2024 16 4 0 113

F8 Gene Splice Donor Mutation (c.1271+1G>A) in Individual with Mild Hemophilia A in Indonesia: A Case Study 2 2 Introduction: Hemophilia A is a bleeding disorder caused by a deficiency of coagulation factor VIII. Hemophilia A is an X-linked recessive disorder. Depending on the level of blood coagulation factor VIII, hemophilia severity is classified as mild (5-40%), moderate (1-5%), or severe (<1%). The absence of hemophilia A mutation studies in Indonesia makes this topic important to study. Methods: This study detected and classified F8 gene mutations. A member of the Indonesian Hemophilia Society Association for the Special Region of Yogyakarta provided saliva for DNA testing. Long-read sequencing data were performed using the next-generation sequencing (NGS) technique via the Oxford Nanopore Technologies plc (ONT) PromethION 24 platform. The mutation was confirmed using Sanger sequencing, after amplifying intron 8 of the F8 gene with the PCR technique. The F8 gene intron 8 nucleotide sequence was aligned using the alignment tool on the Benchling website. Results: The results of this study showed that there was a splice donor site mutation in intron 8 of the F8 gene (c.1271+1G>A) in one patient. This mutation can cause the occurrence of cryptic splice donor sites. Cryptic splice donor site prediction was carried out using the splice donor prediction tool available on the NNSPLICE website. The appearance of cryptic splice donor sites can lead to the formation of out-of-frame proteins. Conclusions: The F8 gene mutation causing hemophilia A was detected using long-read sequencing and the next-generation sequencing (NGS) technique. The type of mutation identified is a splice donor site mutation, specifically the variant c.1271+1G>A, in sample code HM13. 1 8 2024/10/26 1403/8/5 2024/12/24 1403/10/4 Ni Gusti Ayu Galuh Candra Kirana Ni Gusti Ayu Galuh Candra Kirana Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia nigustiayugaluhcandrakirana@mail.ugm.ac.id Suprianto Suprianto Suprianto Suprianto Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia Suprianto1997@mail.ugm.ac.id Indra Lesmana Indra Lesmana Department of Tropical Biology, Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia. indra.lesmana@ugm.ac.id Usi Sukorini Usi Sukorini Department of Clinical Pathology and Laboratory Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia ussi@ugm.ac.id Niken Satuti Nur Handayani Niken Satuti Nur Handayani Department of Tropical Biology, Faculty of Biology, Universitas Gadjah Mada, Yogyakarta, Indonesia. niken_satuti@ugm.ac.id Hemophilia A F8 gene Intron 8 Donor splice mutation c.1271+1G ## ##

Hematology and Hematopathology Insights Powered by Machine Learning: Shaping the Future of Blood Disorder Management 2 2 Introduction: The field of hematology faces significant challenges in data analysis, especially in the diagnosis and prediction of diseases. Traditional methods of analysis are often time-consuming, complex, or inadequate to handle the complex nature of blood-related data. This requires the development of advanced techniques for accurate prediction and classification. Artificial Intelligence (AI)-based methods have emerged as a powerful solution that enables more efficient and accurate analysis of hematological data. This study aims to systematically review published research on the use of different artificial intelligence algorithms in the analysis of this field of data. Methods: Using a combination of keywords related to blood data analysis and artificial intelligence, we searched medical and scientific databases to identify relevant articles. A data extraction form was developed to collect relevant information from selected studies based on predefined inclusion and exclusion criteria. The content analysis method was used to analyze the extracted data and the findings were organized in tables and figures to meet the research objectives. Results: After reviewing 7300 studies, 25 full-text studies were selected for final analysis based on their relevance to the research objectives. The findings showed that AI methods, especially deep learning (DL), are widely used to predict and diagnose hematological and Hematopathological diseases. Among the most common algorithms used in ML were XGBoost, which was one of the most important deep learning algorithms, as well as Convolutional Neural Networks (CNN). AI-based models had Accuracy, Specificity, and Sensitivity of 96.6%, 95%, and 96%, respectively. Conclusion: This review shows that AI-based models have the potential to be significantly applied to the analysis of blood data. As artificial intelligence continues to evolve, medical professionals and researchers will have access to powerful ML-based tools to quickly and accurately diagnose. 9 19 2024/10/262024/11/19 1403/8/29 2024/12/242024/12/2 1403/9/12 Rahime Tajvidi Asr Rahime Tajvidi Asr Health and biomedical informatics Research Centers, Urmia University of Medical Sciences,Urmia,Iran. rahimetajvidy@yahoo.com Milad Rahimi Milad Rahimi Health and biomedical informatics Research Centers, Urmia University of Medical Sciences,Urmia,Iran. rahimimiladofficial@gmail.com Mohammad Hossein Pourasad Mohammad Hossein Pourasad School of paramedical, Kermanshah University of Medical Sciences, Kermanshah, Iran. pourasad.mh@gmail.com Salar Zayer Salar Zayer School of Medicine, Urmia University of Medical Sciences, Urmia, West Azerbaijan, Iran. dr.salarzayer@gmail.com Mohammadreza Momenzadeh Mohammadreza Momenzadeh Department of Artificial Intelligence in Medical Sciences, Smart University of Medical Sciences. momenzadeh.mr@gmail.com Mustafa Ghaderzadeh Mustafa Ghaderzadeh Boukan Faculty of Medical Sciences, Urmia University of Medical Sciences, Urmia, Iran. mustafa.ghaderzadeh@gmail.com Hematology Hematopathology Machine Learning Blood Disorder M. Ghaderzadeh, A. Shalchian, G. Irajian, H. Sadeghsalehi, and B. Sabet, "Artificial intelligence in drug discovery and development against antimicrobial resistance: A narrative review," Iran. J. Med. Microbiol., vol. 18, no. 3, pp. 135-147, 2024.##M. Ghaderzadeh, M. Aria, A. Hosseini, F. Asadi, D. Bashash, and H. Abolghasemi, "A fast and efficient CNN model for B-ALL diagnosis and its subtypes classification using peripheral blood smear images," Int. J. Intell. Syst., vol. 37, no. 8, pp. 5113-5133, 2022.##A. Bazinet et al., "Automated quantification of measurable residual disease in chronic lymphocytic leukemia using an artificial intelligence‐assisted workflow," Cytom. Part B Clin. Cytom., vol. 106, no. 4, pp. 264-271, 2024.##T. Dehkharghanian, Y. Mu, H. R. Tizhoosh, and C. J. V Campbell, "Applied machine learning in hematopathology," Int. J. Lab. Hematol., vol. 45, no. S2, pp. 87-94, 2023.##Y. Hu, Y. Luo, G. Tang, Y. Huang, J. Kang, and D. Wang, "Artificial intelligence and its applications in digital hematopathology," Blood Sci., vol. 4, no. 3, pp. 136-142, 2022.##D. Moher et al., "Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement," Syst. Rev., vol. 4, pp. 1-9, 2015.##P. F. Whiting et al., "QUADAS-2: a revised tool for the quality assessment of diagnostic accuracy studies," Ann. Intern. Med., vol. 155, no. 8, pp. 529-536, 2011.##S. El Hussein, P. Chen, L. J. Medeiros, J. D. Hazle, J. Wu, and J. D. Khoury, "Artificial intelligence-assisted mapping of proliferation centers allows the distinction of accelerated phase from large cell transformation in chronic lymphocytic leukemia," Mod. Pathol., vol. 35, no. 8, pp. 1121-1125, 2022.##N. Aydin Atasoy and A. Faris Abdulla Al Rahhawi, "Examining the classification performance of pre-trained capsule networks on imbalanced bone marrow cell dataset," Int. J. Imaging Syst. Technol., vol. 34, no. 3, p. e23067, May 2024.##S. Koga, "Exploring the pitfalls of large language models: Inconsistency and inaccuracy in answering pathology board examination-style questions," Pathol. Int., vol. 73, no. 12, pp. 618-620, Dec. 2023.##J. S. Mohlman, S. D. Leventhal, T. Hansen, J. Kohan, V. Pascucci, and M. E. Salama, "Improving Augmented Human Intelligence to Distinguish Burkitt Lymphoma from Diffuse Large B-Cell Lymphoma Cases," Am. J. Clin. Pathol., vol. 153, no. 6, pp. 743-759, 2020.##A. M. Tsakiroglou et al., "Lymphoma triage from H;E using AI for improved clinical management," J. Clin. Pathol., vol. 78, no. 1, pp. 28-33, 2025.##K. Sasaki et al., "The LEukemia Artificial Intelligence Program (LEAP) in chronic myeloid leukemia in chronic phase: A model to improve patient outcomes," Am. J. Hematol., vol. 96, no. 2, pp. 241-250, 2021.##S. Fazeli, A. Samiei, T. D. Lee, and M. Sarrafzadeh, "Beyond Labels: Visual Representations for Bone Marrow Cell Morphology Recognition," in Proceedings - 2023 IEEE 11th International Conference on Healthcare Informatics, ICHI 2023, 2023, pp. 111-117.##M. Osman et al., "Classification of monocytes, promonocytes and monoblasts using deep neural network models: An area of unmet need in diagnostic hematopathology," J. Clin. Med., vol. 10, no. 11, 2021.##Z. Lu et al., "Validation of Artificial Intelligence (AI)-Assisted Flow Cytometry Analysis for Immunological Disorders," Diagnostics, vol. 14, no. 4, 2024.##E. Hasan, Q. Eichbaum, A. C. Seegmiller, C. Stratton, and J. S. Trueblood, "Improving Medical Image Decision-Making by Leveraging Metacognitive Processes and Representational Similarity," Top. Cogn. Sci., vol. 14, no. 2, pp. 400-413, Apr. 2022,##Y. Mu, H. R. Tizhoosh, T. Dehkharghanian, and C. J. V Campbell, "Whole slide image representation in bone marrow cytology," Comput. Biol. Med., vol. 166, p. 107530, 2023.##S. Saxena, P. Sanyal, M. Bajpai, R. Prakash, and S. Kumar, "Trials and tribulations: Developing an artificial intelligence for screening malaria parasite from peripheral blood smears," Med. J. Armed Forces India, 2023.##Z. Zhang et al., "The Diagnosis of Chronic Myeloid Leukemia with Deep Adversarial Learning," Am. J. Pathol., vol. 192, no. 7, pp. 1083-1091, 2022.##N. Abele et al., "Noninferiority of Artificial Intelligence-Assisted Analysis of Ki-67 and Estrogen/Progesterone Receptor in Breast Cancer Routine Diagnostics," Mod. Pathol., vol. 36, no. 3, p. 100033, 2023.##G. S. Raju et al., "Natural language processing as an alternative to manual reporting of colonoscopy quality metrics," Gastrointest. Endosc., vol. 82, no. 3, pp. 512-519, 2015.##Y. Mu, H. R. Tizhoosh, T. Dehkharghanian, S. Alfasly, and C. J. V Campbell, "Model-Agnostic Binary Patch Grouping for Bone Marrow Whole Slide Image Representation," Am. J. Pathol., vol. 194, no. 5, pp. 721-734, 2024.##C.-W. Wang, S.-C. Huang, Y.-C. Lee, Y.-J. Shen, S.-I. Meng, and J. L. Gaol, "Deep learning for bone marrow cell detection and classification on whole-slide images," Med. Image Anal., vol. 75, p. 102270, 2022.##T. J. Brinker et al., "Deep learning approach to predict sentinel lymph node status directly from routine histology of primary melanoma tumours," Eur. J. Cancer, vol. 154, pp. 227-234, 2021.##K. Sirinukunwattana et al., "Artificial intelligence-based morphological fingerprinting of megakaryocytes: a new tool for assessing disease in MPN patients," Blood Adv., vol. 4, no. 14, pp. 3284-3294, 2020.##S. El Hussein et al., "Artificial intelligence strategy integrating morphologic and architectural biomarkers provides robust diagnostic accuracy for disease progression in chronic lymphocytic leukemia," J. Pathol., vol. 256, no. 1, pp. 4-14, Jan. 2022.##J. Su, S. Liu, and J. Song, "A segmentation method based on HMRF for the aided diagnosis of acute myeloid leukemia," Comput. Methods Programs Biomed., vol. 152, pp. 115-123, 2017.##Z. Y. Xu-Monette et al., "A refined cell-of-origin classifier with targeted NGS and artificial intelligence shows robust predictive value in DLBCL," Blood Adv., vol. 4, no. 14, pp. 3391-3404, 2020.##A. Acevedo, A. Merino, L. Boldú, Á. Molina, S. Alférez, and J. Rodellar, "A new convolutional neural network predictive model for the automatic recognition of hypogranulated neutrophils in myelodysplastic syndromes," Comput. Biol. Med., vol. 134, p. 104479, 2021.##A. K. Yenamandra, C. Hughes, and A. S. Maris, "Artificial Intelligence in Plasma Cell Myeloma: Neural Networks and Support Vector Machines in the Classification of Plasma Cell Myeloma Data at Diagnosis," J. Pathol. Inform., vol. 12, no. 1, p. 35, 2021.## ##

Predictive Modeling and Spatial Analysis of Cervix Uteri and Breast Cancer in India using Machine Learning and Big Data Frameworks 2 2 Background: Cancer remains a critical public health issue in India, with rising cases of breast cancer and cervical cancer. Accurate predictions and spatial analysis of cancer incidence are essential for shaping prevention strategies and targeting interventions in high-risk regions. Methods: This study utilized a big data framework employing machine learning techniques from the SparkML library to predict cancer cases and analyze spatial distributions across Indian states from 2016 to 2021. Three machine learning models used Random Forest Regressor, Gradient Boosting Regressor, and Geographically Weighted Regression (GWR) were applied to the dataset. Spatial autocorrelation analysis used Moran’s I statistic to identify clustering patterns. Results: The spatial analysis revealed significant clustering of cancer cases, particularly in 2020, with a z-score of 2.23, a p-value of 0.02, and a Moran’s index of 0.15. Among the machine learning models, GWR achieved a predictive accuracy of 98% for both breast cancer and cervical cancer, while the Random Forest Regressor and Gradient Boosting Regressor achieved 95% and 97% accuracy, respectively, over the six-year period. Gradient Boosting outperformed other models in identifying key predictors and ensuring high predictive accuracy. Conclusions: The findings highlight the efficacy of Gradient Boosting and GWR in predicting cancer incidence and analyzing spatial patterns. These models provide critical insights into cancer clustering and risk factors, supporting the development of targeted prevention strategies and policy interventions for high-risk regions in India. The results emphasize the utility of machine learning techniques in public health research and cancer control. 20 29 2024/10/262024/11/192024/11/11 1403/8/21 2024/12/242024/12/22024/12/25 1403/10/5 Durga pujitha Krotha Durga pujitha Krotha Department of Information Technology, Velagapudi Ramakrishna Siddhartha Engineering College, Vijayawada, India. durgapujitha135@gmail.com Fathimabi Shaik Fathimabi Shaik Department of Information Technology, Velagapudi Ramakrishna Siddhartha Engineering College, Vijayawada, India. fathimabi@vrsiddhartha.ac.in Cancer Big data Machine Learning Gradient boosting Geographically weighted Regression ## ##

