02. Master's Thesis
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Item Open Access The Effects of Perturbation-Based Training (PBT) on Functional Balance in Children with Cerebral Palsy: Pre-Post Clinical Trial(Nazarbayev University School of Medicine, 2024-04-03) Karibzhanova, DilnozaThis study investigates the efficacy of a combined perturbation therapy, delivered simultaneously from the ground and in the transverse plane, to enhance gait stability and functional balance in children diagnosed with cerebral palsy at Gross Motor Function Classification System (GMFCS) levels I–II. With a minimum expectation of three participants aged between 14 to 18 years old, our research hypothesizes that combining perturbations will lead to greater improvements in functional balance, endurance, power and Muscle Activation Index. We anticipate that participants receiving combined perturbations will exhibit superior functional balance outcomes. The study employs standard equipment alongside an indigenous autonomous system developed to administer random perturbations to participants. Through this investigation, we aim to determine the effects of perturbations given from the ground and in the transverse plane on postural and functional balance of children with CP to enhance their overall quality of life.Item Restricted DEVELOPMENT OF A PROTOTYPE POINT-OF-CARE LATERAL FLOW ASSAY TEST SYSTEM FOR MEASURING BLOOD OR PLASMA LEVELS OF CTHRC1 PROTEIN, A NEW BIOMARKER FOR THE DIAGNOSIS OF RHEUMATOID ARTHRITIS.(Nazarbayev University School of Medicine, 2024) Zholdybay, AigerimRheumatoid arthritis (RA) is a systemic autoimmune disorder characterized by proliferative synovitis and inflammatory arthritis accompanied by erosions. RA affects symmetrically peripheral joints multiple times and often leads to disability. Early diagnosis and appropriate treatment are essential for the management of RA. This in turn will help to minimize irreversible changes in synovial joints and to achieve remission or low disease activity. Despite the existing biomarkers, such as rheumatoid factor (RF) and anti-citrullinated antibodies (ACPAs), approximately 20-30% of patients are negative for these markers even with the onset of RA and the development of erosions. Collagen triple helix repeat-containing 1 protein (CTHRC1) serves as a secreted modulator of Wnt signaling, plays a crucial role in joint remodeling regulation, and facilitates cell proliferation and migration. CTHRC1 was previously identified as a highly sensitive and specific blood-based biomarker for RA that can enable the differential diagnosis of patients...Item Open Access INVESTIGATING AUTOPHAGY AS A POTENTIAL PATHWAY OF ANTICANCER MECHANISM OF PHENFORMIN(Nazarbayev University School of Medicine, 2024) Khikhmetova, KamilaPhenformin, a representative of the biguanides class, is an anti-diabetic drug that was withdrawn from the market due to its side effects profile is currently being investigated as a potential anticancer agent. Autophagy is an evolutionary conserved mechanism of lysosome-mediated catabolic breakdown of proteins, cellular compartments, and infectious agents for maintaining homeostasis. Activation of autophagy in cancer cell could potentially be one of the mechanisms of phenformin’s anticancer activity. This research aimed to establish the antiproliferative activity of phenformin among different cancer cell lines and to study the effect of phenformin on expression of proteins involved in autophagy in cervical cancer cells. Cervical cancer is the fourth leading cause of cancer mortality as well as the fourth most diagnosed cancer type in females. Our findings demonstrate that phenformin decreases the proliferation of various cancer cell lines in a dose-dependent manner cells and may have an ability to increase autophagic flux in cervical cancer cells.Item Embargo EFFECT OF HYPOCALORIC DIET ON FAT MASS AND LEAN BODY MASS IN POSTMENOPAUSAL WOMEN: A META-ANALYSIS(Nazarbayev University School of Medicine, 2024-06) Kabibolla, SamalIntroduction Postmenopausal women experience significant physiological changes that are associated with an increased risk of metabolic disorders and cardiovascular health risks. One of the strategies to address this issue is to modify dietary intake in response to these changes to maintain health and quality of life. A hypocaloric diet, which involves reduced calorie intake without malnutrition, has been stated as a strategy to target body composition to optimise health outcomes. The objective of this study is to provide a comprehensive assessment of the effectiveness of hypocaloric diets by systematically reviewing the data on the effect of these diets on weight, fat mass, and lean body mass in postmenopausal women. Methods A quantitative, systematic review