2023 15 4 0 303

Clostridium Bacteria: The Team of Microscopic Oncologists 2 2 As we approach the year 2023, the global rise in cancer mortality remains a pressing concern. Recent studies have demonstrated the remarkable potential of bacteria in combating cancer by stimulating the immune system. Exciting evidence suggests that bacterial therapy can revolutionize both the treatment and diagnosis of tumors. To effectively classify and treat tumors, the introduction of obligate or optional anaerobic bacteria into solid tumors may be necessary. Notably, certain strains of Clostridium have proven to be particularly effective in cancer treatment. A fascinating natural phenomenon lies in the ability of Clostridium spores to infiltrate tumors and selectively germinate in hypoxic regions within dense tumors upon injection into a vein. This bacterial invasion directly eliminates tumor cells by enhancing the presence of tumor-specific antigens, enabling the immune system to recognize and attack cancerous cells. Although these bacteria do not directly destroy tumor cells, their activation of the immune system holds great promise for eradicating them. Currently, an extensive range of bacteria is employed for cancer treatment, designing bacteria-carrying pharmaceutical compounds, and facilitating radiotherapy or radiation therapy. Additionally, genetic manipulation techniques can enable bacteria to specifically target tumor tissue and inhibit angiogenesis. In this comprehensive review, we delve into the potential advantages of utilizing Clostridium bacteria in cancer medications. Specifically, we explore the abilities of Clostridium perfringens and Clostridium novi to induce angiogenesis, provoke immune responses, and operate within oxygen-deprived environments.   178 202 2023/06/21 1402/3/31 2023/08/12 1402/5/21 Rosa Behboodi Rosa Behboodi Jawaharlal Nehru Technological University Hyderabad, Hyderabad, India rosa_behboodi@yahoo.com Arman Saadati Partan Arman Saadati Partan Department of Microbiology, Islamic Azad University, Karaj Branch, Karaj, Iran saadati.arman.as@gmail.com Sepideh Meidaninikjeh Sepideh Meidaninikjeh Department of Microbiology, Faculty of Biological Science, Alzahra University, Tehran, Iran sepideh.meidani@yahoo.com Yasamin Morvarid Yasamin Morvarid Medical Genomics Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran yasaminmorvarid@gmail.com Haniyeh Sadat Hosseininia Haniyeh Sadat Hosseininia Department of Cellular and Molecular Biology, Faculty of Advanced Medical Science, Tehran Islamic Azad University of Medical Sciences, Tehran, Iran hanahosseininia75@gmail.com Maryam Sayhinouri Maryam Sayhinouri Department of Immunology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran maryam.sayahinouri@gmail.com Armaghan Shirinsokhan Armaghan Shirinsokhan Department of Biology, Faculty of Sciences, Rasht Branch, Islamic Azad University, Rasht, Iran armaghan.shirin@gmail.com Sahar Javadi Sahar Javadi Department of Microbiology, Faculty of Biological Sciences, Islamic Azad University, North Tehran Branch, Tehran, Iran S.javadii.micro@gmail.com Amin Ebrahimi Sadrabadi Amin Ebrahimi Sadrabadi Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran Amin.ebrahimii@live.com Arsalan Jalili Arsalan Jalili Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACER, Tehran, Iran Jalili.arsalan@yahoo.com Clostridium Cancer Tumor Cancer-fighting bacteria Bacterial therapy Ferlay J, Colombet M, Soerjomataram I, Mathers C, Parkin D, Piñeros M, et al. Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods. International journal of cancer. 2019;144(8):1941-53. doi: 10.1002/ijc.31937. Epub 2018 Dec 6.##Kucerova P, Cervinkova M. Spontaneous regression of tumour and the role of microbial infection-possibilities for cancer treatment. Anti-Cancer Drugs. 2016;27(4):269. doi: 10.1097/CAD.0000000000000337.##Hashimi S, Yu S, Alqurashi N, Ipe D, Wei M. Immunotoxin-mediated targeting of claudin-4 inhibits the proliferation of cancer cells. International journal of oncology. 2013;42(6):1911-8. doi: 10.3892/ijo.2013.1881.##Felgner S, Kocijancic D, Frahm M, Weiss S. Bacteria in cancer therapy: renaissance of an old concept. International journal of microbiology. 2016;2016. doi: 10.1155/2016/8451728.##Pahle J, Menzel L, Niesler N, Kobelt D, Aumann J, Rivera M, et al. Rapid eradication of colon carcinoma by Clostridium perfringens Enterotoxin suicidal gene therapy. BMC cancer. 2017;17(1):1-14. doi: 10.1186/s12885-017-3123-x.##Hoffer A. The Use of Bacterial Toxins in the Treatment of Cancer. Journal of Orthomolecular Medicine. 1992;7:163-.##Oelschlaeger TA. Bacteria as tumor therapeutics? Bioengineered bugs. 2010;1(2):146-Barbé S, Van Mellaert L, Theys J, Geukens N, Lammertyn E, Lambin P, et al. Secretory production of biologically active rat interleukin-2 by Clostridium acetobutylicum DSM792 as a tool for anti-tumor treatment. FEMS microbiology letters. 2005;246(1):67-73. doi: 10.1016/j.femsle.2005.03.037.##Saltzman DA, Heise CP, Hasz DE, Zebede M, Kelly SM, Curtiss III R, et al. Attenuated Salmonella typhimurium containing interleukin-2 decreases MC-38 hepatic metastases: a novel anti-tumor agent. Cancer biotherapy & radiopharmaceuticals. 1996;11(2):145-53. doi: 10.1089/cbr.1996.11.145.##Loeffler M, Le'Negrate G, Krajewska M, Reed JC. IL-18-producing Salmonella inhibit tumor growth. Cancer gene therapy. 2008;15(12):787-94. doi: 10.1038/cgt.2008.48.##Loeffler M, Le'Negrate G, Krajewska M, Reed JC. Salmonella typhimurium engineered to produce CCL21 inhibit tumor growth. Cancer immunology, immunotherapy. 2009;58(5):769-75. doi: 10.1007/s00262-008-0555-9.##Loeffler M, Le'Negrate G, Krajewska M, Reed JC. Attenuated Salmonella engineered to produce human cytokine LIGHT inhibit tumor growth. Proceedings of the National Academy of Sciences. 2007;104(31):12879-83. doi: 10.1073/pnas.0701959104.##Yuhua L, Hui C, Kunyuan G, Yongmei X, Feng W, Kuangcheng X, et al. Prophylaxis of tumor through oral administration of IL-12 GM-CSF gene carried by live attenuated salmonella. Chinese Science Bulletin. 2001;46(13):1107-11. doi: .org/10.1007/BF02900689##Yuhua L, Kunyuan G, Hui C, Yongmei X, Chaoyang S, Xun T, et al. Oral cytokine gene therapy against murine tumor using attenuated Salmonella typhimurium. International journal of cancer. 2001;94(3):438-43. doi: 10.1002/ijc.1489.##Qi H, Li Y, Zheng S. Oral gene therapy via live attenuated Salmonella leads to tumor regression and survival prolongation in mice. Journal of Southern Medical University. 2006;26(12):1738-41.##Ganai S, Arenas R, Forbes N. Tumour-targeted delivery of TRAIL using Salmonella typhimurium enhances breast cancer survival in mice. British journal of cancer. 2009;101(10):1683-91. doi: 10.1038/sj.bjc.6605403.##Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nature medicine. 1999;5(2):157-63. doi: 10.1038/5517.##Torres W, Lameda V, Olivar LC, Navarro C, Fuenmayor J, Pérez A, et al. Bacteria in cancer therapy: beyond immunostimulation. J Cancer Metastasis Treat. 2018;4(4). dOI: 10.20517/2394-4722.2017.49##Klaunig JE, Kamendulis LM. The role of oxidative stress in carcinogenesis. Annu Rev Pharmacol Toxicol. 2004; 44:239-67. doi: 10.1146/annurev.pharmtox.44.101802.121851.##Thomas J, Badini M. The role of innate immunity in spontaneous regression of cancer. Indian journal of cancer. 2011;48(2):246. doi: 10.4103/0019-509X.82887.##Romee R, Leong JW, Fehniger TA. Utilizing cytokines to function-enable human NK cells for the immunotherapy of cancer. Scientifica. 2014;2014. doi: 10.1155/2014/205796.##Gajewski TF, Schreiber H, Fu Y-X. Innate and adaptive immune cells in the tumor microenvironment. Nature immunology. 2013;14(10):1014-22. doi: 10.1038/ni.2703.##Payne KK, Bear HD, Manjili MH. Adoptive cellular therapy of cancer: exploring innate and adaptive cellular crosstalk to improve anti-tumor efficacy. Future Oncology. 2014;10(10):1779-94. doi: 10.2217/fon.14.97.##Forbes NS. Engineering the perfect (bacterial) cancer therapy. Nature Reviews Cancer. 2010;10(11):785-94. doi: 10.1038/nrc2934.##Pollet I, Opina CJ, Zimmerman C, Leong KG, Wong F, Karsan A. Bacterial lipopolysaccharide directly induces angiogenesis through TRAF6-mediated activation of NF-κB and c-Jun N-terminal kinase. Blood. 2003;102(5):1740-2. doi: 10.1182/blood-2003-01-0288.##Tanaka N, Sakamoto N, Korenaga H, Inoue K, Ogawa H, Osada Y. The combination of a bacterial polysaccharide and tamoxifen inhibits angiogenesis and tumour growth. International journal of radiation biology. 1991;60(1-2):79-83. doi: 10.1080/09553009114551601.##Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer research. 1998;58(7):1408-16.##Murdoch C, Muthana M, Lewis CE. Hypoxia regulates macrophage functions in inflammation. The Journal of Immunology. 2005;175(10):6257-63. doi: 10.4049/jimmunol.175.10.6257.##Imtiyaz HZ, Simon MC. Hypoxia-inducible factors as essential regulators of inflammation. Diverse Effects of Hypoxia on Tumor Progression: Springer; 2010. p. 105-20. doi: 10.1007/82_2010_74.##Mamlouk S, Wielockx B. Hypoxia‐inducible factors as key regulators of tumor inflammation. International journal of cancer. 2013;132(12):2721-9. doi: 10.1002/ijc.27901.##Lunt SJ, Chaudary N, Hill RP. The tumor microenvironment and metastatic disease. Clinical & experimental metastasis. 2009;26(1):19-34. doi: 10.1007/s10585-008-9182-2.##Li Z, Fallon J, Mandeli J, Wetmur J, Woo SL. A genetically enhanced anaerobic bacterium for oncopathic therapy of pancreatic cancer. JNCI Journal of the National Cancer Institute. 2008;100(19):1389. doi: 10.1093/jnci/djn308.##Yamada T, Goto M, Punj V, Zaborina O, Chen ML, Kimbara K, et al. Bacterial redox protein azurin, tumor suppressor protein p53, and regression of cancer. Proceedings of the National Academy of Sciences. 2002;99(22):14098-103. doi: 10.1073/pnas.222539699.##Rostami A, Khazaei M. Inflammation and angiogenesis: role of inflammatory cells and mediators. Journal of Isfahan Medical School. 2016;34(384):1-11.##Paul SA, Simons JW, Mabjeesh NJ. HIF at the crossroads between ischemia and carcinogenesis. Journal of cellular physiology. 2004;200(1):20-30. doi: 10.1002/jcp.10479.##Nematbakhsh M, Ghadesi M, Hosseinbalam M, Khazaei M, Gharagozlo M, Dashti G, et al. Oestrogen promotes coronary angiogenesis even under normoxic conditions. Basic & clinical pharmacology & toxicology. 2008;103(3):273-7. doi: 10.1111/j.1742-7843.2008.00286.x.##Kim O-H, Kang G-H, Noh H, Cha J-Y, Lee H-J, Yoon J-H, et al. Proangiogenic TIE2 (+)/CD31 (+) Macrophages Are the Predominant Population of Tumor-Associated Macrophages Infiltrating Metastatic Lymph Nodes (vol 36, pg 432, 2013). 2014. doi: 10.1007/s10059-013-0194-7.##Salven P, Hattori K, Heissig B, Rafii S. Interleukin‐1α (IL‐1α) promotes angiogenesis in vivo via VEGFR‐2 pathway by inducing inflammatory cell VEGF synthesis and secretion. The FASEB Journal. 2002;16(11):1471-3. doi: 10.1096/fj.02-0134fje.##Fisher DT, Appenheimer MM, Evans SS, editors. The two faces of IL-6 in the tumor microenvironment. Seminars in immunology; 2014: Elsevier. doi: 10.1016/j.smim.2014.01.008.##Wikström P, Stattin P, Franck‐Lissbrant I, Damber JE, Bergh A. Transforming growth factor β1 is associated with angiogenesis, metastasis, and poor clinical outcome in prostate cancer. The Prostate. 1998;37(1):19-29. doi: 10.1002/(sici)1097-0045(19980915)37:13.0.co;2-3.##https://doi.org/10.1002/(SICI)1097-0045(19980915)37:13.0.CO;2-3##Vaupel P, Mayer A. Hypoxia in cancer: significance and impact on clinical outcome. Cancer and Metastasis Reviews. 2007;26(2):225-39. doi: 10.1007/s10555-007-9055-1.##Hedley D, Ogilvie L, Springer C. Carboxypeptidase G2-based gene-directed enzyme-prodrug therapy: a new weapon in the GDEPT armoury. Nature Reviews Cancer. 2007;7(11):870-9. doi: 10.1038/nrc2247.##Brown JM, Wilson WR. Exploiting tumour hypoxia in cancer treatment. Nature Reviews Cancer. 2004;4(6):437-47. doi: 10.1038/nrc1367.##Dougan M, Dougan SK. Programmable bacteria as cancer therapy. Nature Medicine. 2019;25(7):1030-1. doi: 10.1038/s41591-019-0513-4.##Garrett WS. Cancer and the microbiota. Science. 2015;348(6230):80-6. doi: 10.1126/science.aaa4972.##Barbé S, Van Mellaert L, Anné J. The use of clostridial spores for cancer treatment. Journal of applied microbiology. 2006;101(3):571-8. doi: 10.1111/j.1365-2672.2006.02886.x.##Shah S, Hankenson J, Pabbathi S, Greene J, Nanjappa S. Clostridium tertium in neutropenic patients: case series at a cancer institute. International Journal of Infectious Diseases. 2016; 51:44-6. doi: 10.1016/j.ijid.2016.08.013.##Westphal K, Leschner S, Jablonska J, Loessner H, Weiss S. Containment of tumor-colonizing bacteria by host neutrophils. Cancer research. 2008;68(8):2952-60. doi: 10.1158/0008-5472.CAN-07-2984.##Morrissey D, O'Sullivan GC, Tangney M. Tumour targeting with systemically administered bacteria. Current gene therapy. 2010;10(1):3-14. doi: 10.2174/156652310790945575.##Needham BD, Carroll SM, Giles DK, Georgiou G, Whiteley M, Trent MS. Modulating the innate immune response by combinatorial engineering of endotoxin. Proceedings of the National Academy of Sciences. 2013;110(4):1464-9. doi: 10.1073/pnas.1218080110.##Gholami A, Roshanfard F, Ghasemi Y. A comprehensive review of gene therapy, recent progress and future prospects n. Razi Journal of Medical Sciences. 2016;23(149):28-45.##Gelman AE, Turka LA. Autoimmunity heats up. Nature medicine. 2003;9(12):1465-6. doi: 10.1038/nm1203-1465.##Kay AB. Allergy and allergic diseases. New England Journal of Medicine. 2001;344(1):30-7. doi: 10.1056/NEJM200101043440106.##Sedighi M, Zahedi Bialvaei A, Hamblin MR, Ohadi E, Asadi A, Halajzadeh M, et al. Therapeutic bacteria to combat cancer; current advances, challenges, and opportunities. Cancer Medicine. 2019;8(6):3167-81. doi: 10.1002/cam4.2148.