Flow Cytometry-based Functional Assay is a Valuable Diagnostic Approach for Confirmation of Heparin-Induced Thrombocytopenia 2 2 Background: Heparin-induced thrombocytopenia (HIT) is a serious immunological adverse drug reaction that rarely occurs in patients receiving heparin. The heparin-induced platelet activation (HIPA) test, a gold-standard assay for HIT, is time-consuming, challenging, and produces qualitative results. We aimed to compare the performance properties of a flow cytometry-based functional assay for HIT diagnosis with HIPA assay. Materials and Methods: This research was carried out on HIT-suspected patients referred to the Iranian Blood Transfusion Organization between 2021 and 2023. After clinical evaluation and 4Ts scores calculation, anti-PF4 screening and HIPA test were conducted. Thirty HIPA-positive and 30 HIPA-negative samples were selected. Subsequently, a flow cytometry-based functional assay, Emo-Test HIT confirm, was performed, and the sensitivity and specificity for HIT diagnosis were measured. Results: Among the 30 samples with negative HIPA results, one was positive with the Emo-test HIT Confirm® assay, and the remaining were negative. Among 30 positive HIPA samples, the result of one sample was inconclusive, two samples were negative with flowcytometry Emo-test and the others were positive. The sensitivity and specificity of this flow cytometry-based functional assay were 90% (95% CI: 79.3-100) and 96.6% (95% CI:90.2-100). The negative predictive value and positive predictive value were 93.5% and 96.4% respectively. Conclusion: Flow cytometry-based functional assay has a good sensitivity and specificity for HIT diagnosis confirmation, indicating that it may be a promising approach in the clinical setting. 30 38 2024/10/262024/11/192024/11/112024/11/10 1403/8/20 2024/12/242024/12/22024/12/252024/12/3 1403/9/13 Mahshaad Norouzi Mahshaad Norouzi Blood Transfusion Research Center, High Institute for Education and Research in Transfusion Medicine, Tehran, Iran. Mahshaadnorozi@gmail.com Sahar Balagholi Sahar Balagholi Blood Transfusion Research Center, High Institute for Education and Research in Transfusion Medicine, Tehran, Iran. saharbalagholi@gmail.com Amir Teimourpour Amir Teimourpour Blood Transfusion Research Center, High Institute for Education and Research in Transfusion Medicine, Tehran, Iran. amir.teimourpour@gmail.com Minoo Ahmadinejad Minoo Ahmadinejad Blood Transfusion Research Center, High Institute for Education and Research in Transfusion Medicine, Tehran, Iran. minooam@gmail.com Heparin-induced thrombocytopenia (HIT) Diagnosis Flow cytometry Functional assay McFarland J, Lochowicz A, Aster R, Chappell B, Curtis B. Improving the specificity of the PF4 ELISA in diagnosing heparin‐induced thrombocytopenia. Am J Hematol. 2012;87(8):776-81.##May J, Westbrook B, Cuker A. Heparin-induced thrombocytopenia: An illustrated review. Res Pract Thromb Haemost. 2023;7(5).##Martel N, Lee J, Wells PS. Risk for heparin-induced thrombocytopenia with unfractionated and low-molecular-weight heparin thromboprophylaxis: a meta-analysis. Blood. 2005;106(8):2710-5.##Arepally GM, Cines DB. Pathogenesis of heparin-induced thrombocytopenia. Transl Res. 2020;225:131-40.##Warkentin TE, Greinacher A, Gruel Y, Aster RH, Chong BH. Laboratory testing for heparin-induced thrombocytopenia: a conceptual framework and implications for diagnosis. J Thromb Haemost. 2011;9(12):2498-500.##Sahu KK, Jindal V, Anderson J, Siddiqui AD, Jaiyesimi IA. Current Perspectives on Diagnostic Assays and Anti-PF4 Antibodies for the Diagnosis of Heparin-Induced Thrombocytopenia. J Blood Med. 2020;11:267-77.##Greinacher A, Eichler P, Lubenow N, Kwasny H, Luz M. Heparin-induced thrombocytopenia with thromboembolic complications: meta-analysis of 2 prospective trials to assess the value of parenteral treatment with lepirudin and its therapeutic aPTT range. Blood. 2000;96(3):846-51.##https://doi.org/10.1182/blood.V96.3.846##Lo GK, Sigouin CS, Warkentin TE. What is the potential for overdiagnosis of heparin-induced thrombocytopenia? Am J Hematol. 2007;82(12):1037-43.##Shaikh N. Heparin Induced Thrombocytopenia: Can Be Excluded. Journal of Blood Disorders and Transfusion. 2013;2011:1-4.##Cuker A, Arepally G, Crowther M, Rice L, Datko F, Hook K, et al. The HIT Expert Probability (HEP) Score: a novel pre‐test probability model for heparin‐induced thrombocytopenia based on broad expert opinion. J Thromb Haemost. 2010;8(12):2642-50.##Younis M, Ya'qoub L, Ali Z, Grover P, Ya'acoub R, Hamarshi MS. Comparison of a clinical-laboratory algorithm, 4t and heparin-induced thrombocytopenia expert probability scores in the diagnosis of heparin-induced thrombocytopenia in the critical care setting. Am J Blood Res. 2019;9(3):25-33.##Cuker A, Gimotty PA, Crowther MA, Warkentin TE. Predictive value of the 4Ts scoring system for heparin-induced thrombocytopenia: a systematic review and meta-analysis. Blood. 2012;120(20):4160-7.##Warkentin TE, Sheppard J-AI. Testing for heparin-induced thrombocytopenia antibodies. Transfus Med Rev. 2006;20(4):259-72.##Minet V, Dogné J-M, Mullier F. Functional assays in the diagnosis of heparin-induced thrombocytopenia: a review. Molecules. 2017;22(4):617.##Greinacher A, Juhl D, Strobel U, Wessel A, Lubenow N, Selleng K, et al. Heparin‐induced thrombocytopenia: a prospective study on the incidence, platelet‐activating capacity and clinical significance of antiplatelet factor 4/heparin antibodies of the IgG, IgM, and IgA classes. J Thromb Haemost. 2007;5(8):1666-73.##Warkentin TE, Sheppard J-AI, Horsewood P, Simpson PJ, Moore JC, Kelton JG. Impact of the patient population on the risk for heparin-induced thrombocytopenia. Blood Adv. 2000;96(5):1703-8.##https://doi.org/10.1182/blood.V96.5.1703##Pouplard C, May MA, Regina S, Marchand M, Fusciardi J, Gruel Y. Changes in platelet count after cardiac surgery can effectively predict the development of pathogenic heparin‐dependent antibodies. Br J Haematol. 2005;128(6):837-41.##Warkentin TE, Sheppard J-AI, Moore JC, Cook RJ, Kelton JG. Studies of the immune response in heparin-induced thrombocytopenia. Blood Adv. 2009;113(20):4963-9.##Althaus K, Pelzl L, Hidiatov O, Amiral J, Marini I, Bakchoul T. Evaluation of a flow cytometer-based functional assay using platelet-rich plasma in the diagnosis of heparin-induced thrombocytopenia. Thromb Res. 2019;180:55-61.##Brodard J, Benites V, Zeerleder DS, Nagler M. Accuracy of the functional, flow cytometer-based Emo-Test HIT Confirm® for the diagnosis of heparin-induced thrombocytopenia. Thromb Res. 2021;203:22-6.##Lo G, Juhl D, Warkentin T, Sigouin C, Eichler P, Greinacher A. Evaluation of pretest clinical score (4 T's) for the diagnosis of heparin‐induced thrombocytopenia in two clinical settings. J Thromb Haemost. 2006;4(4):759-65.##Gonthier M-C, Gendron N, Eloy P, Bourrienne M-C, Alhenc-Gelas M, Pouplard C, et al. Heparin-induced thrombocytopenia diagnosis: a retrospective study comparing heparin-induced platelet activation test to 14C-serotonin release assay. TH Open. 2021;5(04):e507-e12.##Eichler P, Budde U, Haas S, Kroll H, Loreth R, Meyer O, et al. First workshop for detection of heparin-induced antibodies: validation of the heparin-induced platelet-activation test (HIPA) in comparison with a PF4/heparin ELISA. J Thromb Haemost. 1999;81(04):625-9.##Warmerdam P, Van de Winkel J, Gosselin EJ, Capel P. Molecular basis for a polymorphism of human Fc gamma receptor II (CD32). J Exp Med. 1990;172(1):19-25.##Norris CF, Pricop L, Millard SS, Taylor SM, Surrey S, Schwartz E, et al. A naturally occurring mutation in FcγRIIA: AQ to K127 change confers unique IgG binding properties to the R131 allelic form of the receptor. Blood Adv. 1998;91(2):656-62.##https://doi.org/10.1182/blood.V91.2.656##Patel P, Michael JV, Naik UP, McKenzie SE. Platelet FcγRIIA in immunity and thrombosis: adaptive immunothrombosis. J Thromb Haemost. 2021;19(5):1149-60.##ARNOLD D, WARKENTIN T, WARKENTIN A, KELTON J. An algorithm for resolving 'indeterminate'test results in the platelet serotonin release assay for investigation of heparin‐induced thrombocytopenia. J Thromb Haemost. 2008;6(9):1595-7.##Horne III MK, Hutchison KJ. Simultaneous binding of heparin and platelet factor‐4 to platelets: Further insights into the mechanism of heparin‐induced thrombocytopenia. Am J Hematol. 1998;58(1):24-30.##https://doi.org/10.1002/(SICI)1096-8652(199805)58:13.0.CO;2-2##Rauova L, Zhai L, Kowalska MA, Arepally GM, Cines DB, Poncz M. Role of platelet surface PF4 antigenic complexes in heparin-induced thrombocytopenia pathogenesis: diagnostic and therapeutic implications. Blood. 2006;107(6):2346-53.##Maličev E, Kozak M, Rožman P. Evaluation of a flow cytometric assay for the confirmation of heparin‐induced thrombocytopenia. International Journal of Laboratory Hematology. 2016;38(3):240-5.##Sheridan D, Carter C, Kelton JG. A diagnostic test for heparin-induced thrombocytopenia. Blood. 1986;67(1):27-30.##https://doi.org/10.1182/blood.V67.1.27.27##Tardy B, Lecompte T, Mullier F, Vayne C, Pouplard C. Detection of platelet-activating antibodies associated with heparin-induced thrombocytopenia. J Clin Med. 2020;9(4):1226.##Warkentin TE. Clinical picture of heparin-induced thrombocytopenia (HIT) and its differentiation from non-HIT thrombocytopenia. J Thromb Haemost. 2016;116(11):813-22.##Warkentin TE, Greinacher A. Spontaneous HIT syndrome: knee replacement, infection, and parallels with vaccine-induced immune thrombotic thrombocytopenia. Thromb Res. 2021;204:40-51.##Schultz NH, Sørvoll IH, Michelsen AE, Munthe LA, Lund-Johansen F, Ahlen MT, et al. Thrombosis and thrombocytopenia after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384(22):2124-30.##Horlait G, Minet V, Mullier F, Michaux I. Persistent heparin-induced thrombocytopenia: Danaparoid cross-reactivity or delayed-onset heparin-induced thrombocytopenia? A case report. Blood Coagul Fibrinolysis. 2017;28(2):193-7.##Runser A, Schaning C, Allemand F, Amiral J. An optimized and standardized rapid flow cytometry functional method for heparin-induced thrombocytopenia. Biomedicines. 2021;9(3):296.## ##

Effects of the Amino Acid Complex on Biochemical and Morphological Parameters of Hemostasis at Chronic Cadmium Intoxication 2 2 Background: The present study was conducted to investigate the biochemical and morphological changes in the blood coagulation system caused by chronic cadmium intoxication and the anticoagulant activity of the amino acid complex (γ-aminobutyric acid, β-alanine, glutamine, ethanolamine-O-sulphate). Previous studies have investigated the effect of the amino acid complex (AAc) on blood glucose levels in animals with experimental alloxan diabetes. The use of this complex demonstrated the ability to suppress the hyperglycaemic effect of alloxan, while also exhibiting anticoagulant activity. Materials and methods: The experiments were carried out on non-linear white male rats divided into 3 groups: control rats, rats receiving cadmium sulphate and rats with cadmium intoxication injected with AAc. Biochemical (recalcification, prothrombin time, international sensitivity index, thrombin time, activated partial thromboplastin time, fibrinogen level, calcium level) and histological (Haematoxylin & Eosin and Giemsa staining) methods were used in the studies. Results and conclusion: Chronic cadmium intoxication leads to alterations in several blood coagulation parameters, suggesting a predisposition to hypercoagulation. However, administration of AAc reduces blood coagulation. Blood samples from poisoned rats showed the presence of red blood cells and leukocytes with morphological changes, including the presence of numerous platelets in clusters or groups. Conversely, when AAc was administered to cadmium poisoned rats, erythrocytes and neutrophils showed morphologically normal characteristics.  The results obtained confirm the anticoagulant activity of AAc, which may be used in the future for the treatment of various thrombotic conditions. 39 46 2024/10/262024/11/192024/11/112024/11/102024/11/26 1403/9/6 2024/12/242024/12/22024/12/252024/12/32024/12/23 1403/10/3 Zoya Paronyan Zoya Paronyan H. Buniatian Institute of Biochemistry NAS Armenia. aregarpi4@gmail.com Inesa Sahakyan Inesa Sahakyan H. Buniatian Institute of Biochemistry NAS Armenia. inesasahakyan5@gmail.com Hasmik Stepanyan Hasmik Stepanyan H. Buniatian Institute of Biochemistry NAS Armenia. stepanyan.hasmik@yahoo.com Narine Tumasyan Narine Tumasyan H. Buniatian Institute of Biochemistry NAS Armenia. ntumasyan@yahoo.com Lyudmila Araqelyan Lyudmila Araqelyan H. Buniatian Institute of Biochemistry NAS Armenia. aragelyanlyuda3@gmail.com Nune Kocharyan Nune Kocharyan H. Buniatian Institute of Biochemistry NAS Armenia. nunekocharyan466@gmail.com Ani Suqiasyan Ani Suqiasyan H. Buniatian Institute of Biochemistry NAS Armenia. anisuqiasyan2001@mail.ru Torgom Seferyan Torgom Seferyan H. Buniatian Institute of Biochemistry NAS Armenia. seferyant@yahoo.com Lusine Grigoryan Lusine Grigoryan H. Buniatian Institute of Biochemistry NAS Armenia. lusokgrig@gmail.com Silva Abrahamyan Silva Abrahamyan H. Buniatian Institute of Biochemistry NAS Armenia. silva.abrahamyan@gmail.com Amino acid complex (AAc) Hemostasis Cadmium intoxication Indirect anticoagulant Cytotoxicity Hemolysis Ilyinov A.N., Ryazanov I.A., Osipov A.N. Acid erythrograms of mice poisoned with Zn, Cd and Pb. Toxicological Bulletin.1997; 14: 10-14.##Wang Bo, Yanli Du. Cadmium and Its Neurotoxic Effects. Oxid Med Cell Longev. 2013; 2013: 898034.##Charkiewicz A.E., Omeljaniuk W.J., Nowak K.K., Garley M., and Niklinski J. Cadmium Toxicity and Health Effects-A Brief Summary. Molecules. 2023; 28(18): 6620.##Blainey JD, Adams RG, Brewer DB, Harvey TC. Cadmium-induced osteomalacia. Br J Ind Med. 1980; 37(3): 278-84.##Fiévez L., Kirschvink N., Zhang W., Lagente V., Lekeux P., Bureau F., Gustin P. Effects of betamethasone on inflammation and emphysema induced by cadmium nebulisation in rats. Pulmonary, Gastrointestinal and Urogenital Pharmacology. 2009; 606(1-3): 210-214.##Gallagher CM, Meliker JR. Blood and urine cadmium, blood pressure, and hypertension: a systematic review and meta-analysis. Environ Health Perspect.2010;118 (12):1676-84.##Thévenod F. Nephrotoxicity and the Proximal Tubule: Insights from Cadmium Subject Area. Nephron Physiology.2003; 93(4): 87-93..##Helmestam M., Stavreus-Evers A., Olovsson M. Cadmium chloride alters mRNA levels of angiogenesis related genes in primary human endometrial endothelial cells grown in vitro. Reprod.Toxicol. 2010; 30(3): 370-376.doi: 10.1016/j.reprotox.2010.05.003.##Waalkes MP, Rehm S. Cadmium and prostate cancer. J Toxicol Environ Health. 1994 Nov; 43(3):251-69.##Prozialek WC, Edwards JR, Woods JM. The vascular endothelium as a target of cadmium toxicity. Life Sci. 2006; 79: 1493-1506.##Wang X. et al. Low doze cadmium upregulates the expression of von Willebrand factor in endothelial cells. Toxicol. Lett. 2018; 290: 46-54.##Kokame K, Sakata T, Kokiwo Y, Miyata T. von Willebrand factor-to. ADAMTS13 ratio increases with age in a Japanese population. J.Thromb. Haemost. 2011; 9: 1426-1428.##Hasimoto Y, et al. Relationship between age and plasma t-PA, PA-inhibitor, and PA activity. Thromb. Res. 1987; 46: 625-633.##Samoilov M.V., Naumov A.G. Morphofunctional characteristics of erythrocytes as a criterion of the severity of endogenous intoxication. Russian medical journal. 2000; 1: 31-33.##Suwalsky M. , Villena F., Norris B., Cuevas F., Sotomayor C․ Cadmium-induced changes in the membrane of human erythrocytes and molecular models․ J Inorg Biochem, 2004; 98(6): 1061-6. DOI:##Verbost P.M., Flik G., Pang P.K., Lock R.A., Wendelaar Bonga S.E. Cadmium inhibition of the erythrocyte Ca2+ pump. Jour. Biol. Chem. 1989; 264: 5613.##Paronyan, Z. Kh., Khachatryan R. S., Stepanyan A. A., Grigoryan L. S., Arakelyan L. N. Changes in glucose levels and some blood coagulation parameters in rats with experimental alloxan-induced diabetes under the influence of a new amino acid complex. Medical Science of Armenia. NAS RA; 2021: 61(3): 64-72.##Paronyan Z.Kh.,Araqelyan L.N., Grigoryan L.S., Khachatryan R.S., Galstyan A.Z., Stepanyan A.A. The influence of an antidiabetic amino acid complex on some parameters of plasma hemostasis. Medical Science of Armenia. 2023; 63(3): 64-71. doi:10.54503/0514-7484-2023-63.3-64.##Edigarova L.V., Akopyan V.G. Antiplatelet activity of the vascular wall and the possibility of its correction with GABAergic agents in conditions of hypokinesia. Experimental and clinical pharmacology, 2000. 5, p. 41 - 43.##Fischer A, Jacobson KA, Rose J and Zeller R: Hematoxylin and eosin staining of tissue and cell sections. CSH Protoc pdb.prot4986, 2008.##Redginal H: Giemsa preparation for staining blood films. Science 86: 548, 1937.##Zubairov D.M. Coagulation disorders due to vitamin K deficiency and indirect anticoagulants. KAZAN MEDICAL JOURNAL. 1995; 76(4):344-346. doi: ##https://doi.org/10.17816/kazmj105001##Beth H.Shar MD, Christofer D. Hillyer MD. Cryoprecipitate and Fibrinogen Concentrates Transfusion Medicine and Hemostasis (Second Edition). 2013.##Barbier O, Iacqullet G.,Taic M. et al. Acute study of interaction between cadmium, calcium and zinc transport along the rat nephron in vivo, Am. I.Physiol. Renal. Physiol. 2004; 287:1067-1075.##Kranias E.G., Bers D.M. Calcium and cardiomyopathies, Subcell. Biochem. 2007; 45: 523-537.##Chandrasekar Palaniswamy MD, Arunabh Sekhri MD, Wilbert S. Aronow MD, Ankur Kalra MD, Stephen J. Peterson MD, MACP. Association of Warfarin Use With Valvular and Vascular Calcification: A Review. Clinical Cardiology. 2011;34(2): 74-81.##Shea M.K., Cushman, S.L. Booth, G.L. Burke and HCSB Krichevsky, Vitamin K status and vascular calcification: evidence from observational and clinical studies. Advances in Nutrition. 2012; 3(2): 158-165.##Krüger T., Westenfeld R., Schurgers L., Vincent M. Brandenburg. Coagulation Meets Calcification: The Vitamin K System. The International journal of artificial organs. 2009; 32(2): 67-74.##Prorialeck WC, Edwards JR, Woods JM. The vascular endothelium as a target of cadmium toxicity. Life Sci. 2006; 79: 1493-1506.##Wang X, et al. Low doze cadmium upregulates the expression if von Willebrand factor in endothelial cells. Toxicol. Lett. 2018; 290: 46-54.##Albanes S. et al. Aging and ABO blood type influence von Willebrand factor and factor VIII levels through interrelated mechanisms. J. Thromb. Haemost. 2016; 14: 953- 963.## ##