and meta-analysis were conducted. Studies were searched in Pubmed, Web of Science, and Embase databases for relevant studies. Overweight or obese, healthy postmenopausal women that were investigated on the effects of a hypocaloric diet alone in comparison with control groups were included. Meta-analyses were conducted on the outcomes that assessed changes in weight, fat mass, and lean body mass using a random-effects model. Results Six studies and nine interventions with 564 participants were included in the meta-analysis. Dietary intervention groups had significantly greater weight, fat mass, and lean body mass loss than control groups (weight difference in means -4.83, 95% CI, -6.01 to -3.66, P < 0.001; fat mass difference in means -2.94, 95% CI, -3.87 to -2.01, P < 0.001; lean body mass difference in means -1.46, 95% CI, -1.87 to -1.05, P < 0.001). A moderate to high level of heterogeneity was present in all three meta-analyses (weight: Q=30.96, P < 0.001, I2= 73.85%; fat mass: Q=20.98, P < 0.001, I2=82.98%; lean body mass: Q=20.67, P < 0.001, I2=65.40%). Conclusion Postmenopausal women who followed a hypocaloric diet experienced a reduction in weight and fat mass compared to those in the control group. However, the hypocaloric diet did not meet our hypotheses on increasing lean body mass, as the intervention only included a diet without any exercise, implying the use of stored fat and occasionally muscles.Item Open Access SCREENING FOR INHIBITORS OF ZEB1, A KEY REGULATOR OF EPITHELIAL TO MESENCHYMAL TRANSITION (EMT) IN BREAST CANCER CELLS.(Nazarbayev University School of Medicine, 2024-04-26) Abdulsalam, AbdullateefBackground: Breast cancer (BC) has an estimated new cases of about 2.3 million individuals and approximately 685,000 deaths in 2020, thereby making it the most common cause of mortality in women. Different subtypes of BC are categorized breast into three clinical subtypes based on the expression or lack of hormone receptors: progesterone (PR), estrogen (ER), and human epidermal growth factor receptor 2 (Her2). Despite the considerable progress made in the treatment of the various types of BC, more research is still needed to address some major obstacles in breast cancer treatment, especially those associated with poor prognosis and reduced survival rates among BC patients like chemoresistance and cancer metastasis; these processes are mediated by Zeb1, which is the key regulator of the EMT. Methods: Cell culture was used to propagate MCF7 cell lines and do transfection. Western blot was used to assess the effects on the markers of EMT such as Zeb1 and Cdh1. Cell cycle analysis using flow cytometry was used to examine candidate inhibitors of EMT after induction of Zeb1. Results: The induced MCF7 cells show a higher percentage of cell cycle arrests at the G1 phase than non-induced cells after treatment with candidate inhibitors. Conclusion: Out of the three PKC inhibitors tested midostaurin, auranofin, and resveratrol; resveratrol demonstrated a more significant impact on Zeb1-expressing cells than those without expression of Zeb1 by decreasing the percentage of cells at the G1 phase, hence, resveratrol might directly interfere with the activity of Zeb1Item Restricted THE QUALITY OF FAMILY PLANNING SERVICES IN KAZAKHSTAN: MIXED-METHODS STUDY(Nazarbayev University School of Medicine, 2024-04-23) Segizbayeva, AidanaFamily planning encompasses practices that help individuals and couples achieve their desired number of children, along with the preferred spacing and timing of births, integrating all aspects of reproductive and sexual health. This study employs a concurrent mixed-methods design, applying the Donabedian (1988) and Bruce (1990) framework, to evaluate the quality of family planning services in Kazakhstan from the perspectives of female patients and physicians. Quantitative data were gathered through online patient surveys and qualitative data through semi-structured interviews with physicians, recruiting 212 patients and five physicians via convenience and snowball sampling from social media platforms. Analysis of 21 quality indicator questions revealed the highest mean score in interpersonal relations, with overall high reliability (Cronbach’s alpha 0.94). Six semi-structured questions were asked, followed with probing questions from the physicians who provide family planning services. The study found that 43.4% of women use family planning services, aligning with physician observations that women generally consult gynecologists only when facing issues. Patients and physicians both highlight insufficient information and limited contraceptive options as major issues, alongside the cost barrier. However, while 42.4% of women felt that physicians lacked care and compassion during consultations, physicians