##Pawelek JM, Low KB, Bermudes D. Tumor-targeted Salmonella as a novel anticancer vector. Cancer research. 1997;57(20):4537-44.##Nemunaitis J, Cunningham C, Senzer N, Kuhn J, Cramm J, Litz C, et al. Pilot trial of genetically modified, attenuated Salmonella expressing the E. coli cytosine deaminase gene in refractory cancer patients. Cancer gene therapy. 2003;10(10):737-44. doi: 10.1038/sj.cgt.7700634.##Friedlos F, Lehouritis P, Ogilvie L, Hedley D, Davies L, Bermudes D, et al. Attenuated Salmonella targets prodrug activating enzyme carboxypeptidase G2 to mouse melanoma and human breast and colon carcinomas for effective suicide gene therapy. Clinical Cancer Research. 2008;14(13):4259-66. doi: 10.1158/1078-0432.CCR-07-4800.##Swofford CA, St. Jean AT, Panteli JT, Brentzel ZJ, Forbes NS. Identification of Staphylococcus aureus α‐hemolysin as a protein drug that is secreted by anticancer bacteria and rapidly kills cancer cells. Biotechnology and bioengineering. 2014;111(6):1233-45. doi: 10.1002/bit.25184.##Jean ATS, Swofford CA, Panteli JT, Brentzel ZJ, Forbes NS. Bacterial delivery of Staphylococcus aureus α-hemolysin causes regression and necrosis in murine tumors. Molecular Therapy. 2014;22(7):1266-74. doi: 10.1038/mt.2014.36.##Yang N, Zhu X, Chen L, Li S, Ren D. Oral administration of attenuated S. typhimurium carrying shRNA-expressing vectors as a cancer therapeutic. Cancer biology & therapy. 2008;7(1):145-51. doi: 10.4161/cbt.7.1.5195.##Tian Y, Guo B, Jia H, Ji K, Sun Y, Li Y, et al. Targeted therapy via oral administration of attenuated Salmonella expression plasmid-vectored Stat3-shRNA cures orthotopically transplanted mouse HCC. Cancer gene therapy. 2012;19(6):393-401. doi: 10.1038/cgt.2012.12.##Blache CA, Manuel ER, Kaltcheva TI, Wong AN, Ellenhorn JD, Blazar BR, et al. Systemic delivery of Salmonella typhimurium transformed with IDO shRNA enhances intratumoral vector colonization and suppresses tumor growth. Cancer research. 2012;72(24):6447-56. doi: 10.1158/0008-5472.CAN-12-0193.##Kubiak AM, Minton NP. The potential of clostridial spores as therapeutic delivery vehicles in tumour therapy. Research in microbiology. 2015;166(4):244-54. doi: 10.1016/j.resmic.2014.12.006.##Singer HM, Erhardt M, Steiner AM, Zhang M-M, Yoshikami D, Bulaj G, et al. Selective purification of recombinant neuroactive peptides using the flagellar type III secretion system. MBio. 2012;3(3). doi: 10.1128/mBio.00115-12.##Brook I. Clostridium species (Clostridium perfringens, C. butyricum, C. clostridioforme, C. innocuum, C. ramosum, C. septicum, C. sordellii, C. tertium). Доступ на: http://www antimicrobe org/b90 asp. 2016.##Staedtke V, Roberts NJ, Bai R-Y, Zhou S. Clostridium novyi-NT in cancer therapy. Genes & diseases. 2016;3(2):144-52. doi: 10.1016/j.gendis.2016.01.003.##Lan H. Clostridium Difficile Infection: The effects of acid suppression therapy in patients with cancer. Clinical journal of oncology nursing. 2019;23(2). doi: 10.1188/19.CJON.165-171.##Umer B, Good D, Anné J, Duan W, Wei MQ. Clostridial spores for cancer therapy: targeting solid tumour microenvironment. Journal of toxicology. 2012;2012. doi: 10.1155/2012/862764.##Goda N, Dozier SJ, Johnson RS. HIF-1 in cell cycle regulation, apoptosis, and tumor progression. Antioxidants and Redox Signaling. 2003;5(4):467-73. doi: 10.1089/152308603768295212.##Karpiński TM, Adamczak A. Anticancer activity of bacterial proteins and peptides. Pharmaceutics. 2018;10(2):54. doi: 10.3390/pharmaceutics10020054.##Dang LH, Bettegowda C, Huso DL, Kinzler KW, Vogelstein B. Combination bacteriolytic therapy for the treatment of experimental tumors. Proceedings of the National Academy of Sciences. 2001;98(26):15155-60. doi: 10.1073/pnas.251543698.##Rhim T, Lee DY, Lee M. Hypoxia as a target for tissue specific gene therapy. Journal of Controlled Release. 2013;172(2):484-94. doi: 10.1016/j.jconrel.2013.05.021.##Staedtke V, Bai R-Y, Sun W, Huang J, Kibler KK, Tyler BM, et al. Clostridium novyi-NT can cause regression of orthotopically implanted glioblastomas in rats. Oncotarget. 2015;6(8):5536. doi: 10.18632/oncotarget.3627.##Roberts NJ, Zhang L, Janku F, Collins A, Bai R-Y, Staedtke V, et al. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Science translational medicine. 2014;6(249):249ra111-249ra111. doi: 10.1126/scitranslmed.3008982.##Groot AJ, Mengesha A, van der Wall E, van Diest PJ, Theys J, Vooijs M. Functional antibodies produced by oncolytic clostridia. Biochemical and biophysical research communications. 2007;364(4):985-9. doi: 10.1016/j.bbrc.2007.10.126.##Hammerich L, Brody JD. Immunomodulation within a single tumor site to induce systemic antitumor immunity: in situ vaccination for cancer. Novel Immunotherapeutic Approaches to the Treatment of Cancer: Springer; 2016. p. 129-62. doi: org/10.1007/978-3-319-29827-6_6##Eichner M, Protze J, Piontek A, Krause G, Piontek J. Targeting and alteration of tight junctions by bacteria and their virulence factors such as Clostridium perfringens enterotoxin. Pflügers Archiv-European Journal of Physiology. 2017;469(1):77-90. doi: 10.1007/s00424-016-1902-x.##English DP, Santin AD. Claudins overexpression in ovarian cancer: potential targets for Clostridium Perfringens Enterotoxin (CPE) based diagnosis and therapy. International journal of molecular sciences. 2013;14(5):10412-37. doi: 10.3390/ijms140510412.##Patyar S, Joshi R, Byrav DP, Prakash A, Medhi B, Das B. Bacteria in cancer therapy: a novel experimental strategy. Journal of biomedical science. 2010;17(1):21. doi: 10.1186/1423-0127-17-21.##Santin AD, Comper F. Therapy with Clostridium perfringens enterotoxin to treat ovarian and uterine cancer. Google Patents; 2012.##Lameris AL, Huybers S, Burke JR, Monnens LA, Bindels RJ, Hoenderop JG. Involvement of claudin 3 and claudin 4 in idiopathic infantile hypercalcaemia: a novel hypothesis? Nephrology Dialysis Transplantation. 2010;25(11):3504-9. doi: 10.1093/ndt/gfq221.##Santin AD, Zhan F, Bellone S, Palmieri M, Cane S, Bignotti E, et al. Gene expression profiles in primary ovarian serous papillary tumors and normal ovarian epithelium: identification of candidate molecular markers for ovarian cancer diagnosis and therapy. International journal of cancer. 2004;112(1):14-25. doi: 10.1002/ijc.20408.##Hough CD, Sherman-Baust CA, Pizer ES, Montz F, Im DD, Rosenshein NB, et al. Large-scale serial analysis of gene expression reveals genes differentially expressed in ovarian cancer. Cancer Research. 2000;60(22):6281-7.##Lu KH, Patterson AP, Wang L, Marquez RT, Atkinson EN, Baggerly KA, et al. Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clinical cancer research. 2004;10(10):3291-300. doi: 10.1158/1078-0432.CCR-03-0409.##Heinzelmann-Schwarz VA, Gardiner-Garden M, Henshall SM, Scurry J, Scolyer RA, Davies MJ, et al. Overexpression of the cell adhesion molecules DDR1, Claudin 3, and Ep-CAM in metaplastic ovarian epithelium and ovarian cancer. Clinical Cancer Research. 2004;10(13):4427-36. doi: 10.1158/1078-0432.CCR-04-0073.##Santin AD, Bellone S, Siegel ER, McKenney JK, Thomas M, Roman JJ, et al. Overexpression of Clostridium perfringens enterotoxin receptors claudin-3 and claudin-4 in uterine carcinosarcomas. Clinical cancer research. 2007;13(11):3339-46. doi: 10.1158/1078-0432.CCR-06-3037.##Kleinberg L, Holth A, Trope CG, Reich R, Davidson B. Claudin upregulation in ovarian carcinoma effusions is associated with poor survival. Human pathology. 2008;39(5):747-57. doi: 10.1016/j.humpath.2007.10.002.##Hibbs K, Skubitz KM, Pambuccian SE, Casey RC, Burleson KM, Oegema Jr TR, et al. Differential gene expression in ovarian carcinoma: identification of potential biomarkers. The American journal of pathology. 2004;165(2):397-414. doi: 10.1016/S0002-9440(10)63306-8.##Sobel G, Páska C, Szabó I, Kiss A, Kádár A, Schaff Z. Increased expression of claudins in cervical squamous intraepithelial neoplasia and invasive carcinoma. Human pathology. 2005;36(2):162-9. doi: 10.1016/j.humpath.2004.12.001.##Sobel G, Szabó I, Páska C, Kiss A, Kovalszky I, Kádár A, et al. Changes of cell adhesion and extracellular matrix (ECM) components in cervical intraepithelial neoplasia. Pathology & Oncology Research. 2005;11(1):26-31. doi: 10.1007/BF03032402.##Swisshelm K, Macek R, Kubbies M. Role of claudins in tumorigenesis. Advanced drug delivery reviews. 2005;57(6):919-28. doi: 10.1016/j.addr.2005.01.006.##Pan X, Wang B, Che Y, Weng Z, Dai H, Peng W. Expression of claudin-3 and claudin-4 in normal, hyperplastic, and malignant endometrial tissue. International Journal of Gynecologic Cancer. 2007;17(1). doi: 10.1111/j.1525-1438.2006.00748.x.##Banz C, Ungethuem U, Kuban R-J, Diedrich K, Lengyel E, Hornung D. The molecular signature of endometriosis-associated endometrioid ovarian cancer differs significantly from endometriosis-independent endometrioid ovarian cancer. Fertility and sterility. 2010;94(4):1212-7. doi: 10.1016/j.fertnstert.2009.06.039.##Tassi R, Bignotti E, Falchetti M, Ravanini M, Calza S, Ravaggi A, et al. Claudin-7 expression in human epithelial ovarian cancer. International Journal of Gynecologic Cancer. 2008;18(6). doi: 10.1111/j.1525-1438.2008.01194.x.##Dahiya N, Becker KG, Wood III WH, Zhang Y, Morin PJ. Claudin-7 is frequently overexpressed in ovarian cancer and promotes invasion. PloS one. 2011;6(7):e22119. doi: 10.1371/journal.pone.0022119.##Lee J-W, Lee S-J, Seo J, Song SY, Ahn G, Park C-S, et al. Increased expressions of claudin-1 and claudin-7 during the progression of cervical neoplasia. Gynecologic oncology. 2005;97(1):53-9. doi: 10.1016/j.ygyno.2004.11.058.##Resnick MB, Konkin T, Routhier J, Sabo E, Pricolo VE. Claudin-1 is a strong prognostic indicator in stage II colonic cancer: a tissue microarray study. Modern pathology. 2005;18(4):511-8. doi: 10.1038/modpathol.3800301.##Bignotti E, Tassi RA, Calza S, Ravaggi A, Romani C, Rossi E, et al. Differential gene expression profiles between tumor biopsies and short-term primary cultures of ovarian serous carcinomas: identification of novel molecular biomarkers for early diagnosis and therapy. Gynecologic oncology. 2006;103(2):405-16. doi: 10.1016/j.ygyno.2006.03.056.##Cheung ST, Leung KL, Ip YC, Chen X, Fong DY, Ng IO, et al. Claudin-10 expression level is associated with recurrence of primary hepatocellular carcinoma. Clinical Cancer Research. 2005;11(2):551-6.##Sanada Y, Oue N, Mitani Y, Yoshida K, Nakayama H, Yasui W. Down‐regulation of the claudin‐18 gene, identified through serial analysis of gene expression data analysis, in gastric cancer with an intestinal phenotype. The Journal of Pathology: A Journal of the Pathological Society of Great Britain and Ireland. 2006;208(5):633-42. doi: 10.1002/path.1922.##Chen S, Sun C, Wang H, Wang J. The role of Rho GTPases in toxicity of Clostridium difficile toxins. Toxins. 2015;7(12):5254-67. doi: 10.3390/toxins7124874.##Theys J, Lambin P. Clostridium to treat cancer: dream or reality? Annals of translational medicine. 2015;3(Suppl 1). doi: 10.3978/j.issn.2305-5839.2015.03.39.##Hebbard AI, Slavin MA, Reed C, Teh BW, Thursky KA, Trubiano JA, et al. The epidemiology of Clostridium difficile infection in patients with cancer. Expert review of anti-infective therapy. 2016;14(11):1077-85. doi: 10.1080/14787210.2016.1234376.##Huang T, Li S, Li G, Tian Y, Wang H, Shi L, et al. Utility of Clostridium difficile toxin B for inducing anti-tumor immunity. PLoS One. 2014;9(10):e110826. doi: 10.1371/journal.pone.0110826. eCollection 2014.##Li Q, Withoff S, Verma IM. Inflammation-associated cancer: NF-κB is the lynchpin. Trends in immunology. 2005;26(6):318-25. doi: 10.1016/j.it.2005.04.003.##Forbes NS, Coffin RS, Deng L, Evgin L, Fiering S, Giacalone M, et al. White paper on microbial anti-cancer therapy and prevention. Journal for immunotherapy of cancer. 2018;6(1):1-24. doi: 10.1186/s40425-018-0381-3.##Tian Y, Huang T, Li G, Liu J, Wang X, Feng H, et al. RETRACTED: Apoptosis of CT26 colorectal cancer cells induced by Clostridium difficile toxin A stimulates potent anti-tumor immunity. Elsevier; 2012. doi: 10.1016/j.bbrc.2012.04.068.##Sun X, He X, Tzipori S, Gerhard R, Feng H. Essential role of the glucosyltransferase activity in Clostridium difficile toxin-induced secretion of TNF-α by macrophages. Microbial pathogenesis. 2009;46(6):298-305. doi: 10.1016/j.micpath.2009.03.002.##Wang H, Sun X, Zhang Y, Li S, Chen K, Shi L, et al. A chimeric toxin vaccine protects against primary and recurrent Clostridium difficile infection. Infection and immunity. 2012;80(8):2678-88. doi: 10.1128/IAI.00215-12.##Sun C, Wang H, Mao S, Liu J, Li S, Wang J. Reactive oxygen species involved in CT26 immunogenic cell death induced by Clostridium difficile toxin B. Immunology letters. 2015;164(2):65-71. doi: 10.1016/j.imlet.2015.02.007.##Gray PM, Forrest G, Wisniewski T, Porter G, Freed DC, DeMartino JA, et al. Evidence for cyclic diguanylate as a vaccine adjuvant with novel immunostimulatory activities. Cellular immunology. 2012;278(1-2):113-9. doi: 10.1016/j.cellimm.2012.07.006.##Wang L, Wang Q, Tian X, Shi X. Learning from Clostridium novyi-NT: How to defeat cancer. Journal of cancer research and therapeutics. 2018;14(8):1. doi: 10.4103/0973-1482.204841.##Bettegowda C, Dang LH, Abrams R, Huso DL, Dillehay L, Cheong I, et al. Overcoming the hypoxic barrier to radiation therapy with anaerobic bacteria. Proceedings of the National Academy of Sciences. 2003;100(25):15083-8. doi: 10.1073/pnas.2036598100.##Cheong I, Huang X, Bettegowda C, Diaz LA, Kinzler KW, Zhou S, et al. A bacterial protein enhances the release and efficacy of liposomal cancer drugs. Science. 2006;314(5803):1308-11. doi: 10.1126/science.1130651.