Asian Medical Institute, Kyrgyzstan

Background: Chronic Myeloid Leukemia (CML) is a myeloproliferative stem cell malignancy. Chronic Phase CML (CP) is treatable with overall survival equivalent to general public. Nevertheless, a proportion of CP-CML progresses to the accelerated phase (AP-) and ultimately blast crisis (BC), with the later having an overall survival of 3-23 months, making it almost a fatal manifestation. Therefore, treatment of BC-CML is of the biggest challenges in modern cancer medicine. FDA-approved drugs are available against a large number of mutated genes reported in AML and ALL. As BC-CML resembles AML (myeloid BC) or ALL (lymphoid BC), this study was designed to find out AML-/ALL lineage gene mutations in BC-CML, find their druggability and feasibility of their utilization in patient-tailored treatment of BC-CML. Patients & Methods: The study included 141 CML patients (123 CP-CML as control groups; 6 AP-CML and 12 BC-CML as experimental groups). Most of the patients received imatinib mesylate (IM) as first-line treatment. All response criteria were per European LeukemiaNet (ELN) guidelines 2020. Whole exome sequencing (WES) was carried out to find out druggable gene mutations and the druggability of the mutated genes was determined using online tool www.pandrugs.com. SAS/STAT software version 9.4 was used for data analysis (SAS Institute Inc., Cary, NC, USA). For statistical computing, the R package was employed (Vienna, Austria). The study was approved by ethical committee of KAIMRC and carried out per guidelines o of the Helsinki Declaration Results: Overall male-to-female ratio was 1.6:1 and the mean age was 36.4 (range: 9 -67) years. Eighteen (12.8%) patients progressed to AP-CML while 12 (8.5%) to BC-CML finally. BC-ML patients had overall poorer response to TKIs and higher mortality rate (75%) that prompted to look for druggable gene mutations in advanced phase CML. WES showed overall 64 AML-/ALL- associated gene mutated in advanced phase CML patients. AP-CML had 1644 variants, whereas BC-CML had 2531 variants, with a 54% gain in mutations from AP-CML to BC-CML (P< 0.000001). Among AML-/ALL- related mutated genes were NPM1 (%1.98), DNMT3A (%1.86), PML (%1.82), AKT1 (%1.62), CBL (%1.30), JAK2 (%0.71), TET2 (%0.59), IDH1 (%0.32), and BCL2, which have FDA-approved drug to target them. Conclusions: NGS found druggable mutations in many AML-/ALL-lineage genes. Many of the corresponding drugs are either already approved for BC-CML treatment or in clinical trial phase. We conclude that our approach can help in finding druggable gene mutations related to AML-/ALL-lineage genes in almost every BC-CML patients and provide a practical guidance for drug repurposing to individualize BC-CML patient treatment. Keywords: Blast crisis Chronic Myeloid Leukemia; druggable mutations; pa-tient-tailored treatment; AML lineage genes; ALL lineage genes. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was funded by the National Plan for Science, Technology and Innovation (MAARIFAH), King Abdul-Aziz City for Science and Technology, Kingdom of Saudi Arabia, Grant Number 14-Med-2817-02. The study was conducted in accordance with the Declaration of Helsinki. It was approved by Intuitional Review Board (IRB) of King Abdullah International Medical Research Centre (KAIMRC), National Guard Health Affairs, Saudi Arabia through project # RA17/002/A, dated 4th Feb 2019., although no research funding was provided by KAIMRC. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The study was conducted in accordance with the Declaration of Helsinki. It was approved by Intuitional Review Board (IRB) of King Abdullah International Medical Research Centre (KAIMRC), National Guard Health Affairs, Saudi Arabia through project # RA17/002/A, dated 4th Feb 2019., although no research funding was provided by KAIMRC. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Access to data made by next-generation sequencing can be obtained from NCBI, to which it was submitted, at https://www.ncbi.nlm.nih.gov/sra/PRJNA734750 (SRA accession number PRJNA734750; accessed on 24 April 2024).