believed they were empathetic, suggesting a disconnect in perceptions. The findings indicate gaps in the provision of accurate information, compassion in care, and appropriate referrals for unavailable treatments. This study highlights the need for enhanced policies and practices improving family planning services in Kazakhstan, aiming to better serve individuals and their families, and underscores the importance of integrating patient and physician insights to identify and implement improvements.Item Restricted BURNOUT AMONG INFORMAL CAREGIVERS OF DEMENTIA AND ALZHEIMER’S PATIENTS: SYSTEMATIC REVIEW(Nazarbayev University School of Medicine, 2024-04-23) Rakhimzhanova, DilaraBackground: The increasing prevalence of patients with dementia and Alzheimer’s disease has increased demands for informal caregivers. Due to emotional and physical strain of informal caregivers of patients with neurodegenerative diseases there is a high risk of caregivers being exposed to burnout syndrome. This systematic review aims to combine a current knowledge on prevalence and risk factors of burnout syndrome among informal caregivers of demented patients. Methods: This is a systematic review which was conducted using search of three electronic databases: PubMed; Cochrane Library and Web Of Science, from 1993 to 2024. There was a focus on studies quantitatively measuring burnout in informal caregivers of individuals with both dementia and Alzheimer’s disease. Results: This review included twelve studies conducted in 9 different countries across 5 continents. Four of the studies used the Pines Burnout Measure and five studies used Maslach Burnout Inventory to assess burnout. According to findings of this review, anxiety, depressive symptoms, low quality of life, being a female caregiver, initially poor health of caregiver, lack of positive attitude towards caregiving can bring informal caregivers towards burnout. Conclusion: Specific target interventions should be developed in order to ease the strain of informal caregiving with a consideration of risk factors of the burnout syndrome among family caregivers. There is a desperate need for further research of the topic in order to support a growing community of informal caregivers who are at a high risk of burnout.Item Embargo FUNCTIONAL ANALYSIS OF TYRO3 ISOFORMS IN BLADDER CANCER CELLS(Nazarbayev University School of Medicine, 2024-04-26) Ginayatova, IslanaBladder cancer (BC) is the 10th most common cancer type both in men and women and its incidence increases with age. TYRO3 is increased in 50% of muscle invasive bladder cancer (MIBCs), and TYRO3 overexpression confers TYRO3 dependence on bladder tumor cells. The downregulation of TYRO3 was linked to a decrease in bladder cancer cell growth and TYRO3 knockdown caused bladder cancer cell cycle arrest. The utilization of distinct BC cell lines in the investigations may imply that inhibiting TYRO3 has distinct effects. This thesis work hypothesizes that alternatively spliced TYRO3 isoform 2 is present in the nucleus of T24 and RT112 bladder cancer cells and regulates gene expression. Molecular cloning techniques were used to construct the recombinant plasmid, which were further transfected into T24 and RT112 cell lines and expression of protein were analyzed by Western Blotting method. The results of the thesis project are thoroughly presented and future perspectives are described.Item Restricted ELUCIDATION OF AUTOPHAGIC FLUX UNDER GLUCOSE AVAILABILITY(Nazarbayev University School of Medicine, 2024-04-26) Zhuban, AigerimAutophagy, crucial for maintaining cell homeostasis and cell renovation, has a significant role in the pathophysiology of various diseases. However, the association between autophagy and glucose accessibility remains insufficiently researched. The main objective of the research is to investigate autophagic flux under different concentrations of glucose, with a particular focus on its implications for cancer and diabetes. The findings of this study were based on the analysis of autophagic flux dynamics performed in MDA-MB231 and MCF7 human breast cancer cell lines subjected to different concentrations of glucose in the culture media. The methodology consisted of advanced laboratory techniques like MTT Assay, Western blotting, and Immunofluorescence Staining. We hypothesized that the pathways of autophagy may alter based on the different glucose availability within a cell. Investigating these dynamics provided insights into the thorough understanding of glucose-mediated autophagy and its relationship with pathologies, especially diabetes and cancer. A comprehensive understanding of the role of glucose in autophagy may have more considerable implications in the fields of medicine and healthcare, particularly in the development