##Yong AY, Shabahang S, Timiryasova TM, Zhang Q, Beltz R, Gentschev I, et al. Visualization of tumors and metastases in live animals with bacteria and vaccinia virus encoding light-emitting proteins. Nature biotechnology. 2004;22(3):313-20. doi: 10.1038/nbt937.##Liu G, Bettegowda C, Qiao Y, Staedtke V, Chan KW, Bai R, et al. Noninvasive imaging of infection after treatment with tumor‐homing bacteria using Chemical Exchange Saturation Transfer (CEST) MRI. Magnetic resonance in medicine. 2013;70(6):1690-8. doi: 10.1002/mrm.24955.##Agrawal N, Bettegowda C, Cheong I, Geschwind J-F, Drake CG, Hipkiss EL, et al. Bacteriolytic therapy can generate a potent immune response against experimental tumors. Proceedings of the National Academy of Sciences. 2004;101(42):15172-7. doi: 10.1073/pnas.0406242101.##Maletzki C, Gock M, Klier U, Klar E, Linnebacher M. Bacteriolytic therapy of experimental pancreatic carcinoma. World journal of gastroenterology: WJG. 2010;16(28):3546. doi: 10.3748/wjg.v16.i28.3546.##Hajam IA, Dar PA, Won G, Lee JH. Bacterial ghosts as adjuvants: mechanisms and potential. Vet Res. 2017 Jun 24;48(1):37. doi: 10.1186/s13567-017-0442-5.##Schön P, Schrot G, Wanner G, Lubitz W, Witte A. Two-stage model for integration of the lysis protein E of phi X174 into the cell envelope of Escherichia coli. FEMS Microbiol Rev. 1995 Aug;17(1-2):207-12. doi: 10.1111/j.1574-6976.1995.tb00203.x.##Nguyen HN, Romero Jovel S, Nguyen TH. Nanosized minicells generated by lactic acid bacteria for drug delivery. Journal of Nanomaterials. 2017 Jan 1;2017. doi: 10.1155/2017/6847297.##Song S, Vuai MS, Zhong M. The role of bacteria in cancer therapy - enemies in the past, but allies at present. Infect Agent Cancer. 2018 Mar 15;13:9. doi: 10.1186/s13027-018-0180-y.##Rang CU, Proenca A, Buetz C, Shi C, Chao L. Minicells as a Damage Disposal Mechanism in Escherichia coli. mSphere. 2018 Sep 19;3(5):e00428-18. doi: 10.1128/mSphere.00428-18.##Miles B, Safran HP, Monk BJ. Therapeutic options for treatment of human papillomavirus-associated cancers - novel immunologic vaccines: ADXS11-001. Gynecol Oncol Res Pract. 2017 Jul 14;4:10. doi: 10.1186/s40661-017-0047-8##Toso JF, Gill VJ, Hwu P, Marincola FM, Restifo NP, Schwartzentruber DJ, Sherry RM, Topalian SL, Yang JC, Stock F, Freezer LJ, Morton KE, Seipp C, Haworth L, Mavroukakis S, White D, MacDonald S, Mao J, Sznol M, Rosenberg SA. Phase I study of the intravenous administration of attenuated Salmonella typhimurium to patients with metastatic melanoma. J Clin Oncol. 2002 Jan 1;20(1):142-52. doi: 10.1200/JCO.2002.20.1.142.##Heimann DM, Rosenberg SA. Continuous intravenous administration of live genetically modified salmonella typhimurium in patients with metastatic melanoma. J Immunother. 2003 Mar-Apr;26(2):179-80. doi: 10.1097/00002371-200303000-00011.##Cunningham C, Nemunaitis J. A phase I trial of genetically modified Salmonella typhimurium expressing cytosine deaminase (TAPET-CD, VNP20029) administered by intratumoral injection in combination with 5-fluorocytosine for patients with advanced or metastatic cancer. Protocol no: CL-017. Version: April 9, 2001. Hum Gene Ther. 2001 Aug 10;12(12):1594-6.##Roberts NJ, Zhang L, Janku F, Collins A, Bai RY, Staedtke V, Rusk AW, Tung D, Miller M, Roix J, Khanna KV, Murthy R, Benjamin RS, Helgason T, Szvalb AD, Bird JE, Roy-Chowdhuri S, Zhang HH, Qiao Y, Karim B, McDaniel J, Elpiner A, Sahora A, Lachowicz J, Phillips B, Turner A, Klein MK, Post G, Diaz LA Jr, Riggins GJ, Papadopoulos N, Kinzler KW, Vogelstein B, Bettegowda C, Huso DL, Varterasian M, Saha S, Zhou S. Intratumoral injection of Clostridium novyi-NT spores induces antitumor responses. Sci Transl Med. 2014 Aug 13;6(249):249ra111. doi: 10.1126/scitranslmed.3008982.##Solomon BJ, Desai J, Rosenthal M, McArthur GA, Pattison ST, Pattison SL, MacDiarmid J, Brahmbhatt H, Scott AM. A First-Time-In-Human Phase I Clinical Trial of Bispecific Antibody-Targeted, Paclitaxel-Packaged Bacterial Minicells. PLoS One. 2015 Dec 11;10(12):e0144559. doi: 10.1371/journal.pone.0144559.##Cao Z, Liu J. Bacteria and bacterial derivatives as drug carriers for cancer therapy. Journal of Controlled Release. 2020 Oct 10;326:396-407. doi: 10.1016/j.jconrel.2020.07.009.##Badie F, Ghandali M, Tabatabaei SA, Safari M, Khorshidi A, Shayestehpour M, Mahjoubin-Tehran M, Morshedi K, Jalili A, Tajiknia V, Hamblin MR. Use of Salmonella bacteria in cancer therapy: direct, drug delivery and combination approaches. Frontiers in Oncology. 2021 Mar 2;11:624759. doi: 10.3389/fonc.2021.624759.##Chen H, Ji H, Kong X, Lei P, Yang Q, Wu W, Jin L, Sun D. Bacterial Ghosts-Based Vaccine and Drug Delivery Systems. Pharmaceutics. 2021 Nov 8;13(11):1892. doi: 10.3390/pharmaceutics13111892.##Jain RK, Forbes NS. Can engineered bacteria help control cancer? Proceedings of the National Academy of Sciences. 2001 Dec 18;98(26):14748-50. doi: 10.1073/pnas.261606598.##Nuyts S, Van Mellaert L, Theys J, Landuyt W, Lambin P, Anné J. Clostridium spores for tumor-specific drug delivery. Anti-cancer drugs. 2002 Feb 1;13(2):115-25. doi: 10.1097/00001813-200202000-00002.##Kominsky SL, Vali M, Korz D, Gabig TG, Weitzman SA, Argani P, Sukumar S. Clostridium perfringens enterotoxin elicits rapid and specific cytolysis of breast carcinoma cells mediated through tight junction proteins claudin 3 and 4. The American journal of pathology. 2004 May 1;164(5):1627-33. doi: 10.1016/S0002-9440(10)63721-2.##Santin AD, Cané S, Bellone S, Palmieri M, Siegel ER, Thomas M, Roman JJ, Burnett A, Cannon MJ, Pecorelli S. Treatment of chemotherapy-resistant human ovarian cancer xenografts in CB-17/SCID mice by intraperitoneal administration of Clostridium perfringens enterotoxin. Cancer research. 2005 May 15;65(10):4334-42. doi: 10.1158/0008-5472.CAN-04-3472.##Theys J, Pennington O, Dubois L, Anlezark G, Vaughan T, Mengesha A, Landuyt W, Anné J, Burke PJ, Dûrre P, Wouters BG. Repeated cycles of Clostridium-directed enzyme prodrug therapy result in sustained antitumour effects in vivo. British journal of cancer. 2006 Nov;95(9):1212-9. doi: 10.1038/sj.bjc.6603367.##Santin AD, Bellone S, Marizzoni M, Palmieri M, Siegel ER, McKenney JK, Hennings L, Comper F, Bandiera E, Pecorelli S. Overexpression of claudin‐3 and claudin‐4 receptors in uterine serous papillary carcinoma: novel targets for a type‐specific therapy using Clostridium perfringens enterotoxin (CPE). Cancer: Interdisciplinary International Journal of the American Cancer Society. 2007 Apr;109(7):1312-22. doi: 10.1002/cncr.22536.##Liu SC, Ahn GO, Kioi M, Dorie MJ, Patterson AV, Brown JM. Optimized clostridium-directed enzyme prodrug therapy improves the antitumor activity of the novel DNA cross-linking agent PR-104. Cancer research. 2008 Oct 1;68(19):7995-8003. doi: 10.1158/0008-5472.CAN-08-1698.##Cocco E, Casagrande F, Bellone S, Richter CE, Bellone M, Todeschini P, Holmberg JC, Fu HH, Montagna MK, Mor G, Schwartz PE. Clostridium perfringens enterotoxin carboxy-terminal fragment is a novel tumor-homing peptide for human ovarian cancer. BMC cancer. 2010 Dec; 10:1-1. doi: 10.1186/1471-2407-10-349.##Casagrande F, Cocco E, Bellone S, Richter CE, Bellone M, Todeschini P, Siegel E, Varughese J, Arin‐Silasi D, Azodi M, Rutherford TJ. Eradication of chemotherapy‐resistant CD44+ human ovarian cancer stem cells in mice by intraperitoneal administration of clostridium perfringens enterotoxin. Cancer. 2011 Dec 15;117(24):5519-28. doi: 10.1002/cncr.26215.##Maeda T, Murata M, Chiba H, Takasawa A, Tanaka S, Kojima T, Masumori N, Tsukamoto T, Sawada N. Claudin‐4‐targeted therapy using Clostridium perfringens enterotoxin for prostate cancer. The Prostate. 2012 Mar;72(4):351-60. doi: 10.1002/pros.21436.##Shinnoh M, Horinaka M, Yasuda T, Yoshikawa S, Morita M, Yamada T, Miki T, Sakai T. Clostridium butyricum MIYAIRI 588 shows antitumor effects by enhancing the release of TRAIL from neutrophils through MMP-8. International journal of oncology. 2013 Mar 1;42(3):903-11. doi: 10.3892/ijo.2013.1790.##Romanov V, Whyard TC, Waltzer WC, Gabig TG. A claudin 3 and claudin 4-targeted Clostridium perfringens protoxin is selectively cytotoxic to PSA-producing prostate cancer cells. Cancer letters. 2014 Sep 1;351(2):260-4. doi: 10.1016/j.canlet.2014.06.009.##Bhave MS, Hassanbhai AM, Anand P, Luo KQ, Teoh SH. Effect of heat-inactivated Clostridium sporogenes and its conditioned media on 3-dimensional colorectal cancer cell models. Scientific Reports. 2015 Oct 28;5(1):15681. doi: 10.1038/srep15681.##Gabig TG, Waltzer WC, Whyard T, Romanov V. Clostridium perfringens enterotoxin as a potential drug for intravesical treatment of bladder cancer. Biochemical and biophysical research communications. 2016 Sep 16;478(2):887-92. doi: 10.1016/j.bbrc.2016.08.046.##Zhang Y, Li Y, Li H, Chen W, Liu W. Clostridium difficile toxin B recombinant protein inhibits tumor growth and induces apoptosis through inhibiting Bcl-2 expression, triggering inflammatory responses and activating C-erbB-2 and Cox-2 expression in breast cancer mouse model. Biomedicine & Pharmacotherapy. 2018 May 1; 101:391-8. doi: 10.1016/j.biopha.2018.02.045.##Pokrovsky VS, Yu Anisimova N, Zh Davydov D, Bazhenov SV, Bulushova NV, Zavilgelsky GB, Kotova VY, Manukhov IV. Methionine gamma lyase from Clostridium sporogenes increases the anticancer effect of doxorubicin in A549 cells and human cancer xenografts. Investigational New Drugs. 2019 Apr 15; 37:201-9. doi: 10.1007/s10637-018-0619-4.##Tomita Y, Ikeda T, Sakata S, Saruwatari K, Sato R, Iyama S, Jodai T, Akaike K, Ishizuka S, Saeki S, Sakagami T. Association of probiotic clostridium butyricum therapy with survival and response to immune checkpoint blockade in patients with lung cancer. Cancer immunology research. 2020 Oct 1;8(10):1236-42. doi: 10.1158/2326-6066.CIR-20-0051.##Jafari FA, Abdoli A, Pilehchian R, Soleimani N, Hosseini SM. The oncolytic activity of Clostridium novyi nontoxic spores in breast cancer. BioImpacts: BI. 2022;12(5):405. doi: 10.34172/bi.2021.25.##Budu O, Banciu C, Pinzaru I, Sarău C, Lighezan D, Șoica C, Dehelean C, Drăghici G, Dolghi A, Prodea A, Mioc M. A combination of two probiotics, Lactobacillus sporogenes and Clostridium butyricum, inhibits Colon Cancer Development: an in Vitro Study. Microorganisms. 2022 Aug 23;10(9):1692. doi: 10.3390/microorganisms10091692.##Zhang K, Dong Y, Li M, Zhang W, Ding Y, Wang X, Chen D, Liu T, Wang B, Cao H, Zhong W. Clostridium butyricum inhibits epithelial-mesenchymal transition of intestinal carcinogenesis through downregulating METTL3. Cancer Science. 2023 May 26. doi: 10.1111/cas.15839.## ##

From viral encounter to leukemic challenge: a case of isolated molecular relapse in a child with acute promyelocytic leukemia after SARS-CoV-2 infection 2 2 Background: Acute promyelocytic leukemia (APL) is a type of aggressive acute myeloid leukemia (AML), characterized by the presence of abnormal promyelocytes in the bone marrow and bloodstream. The abnormal promyelocytes found in APL can lead to severe complications such as bleeding and blood clot formation. Case presentation: A 7-year-old boy diagnosed with APL encountered a unique occurrence of isolated molecular relapse following a recent episode of SARS-CoV-2 infection while undergoing routine monitoring for treatment response. The relapse was confirmed by the detection of the PML/RARalpha gene abnormality in both the peripheral blood and bone marrow samples. Notably, during relapse, the boy displayed symptoms indicative of a cerebral ischemic stroke; however, effective management was achieved through the administration of low molecular weight heparin (LMWH) and corticosteroids. Subsequently, the patient underwent an allogenic bone marrow transplantation. Of note, throughout an 18-month period of close monitoring, no complications were reported. Discussion: The detection of the PML-RARA transcript in peripheral blood can serve as a valuable tool for detecting isolated molecular relapse in pediatric APL. In cases where patients are undergoing immunosuppressive chemotherapy, the presence of neurological signs and symptoms may be the sole indicator of APL relapse, and it can be thoroughly investigated through the use of MRI with or without diffusion-weighted imaging (DWI). The administration of LMWH is a safe treatment strategy until D-dimer levels return to normal. It has been observed that COVID-19, as seen with other respiratory viruses, may potentially contribute to the relapse of pediatric APL, highlighting its significance in disease progression. 203 211 2023/06/212023/08/8 1402/5/17 2023/08/122023/08/17 1402/5/26 babak abdolkarimi babak abdolkarimi Department of Pediatric Hematology-Oncology, Lorestan University of Medical Sciences, ‎Khorramabad, Iran‎ b.abdolkarimi@yahoo.com ali amanati ali amanati Department of Pediatric Infectious Diseases, Professor Alborzi Clinical Microbiology Research Center, Shiraz University of Medical Sciences, Shiraz, Iran dr.amanati14@gmail.com sedigheh nikbakht sedigheh nikbakht Department of Pediatric Neurology, Lorestan University of Medical Sciences, ‎Khorramabad, Iran dr.sedighenikbakht@yahoo.com leila akhundzadeh leila akhundzadeh Department of radiology, Lorestan University of Medical Sciences, ‎Khorramabad, Iran leila.akhundzadeh@yahoo.com Acute promyelocytic leukemia COVID-19 Relapse SARS-CoV-2 Stroke. Shashank R. Cingam and Nebu V. Koshy, Acute Promyelocytic Leukemia. StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing, 2022.##Hambley, B.C., C. Tomuleasa, and G. Ghiaur, Coagulopathy in acute promyelocytic leukemia: can we go beyond supportive care? Frontiers in Medicine, 2021. 8.##Putaala, J. and T. Nieminen, Stroke risk period after acute myocardial infarction revised. 2018, Am Heart Assoc. p. e011200.##Streiff, M.B., et al., Guidance for the treatment of deep vein thrombosis and pulmonary embolism. Journal of thrombosis and thrombolysis, 2016. 