Currently, the spread of micro- and nanoplastics in the food chain and the environment has become a relevant and social issue. They enter the human body mainly through food, water and drinks packaged in various plastic materials, bottles or containers. It has been established that most urban water sources are contaminated with microplastics due to wastewater. The main objective of the article was to study the awareness of microplastic sources, exposure levels and potential health risks associated with microplastic contamination of food and water by surveying a heterogeneous audience of Internet users. The preventive focus of the survey included: 1) holding an action at the medical faculty of KRSU “Day without plastic”; 2) development, publication and distribution of an information leaflet in the Internet community on the key sources of microplastics in the daily human diet. The test group consisted of 502 Internet users. The author's questionnaire included 26 questions: personal data (5 questions), the size of microplastics, sources of information, an assessment of the risk factors for microplastics entering the body, its content in food and water and the impact on human health (a list of 16 diseases associated with microplastics is provided). Statistical processing of the obtained results was carried out using SPSS version 28.0.1 software. Questionnaires of 502 respondents aged 14–50 years were obtained through an online survey from October 2023 to January 2024 using Google forms. The demographic structure reflected the predominance of female representatives - 52.4%, men accounted for 47.6%. In terms of education level, students dominated among the subjects, incomplete higher education (67.3%), then secondary (14.8%), higher (9.9%) and primary education (8.8%). Most of the respondents lived in the city (80.3%), compared to rural areas (19.7%). Since the survey involved young people, 49.8% of respondents correctly answered the question that microplastics are small particles measuring 5 microns. 50.2% of respondents answered incorrectly, indicating sizes of 10 and 15 microns. Respondents noted that microplastics are most often found in bottled water (29.5%), tea bags (17.3%), natural water (10.3%), fish (8.1%), salt (6.3%), seafood (5.5%) and honey (4.5%). All of the above were noted by 29.5% of respondents. Most respondents to the question: which vegetables are most often contaminated with microplastics, answered that none (38.5%), followed by root vegetables (30.4%), onions (13.1%), cabbage (9.7%) and legumes (8.3%). Among the presented sample - the correct answer is - root crops are most susceptible to contamination. The results of the survey show that in everyday life 45.8% of respondents most often used plastic bags (55.7%), food packaging (18.7%), then cosmetics and hygiene products (17.4%), toys (5.9%) and cutlery (2.3%). Living in a “plastic world”, Internet users somehow do not notice it, to the question of how often the respondents use plastic products, 64.7% of them answered that every day, 26.7% - sometimes, 8.6% — rarely. As the results of the survey showed, most often Internet users received information about the harm of microplastics from social networks 26.5%, Google search engine — 20.7%, scientific articles — 18.9%, news — 17.1%, while communicating with friends, family — 5.5%. At the same time, 11.3% of respondents were not interested in the problem. When comparing the assessment of awareness of the direct and indirect impact of plastic on human health during plastic production and consumer use of plastics, they were aware (46.0% and 37.1%, respectively), slightly aware (31.9% and 37.8%) and did not know (22.1% and 25.1%). The risk that plastic pollution poses to wildlife, as well as to human health, well-being and prosperity, was assessed by respondents as average. 34.6% of respondents were in favor of actively reducing the use of plastic products. 33.7% of survey participants are still at the level of awareness of the problem and attempts to reduce plastic consumption. 31.7% find it difficult to answer, since they do not see an alternative. When asked about awareness of the impact of microplastics (the silent killer) on the development of 16 specific diseases, respondents were most aware of: digestive diseases, allergies, chronic inflammation, respiratory problems, cancer and reproductive problems.

The objective of the present research was intended to formulate multigrain premix powder which could be utilized for the development of nutritional rich products. The multigrain premix was prepared by blending the seeds of pumpkin, jackfruit, and mango with barley, pearl millet, finger millet, sorghum, and other ingredients such as cardamom, and sugar. Before optimizing the composition of premix flour, around 8 combinations of each flour and seed powders were made to obtain the preeminent quality premix with high nutritional value. The formulation of flour was optimized on the basis of sensory analysis done by using 9-hedonic scale. The formulated multigrain premix was analysed for its nutritional and sensorial characteristics. Multigrain premix resulted in protein content of 5.35 g, carbohydrate 80.25 g, fat 6.88 g, ash 3.87 g, dietary fibres 8.67 g, calcium 73.25 mg, and iron 2.94 mg per 100 g of the mixture and many more minerals were also estimated in the given premix. Total energy was noted as 404.32 kcal. The GC–MS analysis was also performed to identify the composition of fat in terms of their saturation. Moreover, the shelf life study of multigrain premix was carried out for a period of 45 days at a temperature and relative humidity of 25 °C and 91

Systemic lupus erythematosus (SLE) is an autoimmune disease that can present with various clinical manifes- tations, and early diagnosis and treatment are crucial to prevent irreversible organ damage. Here, we report a case of a 35-year-old female with chronic hepatitis C virus (HCV) infection who presented with hematolog- ical and musculoskeletal symptoms, ultimately leading to a diagnosis of SLE. The patient’s workup included positive ANA and dsDNA tests and a CT scan revealing an oval-shaped lytic lesion in the medullary cavity of the right iliac bone

Objective: BCR-ABL fusion oncogene is the hallmark of chronic myeloid leukemia (CML), causing genomic instability which leads to accumulation of mutations in BCR-ABL as well as other genes. BCR-ABL mutations are the cause of tyrosine kinase inhibitors (TKIs) resistance in CML. Recently, compound BCR-ABL mutations have been reported to resist all FDA approved TKIs. Therefore, finding novel compound BCR-ABL mutations can help and clinically manage CML. Therefore, our objective was to find out novel drug-resistant compound BCR-ABL mutations in CML and carry out their protein modelling studies. Methodology: Peripheral blood samples were collected from ten imatinib resistant CML patients receiving nilotinib treatment. BCR-ABL transcript mutations were investigated by employing capillary sequencing. Patient follow-up was carried out using European LeukemiaNet guidelines. Protein modeling studies were carried out for new compound mutations using PyMol to see the effects of mutations at structural level. Results: A novel compound mutation (K245N mutation along with G250W mutation) and previously known T351I utation was detected in two of the nilotinib resistance CML patients respectively while in the rest of 8 nilotinib responders, no resistant mutations were detected. Protein modelling studies indicated changes in BCR-ABL mutant protein which may have negatively impacted its binding with nilotinib leading to drug resistance. Conclusion: We report a novel nilotinib resistant BCR-ABL compound mutation (K245N along with G250W mutation) which impacts structural modification in BCR-ABL mutant protein leading to drug resistance. As compound mutations pose a new threat by causing resistance to all FDA approved tyrosine kinase inhibitors in BCR-ABL+ leukemias, our study opens a new direction for in vitro characterization of novel BCR-ABL compound mutations and their resistant to second generation and third generation TKIs.