Analysis of Coagulation Parameters in Patients with Breast Pathology and Their Possible Relevance to a Hypercoagulable State 2 2 Background: To study the alteration in coagulation parameters such as activated partial thromboplastin time (APTT), prothrombin time (PT), thrombin time (TT), D-dimer and fibrinogen among patients with benign and malignant breast lesions when compared to normal controls. Materials and methods: The present study was a prospective cross-sectional study conducted among 50 cases diagnosed with benign and malignant breast cancer and comparing them with 20 age-matched controls. Coagulation parameters such as PT, TT, APTT, fibrinogen, and D-dimer were collected and compared between the malignant cases, benign cases, and age-matched control groups based on clinical and demographic details, the status of Progesterone receptor, Estrogen receptor, Her2 Neu, side and grading of cancer. Results: Significant difference was reported with regard to mean age (p=0.0103) between malignant and benign tumor group (p=0.0103). Mean fibrinogen (p<0.001), thrombin time (p=0.007), and D-dimer (p<0.001) between the three groups also showed a statistically significant difference. Conclusion: Of the biological parameters assessed in the present study; thrombin time, D-dimer and fibrinogen levels show significant differences in patients with benign and malignant breast diseases. This may serve as a biological marker to evaluate the beginning of Cancer-associated venous thrombosis (CAT) in breast cancer patients. 47 55 2024/10/262024/11/192024/11/112024/11/102024/11/262024/11/7 1403/8/17 2024/12/242024/12/22024/12/252024/12/32024/12/232024/12/3 1403/9/13 Nidhya Ganesan Nidhya Ganesan Department of Pathology, PSG Institute of Medical Sciences and Research, Off, Avinashi Rd, Peelamedu, Coimbatore, Tamil Nadu 641004. nidhyaganesan@yahoo.com Stefan Mariano Stefan Mariano Department of Pathology, PSG Institute of Medical Sciences and Research, Off, Avinashi Rd, Peelamedu, Coimbatore, Tamil Nadu 641004. snmariano@icloud.com R Chitra R Chitra Department of Surgery, PSG Institute of Medical Sciences & Research, Avinashi Rd, Peelamedu, Coimbatore, Tamil Nadu 641004. drchitrar@gmail.com Prasanna N Kumar Prasanna N Kumar Department of Pathology, PSG Institute of Medical Sciences and Research, Off, Avinashi Rd, Peelamedu, Coimbatore, Tamil Nadu 641004. drpnkumar2008@gmail.com Biomarkers Blood coagulation Breast neoplasm Fibrin fragments Thrombosis Kyriazi V. Breast cancer as an acquired thrombophilic state. J Breast Cancer. 2012 Jun;15(2):148-56.##Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA A Cancer J Clin. 2021 May;71:209-49.##Heer E, Harper A, Escandor N, Sung H, McCormack V, Fidler-Benaoudia MM. Global burden and trends in premenopausal and postmenopausal breast cancer: a population-based study. Lancet Glob Health. 2020 Aug;8(8):e1027-37.##Arnold M, Morgan E, Rumgay H, Mafra A, Singh D, Laversanne M, et al. Current and future burden of breast cancer: Global statistics for 2020 and 2040. Breast. 2022 Dec; 66:15-23.##Sathishkumar K, Chaturvedi M, Das P, Stephen S, Mathur P. Cancer incidence estimates for 2022 & projection for 2025: Result from National Cancer Registry Programme, India. Indian J Med Res. 2022 Oct-Nov;156(4;5):598-607.##Beinse G, Berger F, Cottu P, Dujaric ME, Kriegel I, Guilhaume MN, et al. Circulating tumor cell count and thrombosis in metastatic breast cancer. J Thromb Haemost. 2017 Oct;15(10):1981-1988.##Rückerl R, Schneider A, Hampel R, Breitner S, Cyrys J, Kraus U, et al. Association of novel metrics of particulate matter with vascular markers of inflammation and coagulation in susceptible populations -results from a panel study. Environ Res. 2016 Oct; 150:337-347.##Campello E, Spiezia L, Radu CM, Simioni P. Microparticles as biomarkers of venous thromboembolic events. Biomark Med. 2016 Jul;10(7):743-55.##Snoderly HT, Boone BA, Bennewitz MF. Neutrophil extracellular traps in breast cancer and beyond: current perspectives on NET stimuli, thrombosis and metastasis, and clinical utility for diagnosis and treatment. Breast Cancer Res. 2019 Dec;21(1):145.##Madhav MR, Nayagam SG, Biyani K, Pandey V, Kamal DG, Sabarimurugan S, et al. Epidemiologic analysis of breast cancer incidence, prevalence, and mortality in India: Protocol for a systematic review and meta-analyses. Medicine (Baltimore). 2018 Dec;97(52):e13680.##Gochhait S, Sahoo SS, Chhabra G, Mukhopahay AK, Sharma S. Role of D-dimer in patients of operable breast cancer withlymph node metastases: A matched cross-sectional study. Oncol J India. 2020 May-Aug;4(2):39-42.##Okello CD, Mulumba Y, Omoding A, Ddungu H, Orem J. Survival of patients with cancer associated thrombosis at the Uganda Cancer Institute. Ecancermedicalscience. 2021 Mar; 15:1212.##Kovac M, Kovac Z, Tomasevic Z, Tomic B, Gvozdenov M, Radojkovic D. Breast cancer and recurrent thrombosis - Results from prospective single center study. Breast J. 2019 Jul;25(4):783-785.##Wang L, Wang J, Li P, Wang X, Wu S, Shi B. Association between short-term heart rate variability and blood coagulation in patients with breast cancer. Sci Rep. 2021 Jul;11(1):15414.##Pang M, Zhao F, Yu P, Zhang X, Xiao H, Qiang W, et al. The significance of coagulation and fibrinolysis-related parameters in predicting postoperative venous thrombosis in patients with breast cancer. Gland Surg. 2021 Apr;10(4):1439-1446.##Hill CN, Hernández-Cáceres MP, Asencio C, Torres B, Solis B, Owen GI. Deciphering the Role of the Coagulation Cascade and Autophagy in Cancer-Related Thrombosis and Metastasis. Front Oncol. 2020 Dec;10:605314.##Mandoj C, Pizzuti L, Sergi D, Sperduti I, Mazzotta M, Lauro LD, et al. Observational study of coagulation activation in early breast cancer: Development of a prognostic model based on data from the real-world setting. J Transl Med. 2018 May;16(1):129.##Dirix LY, Oeyen S, Buys A, Liégois V, Prové A, Van De Mooter T, et al. Coagulation/fibrinolysis and circulating tumor cells in patients with advanced breast cancer. Breast Cancer Res Treat. 2022 Apr;192(3):583-591.##Mi XK, Liu QR, Zhu L, Sang MX, Guo LR, Shan BE. Mechanism of the high coagulation state of breast cancer tissue factor. Eur Rev Med Pharmacol Sci. 2017 May;21(9):2167-2171.##Khan UT, Walker AJ, Baig S, Card TR, Kirwan CC, Grainge MJ. Venous thromboembolism and mortality in breast cancer: cohort study with systematic review and meta-analysis. BMC Cancer. 2017 Nov;17(1):747.## ##

Exploring the Basic Molecular Pathways: Metformin as a Potential Treatment Option for Pancreatic Cancer 2 2 Background: Pancreatic cancer is one of the most aggressive and lethal malignancies, with limited treatment options and a poor prognosis. Recent research has highlighted the potential role of metformin, a widely used antidiabetic drug, in modulating cancer risk and progression. This review aims to explore the current evidence on the impact of metformin on pancreatic cancer outcomes and its potential mechanisms of action. Materials and Methods: A comprehensive literature search was conducted using databases such as PubMed, Scopus, and Web of Science to identify studies investigating the relationship between metformin use and pancreatic cancer. Inclusion criteria encompassed clinical trials, cohort studies, and laboratory research published in the last two decades. Data extraction focused on patient outcomes, metformin dosage, study design, and proposed mechanisms of action. Results: The review indicates that metformin use is associated with improved overall survival and reduced cancer incidence in patients with pancreatic cancer, particularly among those with concurrent diabetes. Mechanistic studies suggest that metformin exerts its anticancer effects through the inhibition of the mTOR pathway, reduction of insulin-like growth factors, and induction of autophagy. However, the results are heterogeneous, and several studies highlight the need for further clinical trials to establish causality and optimal therapeutic regimens. Conclusion: While current evidence supports a potentially beneficial role of metformin in pancreatic cancer management, the findings are preliminary and require further validation through randomized controlled trials. The heterogeneity of the studies underscores the necessity for standardized protocols to assess the efficacy and safety of metformin as an adjunct therapy in pancreatic cancer treatment. 56 68 2024/10/262024/11/192024/11/112024/11/102024/11/262024/11/72024/11/9 1403/8/19 2024/12/242024/12/22024/12/252024/12/32024/12/232024/12/32024/12/22 1403/10/2 Sepehr Ramezani Sepehr Ramezani Babol University of Medical Science, Babol, Iran. sepehr.ramezany74@gmail.com Dariush Moslemi Dariush Moslemi Babol University of Medical Science, Babol, Iran. moslemi_d@yahoo.com Faezeh Firuzpour Faezeh Firuzpour Babol University of Medical Science, Babol, Iran. faezeh.1997@gmail.com Hamidreza Didar Hamidreza Didar Shahid Beheshti University of Medical Science, Tehran, Iran. hamidreza.didar@yahoo.com Seyedamirmohammad Mazloumi Seyedamirmohammad Mazloumi Babol University of Medical Science, Babol, Iran. Amir.mazloumi1996@gmail.com Narjes rezaeiroushan Narjes rezaeiroushan Azad University Sari Branch Faculty of Medicine, Sari, Iran. narjes.rezaee@gmail.com Metformin Pancreatic Cancer Molecular Pathways Cancer Treatment Cellular Energy Metabolism Miller KD, Fidler‐Benaoudia M, Keegan TH, Hipp HS, Jemal A, Siegel RL. Cancer statistics for adolescents and young adults, 2020. CA: a cancer journal for clinicians. 2020;70(6):443-59.##Zyromski NJ, White PB. Pancreatic cancer in obesity: epidemiology, clinical observations, and basic mechanisms. Anticancer Agents Med Chem. 2011;11(5):470-8.##Zhu L, Yang K, Ren Z, Yin D, Zhou Y. Metformin as anticancer agent and adjuvant in cancer combination therapy: Current progress and future prospect. Transl Oncol. 2024;44:101945.##Shi Y-Q, Zhou X-C, Du P, Yin M-Y, Xu L, Chen W-J, Xu C-F. Relationships are between metformin use and survival in pancreatic cancer patients concurrent with diabetes: A systematic review and meta-analysis. Medicine. 2020;99(37):e21687.##Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. Bmj. 2005;330(7503):1304-5.##Sadeghi N, Abbruzzese JL, Yeung S-CJ, Hassan M, Li D. Metformin use is associated with better survival of diabetic patients with pancreatic cancer. Clinical cancer research. 2012;18(10):2905-12.##Bhaw-Luximon A, Jhurry D. Metformin in pancreatic cancer treatment: from clinical trials through basic research to biomarker quantification. Journal of cancer research and clinical oncology. 2016;142:2159-71.##Hu J, Fan H-D, Gong J-P, Mao Q-S. The relationship between the use of metformin and the risk of pancreatic cancer in patients with diabetes: a systematic review and meta-analysis. BMC Gastroenterology. 2023;23(1):50.##Cantoria MJ, Patel H, Boros LG, Meuillet EJ. Metformin and pancreatic cancer metabolism. Pancreatic Cancer-Insights into Molecular Mechanisms and Novel Approaches to Early Detection and Treatment: IntechOpen; 2014.##Wen J, Yi Z, Chen Y, Huang J, Mao X, Zhang L, et al. Efficacy of metformin therapy in patients with cancer: a meta-analysis of 22 randomised controlled trials. BMC Medicine. 2022;20(1):402.##Suissa S, Azoulay L. Metformin and Cancer: Mounting Evidence Against an Association. Diabetes Care. 2014;37(7):1786-8.##Zhu W, Xu H, Ma J, Guo J, Xue W, Gu B, et al. An Open-Label Pilot Study of Metformin as a Concomitant Therapy on Patients with Prostate Cancer Undergoing Androgen Deprivation Treatment. Urol Int. 2017;98(1):79-84.##Zell JA, McLaren CE, Morgan TR, Lawson MJ, Rezk S, Albers CG, et al. A Phase IIa Trial of Metformin for Colorectal Cancer Risk Reduction among Individuals with History of Colorectal Adenomas and Elevated Body Mass Index. Cancer Prev Res (Phila). 2020;13(2):203-12.##van Eijck CWF, Vadgama D, van Eijck CHJ, Wilmink JW, Group DPC. Metformin boosts antitumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study. JNCI: Journal of the National Cancer Institute. 2024.##Hu J, Fan HD, Gong JP, Mao QS. The relationship between the use of metformin and the risk of pancreatic cancer in patients with diabetes: a systematic review and meta-analysis. BMC Gastroenterol. 2023;23(1):50.##van Eijck CWF, Vadgama D, van Eijck CHJ, Wilmink JW. Metformin boosts anti-tumor immunity and improves prognosis in upfront resected pancreatic cancer: an observational study. J Natl Cancer Inst. 2024.##Kim J, Bae YJ, Kang HT. Metformin Use May Increase Risk of Pancreatic Cancer in Diabetic Women: An Analysis of the Korean National Health Insurance Service-National Health Screening Cohort Database. Korean J Fam Med. 2022;43(5):327-33.##https://doi.org/10.4082/kjfm.2013.34.5.327##Andersen HB, Ialchina R, Pedersen SF, Czaplinska D. Metabolic reprogramming by driver mutation-tumor microenvironment interplay in pancreatic cancer: new therapeutic targets. Cancer Metastasis Rev. 2021;40(4):1093-114.##Bhaw-Luximon A, Jhurry D. Metformin in pancreatic cancer treatment: from clinical trials through basic research to biomarker quantification. Journal of Cancer Research and Clinical Oncology. 2016;142(10):2159-71.##Velazquez-Torres G, Fuentes-Mattei E, Choi HH, Yeung S-CJ, Meng X, Lee M-H. Diabetes mellitus type 2 drives metabolic reprogramming to promote pancreatic cancer growth. Gastroenterology Report. 2020;8(4):261-76.##Marini C, Salani B, Massollo M, Amaro A, Esposito AI, Orengo AM, et al. Direct inhibition of hexokinase activity by metformin at least partially impairs glucose metabolism and tumor growth in experimental breast cancer. Cell Cycle. 