41(1): p. 32-67.##Liquori, A., et al., Acute Promyelocytic Leukemia: A Constellation of Molecular Events around a Single PML-RARA Fusion Gene. Cancers, 2020. 12(3): p. 624.##Mazharuddin, S., et al., IRF2BP2-RARA t (1; 17)(q42. 3; q21. 2) APL blasts differentiate in response to all-trans retinoic acid. Leukemia & lymphoma, 2018. 59(9): p. 2246-2249.##Cicconi, L. and F. Lo-Coco, Current management of newly diagnosed acute promyelocytic leukemia. Annals of Oncology, 2016. 27(8): p. 1474-1481.##Liang, H., et al., A case of acute myelogenous leukemia characterized by arterial and venous thrombosis. Cardiovascular Diagnosis and Therapy, 2020. 10(5): p. 1332.##Chotai, P.N., et al., Recurrent arterial thrombosis as a presenting feature of a variant M3-acute promyelocytic leukemia. Vascular Specialist International, 2016. 32(2): p. 65.##Stanko, L.M., et al., Central Nervous System Double Relapse of Acute Promyelocytic Leukemia and Acute Myelomonocytic Leukemia. Case Reports in Hematology, 2019. 2019.##Sanz, M.A. and P. Montesinos, Advances in the management of coagulopathy in acute promyelocytic leukemia. Thrombosis research, 2020. 191: p. S63-S67.##Marchand, T. and S. Pinho, Leukemic Stem Cells: From Leukemic Niche Biology to Treatment Opportunities. Frontiers in Immunology, 2021: p. 4314.##van der Poll, T. and E. de Jonge, Cytokines as regulators of coagulation. Madame Curie Bioscience Database [Internet], 2013.##Kapoor, R., et al., Acute promyelocytic leukemia presenting as ischemic stroke in young. Indian Journal of Hematology and Blood Transfusion, 2013. 29(2): p. 93-95.##Hsu, P.-J., et al., High plasma D-dimer indicates unfavorable outcome of acute ischemic stroke patients receiving intravenous thrombolysis. Cerebrovascular Diseases, 2016. 42(1-2): p. 117-121.##Del Prete, C., et al., The epidemiology and clinical associations of stroke in patients with acute myeloid leukemia: a review of 10,972 admissions from the 2012 national inpatient sample. Clinical Lymphoma Myeloma and Leukemia, 2018. 18(1): p. 74-77. e1.##Li, Y., et al., Acute myocardial/cerebral infarction as first/relapse manifestation in one acute promyelocytic leukemia patient. International Journal of Clinical and Experimental Medicine, 2015. 8(8): p. 14210.##Okorie, C.K., et al., Role of diffusion-weighted imaging in acute stroke management using low-field magnetic resonance imaging in resource-limited settings. West African journal of radiology, 2015. 22(2): p. 61.##Mair, G. and J. Wardlaw, Imaging of acute stroke prior to treatment: current practice and evolving techniques. The British journal of radiology, 2014. 87(1040): p. 20140216.##Hurford, R., et al., Prognostic value of "tissue-based" definitions of TIA and minor stroke: population-based study. Neurology, 2019. 92(21): p. e2455-e2461.##Dardiotis, E., et al., Cancer-associated stroke: pathophysiology, detection and management. International journal of oncology, 2019. 54(3): p. 779-796.##Schulz, U.G., et al., Diffusion-weighted MRI in 300 patients presenting late with subacute transient ischemic attack or minor stroke. Stroke, 2004. 35(11): p. 2459-2465.##Graber, J.J., L. Nayak, and L.M. DeAngelis, Use of recombinant tissue plasminogen activator in cancer patients with acute stroke. Journal of neuro-oncology, 2012. 107(3): p. 571-573.##Fugate, J.E. and A.A. Rabinstein, Absolute and relative contraindications to IV rt-PA for acute ischemic stroke. The Neurohospitalist, 2015. 5(3): p. 110-121.##Wang, J., et al., New perspectives on treatment strategies for patient with acute myeloid leukemia and complex karyotype abnormalities after percutaneous coronary intervention: a case report. Medicine, 2019. 98(30).##Ofran, Y., M.S. Tallman, and J.M. Rowe, How I treat acute myeloid leukemia presenting with preexisting comorbidities. Blood, The Journal of the American Society of Hematology, 2016. 128(4): p. 488-496.##Murthy, S.B., et al., Thrombolysis for acute ischemic stroke in patients with cancer: a population study. Stroke, 2013. 44(12): p. 3573-3576.##Fouzia, N., et al., Management of relapse in acute promyelocytic leukaemia treated with up‐front arsenic trioxide‐based regimens. British journal of haematology, 2021. 192(2): p. 292-299.##Harigae, H., et al., Detection of minimal residual disease in cerebro-spinal fluid of a patient with acute myelogenous leukemia with t (16; 21)(p11; q22) translocation by reverse transcriptase-polymerase chain reaction. The Tohoku Journal of Experimental Medicine, 1997. 183(4): p. 297-302.##Puckrin, R., et al., Measurable residual disease monitoring provides insufficient lead-time to prevent morphological relapse in the majority of patients with core-binding factor acute myeloid leukemia. haematologica, 2021. 106(1): p. 56.##Clozel, T., et al., Slow relapse in acute myeloid leukemia with inv (16) or t (16; 16). haematologica, 2009. 94(10): p. 1466.##Sanz, J., P. Montesinos, and M.A. Sanz, Role of hematopoietic stem cell transplantation in acute promyelocytic leukemia. Frontiers in Oncology, 2021. 11: p. 614215.##Ramadan, S.M., et al., Allogeneic stem cell transplantation for advanced acute promyelocytic leukemia in the ATRA and ATO era. haematologica, 2012. 97(11): p. 1731.##Wu, Y., et al., COVID‐19 in a patient with pre‐existing acute lymphoblastic leukaemia. British journal of haematology, 2020. 190(1): p. e13.##Chiaretti, S., et al., COVID-19 infection in acute lymphoblastic leukemia over 15 months of the pandemic. A Campus ALL report. haematologica, 2022. 107(8): p. 1955.##Al-Samkari, H., et al., COVID-19 and coagulation: bleeding and thrombotic manifestations of SARS-CoV-2 infection. Blood, 2020. 136(4): p. 489-500.##Trimaille, A., et al., Venous thromboembolism in non-critically ill patients with COVID-19 infection. Thrombosis research, 2020. 193: p. 166-169.##Research Ethics Committees of Lorestan University of Medical Sciences, Manifestation of molecular recurrence, isolated as stroke in patients with acute promyelocytic leukemia. 2021-01-12.## ##

Review of endocrine complications in transfusion-dependent thalassemia 2 2 Beta thalassemia is an inherited genetic disorder that often leads to transfusion dependence. One of the significant issues that these patients face is increased iron accumulation in their bodies due to the nature of the disease and regular blood transfusions. Iron overload can cause hemosiderosis and tissue damage in various organs, including the heart, liver, and endocrine systems. Endocrine problems are one of the most common complications in transfusion-dependent thalassemia, and addressing these complications can significantly improve patients' health-related quality of life. The prevalence of endocrinopathy is high, especially in patients with poor compliance with therapy. The most common endocrine disorders include hypogonadism, growth disturbances, short stature, delayed puberty, acquired hypothyroidism and hypoparathyroidism, adrenal dysfunction, osteoporosis, diabetes, fertility issues, and complications during pregnancy. Timely diagnosis and treatment of endocrine disorders can improve patients' quality of life and reduce social problems. This article reviews the literature on the various endocrine complications encountered in thalassemia.   212 235 2023/06/212023/08/82023/06/23 1402/4/2 2023/08/122023/08/172023/08/22 1402/5/31 Pooya Faranoush Pooya Faranoush Pediatric Growth and Development Research Center, Iran University of Medical Sciences, Tehran-Iran pooya1375@yahoo.com Ali Elahinia Ali Elahinia Pediatric Growth and Development Research Center, Iran University of Medical Sciences, Tehran-Iran elahinia.ali47@gmail.com Amir Ziaee Amir Ziaee Pediatric Growth and Development Research Center, Iran University of Medical Sciences, Tehran-Iran aziaee1963@yahoo.com Mohammad Faranoush Mohammad Faranoush Pediatric Growth and Development Research Center, Iran University of Medical Sciences, Tehran-Iran faranoush47@gmail.com Iron overload Endocrinopathy Thalassemia Blood transfusion De Sanctis V, Elsedfy H, Soliman AT, Elhakim IZ, Soliman NA, Elalaily R, et al. Endocrine profile of β-thalassemia major patients followed from childhood to advanced adulthood in a tertiary care center. Indian J Endocrinol Metab. 2016;20(4):451-9.##Singer, S. T., Wu, V., Mignacca, R., Kuypers, F. A., Morel, P., Vichinsky, E. P., & Lee, J. M. (2015). Altered growth and micropenis in male patients with transfusion-dependent thalassemia. Journal of Pediatric Hematology/Oncology, 37(6), 435-440.##Kattamis A, Forni GL, Aydinok Y, Viprakasit V. Changing patterns in the epidemiology of β-thalassemia. Eur J Haematol. 2020;105(6):692-703.##Ehsanipour F, Faranoush P, Foroughi‐Gilvaee MR, Sadighnia N, Fallahpour M, Motamedi M, et al. Evaluation of immune system in patients with transfusion‐dependent beta‐thalassemia in Rasoul‐e‐Akram Hospital in 2021: A descriptive cross‐sectional study. Health Science Reports. 2022;5(6):e871.##Nasiri A, Rahimi Z, Vaisi-Raygani A. Hemoglobinopathies in Iran: An Updated Review. Int J Hematol Oncol Stem Cell Res. 2020;14(2):140-50.##Zamani M, Poustchi H, Shayanrad A, Pourfarzi F, Farjam M, Noemani K, et al. Prevalence and determinants of anemia among Iranian population aged ≥35 years: A PERSIAN cohort-based cross-sectional study. PLoS One. 2022;17(2):e0263795.##Hadipour Dehshal M, Tabrizi Namini M, Hantoushzadeh R, Yousefi Darestani S. β-Thalassemia in Iran: Things Everyone Needs to Know About This Disease. Hemoglobin. 2019;43(3):166-73.##Mehrvar A, Azarkeivan A, Faranoush M, Mehrvar N, Saberinedjad J, Ghorbani R, et al. Endocrinopathies in patients with transfusion-dependent beta-thalassemia. Pediatr Hematol Oncol. 2008;25(3):187-94.##Fleming RE, Ponka P. Iron overload in human disease. N Engl J Med. 2012;366(4):348-59.##Faranoush P, Jahandideh A, Nekouian R, Mortazavi P. Evaluation of the in vitro and in vivo effect of liposomal doxorubicin along with oncolytic Newcastle disease virus on 4T1 cell line: Animal preclinical research. Veterinary Medicine and Science. 2023.##Cao A, Galanello R. Beta-thalassemia. Genet Med. 2010;12(2):61-76.##de Sanctis V. Endocrine Complications. Thalassemia Reports. 2018;8(1):7479.##Taher AT, Weatherall DJ, Cappellini MD. Thalassaemia. Lancet. 2018;391(10116):155-67.##Musallam KM, Taher AT, Cappellini MD, Sankaran VG. Clinical experience with fetal hemoglobin induction therapy in patients with β-thalassemia. Blood. 2013;121(12):2199-212; quiz 372.##Vichinsky E. Advances in the treatment of alpha-thalassemia. Blood Rev. 2012;26 Suppl 1:S31-4.##Weatherall DJ. The inherited diseases of hemoglobin are an emerging global health burden. Blood. 2010;115(22):4331-6.##Arab-Zozani M, Kheyrandish S, Rastgar A, Miri-Moghaddam E. A Systematic Review and Meta-Analysis of Stature Growth Complications in β-thalassemia Major Patients. Ann Glob Health. 2021;87(1):48.##Soliman AT, Yassin MA, De Sanctis V. Final adult height and endocrine complications in young adults with β-thalassemia major (TM) who received oral iron chelation (OIC) in comparison with those who did not use OIC. Acta Biomed. 2018;89(2-s):27-32.##Inati A, Noureldine MA, Mansour A, Abbas HA. Endocrine and bone complications in β-thalassemia intermedia: current understanding and treatment. Biomed Res Int. 2015;2015:813098.##Shamshirsaz AA, Bekheirnia MR, Kamgar M, Pourzahedgilani N, Bouzari N, Habibzadeh M, et al. Metabolic and endocrinologic complications in beta-thalassemia major: a multicenter study in Tehran. BMC Endocr Disord. 2003;3(1):4.##Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, et al. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Blood. 2010;115(10):1886-92.##Toumba M, Sergis A, Kanaris C, Skordis N. Endocrine complications in patients with Thalassaemia Major. Pediatr Endocrinol Rev. 2007;5(2):642-8.##Musallam KM, Cappellini MD, Wood JC, Motta I, Graziadei G, Tamim H, et al. Elevated liver iron concentration is a marker of increased morbidity in patients with β thalassemia intermedia. Haematologica. 2011;96(11):1605-12.##Esteghamati A, Etemad K, Koohpayehzadeh J, Abbasi M, Meysamie A, Noshad S, et al. Trends in the prevalence of diabetes and impaired fasting glucose in association with obesity in Iran: 2005-2011. Diabetes Res Clin Pract. 2014;103(2):319-27.##Vogiatzi MG, Macklin EA, Fung EB, Vichinsky E, Olivieri N, Kwiatkowski J, et al. Prevalence of fractures among the Thalassemia syndromes in North America. Bone. 2006;38(4):571-5.##Aessopos A, Farmakis D, Andreopoulos A, Tsironi M. Assessment and treatment of cardiac iron overload in thalassemia. Hemoglobin. 2009;33 Suppl 1:S87-92.##De Sanctis V, Soliman AT, Elsedfy H, Yassin M, Canatan D, Kilinc Y, et al. Osteoporosis in thalassemia major: an update and the I-CET 2013 recommendations for surveillance and treatment. Pediatr Endocrinol Rev. 2013;11(2):167-80.##Soliman A, De Sanctis V, Elsedfy H, Yassin M, Skordis N, Karimi M, et al. Growth hormone deficiency in adults with thalassemia: an overview and the I-CET recommendations. Georgian Med News. 2013(222):79-88.##De Sanctis V, Soliman AT, Yassin MA, Di Maio S, Daar S, Elsedfy H, et al. Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment. Acta Biomed. 2018;89(2-s):6-15.##Christoforidis A, Kazantzidou E, Tsatra I, Tsantali H, Koliakos G, Hatzipantelis E, et al. Normal lumbar bone mineral density in optimally treated children and young adolescents with beta-thalassaemia major. HORMONES-ATHENS-. 2007;6(4):334.##Christoforidis A, Perifanis V, Tsatra I, Vlachaki E, Athanassiou-Metaxa M. Evolution of OGTT in patients with β-thalassaemia major in relation to chelation therapy. Diabetes Research and Clinical Practice. 2007;76(1):6-11.##Ladis V, Chouliaras G, Berdousi H, Kanavakis E, Kattamis C. Longitudinal study of survival and causes of death in patients with thalassemia major in Greece. Annals of the New York Academy of Sciences. 