of therapeutic approaches to conditions characterized by dysregulated glucose metabolism, such as diabetes. The shift from normal to high glucose conditions did not produce a significant or consistent change in the autophagic flux of the breast cancer cell lines. Consequently, the modifications in glucose concentration within the normal to high range are not sufficient to solely inhibit or induce autophagy in MCF-7 and MDA-MB231 breast cancer cells.Item Restricted THE EFFECT OF METFORMIN TREATMENT ON AUTOPHAGIC FLUX IN BREAST CANCER(Nazarbayev University Graduate School of Medicine, 2024-04-26) Kazbek, IngkarAutophagy is a lysosome-mediated intracellular catabolic process that is involved in many physiological and pathological conditions, playing an essential role in preserving cellular homeostasis. Consequently, several studies have indicated dysregulation of autophagy in pathological diseases such as cancer and neurodegenerative disorders. Among various cancer types, breast cancer remains the most common in the world. The increased demand for breast cancer treatment requires advanced therapies and new approaches. Metformin, a commonly prescribed drug for type 2 diabetes, has recently attracted attention as a possible pharmacological autophagy modulator with an anticancer activity. Therefore, the goal of this thesis is to clarify the intricate connection between autophagy and the antidiabetic medication metformin by examining its impact on autophagic flux in breast cancer cell lines.Item Restricted FACTORS ASSOCIATED WITH ATTITUDES TOWARDS SUCCESSFUL AGING IN MIDDLE-AGED AND OLDER ADULTS IN KAZAKHSTAN: A CROSS-SECTIONAL STUDY(Nazarbayev University School of Medicine, 2024-04-25) Malikova, AigerimBackground: Successful aging is the concept which refers to the ability of an individual to retain a high degree of physical, mental, and social well-being as one ages preferably without the presence of chronic illnesses or other age-related challenges. Attitudes towards aging are a comprehensive personal view of the experience of aging throughout the lifetime, which can be influenced by various factors, such as the levels of health, self-sufficiency, social, physical, psychological and demographic factors. The aim of our study was to identify the factors associated with attitudes towards successful aging among middle-aged and older adults in Kazakhstan by determination of the attitudes towards successful aging and identification of the socio-demographic and health-related factors associated with attitudes towards successful aging among middle-aged and older adults in Kazakhstan. Methods: This study was a quantitative cross-sectional study which involved an online survey targeting middle-aged adults (from 40 to 64) and older seniors (from 65 to 79) with a sample size of 70. The questionnaire was built in Qualtrics survey platform, and the link was disseminated through purposive and convenience sampling methods via social media networks (WhatsApp, Telegram, VK, Instagram). The survey covered socio-demographic information, a 12-item short form of attitudes towards aging questionnaire and health and leisure-time activities questions. The results of the study were obtained through the univariate and bivariate analyses on STATA 18 statistical software. Results: It was found that 27.14% of participants were in the category of 40-49 years, 32.86% in the age group of 50-59 years, 31.43% were the ones who were in 60-69 age category, while only 8.58% of participants belonged to the 70-79 age category. Most of the participants were females (67.14%) and the majority of participants identified themselves as representatives of Kazakh (69.57%) nationality. The average AAQ-SF score was 47.2 (SD ± 4.9) with the high internal consistency of 0.7728 in accordance with Cronbach's alpha score. The average scores of the AAQ-SF scale for the positive dimensions such as physical change and psychological growth were 15.5 (SD ± 2.4) and 16.5 (SD ± 1.6), respectively. While the score for the negative dimension, psychosocial loss, was 14.7 (SD ± 2.9), slightly lower than the other two positive dimensions. The results showed that gender, financial satisfaction, chronic diseases, physical health and mental health were found to be statistically significantly associated with the Attitudes to aging score. Conclusion: Study findings showed that the possible factors positively associated with attitudes towards successful aging were male gender, satisfactory financial status, absence of chronic diseases, good physical and mental health. Findings of this study may serve as one of the potential effective tools to develop public health strategies and health promotion programs aimed to support older adults in maintaining physical health, mental well-being, social