2013;12(22):3490-9.##Cerullo M, Gani F, Chen SY, Canner J, Pawlik TM. Metformin Use Is Associated with Improved Survival in Patients Undergoing Resection for Pancreatic Cancer. J Gastrointest Surg. 2016;20(9):1572-80.##Qin C, Yang G, Yang J, Ren B, Wang H, Chen G, et al. Metabolism of pancreatic cancer: paving the way to better anticancer strategies. Molecular Cancer. 2020;19(1):50.##Cheong JH, Park ES, Liang J, Dennison JB, Tsavachidou D, Nguyen-Charles C, et al. Dual inhibition of tumor energy pathway by 2-deoxyglucose and metformin is effective against a broad spectrum of preclinical cancer models. Mol Cancer Ther. 2011;10(12):2350-62.##Tennakoon JB, Shi Y, Han JJ, Tsouko E, White MA, Burns AR, et al. Androgens regulate prostate cancer cell growth via an AMPK-PGC-1α-mediated metabolic switch. Oncogene. 2014;33(45):5251-61.##Hardie DG, Schaffer BE, Brunet A. AMPK: An Energy-Sensing Pathway with Multiple Inputs and Outputs. Trends Cell Biol. 2016;26(3):190-201.##Faubert B, Vincent EE, Poffenberger MC, Jones RG. The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. Cancer letters. 2015;356(2):165-70.##Kennedy MSN, Masharani U. Pancreatic hormones & antidiabetic drugs. Basic & clinical pharmacology. 2018;13:723-47.##Ferretti AC, Hidalgo F, Tonucci FM, Almada E, Pariani A, Larocca MC, Favre C. Metformin and glucose starvation decrease the migratory ability of hepatocellular carcinoma cells: targeting AMPK activation to control migration. Sci Rep. 2019;9(1):2815.##Wheaton WW, Weinberg SE, Hamanaka RB, Soberanes S, Sullivan LB, Anso E, et al. Metformin inhibits mitochondrial complex I of cancer cells to reduce tumorigenesis. Elife. 2014;3:e02242.##Zuo L, Wijegunawardana D. Redox Role of ROS and Inflammation in Pulmonary Diseases. Adv Exp Med Biol. 2021;1304:187-204.##El-Benna J, Dang P, Gougerot-Pocidalo M-A, Elbim C. Phagocyte NADPH oxidase: a multicomponent enzyme essential for host defenses. Archivum immunologiae et therapiae experimentalis. 2005;53(3):199-206.##Harrison IP, Selemidis S. Understanding the biology of reactive oxygen species and their link to cancer: NADPH oxidases as novel pharmacological targets. Clinical and Experimental Pharmacology and Physiology. 2014;41(8):533-42.##Tan H-Y, Wang N, Li S, Hong M, Wang X, Feng Y. The reactive oxygen species in macrophage polarization: reflecting its dual role in progression and treatment of human diseases. Oxidative medicine and cellular longevity. 2016;2016.##Nassif RM, Chalhoub E, Chedid P, Hurtado-Nedelec M, Raya E, Dang PM-C, et al. Metformin Inhibits ROS Production by Human M2 Macrophages via the Activation of AMPK. Biomedicines. 2022;10(2):319.##Zhu Z, Jiang T, Suo H, Xu S, Zhang C, Ying G, Yan Z. Metformin Potentiates the Effects of Anlotinib in NSCLC via AMPK/mTOR and ROS-Mediated Signaling Pathways. Front Pharmacol. 2021;12:712181.##Melnik BC, Schmitz G. Metformin: an inhibitor of mTORC1 signaling. J Endocrinol Diabetes Obes. 2014;2(2):1029.##Roccio M, Bos J, Zwartkruis F. Regulation of the small GTPase Rheb by amino acids. Oncogene. 2006;25(5):657-64.##Paudel S, Wu G, Wang X. Amino Acids in Cell Signaling: Regulation and Function. In: Wu G, editor. Amino Acids in Nutrition and Health: Amino Acids in Gene Expression, Metabolic Regulation, and Exercising Performance. Cham: Springer International Publishing; 2021. p. 17-33.##Hu X, Guo F. Amino Acid Sensing in Metabolic Homeostasis and Health. Endocrine Reviews. 2020;42(1):56-76.##Kazyken D, Dame SG, Wang C, Wadley M, Fingar DC. Unexpected roles for AMPK in suppression of autophagy and reactivation of mTORC1 signaling during prolonged amino acid deprivation. bioRxiv. 2023:2023.12.20.572593.##Rena G, Hardie DG, Pearson ER. The mechanisms of action of metformin. Diabetologia. 2017;60(9):1577-85.##Ouslimani N, Peynet J, Bonnefont-Rousselot D, Thérond P, Legrand A, Beaudeux J-L. Metformin decreases intracellular production of reactive oxygen species in aortic endothelial cells. Metabolism. 2005;54(6):829-34.##Zyromski NJ, Mathur A, Pitt HA, Wade TE, Wang S, Nakshatri P, et al. Obesity potentiates the growth and dissemination of pancreatic cancer. Surgery. 2009;146(2):258-63.##Ponce-Lopez T, González Álvarez Tostado JA, Dias F, Montiel Maltez KH. Metformin Prevents NDEA-Induced Memory Impairments Associated with Attenuating Beta-Amyloid, Tumor Necrosis Factor-Alpha, and Interleukin-6 Levels in the Hippocampus of Rats. Biomolecules. 2023;13(9).##Zwacka RM, Stark L, Dunlop MG. NF-kappaB kinetics predetermine TNF-alpha sensitivity of colorectal cancer cells. J Gene Med. 2000;2(5):334-43.##https://doi.org/10.1002/1521-2254(200009/10)2:53.0.CO;2-Q##Saini N, Yang X. Metformin as an anti-cancer agent: actions and mechanisms targeting cancer stem cells. Acta Biochimica et Biophysica Sinica. 2017;50(2):133-43.##Mostafavi S, Zalpoor H, Hassan ZM. The promising therapeutic effects of metformin on metabolic reprogramming of cancer-associated fibroblasts in solid tumors. Cellular & Molecular Biology Letters. 2022;27(1):58.##Wu Z, Zhang C, Najafi M. Targeting of the tumor immune microenvironment by metformin. Journal of Cell Communication and Signaling. 2022;16(3):333-48.##Ding L, Liang G, Yao Z, Zhang J, Liu R, Chen H, et al. Metformin prevents cancer metastasis by inhibiting M2-like polarization of tumor associated macrophages. Oncotarget. 2015;6(34):36441.##Kang J, Lee D, Lee KJ, Yoon JE, Kwon J-H, Seo Y, et al. Tumor-suppressive effect of metformin via the regulation of M2 macrophages and myeloid-derived suppressor cells in the tumor microenvironment of colorectal cancer. Cancers. 2022;14(12):2881.##Eikawa S, Nishida M, Mizukami S, Yamazaki C, Nakayama E, Udono H. Immune-mediated antitumor effect by type 2 diabetes drug, metformin. Proceedings of the National Academy of Sciences. 2015;112(6):1809-14.##Kurelac I, Ganesh NU, Iorio M, Porcelli AM, Gasparre G, editors. The multifaceted effects of metformin on tumor microenvironment. Seminars in cell & developmental biology; 2020: Elsevier.##Maruzen S, Munesue S, Okazaki M, Takada S, Nakanuma S, Makino I, et al. Inhibitory Effects of Metformin for Pancreatic Neuroendocrine Neoplasms: Experimental Study on Mitochondrial Function. Onco. 2024;4(2):77-86.##Mary Jo C, Hitendra P, Laszlo GB, Emmanuelle JM. Metformin and Pancreatic Cancer Metabolism. In: Kelly M, editor. Pancreatic Cancer. Rijeka: IntechOpen; 2014. p. Ch. 7.##Nair V, Pathi S, Jutooru I, Sreevalsan S, Basha R, Abdelrahim M, et al. Metformin inhibits pancreatic cancer cell and tumor growth and downregulates Sp transcription factors. Carcinogenesis. 2013;34(12):2870-9.##Baillie R, Tan ST, Itinteang T. Cancer Stem Cells in Oral Cavity Squamous Cell Carcinoma: A Review. Frontiers in Oncology. 2017;7.##Alfaras I, Mitchell SJ, Mora H, Lugo DR, Warren A, Navas-Enamorado I, et al. Health benefits of late-onset metformin treatment every other week in mice. npj Aging and Mechanisms of Disease. 2017;3(1):16.##Baillie R, Tan ST, Itinteang T. Cancer stem cells in oral cavity squamous cell carcinoma: a review. Frontiers in Oncology. 2017;7:112.##Chen X, Li C, He T, Mao J, Li C, Lyu J, Meng QH. Metformin inhibits prostate cancer cell proliferation, migration, and tumor growth through upregulation of PEDF expression. Cancer Biology & Therapy. 2016;17(5):507-14.##Chen K, Qian W, Jiang Z, Cheng L, Li J, Sun L, et al. Metformin suppresses cancer initiation and progression in genetic mouse models of pancreatic cancer. Molecular cancer. 2017;16:1-11.##Saraei P, Asadi I, Kakar MA, Moradi-Kor N. The beneficial effects of metformin on cancer prevention and therapy: a comprehensive review of recent advances. Cancer management and research. 2019:3295-313.##Li J, Wang J, Chen R, Bai Y, Lu X. The prognostic value of tumor-infiltrating T lymphocytes in ovarian cancer. Oncotarget. 2017;8(9):15621.##Shang B, Liu Y, Jiang S-j, Liu Y. Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: a systematic review and meta-analysis. Scientific reports. 2015;5(1):15179.##Farhood B, Najafi M, Mortezaee K. CD8+ cytotoxic T lymphocytes in cancer immunotherapy: A review. Journal of cellular physiology. 2019;234(6):8509-21.##Rukaia S, Yousef H, Asia F, Ahmed Al b, Wafa A. Metformin Effects on Pancreatic Cancer Cells. AlQalam Journal of Medical and Applied Sciences. 2022;5(1):199-205.##O'Connor L, Bailey-Whyte M, Bhattacharya M, Butera G, Hardell KNL, Seidenberg AB, et al. Association of metformin use and cancer incidence: a systematic review and meta-analysis. JNCI: Journal of the National Cancer Institute. 2024;116(4):518-29.##Petrasca A, Hambly R, Kearney N, Smith CM, Pender Emily K, Mac Mahon J, et al. Metformin has anti-inflammatory effects and induces immunometabolic reprogramming via multiple mechanisms in hidradenitis suppurativa. British Journal of Dermatology. 2023;189(6):730-40.## ##

The Potential Role of microRNAs in the Progression and Aggressiveness of Gallbladder Cancer: Molecular Markers to Therapeutic Interventions 2 2 Gallbladder cancer (GBC) is among the utmost pervasive form of biliary tract cancers and remains relatively under-researched. Its prognosis is generally poor, with survival rates varying based on diagnostic stage, from 20% to 65%. The hallmarks of cancer, such as proliferation of cells, migration of cells, invasion, process of programmed cell death, radio/chemosensitivity, and cancer stem cell phenotype, are all influenced by miRNAs, which have been found to be essential actuators in the process of gene expression. This review is an attempt to reveal the molecular pathways influenced by miRNAs that could be targeted for therapeutic purposes in gallbladder cancer (GBC) and also emphasizes the need for precision medicine to target potent pathways, utilizing not only inhibiting receptor or antibody but also investigating miRNAs as a potential treatment strategy. 69 85 2024/10/262024/11/192024/11/112024/11/102024/11/262024/11/72024/11/92024/10/19 1403/7/28 2024/12/242024/12/22024/12/252024/12/32024/12/232024/12/32024/12/222024/12/24 1403/10/4 Naseem Fatima Naseem Fatima Department of Biochemistry, Era’s Lucknow Medical College and Hospital, Lucknow, India. naseemfatima.fatima@gmail.com Syed Tasleem Raza Syed Tasleem Raza Department of Biochemistry, Era’s Lucknow Medical College and Hospital, Lucknow, India. tasleem24@gmail.com Vijay Kumar Vijay Kumar Department of Surgical Oncology, King George’s Medical University, Lucknow, India. drvkumar2007@gmil.com Saliha Rizvi Saliha Rizvi Department of Biotechnology, Era University, Lucknow, India rizvi_saliha@rediffmail.com Farheen Khan Farheen Khan Department of Biotechnology, Era University, Lucknow, India Farheenkh19@gmail.com Gallbladder cancer MicroRNAs Molecular Pathways Target therapy Promising biomarker Nandakumar A, Gupta PC, Gangadharan P, Visweswara RN, Parkin DM. Geographic pathology revisited: Development of an atlas of cancer in India. International Journal of Cancer 2005:116:740-754.##Sachidananda S, Krishnan A, Janani K, Alexander PC, Velayutham V, Rajagopal S, Venkataraman J. Characteristics of gallbladder cancer in South India. Indian J Surg Oncol. 2012:3:228-30.##Rani K, Senger JL , Ahmed S, Kanthan SC. Gallbladder Cancer in the 21st Century. Journal of Oncology 2015:2:1-26.##Hundal R, Shaffer EA. Gallbladder cancer: epidemiology and outcome. Clin Epidemiol. 2014:7:6:99-109.##Fatima N, Srivastava AN, Nigam J, Tandon N, Ahmad R, Kumar V. Clinicopathological correlation of cancer stem cell markers Oct-4 and CD133 expression as prognostic factor in malignant lesions of gallbladder: An immunohistochemical study. Indian J Pathol Microbiol. 2019 Jul-Sep;62(3):384-390.##Verslype C, Prenen H, Van Cutsem E. The role of chemotherapy in biliary tract carcinoma. International Hepato-Pancreato-Biliary Association 2008:10:164-167.##Wu X, Li B, Zheng C, Liu W, Hong T, He X. Incidental gallbladder cancer after laparoscopic cholecystectomy: incidence, management, and prognosis. Asia Pac J Clin Oncol. 2020:16:158-164.##Raza ST, Rizvi S, Afreen S, Srivastava S, Siddiqui Z, Fatima N et al. Association of the circulating micro-RNAs with susceptible and newly diagnosed type 2 diabetes mellitus cases. Advances in Biomarker Sciences and Technology, 2023; 5:57-67.##Goetze TO. Gallbladder carcinoma: Prognostic factors and therapeutic options. World J Gastroenterol. 2015:21:12211-7.##Macha MA, Seshacharyulu P, Krishn SR, Pai P, Rachagani S, Jain M, Batra SK. MicroRNAs (miRNAs) as biomarker(s) for prognosis and diagnosis of gastrointestinal (GI) cancers. Curr Pharm Des. 2014:20:5287-97.##Davis-Dusenbery BN, Hata A. MicroRNA in Cancer: The Involvement of Aberrant MicroRNA Biogenesis Regulatory Pathways. Genes Cancer. 2010:1:1100-14.##Zu Y, Ban J, Xia Z, Wang J, Cai Y, Ping W, Sun W. Genetic variation in a miR-335 binding site in BIRC5 alters susceptibility to lung cancer in Chinese Han populations. Biochemistry Biophysics Research Communication 2013:430:529-534.##Ronchetti D, Lionetti M, Mosca L, Agnelli L, Andronache A, Fabris S, Deliliers GL, Neri A. An integrative genomic approach reveals coordinated expression of intronic miR-335, miR-342, and miR-561 with deregulated host genes in multiple myeloma. BMC Med Genomics. 2008:13:1:37.##Stanczyk J, Pedrioli DM, Brentano F, Sanchez-Pernaute O, Kolling C, Gay RE, Detmar M, Gay S, Kyburz D. Altered expression of MicroRNA in synovial fibroblasts and synovial tissue in rheumatoid arthritis. Arthritis Rheum. 2008:58:1001-9.##Khan MA, Zubair H, Srivastava SK, Singh S, Singh AP. Insights into the Role of microRNAs in Pancreatic Cancer Pathogenesis: Potential for Diagnosis, Prognosis, and Therapy. Adv Exp Med Biol. 2015:889:71-87.##Xu Y, Zhao F, Wang Z, Song S, Luo Y, Zhang X, et al. MicroRNA-335 acts as a metastasis suppressor in gastric cancer by targeting Bcl-w and specificity protein 1. Oncogene. 2012:31:1398-407.##Flynt AS, Lai EC. Biological principles of microRNA-mediated regulation: shared themes amid diversity. Nat Rev Genet. 2008:9:831-42.##Di Leva G, Garofalo M, Croce CM. MicroRNAs in cancer. Annu Rev Pathol. 2014:9:287-314.##Treiber T, Treiber N, Meister G. Regulation of microRNA biogenesis and its crosstalk with other cellular pathways. Nature Reviews Molecular Cell Biology 2019:20:5-20.##O'Brien J, Hayder H, Zayed Y, Peng C. Overview of MicroRNA Biogenesis, Mechanisms of Actions, and Circulation. Front Endocrinol (Lausanne). 2018:9:402.##Kim VN, Han J, Siomi MC. Biogenesis of small RNAs in animals. Nat Rev Mol Cell Biol. 2009:10:126-39.##Benhamed M, Herbig U, Ye T, Dejean A, Bischof O. Senescence is an endogenous trigger for microRNA-directed transcriptional gene silencing in human cells. Nat Cell Biol. 2012:14:266-75.##Gurtner A, Falcone E, Garibaldi F, Piaggio G. Dysregulation of microRNA biogenesis in cancer: the impact of mutant p53 on Drosha complex activity. Journal of Experimental Clinical Cancer Research 2016:35:1-9.##Chong MM, Zhang G, Cheloufi S, Neubert TA, Hannon GJ, Littman DR. Canonical and alternate functions of the microRNA biogenesis machinery. Genes Dev. 2010:24:1951-60.##Kotani A, Ha D, Schotte D, den Boer ML, Armstrong SA, Lodish HF. A novel mutation in the miR-128b gene reduces miRNA processing and leads to glucocorticoid resistance of MLL-AF4 acute lymphocytic leukemia cells. Cell Cycle. 2010:9:1037-42.##MiRBase: the microRNA database, (2019); Release 22.1. http://www.mirbase.org/##Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, Croce CM. Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci U S A. 2004:101:2999-3004.##Olive V, Li Q, He L. mir-17-92: a polycistronic oncomir with pleiotropic functions. Immunol Rev. 2013:253:158-66.