2005;1054(1):445-50.##Angastiniotis M, Christou S, Kolnakou A, Pangalou E, Savvidou I, Farmakis D, et al. The Outcomes of Patients with Haemoglobin Disorders in Cyprus: A Joined Report of the Thalassaemia International Federation and the Nicosia and Paphos Thalassaemia Centres (State Health Services Organisation). Thalassemia Reports. 2022;12(4):143-56.##Teleanu RI, Sarman MA, Epure DA, Matei M, Roşca I, Roza E. Autosomal Dominant Hypocalcemia Type 1 and Neonatal Focal Seizures. Children. 2023;10(6):1011.##Delvecchio M, Cavallo L. Growth and endocrine function in thalassemia major in childhood and adolescence. J Endocrinol Invest. 2010;33(1):61-8.##Soliman AT, Adel A, Al Yafei F, et al. Comprehensive management of endocrine complications in β-thalassemia. Front Endocrinol (Lausanne). 2021;12:624305. doi:10.3389/fendo.2021.624305.##Hamed EA, El-Metwally TH, El-Farahaty RM, et al. Endocrine complications in thalassemia major: a multicenter study in Egypt. Hematology. 2021;26(1):53-61. doi:10.1080/16078454.2020.1866356.##Vitrano A, Musallam KM, Giardina PJ. Updates and current strategies in the management of endocrine complications of thalassemia. Best Pract Res Clin Endocrinol Metab. 2021;35(3):101499. doi:10.1016/j.beem.2021.101499.##Faranoush M, Rahiminejad M, Karamizadeh Z, Ghorbani R, Owji S. Zinc Supplementation Effect on Linear Growth in Transfusion Dependent β Thalassemia. Iranian Journal of Blood and Cancer. 2008;1(1):29-32.##Taher AT, Saliba AN, Musallam KM, et al. Endocrine disorders in β-thalassemia: current perspectives. Metabolism. 2020;112:154354. doi:10.1016/j.metabol.2020.154354.##Shoback D. Clinical practice. Hypoparathyroidism. N Engl J Med. 2008;359(4):391-403.##Zafardoust S, Ansaripor S, Karimi A, Hosseinirad H, Ataei M. Effects of Adjuvant Growth Hormone Therapy on Poor Ovarian Responders in Assisted Reproductive Technology. Maedica (Bucur). 2022;17(2):336-43.##Mohammadian S, Sadeghi-Nejad A. Current State of Growth Hormone Therapy. Int J Endocrinol Metab. 2003;1(2):e94490. .##Souza FM, Collett-Solberg PF. Adverse effects of growth hormone replacement therapy in children. Arq Bras Endocrinol Metabol. 2011;55(8):559-65.##Gaber MA, Elbana RE, Mahmoud AA. Risk factors for hypogonadism in multitransfused thalassemia major male patients. Menoufia Med J 2022;35:439-44.##Golpayegani M, Faranoush p, Rasouli Mh, Foroughi-Gilvaee M, Sadighnia N, Zandi A, et al. Comparative study on the effects of filgrastim and pegfilgrastim in the treatment of fever and neutropenia in patients with leukemia in the west of Iran. Iranian journal of Pediatric Hematology and Oncology. 2022;12(2):76-85.##De Sanctis V, Soliman AT, Daar S, Di Maio S. Adverse events during testosterone replacement therapy in 95 young hypogonadal thalassemic men. Acta Biomed. 2019;90(2):228-32.##De Sanctis V, Soliman AT, Elsedfy H, Di Maio S. Current practice in treating adult female thalassemia major patients with hypogonadism: An International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine survey from Italy. Indian J Endocrinol Metab. 2016;20(6):880-1.##Bhardwaj A, Swe KMM, Sinha NK, Osunkwo I. Treatment for osteoporosis in people with ß-thalassaemia. Cochrane Databaseof Systematic Reviews 2016, Issue 3. Art. No.: CD010429. DOI: 10.1002/14651858.CD010429.pub2. .##Singhal A, Goyal H. Thyroid dysfunction in beta thalassemia major patients. Thyroid Research and Practice. 2020;17(2):70-5.##Mokhtari Dowlatabad H, Mamdouh A, Yousefpour N, Mahdavi R, Zandi A, Hoseinpour P, et al. High-Frequency (30 MHz–6 GHz) Breast Tissue Characterization Stabilized by Suction Force for Intraoperative Tumor Margin Assessment. Diagnostics. 2023;13(2):179.##Moharamipour S, Aminifar M, Foroughi-Gilvaee MR, Faranoush P, Mahdavi R, Abadijoo H, et al. Hydroelectric actuator for 3-dimensional analysis of electrophoretic and dielectrophoretic behavior of cancer cells; suitable in diagnosis and invasion studies. Biomaterials Advances. 2023;151:213476.##Hashemi-madani N, Rahimian N, Khamseh ME, Faranoush P, Malek M, Ghasemi F, et al. Guideline for the diagnosis and treatment of hypothyroidism and hypoparathyroidism in patients with blood transfusion-dependent thalassemia. Iranian Journal of Blood and Cancer. 2023;15(2):89-96.##Gamberini MR, Fortini M, De Sanctis V, Gilli G, Testa MR. Diabetes mellitus and impaired glucose tolerance in thalassaemia major: incidence, prevalence, risk factors and survival in patients followed in the Ferrara Center. Pediatr Endocrinol Rev. 2004;2 Suppl 2:285-91.##Martirosyan D, Jahanbakhshi F, Foroughi-Gilvaee MR, Mousavi F, Faranoush P, Ashoori MR, et al. Evaluation of the effect of electron beam therapy on oxidative stress and some minerals in patients with type 2 diabetes mellitus. Functional Food Science. 2022;2(5):124-35.##He L-N, Chen W, Yang Y, Xie Y-J, Xiong Z-Y, Chen D-Y, et al. Elevated Prevalence of Abnormal Glucose Metabolism and Other Endocrine Disorders in Patients with β-Thalassemia Major: A Meta-Analysis. BioMed Research International. 2019;2019:6573497.##Mowla A, Karimi M, Afrasiabi A, De Sanctis V. Prevalence of diabetes mellitus and impaired glucose tolerance in beta-thalassemia patients with and without hepatitis C virus infection. Pediatr Endocrinol Rev. 2004;2 Suppl 2:282-4.##M. Diab A, S. Abdelmotaleb G, Abdel-Azim Eid K, Sebaey S. Mostafa E, Sabry Ahmed E. Evaluation of glycemic abnormalities in children and adolescents with β-thalassemia major. Egyptian Pediatric Association Gazette. 2021;69(1):9.##Aleem A, Al-Momen AK, Al-Harakati MS, Hassan A, Al-Fawaz I. Hypocalcemia due to hypoparathyroidism in beta-thalassemia major patients. Ann Saudi Med. 2000;20(5-6):364-6.##De Sanctis V, Soliman AT, Canatan D, Elsedfy H, Karimi M, Daar S, et al. An ICET- A survey on Hypoparathyroidism in Patients with Thalassaemia Major and Intermedia: A preliminary report. Acta Biomed. 2018;88(4):435-44.##Matin S, Jahromi MG, Karemizadeh Z, Haghpanah S, De Sanctis V, Soliman A, et al. The Frequency of Adrenal Insufficiency in Adolescents and Young Adults with Thalassemia Major versus Thalassemia Intermedia in Iran. Mediterr J Hematol Infect Dis. 2015;7(1):e2015005.##Baldini M, Mancarella M, Cassinerio E, Marcon A, Ambrogio AG, Motta I. Adrenal insufficiency: An emerging challenge in thalassemia? Am J Hematol. 2017;92(6):E119-e21.##Bhardwaj A, Swe KMM, Sinha NK, Osunkwo I. Treatment for osteoporosis in people with ß‐thalassaemia. Cochrane Database of Systematic Reviews. 2013(3).##Gaudio A, Morabito N, Catalano A, Rapisarda R, Xourafa A, Lasco A. Pathogenesis of Thalassemia Major-associated Osteoporosis: A Review with Insights from Clinical Experience. J Clin Res Pediatr Endocrinol. 2019;11(2):110-7.##Rossi F, Perrotta S, Bellini G, Luongo L, Tortora C, Siniscalco D, et al. Iron overload causes osteoporosis in thalassemia major patients through interaction with transient receptor potential vanilloid type 1 (TRPV1) channels. Haematologica. 2014;99(12):1876-84.##Goldberg EK, Lal A, Fung EB. Nutrition in Thalassemia: A Systematic Review of Deficiency, Relations to Morbidity, and Supplementation Recommendations. J Pediatr Hematol Oncol. 2022;44(1):1-11.##Goldberg EK, Neogi S, Lal A, Higa A, Fung E. Nutritional Deficiencies Are Common in Patients with Transfusion-Dependent Thalassemia and Associated with Iron Overload. J Food Nutr Res (Newark). 2018;6(10):674-81.##Fung EB. Nutritional deficiencies in patients with thalassemia. Ann N Y Acad Sci. 2010;1202:188-96.##Ansari S, Baghersalimi A, Azarkeivan A, Nojomi M, Hassanzadeh Rad A. Quality of life in patients with thalassemia major. Iran J Ped Hematol Oncol. 2014;4(2):57-63.## ##

Wnt7b as a novel candidate in silico analysis of angiogenesis-related expressed genes in non-small cell lung cancer patients 2 2 According to the latest WHO report, lung cancer ranks among the top cancer-associated mortalities. Moreover, it has been related to a high rate of metastasis, which indicates the importance of angiogenesis. Histologically, lung cancer is divided into NSCLC and SCLC, with NSCLC being the most common. Angiogenesis is essential for tumor development. Additionally, immune cells, soluble factors, and ECM play a crucial role in their formation. this study reviews the angiogenesis formation factors in previous studies as well as analyzes in silico angiogenesis-related genes in NSCLCs. It is reported that EPhB2, PIK3R2, HSPB1and Wnt7b were the most upregulated angiogenesis genes. Among them, Wnt7b is the most prevalent in NSCLC subtypes. Moreover, a decrease of 50% in overall survival in both low and high Wnt7b transcripts per million was observed. First, three high-throughput GEO data sets with 18 lung cancer and normal samples were adopted to achieve the study purpose. Then, the up-and-down-regulated genes with p-value <0.05 were isolated. Next, the genes were taken to the Enrichr and the KEGG databases. Lastly, our in-silico analysis confirmed the gene expression connection between angiogenesis and lung cancer invasion.     236 252 2023/06/212023/08/82023/06/232023/07/10 1402/4/19 2023/08/122023/08/172023/08/222023/08/20 1402/5/29 Amin Soltanpor Dehkordi Amin Soltanpor Dehkordi Department of Mycology and Parasitology, Faculty of Medicine, Isfahan University of Medical Sciences, Isfahan, Iran aminsoltanpordehkordi@gmail.com Maryam Sayahinouri Maryam Sayahinouri Department of Immunology, Afzalipour Faculty of Medicine, Kerman University of Medical Sciences, Kerman, Iran maryam.sayahinouri@gmail.com Haniyeh Sadat Hosseininia Haniyeh Sadat Hosseininia Department of Cellular and Molecular Biology, Faculty of Advanced Medical Science, Islamic Azad University of Medical Sciences, Tehran, Iran hanahosseininia75@gmail.com Alireza Kazempour Alireza Kazempour Department of Microbiology, Faculty of Science, Lahijan Branch, Islamic Azad University, Gilan, Iran Ali42153@gmail.com Romina Mehtar Araghinia Romina Mehtar Araghinia Department of Biology, Faculty of Science, Tonekabon Branch, Islamic Azad University, Mazandaran, Iran romina_nia@yahoo.com Arman Saadati Partan Arman Saadati Partan Department of Microbiology, Islamic Azad University, Karaj Branch, Karaj, Iran saadati.arman.as@gmail.com Amin Ebrahimi Sadrabadi Amin Ebrahimi Sadrabadi Department of Stem Cells and Developmental Biology, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran Amin.ebrahimii@live.com Arsalan Jalili Arsalan Jalili Department of Stem Cells and Developmental Biology, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran Jalili.arsalan@yahoo.com Wnt7b EPhB2 Angiogenesis Lung cancer In silico Bioinformatics Akbarian M, Bertassoni LE, Tayebi L. Biological aspects in controlling angiogenesis: current progress. Cell Mol Life Sci. 2022 Jun 7;79(7):349. ##https://doi.org/10.1007/s00018-022-04348-5##Al-Ostoot FH, Salah S, Khamees HA, Khanum SA. Tumor angiogenesis: Current challenges and therapeutic opportunities. Cancer Treat Res Commun. 2021;28:100422. https:// doi: 10.1016/j.ctarc.2021.100422.##Aloe C, Wang H, Vlahos R, Irving L, Steinfort D, Bozinovski S. Emerging and multifaceted role of neutrophils in lung cancer. Transl Lung Cancer Res. 2021 Jun;10(6):2806-2818.##Amin MA, Rabquer BJ, Mansfield PJ, Ruth JH, Marotte H, Haas CS, Reamer EN, Koch AE. Interleukin 18 induces angiogenesis in vitro and in vivo via Src and Jnk kinases. Ann Rheum Dis. 2010 Dec;69(12):2204-12.##Apte RS, Chen DS, Ferrara N. VEGF in Signaling and Disease: Beyond Discovery and Development. Cell. 2019 Mar 7;176(6):1248-1264.##Auerbach R, Auerbach W, Polakowski I. Assays for angiogenesis: a review. Pharmacol Ther. 1991;51(1):1-11. ##https://doi.org/10.1016/0163-7258(91)90038-N##Auerbach, Auerbach R. Angiogenesis inhibition: a review. Pharmacol Ther. 1994 Sep;63(3):265-311. ##https://doi.org/10.1016/0163-7258(94)90027-2##Bancroft CC, Chen Z, Yeh J, Sunwoo JB, Yeh NT, Jackson S, Jackson C, Van Waes C. Effects of pharmacologic antagonists of epidermal growth factor receptor, PI3K, and MEK signal kinases on NF‐κB and AP‐1 activation and IL‐8 and VEGF expression in human head and neck squamous cell carcinoma lines. Int J Cancer. 2002 Jun 1;99(4):538-48. ##https://doi.org/10.1002/ijc.10398##Barta M, Julie A, Powell CA, Wisnivesky JP. Global Epidemiology of Lung Cancer. Ann Glob Health. 2019 Jan 22;85(1):8. ##https://doi.org/10.5334/aogh.2419##Bhadada SV, Goyal BR, Patel MM. Angiogenic targets for potential disorders. Fundam Clin Pharmacol. 2011 Feb;25(1):29-47. ##https://doi.org/10.1111/j.1472-8206.2010.00814.x##Cao Y, Cao R, Hedlund EM. R Regulation of tumor angiogenesis and metastasis by FGF and PDGF signaling pathways. J Mol Med (Berl). 2008 Jul;86(7):785-9. ##https://doi.org/10.1007/s00109-008-0337-z##Caporarello N, Lupo G, Olivieri M, Cristaldi M, Cambria MT, Salmeri M, Anfuso CD. Classical VEGF. Notch and Ang signalling in cancer angiogenesis, alternative approaches and future directions. Mol Med Rep. 2017 Oct;16(4):4393-4402. ##https://doi.org/10.3892/mmr.2017.7179##Carmeliet P. VEGF as a key mediator of angiogenesis in cancer. Oncology 69 Suppl. 2005;69 Suppl 3:4-10. ##https://doi.org/10.1159/000088478##Chandler KB, Costello CE, Rahimi N. Glycosylation in the Tumor Microenvironment: Implications for Tumor Angiogenesis and Metastasis. Cells. 2019 Jun 5;8(6):544. ##https://doi.org/10.3390/cells8060544##Chen Q-Y, Jiao D-M, Wu Y-Q, Chen J, Wang J, Tang X-L, Mou H, Hu H-Z, Song J, Yan J. MiR-206 inhibits HGF-induced. epithelial-mesenchymal transition and angiogenesis in non-small cell lung cancer via c-Met/PI3k/Akt/mTOR pathway. Oncotarget. 