturing Practice or GMP production for human clinical trials) and patent-pending.

Keywords: saliva, head and neck cancer, nanotechnology, controlled drug delivery, xerostomia, mucositis, biopolymers, innovation

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