##Diosdado Calvo MB, van de Wiel MA, Terhaar Sive Droste JS, Mongera S, Postma C, Meijerink WJ, et al. MiR-17-92 cluster is associated with 13q gain and c-myc expression during colorectal adenoma toadenocarcinoma progression. British Journal of Cancer 2009:101:707-714.##Calin GA, Cimmino A, Fabbri M, Ferracin M, Wojcik SE, Shimizu M, Taccioli C, Zanesi N, Garzon R, Aqeilan RI, Alder H, Volinia S, Rassenti L, Liu X, Liu CG, Kipps TJ, Negrini M, Croce CM. MiR-15a and miR-16-1 cluster functions in human leukemia. Proc Natl Acad Sci U S A. 2008:105(13):5166-71.##Bueno MJ, Malumbres M. MicroRNAs and the cell cycle. Biochim Biophys Acta. 2011:1812:592-601.##Andrikopoulou A, Shalit A, Zografos E, Koutsoukos K, Korakiti AM, Liontos M, Dimopoulos MA, Zagouri F. MicroRNAs as Potential Predictors of Response to CDK4/6 Inhibitor Treatment. Cancers (Basel). 2021:13(16):4114.##Otmani K, Lewalle P. Tumor Suppressor miRNA in Cancer Cells and the Tumor Microenvironment: Mechanism of Deregulation and Clinical Implications. Front Oncol. 2021:11:708765.##Wang A, Xu Q, Sha R, Bao T, Xi X, Guo G. MicroRNA-29a inhibits cell proliferation and arrests cell cycle by modulating p16 methylation in cervical cancer. Oncol Lett. 2021:21(4):272.##Wang Y, Wang F, He J, Du J, Zhang H, Shi H, Chen Y, Wei Y, Xue W, Yan J, Feng Y, Gao Y, Li D, Han J, Zhang J. miR-30a-3p Targets MAD2L1 and Regulates Proliferation of Gastric Cancer Cells. Onco Targets Ther. 2019:12:11313-11324##Su, L., Zhang, J., Zhang, X. et al. Identification of cell cycle as the critical pathway modulated by exosome-derived microRNAs in gallbladder carcinoma. Med Oncol 2021:38:141.##Shu YJ, Bao RF, Jiang L, Wang Z, Wang XA, Zhang F, Liang HB, Li HF, Ye YY, Xiang SS, Weng H, Wu XS, Li ML, Hu YP, Lu W, Zhang YJ, Zhu J, Dong P, Liu YB. MicroRNA-29c-5p suppresses gallbladder carcinoma progression by directly targeting CPEB4 and inhibiting the MAPK pathway. Cell Death Differ. 2017:24(3):445-457.##Ma Y, Shen N, Wicha MS, Luo M. The Roles of the Let-7 Family of MicroRNAs in the Regulation of Cancer Stemness. Cells. 2021:10:2415.##Park SM, Gaur AB, Lengyel E, Peter ME. The miR-200 family determines the epithelial phenotype of cancer cells by targeting the E-cadherin repressors ZEB1 and ZEB2. Genes Dev. 2008:22:894-907.##Wiklund ED, Bramsen JB, Hulf T, Dyrskjøt L, Ramanathan R, Hansen TB, Villadsen SB, et al. Coordinated epigenetic repression of the miR-200 family and miR-205 in invasive bladder cancer. Int J Cancer. 2011:128:1327-34.##Paterson EL, Kazenwadel J, Bert AG, Khew-Goodall Y, Ruszkiewicz A, Goodall GJ. Down-regulation of the miRNA-200 family at the invasive front of colorectal cancers with degraded basement membrane indicates EMT is involved in cancer progression. Neoplasia. 2013:15:180-91.##Ladeiro Y, Couchy G, Balabaud C, Bioulac-Sage P, Pelletier L, Rebouissou S, Zucman-Rossi J. MicroRNA profiling in hepatocellular tumors is associated with clinical features and oncogene/tumor suppressor gene mutations. Hepatology. 2008:47:1955-63.##Diaz-Riascos Z, Ginesta MM, Fabregat J, Serrano T, Busquets J, Buscail L, et al. Expression and Role of MicroRNAs from the miR-200 Family in the Tumor Formation and Metastatic Propensity of Pancreatic Cancer. Molecular Therapy: Nucleic Acids 2019:17:491-503.##Nengquan S, Tan G , You W , Chen H, Gong J, Chen D, et al. MiR-145 inhibits human colorectal cancer cell migration and invasion via PAK4-dependent pathway. Cancer Medicine 2017:6:1331-1340.##Xu Y, Zhang X , Hu X, Zhou W, Zhang P, Zhang J, et al. The effects of lncRNA MALAT1 on proliferation, invasion and migration in colorectal cancer through regulating SOX9. Molecular Medicine 2018:2:52-60.##Kuang WB, -C Deng Q, Deng CT, Li WS, Zhang YG, Shu SW, Zhou MR. MiRNA regulates OCT4 expression in breast cancer cells. Eur Rev Med Pharmacol Sci. 2018:22:1351-1357.##Yang B, Huang J, Liu H, Guo W, Li G. miR-335 directly, while miR-34a indirectly modulate survivin expression and regulate growth, apoptosis, and invasion of gastric cancer cells. Tumour Biology 2016:37:1771-1779.##Xu W, Chang J, Du X, Hou J. Long non-coding RNA PCAT-1 contributes to tumorigenesis by regulating FSCN1 via miR-145-5p in prostate cancer. Biomed Pharmacother. 2017:95:1112-1118.##Zhou X, Yue Y, Wang R, Gong B, Duan Z. MicroRNA-145 inhibits tumorigenesis and invasion of cervical cancer stem cells. Int J Oncol. 2017:50:853-862.##Goeppert B, Truckenmueller F, Ori A, Fritz V, Albrecht T, Fraas A, et al. Profiling of gallbladder carcinoma reveals distinct miRNA profiles and activation of STAT1 by the tumor suppressive miRNA-145-5p. Scientific Report 2019:9:4796.##Yuan Y, Yang Z, Zou Q. MiRNA-145 induces apoptosis in a gallbladder carcinoma cell line by targeting DFF45. Open Life Sciences 2018:13:227-235.##Min H, Zhan M, Chen W, Xu S, Long M, Shen H, et al. MiR-143-5p Deficiency Triggers EMT and Metastasis by Targeting HIF-1α in Gallbladder Cancer. Cell Physiology and Biochemistry 2017:42:2078-2092.##Li G, Pu Y. MicroRNA signatures in total peripheral blood of gallbladder cancer patients. Tumour Biol. 2015:36:6985-90.##Jin YP, Hu YP, Wu XS, Wu YS, Ye YY, Li HF, et al. miR-143-3p targeting of ITGA6 suppresses tumour growth and angiogenesis by downregulating PLGF expression via the PI3K/AKT pathway in gallbladder carcinomal. Cell Death and Disease 2018:182:1-15.##Jin K, Xiang Y, Tang J, Wu G, Li J, Xiao H, et al. miR-34 is associated with poor prognosis of patients with gallbladder cancer through regulating telomere length in tumor stem cells. Tumour Biology 2014:35:1503-10.##Ma N, Cheng H, Qin B, Zhong R, Wang B. Adjuvant therapy in the treatment of gallbladder cancer: a meta-analysis. BMC Cancer 2015: 615:1-10.##Lv YP, Shi W , Liu HX, , Kong XJ, Dai DL. Identification of miR-146b-5p in tissues as a novel biomarker for prognosis of gallbladder carcinoma. European Review for Medical and Pharmacological Sciences. 2017:21:518-522##Hua CB, Song SB, Ma HL, Li XZ. MiR-1-5p is down-regulated in gallbladder carcinoma and suppresses cell proliferation, migration and invasion by targeting Notch2. Pathology - Research and Practice 2019:215:200-208.##Yang, G., Lu, Z., Meng, F. et al. Circulating miR-141 as a potential biomarker for diagnosis, prognosis and therapeutic targets in gallbladder cancer. Sci Rep 2022: 12: 10072.##Qin Y, Mi W, Huang C, Li J, Zhang Y, Fu Y. Downregulation of miR-575 Inhibits the Tumorigenesis of Gallbladder Cancer via Targeting p27 Kip1. Onco Targets Ther. 2020:13:3667-3676.##Yang L, Huang S, Ma H, Wu X, Feng F. MicroRNA-125b predicts clinical outcome and suppressed tumor proliferation and migration in human gallbladder cancer.Tumor Biology 2017:39:1-7.##Niu J, Li Z, Li F. Overexpressed microRNA-136 works as a cancer suppressor in gallbladder cancer through suppression of JNK signaling pathway via inhibition of MAP2K4. Am J Physiol Gastrointest Liver Physiol. 2019:317:G670-G681.##Zhang X, Zhang L, Chen M, Liu D. miR-324-5p inhibits gallbladder carcinoma cell metastatic behaviours by downregulation of transforming growth factor beta 2 expression. Artificial Cells, Nanomedicine, And Biotechnology 2020:48:315-324.##Li W, Yan P, Meng X, Zhang J, Yang Y. The microRNA cluster miR-214/miR-3120 prevents tumor cell switching from an epithelial to a mesenchymal-like phenotype and inhibits autophagy in gallbladder cancer. Cell Signal. 2021:80:109887.##Peng HH, Zhang YD, Gong LS, Liu WD, Zhang Y. Increased expression of microRNA-335 predicts a favorable prognosis in primary gallbladder carcinoma. Onco Targets Ther. 2013:6:1625-30.##Fatima N, Srivastava AN, Nigam J, Raza ST, Rizvi S, Siddiqui Z, Kumar V. Low Expression of MicroRNA335-5p Is Associated with Malignant Behavior of Gallbladder Cancer: A Clinicopathological Study. Asian Pac J Cancer Prev. 2019:20:1895-1900.##Song F, Yang Z, Li L, Wei Y, Tang X, Liu S, Yu M, Chen J, Wang S, Fu J, Zhang K, Yang P, Yang X, Chen Z, Zhang B, Wang H. MiR-552-3p promotes malignant progression of gallbladder carcinoma by reactivating the Akt/β-catenin signaling pathway due to inhibition of the tumor suppressor gene RGMA. Ann Transl Med. 2021:9(17):1374.##Liu K, Xu Q. LncRNA PVT1 regulates gallbladder cancer progression through miR-30d-5p. J Biol Regul Homeost Agents. 2020:34:875-883.##Chen J, Yu Y, Li H, Hu Q, Chen X, He Y, Xue C, Ren F, Ren Z, Li J, Liu L, Duan Z, Cui G, Sun R. Long non-coding RNA PVT1 promotes tumor progression by regulating the miR-143/HK2 axis in gallbladder cancer. Mol Cancer. 2019:18:33.##Oda T, Tsutsumi K, Obata T, Ueta E, Kikuchi T, Ako S et al. MicroRNA-34a-5p: A pivotal therapeutictarget in gallbladder cancer. Molecular Therapy: Oncology 2024: 32:1-11.##Srivastava P, Mishra S, Agarwal A, Pandey A, Husain N, Circulating microRNAs in gallbladder cancer: Is serum assay of diagnostic value?, Pathology - Research and Practice 2023:242:154320##Ouyang B, Pan N, Zhang H, Xing C and Ji W: miR 146b 5p inhibits tumorigenesis and metastasis of gallbladder cancer by targeting Toll like receptor 4 via the nuclear factor κB pathway. Oncol Rep 2021:45:15.##Cai J, Xu L, Cai Z, Wang J, Zhou B, Hu H: MicroRNA-146b-5p inhibits the growth of gallbladder carcinoma by targeting epidermal growth factor receptor. Mol Med Rep 2015:12:1549-1555.##Wang N, Xiang X, Chen K, Liu P, Zhu A. Targeting of NT5E by miR-30b and miR-340 attenuates proliferation, invasion and migration of gallbladder carcinoma, Biochimie. 2018:146:56-67.##Li XU, Li XZ, Wu CX and Xing XH. miR-188-5p inhibits proliferation, migration, and invasion in gallbladder carcinoma by targeting Wnt2b and Smad2. Kaohsiung J Med Sci. 2021;37:294-304##Zheng H, Wang JJ, Zhao LJ, Yang XR, Yu YL. Exosomal miR-182 regulates the effect of RECK on gallbladder cancer. World J Gastroenterol 2020:26: 933-946.##Zhang J, Hu Z, Wen C, Liao Q, He B, Peng J, Tang X, Chen Z and Xie Y: MicroRNA 182 promotes epithelial mesenchymal transition by targeting FOXN3 in gallbladder cancer. Oncol Lett 2021:21:200.##Qiu YH, Luo XJ, Kan T, et al. TGF-β upregulates miR-182 expression to promote gallbladder cancer metastasis by targeting CADM1. Mol Biosyst. 2014:10:679- 685.##Hu X, Zhang J, Bu J, Yang K, Xu S, Pan M, Xiang D, Chen W. MiR-4733-5p promotes gallbladder carcinoma progression via directly targeting kruppel like factor 7. Bioengineered. 2022:13(4):10691-10706.##Zhou J, Gao F, Zhang H, Xing M, Xu Z, Zhang R. MiR-520b inhibits proliferation, migration and invasion in gallbladder carcinoma by targeting RAB22A. Arch Med Sci. 2019:17(2):481-491.##Hu YP, Jin YP, Wu X., Yang Y, Li YS, Li HF, et al. LncRNA-HGBC stabilized by HuR promotes gallbladder cancer progression by regulating miR-502-3p/SET/AKT axis. Mol. Cancer. 2019:18:167.##Zhu H, Chen Z, Yu J, Wu J, Zhuo X. MiR-195-5p suppresses the proliferation, migration, and invasion of gallbladder cancer cells by targeting FOSL1 and regulating the Wnt/β-catenin pathway . Ann Transl Med 2022:10:893.##Liu S, Chu B, Cai C, Wu X, Yao W, Wu Z, Yang Z, Li F, Liu Y, Dong P, Gong W. DGCR5 Promotes Gallbladder Cancer by Sponging MiR-3619-5p via MEK/ERK1/2 and JNK/p38 MAPK Pathways. J Cancer. 2020:11:5466-5477.##Chen Y, Wang Y, Zhao D, Kong D, Yong Wang. Clinical significance of serum miR-187 and miR-143 in the diagnosis of gallbladder cancer. Chinese Journal of Hepatobiliary Surgery 2020:12:128-133.##Fatima N, Raza ST, Singh M, Rizvi S,Siddiqui Z, Eba A et al. Prognostic signifcance of miR 499 expression and Helicobacter pylori infection in malignant lesions of gallbladder cancer: A clinicopathological study. Egyptian Journal of Medical Human Genetic. 2024; 25:96##Ahmed SA, Parama D, Daimari E, Girisa S, Banik K, Harsha C, et al. Rationalizing the therapeutic potential of apigenin against cancer. Life Sci. 2021, 267, 118814.##Siveen KS, Nguyen AH, Lee JH, Li F, Singh SS, Kumar AP, et al. Negative regulation of signal transducer and activator of transcription-3 signalling cascade by lupeol inhibits growth and induces apoptosis in hepatocellular carcinoma cells. Br. J. Cancer 2014:111:1327-1337.##Wang S, Zhang Y, Cai Q, Ma M, Jin LY, Weng M, et al. Circular RNA FOXP1 promotes tumor progression and Warburg effect in gallbladder cancer by regulating PKLR expression. Mol. Cancer 2019:18:145.##Kai D, Yannian L, Yitian C, Dinghao G, Xin Z, Wu J. Circular RNA HIPK3 promotes gallbladder cancer cell growth by sponging microRNA-124. Biochem. Biophys. Res. Commun. 2018:503:863-869.##Wang S, Zhang W, Wu X, Weng M, Zhang M, Cai Q, et al. The lnc RNA MALAT 1 functions as a competing endogenous RNA to regulate MCL-1 expression by sponging miR-363-3p in gallbladder cancer. J. Cell. Mol. Med. 2016:20:2299-2308.##Ma F, Zhang M, Gong W, Weng M, Quan Z. MiR-138 Suppresses Cell Proliferation by Targeting Bag-1 in Gallbladder Carcinoma. PLoS ONE 2015:10:e0126499##Ueta E, Tsutsumi K, Kato H, et al. Extracellular vesicle-shuttled miRNAs as a diagnostic and prognostic biomarker and their potential roles in gallbladder cancer patients. Sci Rep 2021:11:12298.##Li Z, Yu X, Shen J, Law PTY, Chan MTV, Wu WKK. MicroRNA expression and its implications for diagnosis and therapy of gallbladder cancer. Oncotarget. 2015:6: 13914-13921.##Puar YR, Shanmugam MK, Fan L, Arfuso F, Sethi G, Tergaonkar V. Evidence for the Involvement of the Master Transcription Factor NF-kappaB in Cancer Initiation and Progression. Biomedicines 2018:6:82.##Wang W, Chen LC, Qian JY, Zhang Q. MiR-335 promotes cell proliferation by inhibiting MEF2D and sensitizes cells to 5-Fu treatment in gallbladder carcinoma. Eur. Rev. Med Pharmacol. Sci. 2019:23:9829-9839.##Bao RF, Shu YJ, Hu YP, Wang XA, Zhang F, Liang HB, et al. miR-101 targeting ZFX suppresses tumor proliferation and metastasis by regulating the MAPK/Erk and Smad pathways in gallbladder carcinoma. Oncotarget 2016:7:22339-22354.##Kang C, Xinyan B. The microRNA cluster miR-30b/-30d prevents tumor cell switch from an epithelial to a mesenchymal-like phenotype in GBC,Molecular Therapy - Methods & Clinical Development 2021:20: 716-725.##Xu G, Wei X, Tu Q, Zhou C. Up-regulated microRNA-33b inhibits epithelial-mesenchymal transition in gallbladder cancer through down-regulating CROCC. Biosci Rep 2020:40(1): BSR20190108.##Ma MZ, Chu BF, Zhang Y, Weng MZ, Qin YY, Gong W, et al. Long non-coding RNA CCAT1 promotes gallbladder cancer development via negative modulation of miRNA-218-5p. Cell Death Dis. 2015:6:e1583.##Cao J, Shao H, Hu J, Jin R, Feng A, Zhang B, et al. Identification of invasion-metastasis associated MiRNAs in gallbladder cancer by bioinformatics and experimental validation. J Transl Med. 2022:20(1):188.##Ye YY, Mei JW, Xiang SS, Li HF, Ma Q, Song XL et al. MicroRNA-30a-5p inhibits gallbladder cancer cell proliferation, migration and metastasis by targeting E2F7. Cell Death Dis. 2018:9:410.##Wang H, Zhan M, Xu S, Chen W, Long MM, Shi YH, et al. miR-218-5p restores sensitivity to gemcitabine through PRKCE/MDR1 axis in gallbladder cancer. Cell Death Dis. 2017:8:e2770.##Zhan M, Zhao X, Wang H, Chen W, Xu S, Wang W, et al. miR-145 sensitizes gallbladder cancer to cisplatin by regulating multidrug resistance associated protein 1. Tumor Biol. 2016:37:10553-10562.##Lu W, Hu Y, Ma Q, Zhou L, Jiang L, Li Z, et al. miR-223 increases gallbladder cancer cell sensitivity to docetaxel by downregulating STMN1. Oncotarget 2016:7:62364-62376##Manikkath J, Jishnu PV, Wich PR, Manikkath A, Radhakrishnan R. Nanoparticulate strategies for the delivery of miRNA mimics and inhibitors in anticancer therapy and its potential utility in oral submucous fibrosis. Nanomedicine 2022:17:181-195.