2016 Apr 5;7(14):18247-61. ##https://doi.org/10.18632/oncotarget.7570##Choi SH, Yoo SS, Lee SY, Park JY. Anti-angiogenesis revisited: reshaping the treatment landscape of advanced non-small cell lung cancer. Arch Pharm Res. 2022 Apr;45(4):263-279. ##https://doi.org/10.1007/s12272-022-01382-6##Choi Y-S, Choi H-J, Min J-K, Pyun B-J, Maeng Y-S, Park H, Kim J, Kim Y-M, Kwon Y-G. Interleukin-33 induces angiogenesis and vascular permeability through ST2/TRAF6-mediated endothelial nitric oxide production. Blood, The Journal of the American Society of Hematology. 2009 Oct 1;114(14):3117-26. ##https://doi.org/10.1182/blood-2009-02-203372##Chung AS, Lee J, Ferrara N. Targeting the tumour vasculature: insights from physiological angiogenesis. Nat Rev Cancer. 2010 Jul;10(7):505-14. ##https://doi.org/10.1038/nrc2868##Dabrosin C. Sex steroid regulation of angiogenesis in breast tissue. Angiogenesis. 2005;8(2):127-36. ##https://doi.org/10.1007/s10456-005-9002-0##De Martel C, Georges D, Bray F, Ferlay J, Clifford GM. Global burden of cancer attributable to infections in 2018: a worldwide incidence analysis. Lancet Glob Health. 2020 Feb;8(2):e180-e190. ##https://doi.org/10.1016/S2214-109X(19)30488-7##De Oliveira THA, Do Amaral CM, De Franca Sao Marcos B, Nascimento KCG, De Miranda Rios AC, Quixabeira DCA, Muniz MTC, Silva Neto JDC, De Freitas AC. Presence and activity of HPV in primary lung cancer. J Cancer Res Clin Oncol. 2018 Dec;144(12):2367-2376. ##https://doi.org/10.1007/s00432-018-2748-8##Malik Y, Jens A. miRNomics: MicroRNA Biology and Computational Analysis MIMB. 2014; https://doi.org/ 10.1007/978-1-62703-748-8##Dogan S, Shen R, Ang DC, Johnson ML, D'angelo SP, Paik PK, Brzostowski EB, Riely GJ, Kris MG, Zakowski MF. Molecular epidemiology of EGFR and KRAS mutations in 3,026 lung adenocarcinomas: higher susceptibility of women to smoking-related KRAS-mutant cancers. Clin Cancer Res. 2012 Nov 15;18(22):6169-77. ##https://doi.org/10.1158/1078-0432.CCR-11-3265##Doherty DF, Roets L, Krasnodembskaya AD. The role of lung resident mesenchymal stromal cells in the pathogenesis and repair of chronic lung disease. Stem Cells: sxad014. 2023 May 15;41(5):431-443. ##https://doi.org/10.1093/stmcls/sxad014##Dumont DJ, Gradwohl G, Fong GH, Puri MC, Gertsenstein M, Auerbach A, Breitman ML. Dominant-negative and targeted null mutations in the endothelial receptor tyrosine kinase, tek, reveal a critical role in vasculogenesis of the embryo. Genes Dev 8:1897-1909. 1994 Aug 15;8(16):1897-909. ##https://doi.org/10.1101/gad.8.16.1897##Fantin A, Vieira JM, Gestri G, Denti L, Schwarz Q, Prykhozhij S, Peri F, Wilson SW, Ruhrberg C. Tissue macrophages act as cellular chaperones for vascular anastomosis downstream of VEGF-mediated endothelial tip cell induction. Blood. 2010 Aug 5;116(5):829-40. ##https://doi.org/10.1182/blood-2009-12-257832##Farhood B, Raei B, Ameri H, Shirvani M, Alizadeh A, Najafi M, Mortezazadeh T. A review of incidence and mortality of colorectal, lung, liver, thyroid, and bladder cancers in Iran and compared to other countries. Contemp Oncol (Pozn). 2019;23(1):7-15. ##https://doi.org/10.5114/wo.2019.84112##Farooqi AA, Siddik ZH. Platelet-derived growth factor (PDGF) signalling in cancer: rapidly emerging signalling landscape. Cell Biochem Funct. 2015 Jul;33(5):257-65. ##https://doi.org/10.1002/cbf.3120##Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F. Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 2015 Mar 1;136(5):E359-86. ##https://doi.org/10.1002/ijc.29210##Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004 Aug;25(4):581-611. ##https://doi.org/10.1210/er.2003-0027##Folkman J. Tumor angiogenesis: therapeutic implications. N Engl J Med. 1971 Nov 18;285(21):1182-6. ##https://doi.org/10.1056/NEJM197111182852108##Folkman J. Role of angiogenesis in tumor growth and metastasis. Semin Oncol. 2002 Dec;29(6 Suppl 16):15-8. https://doi.org/ 10.1053/sonc.2002.37263.##https://doi.org/10.1053/sonc.2002.37263##Folkman J. Fundamental concepts of the angiogenic process. Curr Mol Med. 2003 Nov;3(7):643-51. ##https://doi.org/10.2174/1566524033479465##François-Fiquet C, Poli-Merol M, Nguyen P, Landais E, Gaillard D, Doco-Fenzy M. Role of angiogenesis-related genes in cleft lip/palate: review of the literature. Int J Pediatr Otorhinolaryngol. 2014 Oct;78(10):1579-85. ##https://doi.org/10.1016/j.ijporl.2014.08.001##Frezzetti D, Gallo M, Roma C, D'alessio A, Maiello MR, Bevilacqua S, Normanno N, De Luca A. Vascular endothelial growth factor a regulates the secretion of different angiogenic factors in lung cancer cells. J Cell Physiol. 2016 Jul;231(7):1514-21. ##https://doi.org/10.1002/jcp.25243##Gallini R, Lindblom P, Bondjers C, Betsholtz C, Andrae J. PDGF-A and PDGF-B induces cardiac fibrosis in transgenic mice. Exp Cell Res. 2016 Dec 10;349(2):282-290. ##https://doi.org/10.1016/j.yexcr.2016.10.022##Goel HL, Mercurio AM. VEGF targets the tumour cell. Nat Rev Cancer. 2013 Dec;13(12):871-82. ##https://doi.org/10.1038/nrc3627##Guerra A, Belinha J, Jorge RN. Modelling skin wound healing angiogenesis: A review. J Theor. 2018 Dec 14;459:1-17. ##https://doi.org/10.1016/j.jtbi.2018.09.020##Hall RD, Le TM, Haggstrom DE, Gentzler RD. Angiogenesis inhibition as a therapeutic strategy in non-small cell lung cancer (NSCLC). Transl Lung Cancer Res. 2015 Oct;4(5):515-23.##Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011 Mar 4;144(5):646-74. ##https://doi.org/10.1016/j.cell.2011.02.013##Hanahan D WR. The hallmarks of cancer. Cell. 2000 Jan 7;100(1):57-70. ##https://doi.org/10.1016/S0092-8674(00)81683-9##Hsu Y, Hung J, Chang W, Lin Y, Pan Y, Tsai P, Wu C, Kuo P. Hypoxic lung cancer-secreted exosomal miR-23a increased angiogenesis and vascular permeability by targeting prolyl hydroxylase and tight junction protein ZO-1. Oncogene. 2017 Aug 24;36(34):4929-4942. ##https://doi.org/10.1038/onc.2017.105##Huang Q, Duan L, Qian X, Fan J, Lv Z, Zhang X, Han J, Wu F, Guo M, Hu G. IL-17 promotes angiogenic factors IL-6, IL-8, and Vegf production via Stat1 in lung adenocarcinoma. Sci Rep. 2017 Aug 24;36(34):4929-4942. ##https://doi.org/10.1038/srep36551##Hung MS, Chen I, Lin PY, Lung JH, Li YC, Lin YC, Yang CT, Tsai YH. Epidermal growth factor receptor mutation enhances expression of vascular endothelial growth factor in lung cancer. Oncol Lett. 2016 Dec;12(6):4598-4604. ##https://doi.org/10.3892/ol.2016.5287##Inamura K. Lung Cancer: Understanding Its Molecular Pathology and the 2015 WHO Classification. Front Oncol. 2017 Aug 28;7:193. ##https://doi.org/10.3389/fonc.2017.00193##Kang JK, Seo S, Jin YW. Health Effects of Radon Exposure. Yonsei Med J. 2019 Jul;60(7):597-603. ##https://doi.org/10.3349/ymj.2019.60.7.597##Kuo YC, Lo YS, Guo HR. Lung Cancer Associated with Arsenic Ingestion: Cell-type Specificity and Dose Response. Epidemiology 28 Suppl. 2017 Oct;28 Suppl 1:S106-S112. https://doi.org/ 10.1097/EDE.0000000000000743.##https://doi.org/10.1097/EDE.0000000000000743##Laddha AP, Kulkarni YA. VEGF and FGF-2: Promising targets for the treatment of respiratory disorders. Respir Med. 2019 Sep;156:33-46. ##https://doi.org/10.1016/j.rmed.2019.08.003##Lichtenauer M, Jung C. Microvesicles and ectosomes in angiogenesis and diabetes-message in a bottle in the vascular ocean. Theranostics. 2018 Jul 1;8(14):3974-3976. ##https://doi.org/10.7150/thno.27154##Liekens S, De Clercq E, Neyts J. Angiogenesis: regulators and clinical applications. Biochem Pharmacol. 2001 Feb 1;61(3):253-70. ##https://doi.org/10.1016/S0006-2952(00)00529-3##Lužnik Z, Anchouche S, Dana R, Yin J. Regulatory T cells in angiogenesis. J Immunol. 2020 Nov 15;205(10):2557-2565. ##https://doi.org/10.4049/jimmunol.2000574##Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H, Gemma A, Harada M, Yoshizawa H, Kinoshita I. Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2015 May;88(2):181-6. https://doi.org/ 10.1056/NEJMoa0909530.##Maeshima Y, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR, Sonenberg N, Hynes RO, Kalluri R. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science. 2002 Jan 4;295(5552):140-3. ##https://doi.org/10.1126/science.1065298##Mantovani A, Barajon I, Garlanda C. IL‐1 and IL‐1 regulatory pathways in cancer progression and therapy. Immunol Rev. 2018 Jan;281(1):57-61. ##https://doi.org/10.1111/imr.12614##Newman DR, Sills WS, Hanrahan K, Ziegler A, Tidd KM, Cook E, Sannes PL. Expression of WNT5A in idiopathic pulmonary fibrosis and its control by TGF-β and WNT7B in human lung fibroblasts. J Histochem Cytochem. 2016 Feb;64(2):99-111. ##https://doi.org/10.1369/0022155415617988##Oberkersch RE, Santoro MM. Role of amino acid metabolism in angiogenesis. Vascul Pharmacol. 2019 Jan;112:17-23. ##https://doi.org/10.1016/j.vph.2018.11.001##Organization WH. Assessing national capacity for the prevention and control of noncommunicable diseases: report of the 2019 global survey. 2020; https://apps.who.int/iris/handle/10665/331452##Otrock ZK, Mahfouz RA, Makarem JA, Shamseddine AI. Understanding the biology of angiogenesis: review of the most important molecular mechanisms. Blood Cells Mol Dis. 2007 Sep-Oct;39(2):212-20. ##https://doi.org/10.1016/j.bcmd.2007.04.001##Pan B, Shen J, Cao J, Zhou Y, Shang L, Jin S, Cao S, Che D, Liu F, Yu Y. Interleukin-17. promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer. Sci Rep. 2015 Nov 3;5:16053. ##https://doi.org/10.1038/srep16053##Pandya NM, Dhalla NS, Santani DD. Angiogenesis-a new target for future therapy. Vascul Pharmacol. 2006 May;44(5):265-74. ##https://doi.org/10.1016/j.vph.2006.01.005##Papetti M, Herman IM. Mechanisms of normal and tumor-derived angiogenesis. Am J Physiol Cell Physiol. 2002 May;282(5):C947-70. ##https://doi.org/10.1152/ajpcell.00389.2001##Partanen J PM, Schwartz L, Fischer Kd, Bernstein A, Rossant J. Cell autonomous functions of the receptor tyrosine kinase TIE in a late phase of angiogenic capillary growth and endothelial cell survival during murine development. Development. 1996 Oct;122(10):3013-21. ##https://doi.org/10.1242/dev.122.10.3013##Patel AJ, Richter A, Drayson MT, Middleton GW. The role of B lymphocytes in the immuno-biology of non-small-cell lung cancer. Cancer Immunol Immunother. 2020 Mar;69(3):325-342. ##https://doi.org/10.1007/s00262-019-02461-2##Piñeros M, Mery L, Soerjomataram I, Bray F, Steliarova-Foucher E. Scaling up the surveillance of childhood cancer: a global roadmap. J Natl Cancer Inst. 2021 Jan 4;113(1):9-15. ##https://doi.org/10.1093/jnci/djaa069##Protopsaltis NJ, Liang W, Nudleman E, Ferrara N. Interleukin-22 promotes tumor angiogenesis. Angiogenesis. 2019 May;22(2):311-323. ##https://doi.org/10.1007/s10456-018-9658-x##Qu J, Zhang Y, Chen X, Yang H, Zhou C, Yang N. Newly developed anti-angiogenic therapy in non-small cell lung cancer. Oncotarget. 2019 May;22(2):311-323. ##https://doi.org/10.18632/oncotarget.23755##Ramakrishnan S, Subramanian I, Yokoyama Y, Geller M. Angiogenesis in normal and neoplastic ovaries. Angiogenesis. 2005;8(2):169-82. ##https://doi.org/10.1007/s10456-005-9001-1##Ramjiawan RR, Griffioen AW, Duda DG. Anti-angiogenesis for cancer revisited: Is there a role for combinations with immunotherapy?. Angiogenesis. 2017 May;20(2):185-204. ##https://doi.org/10.1007/s10456-017-9552-y##Roker LA, Nemri K, Yu J. Wnt7b signaling from the ureteric bud epithelium regulates medullary capillary development. J Am Soc Nephrol. 2017 Jan;28(1):250-259. ##https://doi.org/10.1681/ASN.2015111205##Rudin CM, Avila-Tang E, Samet JM. Lung cancer in never smokers: a call to action. Clin Cancer Res. 2009 Sep 15;15(18):5622-5. ##https://doi.org/10.1158/1078-0432.CCR-09-0373##Sajib S, Zahra FT, Lionakis MS, German NA, Mikelis CM. Mechanisms of angiogenesis in microbe-regulated inflammatory and neoplastic conditions. Angiogenesis. 2018 Feb;21(1):1-14. ##https://doi.org/10.1007/s10456-017-9583-4##Salem A, Asselin M-C, Reymen B, Jackson A, Lambin P, West CM, O'connor JP, Faivre-Finn C. Targeting hypoxia to improve non-small cell lung cancer outcome. J Natl Cancer Inst. 2018 Jan 1;110(1). ##https://doi.org/10.1093/jnci/djx160##Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. ##https://doi.org/10.1056/NEJMoa011954##Schito L. Bridging angiogenesis and immune evasion in the hypoxic tumor microenvironment. American journal of physiology. Am J Physiol Regul Integr Comp Physiol. 2018 Dec 1;315(6):R1072-R1084. ##https://doi.org/10.1152/ajpregu.00209.2018##Semrad TJ, Mack PC. Fibroblast growth factor signaling in non-small-cell lung cancer. Clin Lung Cancer. 2012 Mar;13(2):90-5. ##https://doi.org/10.1016/j.cllc.2011.08.001##Seo S, Ha WH, Kang JK, Lee D, Park S, Kwon TE, Jin YW. Health effects of exposure to radon: implications of the radon bed mattress incident in Korea. Epidemiol Health. 2019;41:e2019004. ##https://doi.org/10.4178/epih.e2019004##Shi Y, Au JS-K, Thongprasert S, Srinivasan S, Tsai C-M, Khoa MT, Heeroma K, Itoh Y, Cornelio G, Yang P-C. A prospective, molecular epidemiology study of EGFR mutations in Asian patients with advanced non-small-cell lung cancer of adenocarcinoma histology (PIONEER). J Thorac Oncol. 2014 Feb;9(2):154-62. ##https://doi.org/10.1097/JTO.0000000000000033##Siveen KS, Prabhu K, Krishnankutty R, Kuttikrishnan S, Tsakou M, Alali FQ, Dermime S, Mohammad RM, Uddin S. Vascular Endothelial Growth Factor (VEGF) Signaling in Tumour Vascularization: Potential and Challenges. Curr Vasc Pharmacol. 2017;15(4):339-351. ##https://doi.org/10.2174/1570161115666170105124038##Spitz MR, Hong WK, Amos CI, Wu X, Schabath MB, Dong Q, Shete S, Etzel CJ. A risk model for prediction of lung cancer. J Natl Cancer Inst. 2007 May 2;99(9):715-26. ##https://doi.org/10.1093/jnci/djk153##Stan R. Endothelial stomatal and fenestral diaphragms in normal vessels and angiogenesis. J Cell Mol Med. 2007 Jul-Aug;11(4):621-43. ##https://doi.org/10.1111/j.1582-4934.2007.00075.x##Suzuki J, Tsuboi M, Ishii G. Cancer-associated fibroblasts and the tumor microenvironment in non-small cell lung cancer. Expert Rev Anticancer Ther. 2022 Feb;22(2):169-182. ##https://doi.org/10.1080/14737140.2022.2019018##Bing Z, Jian-Ru Y, Yao-Quan J, Shi-Feng C. Evaluation of angiogenesis in non-small cell lung carcinoma by CD34 immunohistochemistry. Cell Biochem Biophys. 