connections, and overall quality of life. Keywords: Successful aging, Attitudes to successful aging, Factors influencing attitudes to aging, Middle-aged adults, Older adults, Cross-sectional studyItem Embargo THE REGIONAL BURDEN OF PARKINSON’S DISEASE IN KAZAKHSTAN 2014–2021: INSIGHTS FROM NATIONAL HEALTH DATA(Nazarbayev University School of Medicine, 2024-04-24) Akhmedullin, RuslanBackground. Globally, neurological illnesses are the primary cause of disability, with Parkinson's disease (PD) showing the greatest rate of growth. The Global Burden of Disease (GBD) study evaluated 5.5 million Disability-adjusted life-years (DALYs) in 2017. The GBD study underscores the need for research in regions lacking data, such as Central Asia (CA). Methods. Using the Unified National Electronic Health System of Kazakhstan over eight-year span (2014-2021), we explored the epidemiology, DALYs, and all-cause mortality in the PD cohort. Cox proportional hazards regression models and Kaplan-Meier analysis with sensitivity analyses were performed to evaluate the sociodemographic, hypertension and Charlson Comorbidity Index (CCI) affecting survival. Results. The total cohort comprised 10,125 patients, with a significant increase in the prevalence from 4.2 in 2014 to 44.1 in 2021. While mortality rates varied, the eldest (≥80) and youngest (<50) age groups had the highest (137.05) and lowest (16.40) rates per 1000 person-years, respectively. Over the course of observation, 29,474 DALYs were lost due to PD, with a substantial contribution of years of life lost. Finally, there was an increased risk of all-cause mortality among the male sex (adjusted hazard ratio (aHR) 1.6; 1.5-1.8), older age (1.02; 1.01-1.03), greater CCIs and Kazakh ethnicity. Interestingly, patients with comorbid hypertension had higher probability to survive (0.63; 0.57-0.70). Conclusion. To our knowledge, this is the first study in CA to explore the burden of PD. The increasing burden of PD among males and ethnic Kazakhs underscores the necessity for focused interventions. Further efforts must be made to understand the inverse association of hypertension in PD cohort.Item Embargo FACTORS ASSOCIATED WITH MENTAL HEALTH AND WELLBEING OF ADULT PEOPLE LIVING WITH HIV IN KAZAKHSTAN(Nazarbayev University School of Medicine, 2024-04-24) Abenova, AdelAbstract Objectives The purpose of the current study was to investigate the association of a range of demographic, physical and psychosocial factors with positive mental health and mental illnesses (depression and anxiety), in adults living with HIV in Kazakhstan. Methods To conduct the current cross-sectional study, the Qualtrics online survey platform was utilized. We collected date from January to February 2024. The study included 170 individuals (18 years and older) living with HIV in Kazakhstan who agreed to participate by signing electronic informed consent. The online survey consisted of overall 48 questions and four parts: (1) Socio-demographic information ; (2) General health information, (3) Mental health , and (4) HIV related stigma. Results Only 33.53% of adults living with HIV are flourishing and have no mental illness. People in flourishing without mental illness group receive more social support. People who rated their physical functioning as mostly able and complete were least likely to fall into the flourishing with mental illness group. People who see themselves as not flourishing or languishing in life, can be more at risk for depression and anxiety due to lack of flourishing. Mental illness without flourishing (languishing) group accounted for 20.59% of the sample. People older than 44 years old are less likely to fall into this group. People who have a good assessment of their ability to perform daily physical activity are less likely to fall into this group. This group presented a high association with internal stigma. People living with HIV falling into this group receive less social support. Conclusions Our study demonstrated that a third of the present sample have positive mental health and are flourishing, and this was associated with high social support. People with more advanced levels of physical functioning were less likely to flourish in the presence of mental illness. Insufficient social support, internal stigma, difficulty in performing daily physical activities and younger age have an significant association with anxiety and depression without flourishing. Continued efforts are recommended on increasing public awareness of HIV infection in Kazakhstan, with a special focus on reducing discrimination in various spheres of life, which affects internal stigmatization and mental health of individuals with HIV in Kazakhstan. Practice implications It is recommended to increase availability of social