##Reda El Sayed S, Cristante J, Guyon L, Denis J, Chabre O, Cherradi N. MicroRNA Therapeutics in Cancer: Current Advances and Challenges. Cancers 2021:13:2680.##Gumireddy K., Young D.D., Xiong X., Hogenesch J.B., Huang Q., Deiters A. Small-molecule inhibitors of microrna miR-21 function. Angew. Chem. 2008;120:7592-7594.##Watashi K., Yeung M.L., Starost M.F., Hosmane R.S., Jeang K.-T. Identification of small molecules that suppress microRNA function and reverse tumorigenesis. J. Biol. Chem. 2010;285:24707-24716.##Hei Y.-Y., Wang S., Xi X.-X., Wang H.-P., Guo Y., Xin M., Jiang C., Lu S., Zhang S.-Q. Design, synthesis, and evaluation of fluoroquinolone derivatives as MicroRNA-21 small-molecule inhibitors. J. Pharm. Anal. 2022;12:653-663.##Melo S., Villanueva A., Moutinho C., Davalos V., Spizzo R., Ivan C., Rossi S., Setien F., Casanovas O., Simo-Riudalbas L. Small molecule enoxacin is a cancer-specific growth inhibitor that acts by enhancing TAR RNA-binding protein 2-mediated microRNA processing. Proc. Natl. Acad. Sci. USA. 2011;108:4394-4399.##Jie J, Liu D, Wang Y, Wu Q, Wu T, Fang R. Generation of MiRNA sponge constructs targeting multiple MiRNAs. J. Clin. Lab. Anal. 2022:36:e24527.##Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, et al. miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat. Cell Biol. 2010:12:247-256.##Wang P, Zhou C, Li D, Zhang D, Wei L, Deng Y. circMTO1 sponges microRNA-219a-5p to enhance gallbladder cancer progression via the TGF-β/Smad and EGFR pathways. Oncol Lett. 2021 Jul;22(1):563.##Quemener AM, Bachelot L, Forestier A, Donnou-Fournet E, Gilot D, Galibert MD. The powerful world of antisense oligonucleotides: From bench to bedside. Wiley Interdiscip. Rev. RNA 2020:11:e1594.##Shadid M, Badawi M, Abulrob A. Antisense oligonucleotides: Absorption, distribution, metabolism, and excretion. Expert. Opin. Drug Metab. Toxicol. 2021:17:1281-1292.##Fei J, Lan F, Guo M, Li Y, Liu Y. Inhibitory effects of anti-miRNA oligonucleotides (AMOs) on A549 cell growth. J. Drug Target. 2008:16:688-693.##Park JK, Lee EJ, Esau C, Schmittgen TD. Antisense inhibition of microRNA-21 or -221 arrests cell cycle, induces apoptosis, and sensitizes the effects of gemcitabine in pancreatic adenocarcinoma. Pancreas 2009:38:e190-e199.##Saxena R, Chakrapani B, Sarath Krishnan MP, Gupta A, Gupta S, Das J, Gupta SC, Mirza AA, Rao S, Goyal B. Next generation sequencing uncovers multiple miRNAs associated molecular targets in gallbladder cancer patients. Sci Rep. 2023:13:19101.##Zhang Y, Zuo C, Liu L, Hu Y, Yang B, Qiu S, et al. Single-cell RNA-sequencing atlas reveals an MDK-dependent immunosuppressive environment in ErbB pathway-mutated gallbladder cancer. J. Hepatol. 2021:75:1128-1141.##de Bitter TJJ, de Reuver PR, de Savornin Lohman EAJ, Kroeze LI, Vink-Börger ME, van Vliet S, et al. Comprehensive clinicopathological and genomic profiling of gallbladder cancer reveals actionable targets in half of patients. NPJ Precis. Oncol. 2022:6:83.##Ghosh M, Sakhuja P, Singh S, Agarwal AK. p53 and beta-catenin expression in gallbladder tissues and correlation with tumor progression in gallbladder cancer. Saudi J Gastroenterol. 2013:19:34-9.##Costa PM, Pedroso de Lima MC. MicroRNAs as Molecular Targets for Cancer Therapy: On the Modulation of MicroRNA Expression. Pharmaceuticals. 2013:6:1195-1220.##Yang D, Zhan M, Chen T, Chen W, Zhang Y, Xu S, et al. miR-125b-5p enhances chemotherapy sensitivity to cisplatin by down-regulating Bcl2 in gallbladder cancer. Sci Rep. 2017:7:43109.##Lu W, Zhang Y, Zhou L, Wang X, Mu J, Jiang L, et al. miR-122 inhibits cancer cell malignancy by targeting PKM2 in gallbladder carcinoma. Tumour Biol. 2015:37:15615-15625.##Ishigami K, Nosho K, Koide H, Kanno S, Mitsuhashi K, Igarashi H, et al. MicroRNA-31 reflects IL-6 expression in cancer tissue and is related with poor prognosis in bile duct cancer. Carcinogenesis. 2018:39:1127-1134.##Lundberg IV, Wikberg ML, Ljuslinder I, Li X, Myte R, Zingmark C, et al. R. MicroRNA expression in KRAS-and BRAF-mutated colorectal cancers. Anticancer Res. 2018:38:677-683.##Yang G, Yin B. Therapeutic effects of long-circulating miR-135a-containing cationic immunoliposomes against gallbladder carcinoma. Sci. Rep. 2017:7:5982.##Obata T, Tsutsumi K, Ueta E, Oda T, Kikuchi T, Ako S et al. MicroRNA-451a inhibits gemcitabine-refractory biliary tract cancer progression by suppressing the MIF-mediated PI3K/AKT pathway. Molecular Therapy: Nucleic Acids 2023:34:13.##Hong DS, Kang YK, Borad M, Sachdev J, Ejadi S, Lim HY, et al. Phase 1 study of MRX34, a liposomal miR-34a mimic, in patients with advanced solid tumours. Br. J. Cancer 2020:122:1630-1637.##De Silva F, Alcorn J. A tale of two cancers: A current concise overview of breast and prostate cancer. Cancers 2022:14:2954.##Soerjomataram I, Bray F. Planning for tomorrow: Global cancer incidence and the role of prevention 2020-2070. Nat. Rev. Clin. Oncol. 2021:18:663-672.##Holjencin C, Jakymiw A. MicroRNAs and their big therapeutic impacts: Delivery strategies for cancer intervention. Cells 2022:11:2332.##He W, Turkeshi A, Li X, Zhang H. Progress in systemic co-delivery of microRNAs and chemotherapeutics for cancer treatment by using lipid-based nanoparticles. Ther. Deliv. 2020:11:591-603.##O'Neill CP, Dwyer RM. Nanoparticle-Based Delivery of Tumor Suppressor microRNA for Cancer Therapy. Cells. 2020:9(2):521.##Kara G, Calin GA, Ozpolat B. RNAi-based therapeutics and tumor targeted delivery in cancer. Adv. Drug Deliv. Rev. 2022:182:114113.##Wang H, Ellipilli S, Lee WJ, Li X, Vieweger M, Ho YS, et al. Multivalent rubber-like RNA nanoparticles for targeted co-delivery of paclitaxel and MiRNA to silence the drug efflux transporter and liver cancer drug resistance. J. Control. Release :2021:330: 173-184.## ##

Poly (amidoamine) Dendrimers in Cancer Therapy: Chemotherapy, Radiotherapy and Imaging Advances 2 2 Cancer is estimated to overtake cardiovascular diseases and take the top spot as the leading and most important cause of mortality globally in the near future. Given the importance of early diagnosis to reduce mortality, many efforts have been made to discover a theranostic system for simultaneous cancer diagnosis and treatment. So far, the use of nanotechnology has greatly contributed to the improvement and development of these systems. Meanwhile, dendrimer nanoparticles have attracted considerable attention in medical research due to their unique properties. Poly(amidoamine) (PAMAM) dendrimers have become the primary category of dendrimers and have been widely studied for their possible application in cancer treatments. These nanoparticles have features including interior cavities and peripheral functional groups that allow the encapsulation of diverse medications or diagnostic agents. As a result, these particles can function as efficient nanocarriers and vectors for medical applications. This capability allows for the resolution of the obstacles presented by the tumor microenvironment. The prospective use of multifunctional PAMAM holds promise in enabling thorough monitoring of different stages of treated cancer tissue, hence providing substantial support in the early detection and prediction of tumor response. The primary focus of this study will be to investigate the most recent developments of PAMAM dendrimers in the field of cancer theranostics. The employment of NPs in anticancer medicine administration for radiation treatment, chemotherapy, and diagnostic imaging is underscored due to its significant potential. 86 104 2024/10/262024/11/192024/11/112024/11/102024/11/262024/11/72024/11/92024/10/192024/11/20 1403/8/30 2024/12/242024/12/22024/12/252024/12/32024/12/232024/12/32024/12/222024/12/242024/12/17 1403/9/27 Mahdieh Ahmadi Kamalabadi Mahdieh Ahmadi Kamalabadi Social Determinants of Health Research Center, Rafsanjan University of Medical Sciences, Rafsanjan, Iran mkniloo@yahoo.com Somayeh Kazempour Somayeh Kazempour Department of Radiology, Faculty of Allied Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran skazempour.sunny@gmail.com.com Asieh Fatemidokht Asieh Fatemidokht Department of Radiology, Faculty of Allied Medical Sciences, Rafsanjan University of Medical Sciences, Rafsanjan, Iran a_fatemidokht@yahoo.com Mikaeil Molazadeh Mikaeil Molazadeh Department of Medical Physics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran Fereshteh Koosha Fereshteh Koosha Department of Radiology Technology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. frshtkoosha@yahoo.com PAMAM dendrimers Chemotherapy Radio sensitization Imaging Piñeros M, Mery L, Soerjomataram I, Bray F, Steliarova-Foucher E. Scaling up the surveillance of childhood cancer: a global roadmap. JNCI: Journal of the National Cancer Institute. 2021;113(1):9-15.##Schiffman JD, Fisher PG, Gibbs P. Early detection of cancer: past, present, and future. American Society of Clinical Oncology Educational Book. 2015;35(1):57-65.##Ott JJ, Ullrich A, Miller AB. The importance of early symptom recognition in the context of early detection and cancer survival. European Journal of Cancer. 2009;45(16):2743-8.##Lopez-Campos F, Candini D, Carrasco E, Francés MAB. Nanoparticles applied to cancer immunoregulation. Reports of Practical Oncology & Radiotherapy. 2019;24(1):47-55.##Miller KD, Nogueira L, Mariotto AB, Rowland JH, Yabroff KR, Alfano CM, et al. Cancer treatment and survivorship statistics, 2019. CA: a cancer journal for clinicians. 2019;69(5):363-85.##Baker Jr JR. Dendrimer-based nanoparticles for cancer therapy. ASH Education Program Book. 2009;2009(1):708-19.##Shreyash N, Sonker M, Bajpai S, Tiwary SK. Review of the mechanism of nanocarriers and technological developments in the field of nanoparticles for applications in cancer theragnostics. ACS Applied Bio Materials. 2021;4(3):2307-34.##Karthikeyan L, Sobhana S, Yasothamani V, Gowsalya K, Vivek R. Multifunctional Theranostic Nanomedicines for Cancer Treatment: A Recent Progress and Challenges. Biomedical Engineering Advances. 2023:100082.##Ambekar RS, Choudhary M, Kandasubramanian B. Recent advances in dendrimer-based nanoplatform for cancer treatment: A review. European polymer journal. 2020;126:109546.##Sampathkumar SG, Yarema KJ. Dendrimers in cancer treatment and diagnosis. Nanotechnologies for the Life Sciences: Online. 2007.##Palmerston Mendes L, Pan J, Torchilin VP. Dendrimers as nanocarriers for nucleic acid and drug delivery in cancer therapy. Molecules. 2017;22(9):1401.##Fan Y, Sun W, Shi X. Design and Biomedical Applications of Poly (amidoamine)‐Dendrimer‐Based Hybrid Nanoarchitectures. Small Methods. 2017;1(12):1700224.##Bober Z, Bartusik-Aebisher D, Aebisher D. Application of dendrimers in anticancer diagnostics and therapy. Molecules. 2022;27(10):3237.##Wang J, Li B, Qiu L, Qiao X, Yang H. Dendrimer-based drug delivery systems: History, challenges, and latest developments. Journal of Biological Engineering. 2022;16(1):1-12.##https://doi.org/10.1186/s13036-023-00401-4##Najafi F, Salami-Kalajahi M, Roghani-Mamaqani H. A review on synthesis and applications of dendrimers. Journal of the Iranian Chemical Society. 2021;18:503-17.##Vögtle F, Richardt G, Werner N. Types of Dendrimers and their Syntheses. Dendrimer Chemistry: Concepts, Syntheses, Properties, Applications. 2009:81-167.##Kesharwani P, Jain K, Jain NK. Dendrimer as nanocarrier for drug delivery. Progress in Polymer Science. 2014;39(2):268-307.##Kaurav M, Ruhi S, Al-Goshae HA, Jeppu AK, Ramachandran D, Sahu RK, et al. Dendrimer: An update on recent developments and future opportunities for the brain tumors diagnosis and treatment. Frontiers in pharmacology. 2023;14:1159131.##Kaur D, Jain K, Mehra NK, Kesharwani P, Jain NK. A review on comparative study of PPI and PAMAM dendrimers. Journal of Nanoparticle Research. 2016;18:1-14.##Tripathy S, Das MK. Dendrimers and their applications as novel drug delivery carriers. Journal of Applied Pharmaceutical Science. 2013;3(9):142-9.##Kaurav M, Ruhi S, Al-Goshae HA, Jeppu AK, Ramachandran D, Sahu RK, et al. Dendrimer: An update on recent developments and future opportunities for the brain tumors diagnosis and treatment. (1663-9812 (Print)).##Patri AK, Majoros IJ, Baker Jr JR. Dendritic polymer macromolecular carriers for drug delivery. Current opinion in chemical biology. 2002;6(4):466-71.##Lyu Z, Ding L, Huang A-T, Kao C-L, Peng L. Poly (amidoamine) dendrimers: Covalent and supramolecular synthesis. Materials Today Chemistry. 2019;13:34-48.##Kharwade R, More S, Warokar A, Agrawal P, Mahajan N. Starburst pamam dendrimers: Synthetic approaches, surface modifications, and biomedical applications. Arabian Journal of Chemistry. 2020;13(7):6009-39.##Sebestik J, Reinis M, Jezek J, Šebestík J, Reiniš M, Ježek J. Synthesis of dendrimers: Convergent and divergent approaches. Biomedical Applications of Peptide-, Glyco-and Glycopeptide Dendrimers, and Analogous Dendrimeric Structures. 2012:55-81.##Santos AA-O, Veiga F, Figueiras AA-O. Dendrimers as Pharmaceutical Excipients: Synthesis, Properties, Toxicity and Biomedical Applications. LID - 10.3390/ma13010065 [doi] LID - 65. (1996-1944 (Print)).##Mittal P, Saharan A, Verma R, Altalbawy F, Alfaidi MA, Batiha GE-S, et al. Dendrimers: a new race of pharmaceutical nanocarriers. BioMed Research International. 2021;2021.##Li D, Lin L, Fan Y, Liu L, Shen M, Wu R, et al. Ultrasound-enhanced fluorescence imaging and chemotherapy of multidrug-resistant tumors using multifunctional dendrimer/carbon dot nanohybrids. Bioactive materials. 2021;6(3):729-39.##Abedi-Gaballu F, Dehghan G, Ghaffari M, Yekta R, Abbaspour-Ravasjani S, Baradaran B, et al. PAMAM dendrimers as efficient drug and gene delivery nanosystems for cancer therapy. Applied materials today. 2018;12:177-90.##Liu Y, K Tee J, NC Chiu G. Dendrimers in oral drug delivery application: current explorations, toxicity issues and strategies for improvement. Current pharmaceutical design. 2015;21(19):2629-42.##Braun CS, Vetro JA, Tomalia DA, Koe GS, Koe JG, Middaugh CR. Structure/function relationships of polyamidoamine/DNA dendrimers as gene delivery vehicles. Journal of pharmaceutical sciences. 2005;94(2):423-36.##Malik N, Duncan R, Tomalia DA, Esfand R. Dendritic-antineoplastic drug delivery system. Google Patents; 2006.##Cruz A, Barbosa J, Antunes P, Bonifácio VD, Pinto SN. A Glimpse into Dendrimers Integration in Cancer Imaging and Theranostics. International Journal of Molecular Sciences. 2023;24(6):5430.##Li X, Takashima M, Yuba E, Harada A, Kono K. PEGylated PAMAM dendrimer-doxorubicin conjugate-hybridized gold nanorod for combined photothermal-chemotherapy. Biomaterials. 2014;35(24):6576-84.##Carvalho MR, Carvalho CR, Maia FR, Caballero D, Kundu SC, Reis RL, et al. Peptide‐Modified Dendrimer Nanoparticles for Targeted Therapy of Colorectal Cancer. Advanced Therapeutics. 2019;2(11):1900132.##Chen M, Betzer O, Fan Y, Gao Y, Shen M, Sadan T, et al. Multifunctional dendrimer-entrapped gold nanoparticles for labeling and tracking T cells via dual-modal computed tomography and fluorescence imaging. Biomacromolecules. 2020;21(4):1587-95.##Marcinkowska M, Sobierajska E, Stanczyk M, Janaszewska A, Chworos A, Klajnert-Maculewicz B. Conjugate of PAMAM dendrimer, doxorubicin and monoclonal antibody-trastuzumab: the new approach of a well-known strategy. Polymers. 2018;10(2):187.##Ma J, Yao H. Dendrimer-paclitaxel complexes for efficient treatment in ovarian cancer: study on OVCAR-3 and HEK293T cells. Acta Biochimica Polonica. 2018;65(2):219-25.##Zeqiri B, Hodnett M, Carroll AJ. Studies of a novel sensor for assessing the spatial distribution of cavitation activity within ultrasonic cleaning vessels. Ultrasonics. 