2014 Sep;70(1):327-31. ##https://doi.org/10.1007/s12013-014-9916-5##Thijssen VL, Paulis YW, Nowak‐Sliwinska P, Deumelandt KL, Hosaka K, Soetekouw PM, Cimpean AM, Raica M, Pauwels P, Van Den Oord JJ. Targeting PDGF‐mediated recruitment of pericytes blocks vascular mimicry and tumor growth. J Pathol. 2018 Dec;246(4):447-458. ##https://doi.org/10.1002/path.5152##Thorpe LM, Yuzugullu H, Zhao JJ. PI3K in cancer: divergent roles of isoforms, modes of activation and therapeutic targeting. Nat Rev Cancer. 2015 Jan;15(1):7-24. ##https://doi.org/10.1038/nrc3860##Tiwari A, Mukherjee B, Dixit M. MicroRNA key to angiogenesis regulation: miRNA biology and therapy. Curr Cancer Drug Targets. 2018;18(3):266-277. ##https://doi.org/10.2174/1568009617666170630142725##Tripurani SK, Cook RW, Eldin KW, Pangas SA. BMP-specific SMADs function as novel repressors of PDGFA and modulate its expression in ovarian granulosa cells and tumors. Oncogene. 2013 Aug 15;32(33):3877-85. ##https://doi.org/10.1038/onc.2012.392##Uutela M, Wirzenius M, Paavonen K, Rajantie I, He Y, Karpanen T, Lohela M, Wiig H, Salven P, Pajusola K. PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Blood. 2004 Nov 15;104(10):3198-204. ##https://doi.org/10.1182/blood-2004-04-1485##Vallejo-Díaz J, Olazabal-Morán M, Cariaga-Martínez AE, Pajares MJ, Flores JM, Pio R, Montuenga LM, Carrera AC. Targeted depletion of PIK3R2 induces regression of lung squamous cell carcinoma. Oncotarget. 2016 Dec 20;7(51):85063-85078. ##https://doi.org/10.18632/oncotarget.13195##Van Zandwijk N, Reid G, Frank AL. Asbestos-related cancers: the 'Hidden Killer' remains a global threat. Expert Rev Anticancer Ther. 2020 Apr;20(4):271-278. ##https://doi.org/10.1080/14737140.2020.1745067##Vermeulen P, Gasparini G, Fox S, Toi M, Martin L, Mcculloch P, Pezzella F, Viale G, Weidner N, Harris A. Quantification of angiogenesis in solid human tumours: an international consensus on the methodology and criteria of evaluation. Eur J Cancer. 1996 Dec;32A(14):2474-84. ##https://doi.org/10.1016/S0959-8049(96)00379-6##Viallard C, Larrivee B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. 2017 Nov;20(4):409-426. ##https://doi.org/10.1007/s10456-017-9562-9##Wang J, Chen J, Guo Y, Wang B, Chu H. Strategies targeting angiogenesis in advanced non-small cell lung cancer. Oncotarget. 2017 May 17;8(32):53854-53872. ##https://doi.org/10.18632/oncotarget.17957##Wang N, Zhou F, Xiong H, Du S, Ma J, Okai I, Wang J, Suo J, Hao L, Song Y. Screening and Identification of Distant Metastasis‐Related Differentially Expressed Genes in Human Squamous Cell Lung Carcinoma. Anat Rec (Hoboken). 2012 May;295(5):748-57. ##https://doi.org/10.1002/ar.22441##Wang R, Cai Y, Zhang B, Wu Z. A 16-gene expression signature to distinguish stage I from stage II lung squamous carcinoma. Int J Mol Med. 2018 Mar;41(3):1377-1384. ##https://doi.org/10.3892/ijmm.2017.3332##Wang R, Lou X, Feng G, Chen J, Zhu L, Liu X, Yao X, Li P, Wan J, Zhang Y. IL-17A-stimulated endothelial fatty acid β-oxidation promotes tumor angiogenesis. Life Sci. 2019 Jul 15;229:46-56. ##https://doi.org/10.1016/j.lfs.2019.05.030##Wang S, Dang H, Xu F, Deng J, Zheng X. The Wnt7b/β-catenin signaling pathway is involved in the protective action of calcitonin gene-related peptide on hyperoxia-induced lung injury in premature rats. Cell Mol Biol Lett. 2018 Jan 25;23:4. ##https://doi.org/10.1186/s11658-018-0071-7##Xing S, Pan N, Xu W, Zhang J, Li J, Dang C, Liu G, Pei Z, Zeng J. EphrinB2 activation enhances angiogenesis, reduces amyloid-β deposits and secondary damage in thalamus at the early stage after cortical infarction in hypertensive rats. J Cereb Blood Flow Metab. 2019 Sep;39(9):1776-1789. ##https://doi.org/10.1177/0271678X18769188##Xu F, Wei Y, Tang Z, Liu B, Dong J. Tumor associated macrophages in lung cancer: Friend or foe? Mol Med Rep. 2020 Nov;22(5):4107-4115. ##https://doi.org/10.3892/mmr.2020.11518##Xue Y, Lim S, Yang Y, Wang Z, Jensen LDE, Hedlund E-M, Andersson P, Sasahara M, Larsson O, Galter D. PDGF-BB modulates hematopoiesis and tumor angiogenesis by inducing erythropoietin production in stromal cells. Nat Med. 2011 Dec 4;18(1):100-10. ##https://doi.org/10.1038/nm.2575##Yang L, Zhou F, Zheng D, Wang D, Li X, Zhao C, Huang X. FGF/FGFR signaling: From lung development to respiratory diseases. Cytokine Growth Factor Rev. 2021 Dec;62:94-104. ##https://doi.org/10.1016/j.cytogfr.2021.09.002##Yang T, Lin Q, Zhao M, Hu Y, Yu Y, Jin J, Zhou H, Hu X, Wei R, Zhang X. IL-37 is a novel proangiogenic factor of developmental and pathological angiogenesis. Arterioscler Thromb Vasc Biol. 2015 Dec;35(12):2638-46. ##https://doi.org/10.1161/ATVBAHA.115.306543##Yu T, Guo F, Yu Y, Sun T, Ma D, Han J, Qian Y, Kryczek I, Sun D, Nagarsheth N, Chen Y, Chen H, Hong J, Zou W, Fang J-Y. Fusobacterium nucleatum Promotes Chemoresistance to Colorectal Cancer by Modulating Autophagy. Cell. 2017 Jul 27;170(3):548-563.e16. ##https://doi.org/10.1016/j.cell.2017.07.008##Zahir ST, Mirtalebi M. Survival of patients with lung cancer, Yazd, Iran. Asian Pac J Cancer Prev. 2012;13(9):4387-91. ##https://doi.org/10.7314/APJCP.2012.13.9.4387##Zhang A, Tian S. Classification of early‐stage non‐small cell lung cancer by weighing gene expression profiles with connectivity information. Biom J. 2018 May;60(3):537-546. ##https://doi.org/10.1002/bimj.201700010##Zhao C, Wang A, Lu F, Chen H, Fu P, Zhao X, Chen H. Overexpression of junctional adhesion molecule-A and EphB2 predicts poor survival in lung adenocarcinoma patients. Tumour Biol. 2017 Feb;39(2):1010428317691000. ##https://doi.org/10.1177/1010428317691000##Zhao M, Hu Y, Jin J, Yu Y, Zhang S, Cao J, Zhai Y, Wei R, Shou J, Cai W. Interleukin 37 promotes angiogenesis through TGF-β signaling. Sci Rep. 2017 Jul 21;7(1):6113. ##https://doi.org/10.1038/s41598-017-06124-z##Zheng M. Classification and Pathology of Lung Cancer. Surg Oncol Clin N Am. 2016 Jul;25(3):447-68. ##https://doi.org/10.1016/j.soc.2016.02.003##Ko J, Winslow MM, Sage J. Mechanisms of small cell lung cancer metastasis. EMBO Mol Med. 2021 Jan 11;13(1):e13122. ##https://doi.org/10.15252/emmm.202013122##Zhu H, Zhang S. Hypoxia inducible factor‐1α/vascular endothelial growth factor signaling activation correlates with response to radiotherapy and its inhibition reduces hypoxia‐induced angiogenesis in lung cancer. J Cell Biochem. 2018 Sep;119(9):7707-7718. ##https://doi.org/10.1002/jcb.27120##Ziyad S, Iruela-Arispe ML. Molecular mechanisms of tumor angiogenesis. Genes Cancer. 2011 Dec;2(12):1085-96. ##https://doi.org/10.1177/1947601911432334##Wang J, Yang Q, Tang M, Liu W. Validation and analysis of expression, prognosis and immune infiltration of WNT gene family in non-small cell lung cancer. Front Oncol. 2022 Jul 25;12:911316. ##https://doi.org/10.3389/fonc.2022.911316##Cui Y, Luo Y, Qian Q, Tian J, Fang Z, Wang X, Zeng Y, Wu J, Li Y. Sanguinarine regulates tumor-associated macrophages to prevent lung cancer angiogenesis through the WNT/β-catenin pathway. Front Oncol. 2022 Jun 30;12:732860. ##https://doi.org/10.3389/fonc.2022.732860## ##

Digging deep into molecular pathways: Investigating the effects of 9S-HOD on leukemia cells using a systems biology approach 2 2 Background: Acute myeloid leukemia (AML) is a malignant disorder characterized by a poor prognosis. Current therapeutic approaches include chemotherapy, steroids administration, and blood transfusion. Previous studies have highlighted the potential anticancer property of 9-hydroxyoctadecadienoic acid (9S-HOD). This molecular computational research aims to investigate the intricate molecular mechanism underlying the effects of 9S-HOD on leukemia cells. Methods: Utilizing proteomic data and the optimum numbers of the first neighbors from the STRING database, Cytoscape 3.9.1 along with its applications, NetworkAnalyzer and ClueGO+CuePedia were employed to analyze the constructed protein-protein interaction (PPI) network, its centrality and enrichments. Results: The analysis identified five proteins namely ACTB, HSP90AA1, GAPDH, TP53, and HSP90AB1 as potential central nodes within the PPI network. Furthermore, gene ontology analysis revealed “Response to salt stress” and “Positive regulation of type 1 interferon production” as enriched biological processes associated with these key elements of the PPI network. HSPA8, MYC, and KAT5 were identified as seed proteins within the sub-networks. Conclusion: The findings suggest that the effect of 9S-HOD on the leukemia cells primarily involves the regulation of ACTB, HSP90AA1, HSP90AB1, GAPDH, and TP53.  additionally, HSPA8, MYC, and KAT5 emerged as important proteins influenced by 9S-HOD. 253 261 2023/06/212023/08/82023/06/232023/07/102023/06/30 1402/4/9 2023/08/122023/08/172023/08/222023/08/202023/09/2 1402/6/11 Vahid Mansouri Vahid Mansouri Proteomics research center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran Mona Zamanian Azodi Mona Zamanian Azodi Proteomics research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. mona.azodi@gmail.com Reza M Robati Reza M Robati Skin research center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. rezarobati@sbmu.ac.ir Zahra Razzagh Zahra Razzagh Laser Application in Medical Sciences Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. z.razaghi@gmail.com Babak Arjmand Babak Arjmand Cell Therapy and Regenerative Medicine Research Center, Endocrinology and Metabolism Molecular-Cellular Sciences Institute, Tehran University of Medical Sciences, Tehran, Iran. and Iranian Cancer Control Center (MACSA), Tehran, Iran mgrc.tums@gmail.com Mostafa Rezaei Tavirani Mostafa Rezaei Tavirani Proteomics research center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran. tavirany@yahoo.com Mohammad Rostami Nejad Mohammad Rostami Nejad Celiac Disease and Gluten Related Disorders Research Center, Research Institute for Gastroenterology and Liver Disease, Shahid Beheshti University of Medical Sciences, Tehran, Iran. m.rostamii@gmail.com 9-hydroxyoctadecadienoic acid (9S-HOD) Leukemia cells Protein-protein interaction network analysis Centrality Gene ontology. Coccaro N, Anelli L, Zagaria A, Specchia G, Albano F. Next-generation sequencing in acute lymphoblastic leukemia. Int J Mol Sci. 2019 Jun 15;20(12):2929.##Brady SW, Roberts KG, Gu Z, Shi L, Pounds S, Pei D, Cheng C, Dai Y, Devidas M, Qu C, Hill AN, Payne-Turner D, Ma X, Iacobucci I, Baviskar P, Wei L, Arunachalam S, Hagiwara K, Liu Y, Flasch DA, Liu Y, Parker M, Chen X, Elsayed AH, Pathak O, Li Y, Fan Y, Michael JR, Rusch M, Wilkinson MR, Foy S, Hedges DJ, Newman S, Zhou X, Wang J, Reilly C, Sioson E, Rice SV, Pastor Loyola V, Wu G, Rampersaud E, Reshmi SC, Gastier-Foster J, Guidry Auvil JM, Gesuwan P, Smith MA, Winick N, Carroll AJ, Heerema NA, Harvey RC, Willman CL, Larsen E, Raetz EA, Borowitz MJ, Wood BL, Carroll WL, Zweidler-McKay PA, Rabin KR, Mattano LA, Maloney KW, Winter SS, Burke MJ, Salzer W, Dunsmore KP, Angiolillo AL, Crews KR, Downing JR, Jeha S, Pui CH, Evans WE, Yang JJ, Relling MV, Gerhard DS, Loh ML, Hunger SP, Zhang J, Mullighan CG. The genomic landscape of pediatric acute lymphoblastic leukemia. Nat Genet. 2022 Sep;54(9):1376-1389.##Kato M, Manabe A. Treatment and biology of pediatric acute lymphoblastic leukemia. Pediatr Int. 2018 Jan;60(1):4-12.##Zhao H, Zhou H, Cao Q, Wang C, Bai J, Lv P, Zhao F. Effect of allogeneic blood transfusion on levels of IL-6 and sIL-R2 in peripheral blood of children with acute lymphocytic leukemia. Oncol Lett. 2018 Jul;16(1):849-852.##Verrills NM, Walsh BJ, Cobon GS, Hains PG, Kavallaris M. Proteome analysis of vinca alkaloid response and resistance in acute lymphoblastic leukemia reveals novel cytoskeletal alterations. J Biol Chem. 2003 Nov 14;278(46):45082-93.##Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med. 2006 Jan 12;354(2):166-78.##Moorman AV. New and emerging prognostic and predictive genetic biomarkers in B-cell precursor acute lymphoblastic leukemia. Haematologica. 2016 Apr;101(4):407-16.##Nabizadeh F, Momtaz S, Ghanbari-Movahed M, Qalekhani F, Mohsenpour H, Aneva IY, Bishayee A, Farzaei MH, Bishayee A. Pediatric acute lymphoblastic leukemia management using multitargeting bioactive natural compounds: A systematic and critical review. Pharmacol Res. 2022 Mar;177:106116.##Li Z, Chen B, Wang P, Li X, Cai G, Wei W, Dong W. A proteomic analysis of acute leukemia cells treated with 9-hydroxyoctadecadienoic acid. Lipids Health Dis. 2016 Nov 10;15(1):192.##Vangaveti V, Baune BT, Kennedy RL. Hydroxyoctadecadienoic acids: novel regulators of macrophage differentiation and atherogenesis. Ther Adv Endocrinol Metab. 2010 Apr;1(2):51-60.##Chu LH, Chen BS. Construction of a cancer-perturbed protein-protein interaction network for discovery of apoptosis drug targets. BMC Syst Biol. 2008 Jun 30;2:56##Arjmand B, Rezaei-Tavirani M, Hamzeloo-Moghadam M, Razzaghi Z, Khodadoost M, Okhovatian F, Zamanian-Azodi M, Ansari M. Hypofractionated radiation versus conventional fractionated radiation: A network analysis. J Lasers Med Sci. 2022 Sep 23;13:e39##Roy S. Systems biology beyond degree, hubs and scale-free networks: the case for multiple metrics in complex networks. Syst Synth Biol. 2012 Jun;6(1-2):31-4.##Zamanian Azodi M, Arjmand B, Zali A, Razzaghi M. Introducing APOA1 as a key protein in COVID-19 infection: a bioinformatics approach. Gastroenterol Hepatol Bed Bench. 2020 Fall;13(4):367-373.