services and support for individuals with HIV, as this could benefit their mental health and well-being.Item Restricted EXAMINATION OF THE EFFECTS OF SOCIAL MEDIA ON MENTAL HEALTH OF YOUNG ADULTS IN KAZAKHSTAN: A CROSS SECTIONAL PILOT STUDY(Nazarbayev University School of Medicine, 2024-04-23) Zhamashova, DinaraIntroduction. Previous investigations have shown that the presence and use of SM affects aspects of a person's life, both negatively and positively. The purpose of our study was to examine the association between the amount of screen time, multiple use of SM and level of engagement with SM on mental health of young people in Kazakhstan, focusing on positive mental health, and adjusting for the effect of demographic and health behaviors factors. Methods. A cross-sectional study was used as the study design. Data were collected from December 2023 through January 2024. The inclusion criteria were age from 18 to 35 years old and having a profile in any SM. Questionnaire consisted of 30 questions. Positive mental health (PMH) was measured using Short Warwick–Edinburgh Mental Well-Being Scale (SWEMWBS) scale; depression and anxiety with one-item questions. A total of 235 people participated. Linear and logistic regression were performed for multivariate analysis to predict PMH, depression and anxiety (p<0.05). Variables were also checked for interactions and multicollinearity. Results. Being moderately or not addicted to social media has a positive relationship with PMH. Individuals who spend more than 7 hours of time on social networks and have moderate to severe fear of missing out have increased odds of depression. Furthermore, those who consider themselves very addicted to social networks have higher odds of having anxiety. Conclusion. High amount of screen time and addiction to SM has been found to negatively impact psychological health. Whereas, moderate use of social networks, on the contrary, improves PMH. Further studies are recommended to examine how the nature of the content affects psychological health. In order to improve positive mental health and reduce depressive and anxiety symptoms, moderate use of social media, adequate quality sleep, and exercise are recommended.Item Restricted STUDYING EFFECTS OF ZEB1 KO IN TRIPLE-NEGATIVE BREAST CANCER CELLS MDA-MB-231(Nazarbayev University School of Medicine, 2024-04-26) Issakhanov, DarkhanOne of the main problems in cancer therapy is the resistance of cancer cells to various anticancer drugs. Targeted anticancer drugs categorized on their effect to cancer hallmarks. According to the principles of functioning, anticancer drugs are divided into: growth factor inhibitors, pro-apoptotic drugs, immune checkpoint inhibitors, telomerase inhibitors, inhibitors of VEGF signaling, PARP inhibitors, metastasis suppressors, inhibitors of glycolysis and aerobic metabolism, inactivators of drug efflux and detoxication machinery etc (Dembic, 2020). The main mechanisms of resistance to them are: increased DNA repair, increased efflux of drugs, enhanced metabolism of drugs, growth factor compensation, genetic and epigenetic factors modification (Holohan et al., 2013; Kachalaki et al., 2016; Mansoori et al., 2017). One of these mechanisms which helps to avoid drugs effect is epithelial-mesenchymal transition (EMT) (Hashemi et al., 2022). EMT can give resistance to such drugs as doxorubicin via AMPK overexpression (Andugulapati et al., 2022), cisplatin via 14,15-epoxyeicosatrienoic acid (Luo et al., 2018), tamoxifen via Cx43 loss (Wu et al., 2021) etc. Also EMT is activated for metastasis of cancer cells and as a result, unfavorable prognosis in treatment. That’s why EMT has particular importance in treating of triple-negative breast cancer (TNBC) (Grasset et al., 2022) the most aggressive type of breast cancer. TNBC is characterized by high heterogeneity and the absence of major target receptors: estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2). Many research groups reported about mesenchymal gene expression in TNBC, suggesting EMT (Jang et al., 2015). One of the regulators of EMT are Zinc finger E-Box binding homeobox 1 (ZEB1), proteins that encoded by ZEB1 gene, located on chromosome 10p11.2 (Williams et al., 1992). Main function of this transcription factor is linked to the promotor region of the epithelial cell marker protein E-cadherin, causing the cells to lose their epithelial properties (Larsen et al., 2016). The importance of ZEB1 in TNBC therapy is due to its ability to promote chemoresistance through various mechanisms such as activated ataxia-telangiectasia mutated (ATM) kinase expression by forming a ZEB1/p300/PCAF complex (X. Zhang et al., 2018) or by repression of E-cadherin in AR-negative docetaxel-resistant sublines (Hanrahan et al., 2017). This work