2006;44(1):73-82.##Lin L, Fan Y, Gao F, Jin L, Li D, Sun W, et al. UTMD-promoted co-delivery of gemcitabine and miR-21 inhibitor by dendrimer-entrapped gold nanoparticles for pancreatic cancer therapy. Theranostics. 2018;8(7):1923.##Laheru D, Jaffee EM. Immunotherapy for pancreatic cancer-science driving clinical progress. Nature Reviews Cancer. 2005;5(6):459-67.##Xu L, Kittrell S, Yeudall WA, Yang H. Folic acid-decorated polyamidoamine dendrimer mediates selective uptake and high expression of genes in head and neck cancer cells. Nanomedicine. 2016;11(22):2959-73.##Xu X, Li J, Han S, Tao C, Fang L, Sun Y, et al. A novel doxorubicin loaded folic acid conjugated PAMAM modified with borneol, a nature dual-functional product of reducing PAMAM toxicity and boosting BBB penetration. European Journal of Pharmaceutical Sciences. 2016;88:178-90.##Grześkowiak BF, Maziukiewicz D, Kozłowska A, Kertmen A, Coy E, Mrówczyński R. Polyamidoamine dendrimers decorated multifunctional polydopamine nanoparticles for targeted chemo-and photothermal therapy of liver cancer model. International Journal of Molecular Sciences. 2021;22(2):738.##Han S, Zheng H, Lu Y, Sun Y, Huang A, Fei W, et al. A novel synergetic targeting strategy for glioma therapy employing borneol combination with angiopep-2-modified, DOX-loaded PAMAM dendrimer. Journal of drug targeting. 2018;26(1):86-94.##Lu Y, Han S, Zheng H, Ma R, Ping Y, Zou J, et al. A novel RGDyC/PEG co-modified PAMAM dendrimer-loaded arsenic trioxide of glioma targeting delivery system. International journal of nanomedicine. 2018:5937-52.##Gaitsch H, Hersh AM, Alomari S, Tyler BM. Dendrimer Technology in Glioma: Functional Design and Potential Applications. Cancers. 2023;15(4):1075.##Dubey SK, Kali M, Hejmady S, Saha RN, Alexander A, Kesharwani P. Recent advances of dendrimers as multifunctional nano-carriers to combat breast cancer. European Journal of Pharmaceutical Sciences. 2021;164:105890.##Sunoqrot S, Bugno J, Lantvit D, Burdette JE, Hong S. Prolonged blood circulation and enhanced tumor accumulation of folate-targeted dendrimer-polymer hybrid nanoparticles. Journal of controlled release. 2014;191:115-22.##Camacho C, Maciel D, Tomás H, Rodrigues J. Biological Effects in Cancer Cells of Mono-and Bidentate Conjugation of Cisplatin on PAMAM Dendrimers: A Comparative Study. Pharmaceutics. 2023;15(2):689.##Torres-Pérez SA, Ramos-Godínez MdP, Ramón-Gallegos E, editors. Effect of methotrexate conjugated PAMAM dendrimers on the viability of breast cancer cells. AIP Conference Proceedings; 2019: AIP Publishing.##Xu X, Li Y, Lu X, Sun Y, Luo J, Zhang Y. Glutaryl polyamidoamine dendrimer for overcoming cisplatin-resistance of breast cancer cells. Journal of Nanoscience and Nanotechnology. 2018;18(10):6732-9.##Nabavizadeh F, Fanaei H, Imani A, Vahedian J, Amoli FA, Ghorbi J, et al. Evaluation of nanocarrier targeted drug delivery of Capecitabine-PAMAM dendrimer complex in a mice colorectal cancer model. Acta Medica Iranica. 2016:485-93.##Hao Y, Gao Y, Fan Y, Zhang C, Zhan M, Cao X, et al. A tumor microenvironment-responsive poly (amidoamine) dendrimer nanoplatform for hypoxia-responsive chemo/chemodynamic therapy. Journal of Nanobiotechnology. 2022;20(1):1-15.##Song X, Sun Z, Li L, Zhou L, Yuan S. Application of nanomedicine in radiotherapy sensitization. Frontiers in Oncology. 2023;13:1088878.##Saluja V, Mishra Y, Mishra V, Giri N, Nayak P. Dendrimers based cancer nanotheranostics: An overview. International Journal of Pharmaceutics. 2021;600:120485.##Zhu J, Zhao L, Cheng Y, Xiong Z, Tang Y, Shen M, et al. Radionuclide 131 I-labeled multifunctional dendrimers for targeted SPECT imaging and radiotherapy of tumors. Nanoscale. 2015;7(43):18169-78.##Zhao L, Zhu J, Cheng Y, Xiong Z, Tang Y, Guo L, et al. Chlorotoxin-conjugated multifunctional dendrimers labeled with radionuclide 131I for single photon emission computed tomography imaging and radiotherapy of gliomas. ACS Applied Materials & Interfaces. 2015;7(35):19798-808.##Lu S, Li X, Zhang J, Peng C, Shen M, Shi X. Dendrimer‐stabilized gold nanoflowers embedded with ultrasmall iron oxide nanoparticles for multimode imaging-guided combination therapy of tumors. Advanced Science. 2018;5(12):1801612.##Kobayashi H, Sato N, Saga T, Nakamoto Y, Ishimori T, Toyama S, et al. Monoclonal antibody-dendrimer conjugates enable radiolabeling of antibody with markedly high specific activity with minimal loss of immunoreactivity. European journal of nuclear medicine. 2000;27:1334-9.##Mendoza-Nava H, Ferro-Flores G, Ramírez FdM, Ocampo-García B, Santos-Cuevas C, Aranda-Lara L, et al. 177 Lu-dendrimer conjugated to folate and bombesin with gold nanoparticles in the dendritic cavity: a potential theranostic radiopharmaceutical. Journal of Nanomaterials. 2016;2016.##Hosseini SM, Mohammadnejad J, Salamat S, Zadeh ZB, Tanhaei M, Ramakrishna S. Theranostic polymeric nanoparticles as a new approach in cancer therapy and diagnosis: a review. Materials Today Chemistry. 2023;29:101400.##Hu Z, Chen W-H, Tian J, Cheng Z. NIRF nanoprobes for cancer molecular imaging: approaching clinic. Trends in Molecular medicine. 2020;26(5):469-82.##Shi X, Wang SH, Shen M, Antwerp ME, Chen X, Li C, et al. Multifunctional dendrimer-modified multiwalled carbon nanotubes: synthesis, characterization, and in vitro cancer cell targeting and imaging. Biomacromolecules. 2009;10(7):1744-50.##Liu L, Chen Q, Wen L, Li C, Qin H, Xing D. Photoacoustic therapy for precise eradication of glioblastoma with a tumor site blood-brain barrier permeability upregulating nanoparticle. Advanced Functional Materials. 2019;29(11):1808601.##Zhao L, Zhu M, Li Y, Xing Y, Zhao J. Radiolabeled dendrimers for nuclear medicine applications. Molecules. 2017;22(9):1350.##Uehara T, Yokoyama M, Suzuki H, Hanaoka H, Arano Y. A gallium-67/68-labeled antibody fragment for immuno-SPECT/PET shows low renal radioactivity without loss of tumor uptake. Clinical Cancer Research. 2018;24(14):3309-16.##Xiao T, Li D, Shi X, Shen M. PAMAM Dendrimer‐Based Nanodevices for Nuclear Medicine Applications. Macromolecular Bioscience. 2020;20(2):1900282.##Tassano MR, Audicio PF, Gambini JP, Fernandez M, Damian JP, Moreno M, et al. Development of 99mTc (CO) 3-dendrimer-FITC for cancer imaging. Bioorganic & medicinal chemistry letters. 2011;21(18):5598-601.##Zhang Y, Sun Y, Xu X, Zhang X, Zhu H, Huang L, et al. Synthesis, biodistribution, and microsingle photon emission computed tomography (SPECT) imaging study of technetium-99m labeled PEGylated dendrimer poly (amidoamine)(PAMAM)− folic acid conjugates. Journal of medicinal chemistry. 2010;53(8):3262-72.##Ding L, Lyu Z, Tintaru A, Laurini E, Marson D, Louis B, et al. A self-assembling amphiphilic dendrimer nanotracer for SPECT imaging. Chemical Communications. 2020;56(2):301-4.##Li X, Xiong Z, Xu X, Luo Y, Peng C, Shen M, et al. 99mTc-labeled multifunctional low-generation dendrimer-entrapped gold nanoparticles for targeted SPECT/CT dual-mode imaging of tumors. ACS applied materials & interfaces. 2016;8(31):19883-91.##Trembleau L, Simpson M, Cheyne RW, Escofet I, Appleyard MVCAL, Murray K, et al. Development of 18 F-fluorinatable dendrons and their application to cancer cell targeting. New Journal of Chemistry. 2011;35(11):2496-502.##Werner RA, Chen X, Lapa C, Koshino K, Rowe SP, Pomper MG, et al. The next era of renal radionuclide imaging: novel PET radiotracers. European journal of nuclear medicine and molecular imaging. 2019;46:1773-86.##Ma W, Fu F, Zhu J, Huang R, Zhu Y, Liu Z, et al. 64 Cu-Labeled multifunctional dendrimers for targeted tumor PET imaging. Nanoscale. 2018;10(13):6113-24.##Bouziotis P, Stellas D, Thomas E, Truillet C, Tsoukalas C, Lux F, et al. 68Ga-radiolabeled AGuIX nanoparticles as dual-modality imaging agents for PET/MRI-guided radiation therapy. Nanomedicine. 2017;12(13):1561-74.##Yang J, Lu W, Xiao J, Zong Q, Xu H, Yin Y, et al. A positron emission tomography image-guidable unimolecular micelle nanoplatform for cancer theranostic applications. Acta Biomaterialia. 2018;79:306-16.##Lee JH, Kim GG, Kim SW, Park J-H. Zr-89 Labeled PAMAM Dendrimers 5G without a Chelator for a Cancer Diagnostic Agent. Journal of the Korean Physical Society. 2020;77:409-13.##Xing Y, Zhu J, Zhao L, Xiong Z, Li Y, Wu S, et al. SPECT/CT imaging of chemotherapy-induced tumor apoptosis using (99m)Tc-labeled dendrimer-entrapped gold nanoparticles. (1521-0464 (Electronic)).##Alibolandi M, Hoseini F, Mohammadi M, Ramezani P, Einafshar E, Taghdisi SM, et al. Curcumin-entrapped MUC-1 aptamer targeted dendrimer-gold hybrid nanostructure as a theranostic system for colon adenocarcinoma. International journal of pharmaceutics. 2018;549(1-2):67-75.##Wei P, Chen J, Hu Y, Li X, Wang H, Shen M, et al. Dendrimer‐Stabilized gold nanostars as a multifunctional theranostic nanoplatform for CT imaging, photothermal therapy, and gene silencing of tumors. Advanced healthcare materials. 2016;5(24):3203-13.##Chen Q, Li K, Wen S, Liu H, Peng C, Cai H, et al. Targeted CT/MR dual mode imaging of tumors using multifunctional dendrimer-entrapped gold nanoparticles. Biomaterials. 2013;34(21):5200-9.##Mekuria SL, Debele TA, Tsai H-C. Encapsulation of gadolinium oxide nanoparticle (Gd2O3) contrasting agents in PAMAM dendrimer templates for enhanced magnetic resonance imaging in vivo. ACS applied materials & interfaces. 2017;9(8):6782-95.##Markowicz-Piasecka M, Sikora J, Szymański P, Kozak O, Studniarek M, Mikiciuk-Olasik E. PAMAM Dendrimers as Potential Carriers of Gadolinium Complexes of Iminodiacetic Acid Derivatives for Magnetic Resonance Imaging. Journal of Nanomaterials. 2015;2015:394827.##Xu R, Wang Y, Wang X, Jeong E-K, Parker DL, Lu Z-R. In vivo evaluation of a PAMAM-cystamine-(Gd-DO3A) conjugate as a biodegradable macromolecular MRI contrast agent. Experimental Biology and Medicine. 2007;232(8):1081-9.##Karki K, Ewing JR, Ali MM. Targeting glioma with a dual mode optical and paramagnetic nanoprobe across the blood-brain tumor barrier. Journal of nanomedicine & nanotechnology. 2016;7(4).##Liu J, Xiong Z, Zhang J, Peng C, Klajnert-Maculewicz B, Shen M, et al. Zwitterionic Gadolinium(III)-Complexed Dendrimer-Entrapped Gold Nanoparticles for Enhanced Computed Tomography/Magnetic Resonance Imaging of Lung Cancer Metastasis. ACS Applied Materials & Interfaces. 2019;11(17):15212-21.##Jędrzak A, Grześkowiak BF, Coy E, Wojnarowicz J, Szutkowski K, Jurga S, et al. Dendrimer based theranostic nanostructures for combined chemo-and photothermal therapy of liver cancer cells in vitro. Colloids and Surfaces B: Biointerfaces. 2019;173:698-708.##Jamshidi N, Tarighatnia A, Ghaziyani MF, Sajadian F, Nader ND. Folic acid-conjugated Fe-Au-based nanoparticles for dual detection of breast cancer cells by magnetic resonance imaging and computed tomography. Frontiers in Biomedical Technologies. 2023.##Xu X, Xiao T, Zhang C, Wang Z, Li G, Chen J, et al. Multifunctional Low-Generation Dendrimer Nanogels as an Emerging Probe for Tumor-Specific CT/MR Dual-Modal Imaging. Biomacromolecules. 2023;24(2):967-76.##Luong D, Sau S, Kesharwani P, Iyer AK. Polyvalent folate-dendrimer-coated iron oxide theranostic nanoparticles for simultaneous magnetic resonance imaging and precise cancer cell targeting. Biomacromolecules. 2017;18(4):1197-209.##Chang Y, Liu N, Chen L, Meng X, Liu Y, Li Y, et al. Synthesis and characterization of DOX-conjugated dendrimer-modified magnetic iron oxide conjugates for magnetic resonance imaging, targeting, and drug delivery. Journal of Materials Chemistry. 2012;22(19):9594-601.##Liu R, Guo H, Ouyang Z, Fan Y, Cao X, Xia J, et al. Multifunctional core-shell tecto dendrimers incorporated with gold nanoparticles for targeted dual mode CT/MR imaging of tumors. ACS Applied Bio Materials. 2021;4(2):1803-12.##Chen JS, Chen J, Bhattacharjee S, Cao Z, Wang H, Swanson SD, et al. Functionalized nanoparticles with targeted antibody to enhance imaging of breast cancer in vivo. (1477-3155 (Electronic)).## ##

Nutritional Supportive Care in Head and Neck Cancer Patients – A Narrative Review 2 2 Head and neck cancer patients are more at high risk for malnutrition before, during, and after the cancer treatment procedures due to the proximity of key anatomical structures that are essential for mastication and deglutition. A multidisciplinary approach beginning with preliminary nutritional screening, comprehensive assessment, and nutritional supportive care is mandatory for all head and neck cancer patients. Such interventions not only improve quality of life but also increase the survival rate of the head and neck cancer patients. This updated narrative review focused on the recent updates of the various steps involved in the nutritional management of head and neck cancer patients, like pre-treatment nutritional care, screening and assessment, and nutritional interventions during and after cancer therapy with updates on nanoformulations of nutraceuticals. We reviewed all published literature between 2014 and 2024 about nutrition in head and neck cancer patients from major databases such as Embase, Web of Science, and PubMed. In addition to the nutritional parameters that should be considered during the nutritional assessment of patients with head and neck cancer, this review underscores the therapeutic efficacy of nutraceuticals in treating this disease. This narrative review added a note on recent updates on the use of a combination of novel nanoformulated nutraceuticals with chemotherapeutic agents, which were known for the improved drug delivery, such as targeting the neoplastic cells and thus preventing adverse effects. 105 113 2024/10/262024/11/192024/11/112024/11/102024/11/262024/11/72024/11/92024/10/192024/11/202024/11/5 1403/8/15 2024/12/242024/12/22024/12/252024/12/32024/12/232024/12/32024/12/222024/12/242024/12/172024/12/4 1403/9/14 Doppalapudi Radhika Doppalapudi Radhika Department of Oral Medicine and Radiology, Saveetha Dental college and hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamilnadu, India. radhikav21@gmail.com Arvind Muthukrishnan Arvind Muthukrishnan Department of Oral Medicine and Radiology, Saveetha Dental college and hospitals, Saveetha Institute of Medical and Technical Sciences (SIMATS), Saveetha University, Chennai, Tamilnadu, India. arvindm@saveetha.com Rakhi Issrani Rakhi Issrani Department of Preventive Dentistry, College of Dentistry, Jouf University, Sakaka, Kingdom of Saudi Arabia. dr.rakhi.issrani@jodent.org Cancer Immunonutrition Malnutrition Nutritional support Nano formulations Nutraceuticals Argiris A, Karamouzis MV, Raben D, Ferris RL. Head and neck cancer. Lancet. 2008;371(9625):1695-709.##Gormley M, Creaney G, Schache A, Ingarfield K, Conway DI. Reviewing the epidemiology of head and neck cancer: definitions, trends and risk factors. Br Dent J. 2022;233(9):780-6.##Mesia R, Iglesias L, Lambea J, Martínez-Trufero J, Soria A, Taberna M, et al. SEOM clinical guidelines for the treatment of head and neck cancer (2020). Clin Transl Oncol. 2021;23(5):913-21.##Casas Rodera P, de Luis DA, Gómez Candela C, Culebras JM. Immunoenhanced enteral nutrition formulas in head and neck cancer surgery: a systematic review. Nutr Hosp. 2012;27(3):681-90.##Ni J, Zhang L. Cancer Cachexia: Definition, Staging, and Emerging Treatments. Cancer Manag Res. 2020;12:5597-605.##Nishikawa H, Goto M, Fukunishi S, Asai A, Nishiguchi S, Higuchi K. Cancer Cachexia: Its Mechanism and Clinical Significance. Int J Mol Sci. 2021;22(16).##Mäkitie AA, Alabi RO, Orell H, Youssef O, Almangush A, Homma A, et al. Managing Cachexia in Head and Neck Cancer: a Systematic Scoping Review. Adv Ther. 2022;39(4):1502-23.