shows the effect of a knockout of the gene responsible for the synthesis of ZEB1 using the CRISPR-CAS-9 technology.Item Open Access ROLE OF THE RETROMER COMPLEX IN FERROPTOSIS(Nazarbayev University School of Medicine, 2024-04-26) Abdukarimov, NurzhanFerroptosis is a recently discovered mechanism of regulated cell death that occurs due to the excessive peroxidation of plasma membrane lipids. This reaction depends on catalysis by intracellular ferrous iron (Fe2+) and is counteracted by antioxidant defense systems. Transferrin receptor 1 (TFRC) is an essential contributor to intracellular iron metabolism because it facilitates the import of extracellular iron. Unsurprisingly, the overexpression of TFRC is an accurate marker of ferroptosis. Recent findings highlight the potential involvement of TFRC recycling in ferroptosis regulation. In particular, sorting nexin 3 (SNX3), a component of the retromer complex responsible for retrograde trafficking of TFRC, has been implicated in ferroptosis-induced cardiomyopathy. This makes SNX3 a potential target for therapeutic intervention or a marker of ferroptosis sensitivity. SNX3 expression is correlated with increased iron burden and epithelial–mesenchymal transition in breast cancer patients. Therefore, we hypothesize that SNX3 could play a role in promoting cancer development by increasing the amount of intracellular iron. Moreover, SNX3 might also sensitize cancer cells to ferroptosis-inducing agents.Item Restricted KRAS MUTANTS, A KEY ONCOGENE IN NON-SMALL CELL LUNG CANCER(Nazarbayev University School of Medicine, 2024-04-26) Samarkhanova, DianaCancer, a disease with a high risk of mortality, continues to pose a significant global health challenge, affecting millions of individuals every year. Non-small cell lung cancer (NSCLC), which accounts for 80–85% of lung cancer cases, is one of the most prevalent cancer types (Xie et al., 2021). The Kirsten rat sarcoma viral oncogene homologue (KRAS) is one of the most commonly mutated genes in NSCLC. KRAS encodes a protein that has both active and inactive states. In cancer, this protein remains persistently active, leading to angiogenesis and tumorigenesis (Matsuo et al., 2009). More than 80% of KRAS mutations are found at codon 12, with the most prevalent mutations being KRAS G12C (40%), KRAS G12V (18–21%), and KRAS G12D (17–18%), among others (Xie et al., 2021). Current research on G12C inhibitors has shown promising cancer therapy candidates such as sotorasib and adagrasib (Kwan et al., 2022). However, acquired resistance to inhibitors of the G12C mutation has been observed over time (Blaquier et al., 2021). Therefore, it is necessary to generate KRAS mutants that can be used for drug screening to analyze the efficacy of drugs and resistance mechanisms. The purpose of this project is to use CRISPR/Cas9-mediated introduction of mutations to develop KRAS mutant models with G12C, G12V and G12D mutation in the H1299 cell line. KRAS mutants further can be used to screen new drug candidates for the KRAS-dependent NSCLC. The motivation behind this effort is the generating cell lines with endogenous mutations by homology-directed repair (HDR) in the KRAS second exon that will mimic natural conditions and show more physiologically relevant data, which is necessary to analyze the effectiveness of different treatments. In summary, this project tested the efficacy of generating knockout of the KRAS gene and the introduction of G12C, G12V and G12D mutations to the second exon of KRAS in the H1299 cell line using CRISPR/Cas9 system. The results of the research project showed the low efficacy of HDR to generate endogenous mutations and the successful application of CRISPR/Cas9 to generate KRAS knockout clones.Item Embargo ROLE OF PERIOSTIN IN RHEUMATOID ARTHRITIS(Nazarbayev University School of Medicine, 2024-04-26) Kurmanova, AsiyaRheumatoid Arthritis (RA) is defined as an autoimmune disease of chronic character that principally leads to inflammation in synovial joints. Periostin belongs to the extracellular matrix protein family. It plays a role in ontogenesis and is produced in adult tissues subjected to mechanical forces inclusive of bones and joints. It has been shown to have increased expression in the synovium of patients with RA (Kasperovitz et al., 2005). In research by Chijimatsu et al. (2015), human primary chondrocytes expressed interleukin (IL)-6, IL-8, IL-1, matrix metalloproteinase (MMP)-1, MMP-3, MMP-13, as well as nitric oxide synthase-2 (NOS2) in response to periostin. This suggests that periostin may amplify inflammatory events. Per contra, in the results demonstrated by Cheon (2017), mean histologic severity scores were elevated in periostin-deficient mice compared to wild type implying a protective role of periostin in RA. Considering the contradictory results of the abovementioned studies and the lack of information regarding the presence of periostin splice variants, further investigations are needed. This project examines periostin's anti-inflammatory role in a mouse RA model. In this study, 4 wild type and 2 periostin-KO underwent immunization injections to establish a collagen-induced arthritis (CIA) mouse model (Brand et al., 2007). The effect was evaluated observationally, by taking weight and hind paw measurements, histologically and immunohistochemically by staining for periostin and RAR-related orphan receptor gamma (RORγ).Item Open Access DELIVERY OF BIOMATERIALS WITH CYTOKINES AND GROWTH FACTORS FOR MYOCARDIAL INFARCTION TREATMENT(Nazarbayev University School of Medicine, 2024-04-26) Khoschanova, DianaOne of the crucial and highly specialized organs in the human body is heart. It has limited regenerative and self-healing potential after the event of injury or illness. Therefore, heart transplantation is the primary treatment for end-stage cardiovascular disorders at the moment. Cardiovascular disease, particularly ischemic heart disease, continues to be one of the main causes of mortality worldwide. After a heart attack, the injured cardiomyocytes are lost and replaced with fibrotic scar tissue (Hashimoto et al., 2018). Cardiomyocyte loss has several consequences, for instance, the reduction of ventricular contraction, which triggers more cardiomyocyte loss, pathological cardiac dilatation, and ultimately heart failure. These series of events fall under the term “cardiac remodeling” (Tenreiro et al., 2021). The main objective of many treatments has been to prevent the gradual cardiac remodeling that leads to heart failure. Currently available effective treatments are medications, coronary artery bypass grafting, percutaneous coronary intervention and heart transplantation (Head et al., 2018). This paper aims to describe a treatment protocol that includes the sequential administration of a composite cryogel with specific cytokines and growth factors. Firstly, the cryogel containing interleukin-10 (IL-10) was directly injected intramyocardially immediately after the induction of myocardial infarction, with the aim to target the acute inflammatory response. A second injection of cryogel loaded with vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2) was done on day 7 post-MI. The purpose of the second injection was to stimulate tissue regeneration and the formation of new blood vessels (neoangiogenesis). In the cohort treated with Cryogel/GF, the study’s results demonstrated significant myocardial tissue regeneration. Masson’s Trichrome staining verified the echocardiographic findings, which showed decreased fibrotic areas and increased ejection fraction as well as fractional shortening. Therefore, the newly-developed chitosan-based cryogel contains anti-inflammatory and proangiogenic components, making this biomaterial an excellent cargo for the controlled release of therapeutic factors. Consequently, this will significantly improve tissue regeneration post-myocardial infarction. Hypothesis: cryogel containing IL-10 cytokine and VEGF/FGF-2 growth factors delivered sequentially will improve cardiac regeneration after MI.Item Restricted OPTIC NERVE ULTRASONOGRAPHY FOR DETECTING INTRACRANIAL PRESSURE IN PATIENTS WITH CEREBROVASCULAR DISEASES: A SYSTEMATIC REVIEW(Nazarbayev University School of Medicine, 2024-04-23) Tungushpayev, MeiramIntroduction: Ultrasonography shows potential as a diagnostic method for identifying intracranial hypertension. Nevertheless, its diagnostic performance in measuring optic nerve parameters remains ambiguous. To address this uncertainty and assess its significance in clinical practice, a systematic review of the literature was conducted. Methods: A systematic search was carried out across PubMed, Google Scholar, and the Cochrane Library databases. The quality of evidence was evaluated utilizing the Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology, while the risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) checklist. Results: 507 records were identified, following the removal of 499 records, 8 observational studies remained for final review covering 329 participants. The reported diagnostic accuracy of ultrasonography ranged between 58.8% to 100% concerning sensitivity, 67% to 100% for specificity, 43.5% to 100% for positive predictive values (PPV), and 50% to 100% for negative predictive values (NPV). Conclusion: The literature suggests that ultrasonography demonstrates comparable accuracy to reference computed tomography in measuring the optic nerve, but depends on the expertise of the sonographer. Further investigation is required to fully understand its diagnostic performance.