##Elia M. Defining, Recognizing, and Reporting Malnutrition. Int J Low Extrem Wounds. 2017;16(4):230-7.##Castillo-Martínez L, Castro-Eguiluz D, Copca-Mendoza ET, Pérez-Camargo DA, Reyes-Torres CA, Ávila EA, et al. Nutritional Assessment Tools for the Identification of Malnutrition and Nutritional Risk Associated with Cancer Treatment. Rev Invest Clin. 2018;70(3):121-5.##Reber E, Schönenberger KA, Vasiloglou MF, Stanga Z. Nutritional Risk Screening in Cancer Patients: The First Step Toward Better Clinical Outcome. Front Nutr. 2021;8:603936.##Bianchini C, Ciorba A, Stomeo F, Pelucchi S, Pastore A. Immunonutrition in head and neck cancer: have a look before surgery! Eur Arch Otorhinolaryngol. 2012;269(1):5-8.##Ackerman D, Laszlo M, Provisor A, Yu A. Nutrition Management for the Head and Neck Cancer Patient. Cancer Treat Res. 2018;174:187-208.##Findlay M, Rankin NM, Shaw T, White K, Boyer M, Milross C, et al. Best Evidence to Best Practice: Implementing an Innovative Model of Nutrition Care for Patients with Head and Neck Cancer Improves Outcomes. Nutrients. 2020;12(5).##Sandmael JA, Sand K, Bye A, Solheim TS, Oldervoll L, Helvik AS. Nutritional experiences in head and neck cancer patients. Eur J Cancer Care (Engl). 2019;28(6):e13168.##Kubrak C, Olson K, Jha N, Jensen L, McCargar L, Seikaly H, et al. Nutrition impact symptoms: key determinants of reduced dietary intake, weight loss, and reduced functional capacity of patients with head and neck cancer before treatment. Head Neck. 2010;32(3):290-300.##Talwar B, Donnelly R, Skelly R, Donaldson M. Nutritional management in head and neck cancer: United Kingdom National Multidisciplinary Guidelines. J Laryngol Otol. 2016;130(S2):S32-s40.##Bossola M. Nutritional interventions in head and neck cancer patients undergoing chemoradiotherapy: a narrative review. Nutrients. 2015;7(1):265-76.##Brown TE, Banks MD, Hughes BGM, Lin CY, Kenny LM, Bauer JD. Comparison of Nutritional and Clinical Outcomes in Patients with Head and Neck Cancer Undergoing Chemoradiotherapy Utilizing Prophylactic versus Reactive Nutrition Support Approaches. J Acad Nutr Diet. 2018;118(4):627-36.##Silver HJ, Dietrich MS, Murphy BA. Changes in body mass, energy balance, physical function, and inflammatory state in patients with locally advanced head and neck cancer treated with concurrent chemoradiation after low-dose induction chemotherapy. Head Neck. 2007;29(10):893-900.##Cantwell LA, Fahy E, Walters ER, Patterson JM. Nutritional prehabilitation in head and neck cancer: a systematic review. Support Care Cancer. 2022;30(11):8831-43.##Howes N, Atkinson C, Thomas S, Lewis SJ. Immunonutrition for patients undergoing surgery for head and neck cancer. Cochrane Database Syst Rev. 2018;8(8):Cd010954.##Arends J. Struggling with nutrition in patients with advanced cancer: nutrition and nourishment-focusing on metabolism and supportive care. Ann Oncol. 2018;29(suppl_2):ii27-ii34.##Nesemeier R, Dunlap N, McClave SA, Tennant P. Evidence-Based Support for Nutrition Therapy in Head and Neck Cancer. Curr Surg Rep. 2017;5(8):18.##List MA, Knackstedt M, Liu L, Kasabali A, Mansour J, Pang J, et al. Enhanced recovery after surgery, current, and future considerations in head and neck cancer. Laryngoscope Investig Otolaryngol. 2023;8(5):1240-56.##Frydrych AM, Parsons R, Kujan O. Use of oral nutritional supplements in irradiated patients with head and neck cancer. Oral Dis. 2024;30(7):4165-73.##Dai T, Xian J, Li X, Wang Z, Hu W. Effect of nutrition impact symptoms on oral nutritional supplements energy intake and use days in patients with head and neck cancer: A cross-sectional study. Cancer Med. 2024;13(10):e7288.##Mueller SA, Mayer C, Bojaxhiu B, Aeberhard C, Schuetz P, Stanga Z, et al. Effect of preoperative immunonutrition on complications after salvage surgery in head and neck cancer. J Otolaryngol Head Neck Surg. 2019;48(1):25.##Maschke J, Kruk U, Kastrati K, Kleeberg J, Buchholz D, Erickson N, et al. Nutritional care of cancer patients: a survey on patients' needs and medical care in reality. Int J Clin Oncol. 2017;22(1):200-6.##Halilova KI, Pisu M, Azuero A, Williams CP, Kenzik KM, Williams GR, et al. Healthy lifestyle discussions between healthcare providers and older cancer survivors: Data from 12 cancer centers in the Southeastern United States. Cancer Med. 2019;8(16):7123-32.##Keinki C, Seilacher E, Ebel M, Ruetters D, Kessler I, Stellamanns J, et al. Information Needs of Cancer Patients and Perception of Impact of the Disease, of Self-Efficacy, and Locus of Control. J Cancer Educ. 2016;31(3):610-6.##van Veen MR, Beijer S, Adriaans AM, Vogel-Boezeman J, Kampman E. Development of a Website Providing Evidence-Based Information About Nutrition and Cancer: Fighting Fiction and Supporting Facts Online. JMIR Res Protoc. 2015;4(3):e110.##Avancini A, Sartori G, Gkountakos A, Casali M, Trestini I, Tregnago D, et al. Physical Activity and Exercise in Lung Cancer Care: Will Promises Be Fulfilled? Oncologist. 2020;25(3):e555-e69.##Cormie P, Zopf EM, Zhang X, Schmitz KH. The Impact of Exercise on Cancer Mortality, Recurrence, and Treatment-Related Adverse Effects. Epidemiol Rev. 2017;39(1):71-92.##Dean E, Skinner M, Myezwa H, Mkumbuzi V, Mostert K, Parra DC, et al. Health Competency Standards in Physical Therapist Practice. Phys Ther. 2019;99(9):1242-54.##van Veen MR, Mols F, Smeets L, Kampman E, Beijer S. Colorectal cancer survivors' beliefs on nutrition and cancer; correlates with nutritional information provision. Support Care Cancer. 2020;28(3):1255-63.##van Veen MR, Winkels RM, Janssen SHM, Kampman E, Beijer S. Nutritional Information Provision to Cancer Patients and Their Relatives Can Promote Dietary Behavior Changes Independent of Nutritional Information Needs. Nutr Cancer. 2018;70(3):483-9.##Deftereos I, Yeung JMC, Arslan J, Carter VM, Isenring E, Kiss N, et al. Assessment of Nutritional Status and Nutrition Impact Symptoms in Patients Undergoing Resection for Upper Gastrointestinal Cancer: Results from the Multi-Centre NOURISH Point Prevalence Study. Nutrients. 2021;13(10).##Erickson N, Paradies K, Buchholz D, Huebner J. Nutrition care of cancer patients-A survey among physicians and nurses. Eur J Cancer Care (Engl). 2018;27(4):e12855.##Philip EJ, Coups EJ, Feinstein MB, Park BJ, Wilson DJ, Ostroff JS. Physical activity preferences of early-stage lung cancer survivors. Support Care Cancer. 2014;22(2):495-502.##AuYoung M, Linke SE, Pagoto S, Buman MP, Craft LL, Richardson CR, et al. Integrating Physical Activity in Primary Care Practice. Am J Med. 2016;129(10):1022-9.##Hübner J, Muenstedt K, Muecke R, Micke O, Stoll C, Kleeberg UR, et al. Counseling cancer patients on complementary and alternative medicine. Background, theory, and implementation of nationwide counseling facilities. Strahlenther Onkol. 2013;189(8):613-7.##Waterland JL, Edbrooke L, Appathurai A, Lawrance N, Temple-Smith M, Denehy L. 'Probably better than any medication we can give you': General practitioners' views on exercise and nutrition in cancer. Aust J Gen Pract. 2020;49(8):513-8.##Cereda E, Turri A, Klersy C, Cappello S, Ferrari A, Filippi AR, et al. Whey protein isolate supplementation improves body composition, muscle strength, and treatment tolerance in malnourished advanced cancer patients undergoing chemotherapy. Cancer Med. 2019;8(16):6923-32.##Hoang BV, Tran TT, Duong YT, Nguyen LT, Ngo DQ, Nguyen DV, et al. The Effects of nutrition intervention on postoperative patients with tongue cancer and floor of mouth cancer. J Nutr Sci Vitaminol (Tokyo). 2022;68(6):488-95.##Yeh KY, Wang HM, Chang JW, Huang JS, Lai CH, Lan YJ, et al. Omega-3 fatty acid-, micronutrient-, and probiotic-enriched nutrition helps body weight stabilization in head and neck cancer cachexia. Oral Surg Oral Med Oral Pathol Oral Radiol. 2013;116(1):41-8.##Dai W, Wang SA, Wang K, Chen C, Wang J, Chen X, et al. Impact of nutrition counseling in head and neck cancer sufferers undergoing antineoplastic therapy: a randomized controlled pilot study. Curr Oncol. 2022;29(10):6947-55.##Sykes KJ, Gibbs H, Farrokhian N, Arthur A, Flynn J, Shnayder Y, et al. Pilot randomized, controlled, preoperative intervention for nutrition trial in head and neck cancer. Head Neck. 2023;45(1):156-66.##Dechaphunkul T, Arundon T, Raungkhajon P, Jiratrachu R, Geater SL, Dechaphunkul A. Benefits of immunonutrition in patients with head and neck cancer receiving chemoradiation: A phase II randomized, double-blind study. Clin Nutr. 2022;41(2):433-40.##Barajas-Galindo DE, Vidal-Casariego A, Pintor-de la Maza B, Fernández-Martínez P, Ramos-Martínez T, García-Arias S, et al. Postoperative enteral immunonutrition in head and neck cancer patients: Impact on clinical outcomes. Endocrinol Diabetes Nutr (Engl Ed). 2020;67(1):13-9.##https://doi.org/10.1016/j.endinu.2019.05.006##Della Valle S, Colatruglio S, La Vela V, Tagliabue E, Mariani L, Gavazzi C. Nutritional intervention in head and neck cancer patients during chemo-radiotherapy. Nutrition. 2018;51-52:95-7.##Cereda E, Cappello S, Colombo S, Klersy C, Imarisio I, Turri A, et al. Nutritional counseling with or without systematic use of oral nutritional supplements in head and neck cancer patients undergoing radiotherapy. Radiother Oncol. 2018;126(1):81-8.##Lages PC, Generoso SV, Correia M. Postoperative symbiotic in patients with head and neck cancer: a double-blind randomised trial. Br J Nutr. 2018;119(2):190-5.##Müller-Richter U, Betz C, Hartmann S, Brands RC. Nutrition management for head and neck cancer patients improves clinical outcome and survival. Nutr Res. 2017;48:1-8.##Azman M, Mohd Yunus MR, Sulaiman S, Syed Omar SN. Enteral glutamine supplementation in surgical patients with head and neck malignancy: A randomized controlled trial. Head Neck. 2015;37(12):1799-807.##Boisselier P, Kaminsky MC, Thézenas S, Gallocher O, Lavau-Denes S, Garcia-Ramirez M, et al. A double-blind phase III trial of immunomodulating nutritional formula during adjuvant chemoradiotherapy in head and neck cancer patients: IMPATOX. Am J Clin Nutr. 2020;112(6):1523-31.##Aeberhard C, Mayer C, Meyer S, Mueller SA, Schuetz P, Stanga Z, et al. Effect of preoperative immunonutrition on postoperative short-term outcomes of patients with head and neck squamous cell carcinoma. Head Neck. 2018;40(5):1057-67.##Hanai N, Terada H, Hirakawa H, Suzuki H, Nishikawa D, Beppu S, et al. Prospective randomized investigation implementing immunonutritional therapy using a nutritional supplement with a high blend ratio of ω-3 fatty acids during the perioperative period for head and neck carcinomas. Jpn J Clin Oncol. 2018;48(4):356-61.##Alam S, Lee J, Sahebkar A. Curcumin in Cancer prevention: insights from clinical trials and strategies to enhance bioavailability. Curr Pharm Des. 2024;30(23):1838-51.##Zhao C, Zhou X, Cao Z, Ye L, Cao Y, Pan J. Curcumin and analogues against head and neck cancer: From drug delivery to molecular mechanisms. Phytomedicine. 2023;119:154986.##Wilken R, Veena MS, Wang MB, Srivatsan ES. Curcumin: A review of anti-cancer properties and therapeutic activity in head and neck squamous cell carcinoma. Mol Cancer. 2011;10:12.##Ahmad I, Ahmad S, Ahmad A, Zughaibi TA, Alhosin M, Tabrez S. Curcumin, its derivatives, and their nanoformulations: Revolutionizing cancer treatment. Cell Biochem Funct. 2024;42(1):e3911.##Abd El-Hack ME, El-Saadony MT, Swelum AA, Arif M, Abo Ghanima MM, Shukry M, et al. Curcumin, the active substance of turmeric: its effects on health and ways to improve its bioavailability. J Sci Food Agric. 2021;101(14):5747-62.##Kia SJ, Basirat M, Saedi HS, Arab SA. Effects of nanomicelle curcumin capsules on prevention and treatment of oral mucosits in patients under chemotherapy with or without head and neck radiotherapy: a randomized clinical trial. BMC Complement Med Ther. 2021;21(1):232.##Shah S, Rath H, Sharma G, Senapati SN, Mishra E. Effectiveness of curcumin mouthwash on radiation-induced oral mucositis among head and neck cancer patients: A triple-blind, pilot randomised controlled trial. Indian J Dent Res. 2020;31(5):718-27.##Mazzarino L, Loch-Neckel G, Bubniak Ldos S, Mazzucco S, Santos-Silva MC, Borsali R, et al. Curcumin-Loaded Chitosan-Coated Nanoparticles as a New Approach for the Local Treatment of Oral Cavity Cancer. J Nanosci Nanotechnol. 2015;15(1):781-91.##Ramezani V, Ghadirian S, Shabani M, Boroumand MA, Daneshvar R, Saghafi F. Efficacy of curcumin for amelioration of radiotherapy-induced oral mucositis: a preliminary randomized controlled clinical trial. BMC Cancer. 2023;23(1):354.##Delavarian Z, Pakfetrat A, Ghazi A, Jaafari MR, Homaei Shandiz F, Dalirsani Z, et al. Oral administration of nanomicelle curcumin in the prevention of radiotherapy-induced mucositis in head and neck cancers. Spec Care Dentist. 2019;39(2):166-72.##Cocetta V, Tinazzi M, Giacomini I, Rosato B, Ragazzi E, Berretta M, et al. Clinical evidence of interaction between nutraceutical supplementation and platinum-based chemotherapy. Curr Med Chem. 2023;30(19):2141-64.##Filippini T, Malavolti M, Borrelli F, Izzo AA, Fairweather-Tait SJ, Horneber M, et al. Green tea (Camellia sinensis) for the prevention of cancer. Cochrane Database Syst Rev. 2020;3(3):Cd005004.##Belobrov S, Seers C, Reynolds E, Cirillo N, McCullough M. Functional and molecular effects of a green tea constituent on oral cancer cells. J Oral Pathol Med. 2019;48(7):604-10.##Liao YC, Hsu LF, Hsieh LY, Luo YY. Effectiveness of green tea mouthwash for improving oral health status in oral cancer patients: A single-blind randomized controlled trial. Int J Nurs Stud. 2021;121:103985.##Rafieian N, Azimi S, Manifar S, Julideh H, ShirKhoda M. Is there any association between green tea consumption and the risk of head and neck squamous cell carcinoma: Finding from a case-control study. Arch Oral Biol. 2019;98:280-4.##Radoï L, Paget-Bailly S, Menvielle G, Cyr D, Schmaus A, Carton M, et al. Tea and coffee consumption and risk of oral cavity cancer: results of a large population-based case-control study, the ICARE study. Cancer Epidemiol. 2013;37(3):284-9.##Neetha MC, Panchaksharappa MG, Pattabhiramasastry S, Shivaprasad NV, Venkatesh UG. Chemopreventive synergism between green tea extract and curcumin in patients with potentially malignant oral disorders: a double-blind, randomized preliminary study. J Contemp Dent Pract. 2020;21(5):521-31.##Almatroodi SA, M AA, A SMA, Alhumaydhi FA, Babiker AY, Khan AA, et al. Potential therapeutic targets of resveratrol, a plant polyphenol, and its role in the therapy of various types of cancer. Molecules. 2022;27(9).##de Sá Coutinho D, Pacheco MT, Frozza RL, Bernardi A. Anti-inflammatory effects of resveratrol: mechanistic insights. Int J Mol Sci. 2018;19(6).##Mohammadi S, Moghadam MD, Nasiriasl M, Akhzari M, Barazesh M. Insights into the therapeutic and pharmacological properties of resveratrol as a nutraceutical antioxidant polyphenol in health promotion and disease prevention. Curr Rev Clin Exp Pharmacol. 2024;19(4):327-54.##Rauf A, Imran M, Butt MS, Nadeem M, Peters DG, Mubarak MS. Resveratrol as an anti-cancer agent: A review. Crit Rev Food Sci Nutr. 2018;58(9):1428-47.##Annaji M, Poudel I, Boddu SHS, Arnold RD, Tiwari AK, Babu RJ. Resveratrol-loaded nanomedicines for cancer applications. Cancer Rep (Hoboken). 2021;4(3):e1353.##Mohan A, Narayanan S, Sethuraman S, Krishnan UM. Novel resveratrol and 5-fluorouracil coencapsulated in PEGylated nanoliposomes improve chemotherapeutic efficacy of combination against head and neck squamous cell carcinoma. Biomed Res Int. 2014;2014:424239.## ##