##Ansari M, Rezaei-Tavirani M, Hamzeloo-Moghadam M, Razzaghi M, Arjmand B, Zamanian Azodi M, Khodadoost M, Okhovatian F. Investigation into Chronic Low-Dose Ionizing Radiation Effect on Gene Expression Profile of Human HUVECs Cells. J Lasers Med Sci. 2022 Aug 27;13:e35.##Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, Amin N, Schwikowski B, Ideker T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003 Nov;13(11):2498-504.##Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, Simonovic M, Roth A, Santos A, Tsafou KP, Kuhn M, Bork P, Jensen LJ, von Mering C. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015 Jan;43(Database issue):D447-52.##Saito R, Smoot ME, Ono K, Ruscheinski J, Wang PL, Lotia S, Pico AR, Bader GD, Ideker T. A travel guide to Cytoscape plugins. Nat Methods. 2012 Nov;9(11):1069-76.##Bindea G, Mlecnik B, Hackl H, Charoentong P, Tosolini M, Kirilovsky A, Fridman WH, Pagès F, Trajanoski Z, Galon J. ClueGO: a Cytoscape plug-in to decipher functionally grouped gene ontology and pathway annotation networks. Bioinformatics. 2009 Apr 15;25(8):1091-3##Bindea G, Galon J, Mlecnik B. CluePedia Cytoscape plugin: pathway insights using integrated experimental and in silico data. Bioinformatics. 2013 Mar 1;29(5):661-3.##Arjmand B, Jahani Sherafat S, Rezaei Tavirani M, Ahmadzadeh A, Zamanian-Azodi M, Khodadoost M. Onion extract on cell gene expression profile: a system biology approach. Res J Pharmacogn. 2023;10(2):19-27.##Vafaee R, Zamanian Azodi M, Rezaei-Tavirani M, Razzaghi Z, Arjmand B, Esmaeili S. Cancer chemo-preventive effects of red propolis: a system biology approach. Res J Pharmacogn. 2023;10(1):23-9.##Guo C, Liu S, Wang J, Sun MZ, Greenaway FT. ACTB in cancer. Clin Chim Acta. 2013 Feb 18;417:39-44.##Zuehlke AD, Beebe K, Neckers L, Prince T. Regulation and function of the human HSP90AA1 gene. Gene. 2015 Oct 1;570(1):8-16.##Cabaud-Gibouin V, Durand M, Quéré R, Girodon F, Garrido C, Jego G. Heat-Shock Proteins in Leukemia and Lymphoma: Multitargets for Innovative Therapeutic Approaches. Cancers (Basel). 2023 Feb 3;15(3):984.##Wang H, Deng G, Ai M, Xu Z, Mou T, Yu J, Liu H, Wang S, Li G. Hsp90ab1 stabilizes LRP5 to promote epithelial-mesenchymal transition via activating of AKT and Wnt/β-catenin signaling pathways in gastric cancer progression. Oncogene. 2019 Feb;38(9):1489-1507.##Wang L, Zhao H, Zhang L, Luo H, Chen Q, Zuo X. HSP90AA1, ADRB2, TBL1XR1 and HSPB1 are chronic obstructive pulmonary disease-related genes that facilitate squamous cell lung cancer progression. Oncol Lett. 2020 Mar;19(3):2115-2122.##Tang Z, Yuan S, Hu Y, Zhang H, Wu W, Zeng Z, Yang J, Yun J, Xu R, Huang P. Over-expression of GAPDH in human colorectal carcinoma as a preferred target of 3-bromopyruvate propyl ester. J Bioenerg Biomembr. 2012 Feb;44(1):117-25.##Zhang JY, Zhang F, Hong CQ, Giuliano AE, Cui XJ, Zhou GJ, Zhang GJ, Cui YK. Critical protein GAPDH and its regulatory mechanisms in cancer cells. Cancer Biol Med. 2015 Mar;12(1):10-22.##Guo C, Liu S, Sun MZ. Novel insight into the role of GAPDH playing in tumor. Clin Transl Oncol. 2013 Mar;15(3):167-72.##Danova M, Giordano M, Mazzini G, Riccardi A. Expression of p53 protein during the cell cycle measured by flow cytometry in human leukemia. Leuk Res. 1990;14(5):417-22.##Klimovich B, Meyer L, Merle N, Neumann M, König AM, Ananikidis N, Keber CU, Elmshäuser S, Timofeev O, Stiewe T. Partial p53 reactivation is sufficient to induce cancer regression. J Exp Clin Cancer Res. 2022 Mar 2;41(1):80.##Li J, Ge Z. High HSPA8 expression predicts adverse outcomes of acute myeloid leukemia. BMC Cancer. 2021 Apr 29;21(1):475.##Ohanian M, Rozovski U, Kanagal-Shamanna R, Abruzzo LV, Loghavi S, Kadia T, Futreal A, Bhalla K, Zuo Z, Huh YO, Post SM, Ruvolo P, Garcia-Manero G, Andreeff M, Kornblau S, Borthakur G, Hu P, Medeiros LJ, Takahashi K, Hornbaker MJ, Zhang J, Nogueras-González GM, Huang X, Verstovsek S, Estrov Z, Pierce S, Ravandi F, Kantarjian HM, Bueso-Ramos CE, Cortes JE. MYC protein expression is an important prognostic factor in acute myeloid leukemia. Leuk Lymphoma. 2019 Jan;60(1):37-48.##Watts J, Nimer S. Recent advances in the understanding and treatment of acute myeloid leukemia. F1000Res. 2018 Aug 6;7:F1000 Faculty Rev-1196.##Manzella L, Tirrò E, Pennisi MS, Massimino M, Stella S, Romano C, Vitale SR, Vigneri P. Roles of Interferon Regulatory Factors in Chronic Myeloid Leukemia. Curr Cancer Drug Targets. 2016;16(7):594-605.## ##

The prevalence of Lupus Anticoagulant in Iranian children and adolescents; Current status and literature review of diagnosis 2 2 Background: Lupus anticoagulant (LAC) is an acquired IgG or IgM autoimmune antibody against platelet membrane phospholipids. LAC is an important cause of aPTT prolongation in children. We determined the prevalence of LA-positive results in ≤ 18 years patients referred to the Iranian Blood Transfusion Organization (IBTO) special reference coagulation laboratory. Method: During a period of 27 months all patients ≤ 18 years old who were referred to IBTO and had results of aPTT and LAC were evaluated. LAC test panel included screening tests (aPTT-LA and DRVVT screen) and the mixing test and confirmatory tests (Hexagonal assay and/or DRVVT confirm) all performed by STAGO reagents and instruments. In cases with positive LAC, their follow-up refers to IBTO coagulation lab were evaluated after 12 weeks. Results: Our data revealed a LAC prevalence of 2.4% in the referred patients ≤ 18 years who had aPTT test result and 31% in those whom the LAC test was performed for them. In more than half of the LA-positive patients, the main reason for referring was an incidental finding of aPTT prolongation noticed before surgery or during hospitalization. Interestingly only 21.6% of the patients with positive LAC results were requested by the physician. Conclusions: LAC is not infrequent in children and adolescents however in most cases it is a transient problem without any significant clinical findings. Most of the cases (78.4%) were not suspected of LAC by their physicians so it may be frequently missed in children clinically. 262 271 2023/06/212023/08/82023/06/232023/07/102023/06/302023/06/29 1402/4/8 2023/08/122023/08/172023/08/222023/08/202023/09/22023/09/18 1402/6/27 Minoo Ahmadinejad Minoo Ahmadinejad Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. minooam@gmail.com Sahar Balagholi Sahar Balagholi Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. saharbalagholi@gmail.com Maryam Mashkooli Maryam Mashkooli Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran. maryammashkooli99@gmail.com aPTT DRVVT screen Lupus anticoagulant (LA) Conley C. A hemorrhagic disorder caused by circulating anticoagulants in patients with disseminated lupus erythematosus. J Clin Invest. 1952;31:621-2.##Dhir V, Pinto B. Antiphospholipid syndrome: A review. Journal of Mahatma Gandhi Institute of Medical Sciences. 2014;19(1):19.##Miyakis S, Lockshin MD, Atsumi T, Branch DW, Brey RL, Cervera R, et al. International consensus statement on an update of the classification criteria for definite antiphospholipid syndrome (APS). Journal of Thrombosis and Haemostasis. 2006;4(2):295-306.##Dusse LMS, Freitas LG, Rios DRA, Armond SC, Marcolino MS. Antiphospholipid syndrome: a clinical and laboratory challenge. Revista da Associação Médica Brasileira. 2014;60(2):181-6.##Urbanus RT, Siegerink B, Roest M, Rosendaal FR, de Groot PG, Algra A. Antiphospholipid antibodies and risk of myocardial infarction and ischaemic stroke in young women in the RATIO study: a case-control study. The Lancet Neurology. 2009;8(11):998-1005.##Shi W, Kris S, Chong B, Gordon S, Chesterman C. Prevalence of lupus anticoagulant and anticardiolipin antibodies in a healthy population. Australian and New Zealand journal of medicine. 1990;20(3):231-6.##Male C, Lechner K, Eichinger S, Kyrle PA, Kapiotis S, Wank H, et al. Clinical significance of lupus anticoagulants in children. The Journal of Pediatrics. 1999;134(2):199-205.##Cabiedes J, Trejo-Hernández J, Loredo-Abdalá A, Castilla-Serna L, López-Mendoza AT, Cordero-Esperón HA, et al. Anti-Cardiolipin, Anti-Cardiolipin Plus Bovine, or Human β 2 Glycoprotein-I and Anti-Human β 2 Glycoprotein-I Antibodies in a Healthy Infant Population. Archives of medical research. 2002;33(2):175-9.##Burk CD, Cohen AR, Miller L, Handler SD. Preoperative history and coagulation screening in children undergoing tonsillectomy. Pediatrics. 1992;89(4):691-5.##Ciaudo M, Horellou M, De Carbonnieres C, Conard J, Samama M, Audouin J. Lupus anticoagulant associated with primary malignant lymphoplasmacytic lymphoma of the spleen: a report of four patients. American journal of hematology. 1991;38(4):271-6.##Ashley S, Kruger A, McMullen KW, Darke S. Prosthetic graft thrombosis associated with lupus anticoagulant. European journal of vascular surgery. 1988;2(1):57-60.##Dlott JS, Roubey RA. Drug-induced lupus anticoagulants and antiphospholipid antibodies. Current rheumatology reports. 2012;14(1):71-8.##Peker E, Kavakli K, Balkan C, Karapinar D, Aydemir B. Incidence and clinical importance of lupus anticoagulant in children with recurrent upper respiratory tract infection. Clinical and Applied Thrombosis/Hemostasis. 2009.##Mizumoto H, Maihara T, Hiejima E, Shiota M, Hata A, Seto S, et al. Transient antiphospholipid antibodies associated with acute infections in children: a report of three cases and a review of the literature. European journal of pediatrics. 2006;165(7):484-8.##Giordano P, Tesse R, Lassandro G, Fracchiolla D, Ranieri P, Lotito A, et al. Clinical and laboratory characteristics of children positive for antiphospholipid antibodies. Blood Transfusion. 2012;10(3):296.##Molta C, Meyer O, Dosquet C, de Oca MM, Babron M-C, Danon F, et al. Childhood-onset systemic lupus erythematosus: antiphospholipid antibodies in 37 patients and their first-degree relatives. Pediatrics. 1993;92(6):849-53.##Shapiro S, Thiagarajan P. Lupus anticoagulants. Progress in hemostasis and thrombosis. 1982;6:263.##JUDE B, GOUDEMAND J, DOLLE I, CARON C, WATEL A, TIRY C, et al. Lupus anticoagulant: a clinical and laboratory study of 100 cases. Clinical & Laboratory Haematology. 1988;10(1):41-51.##Kallanagowdar C, Chauhan A, Puertolas MV, Warrier R. Prevalence and Resolution of Lupus Anticoagulant in Children. The Ochsner Journal. 2016;16(2):172-5.##Malbora B, Bilaloglu E. Lupus anticoagulant positivity in pediatric patients with prolonged activated partial thromboplastin time: A single-center experience and review of the literature. Pediatric hematology and oncology. 2015;32(7):495-504.##Guideline CL. Laboratory testing for the lupus anticoagulant; Approved guideline. CLSI document H60‐A. 2014;2014.##Barbhaiya M, Zuily S, Naden R, Hendry A, Manneville F, Amigo MC, Amoura Z, Andrade D, Andreoli L, Artim-Esen B, Atsumi T. 2023 ACR/EULAR antiphospholipid syndrome classification criteria. Annals of the Rheumatic Diseases. 2023 Oct 1;82(10):1258-70.##Galli M, Luciani D, Bertolini G, Barbui T. Lupus anticoagulants are stronger risk factors for thrombosis than anticardiolipin antibodies in the antiphospholipid syndrome: a systematic review of the literature. Blood. 2003;101:1827-1832.##CURRIMBHOY Z. Transitory anticoagulants in healthy children. Journal of Pediatric Hematology/Oncology. 1984;6(2):210-1.##Male C, Lechner K, Eichinger S, Kyrle PA, Kapiotis S, Wank H, Kaider A, Pabinger I. Clinical significance of lupus anticoagulants in children. The Journal of Pediatrics. 1999 Feb 1;134(2):199-205.##Frauenknecht K, Lackner K, von Landenberg P. Antiphospholipid antibodies in pediatric patients with prolonged activated partial thromboplastin time during infection. Immunobiology. 2005 Dec 13;210(10):799-805.##Venugopalan P, Bushra R, Gravell D. Accidental detection of lupus anticoagulants in children. Ann Trop Paediatr. 2001;21:277-279##Ravelli A, Martini A, Burgio GR. Antiphospholipid antibodies in pediatrics. Eur J Pediatr. 1994;153:472-479.##Molta C, Meyer O, Dosquet C, et al. Childhood-onset systemic lupus erythematosus: antiphospholipid antibodies in 37 patients and their first-degree relatives. Pediatrics. 1993;92:849-853.##Seaman DE, Londino AV Jr, Kwoh CK, et al. Antiphospholipid antibodies in pediatric systemic lupus erythematosus. Pediatrics. 1995;96:1040-1045.##Gattorno M, Buoncompagni A, Molinari AC, et al. Antiphospholipid antibodies in paediatric systemic lupus erythematosus, juvenile chronic arthritis and overlap syndromes: SLE patients with both lupus anticoagulant and high-titre anticardiolipin antibodies are at risk for clinical manifestations related to the antiphospholipid syndrome. Br J Rheumatol. 1995;34:873-881.##Shergy WJ, Kredich DW, Pisetsky DS. The relationship of anticardiolipin antibodies to disease manifestations in pediatric systemic lupus erythematosus. J Rheumatol. 1988;15:1389-1394.##Ravelli A, Caporali R, Di Fuccia G, et al. Anticardiolipin antibodies in pediatric systemic lupus erythematosus. Arch Pediatr Adolesc Med. 1994;148:398-402.##Dlott JS, Rpubey RA. Drug-induced lupus anticoagulants and antiphospholipid antibodies. Curr Rheumatol Rep. 2012;14:71-78.##Brodeur GM, O'Neill PJ,Willimas JA. Acquired inhibitors of coagulation in nonhemophiliac children. J Pediatr. 1980;96:439-441##Orris DJ, Lewis JH, Spero JA, Hasiba U. Blocking coagulation inhibitors in children taking penicillin. J Pediatr. 1980;97:426-429.##Pazzola G, Zuily S, Erkan D. The challenge of bleeding in antiphospholipid antibody- positive patients. Curr Rhematol Rep. 2015;17:1-11.##Becton DL, Stine KC. Transient lupus anticoagulants associated with hemorrhage rather than thrombosis: the hemorrhagic lupus anticoagulant syndrome. J Pediatr. 1997;130:998-1000##Giordano P, Tesse R, Lassandro G, et al. Clinical and laboratory characteristics of children positive for antiphospholipid antibodies. Blood Transfus. 2012;10:296-301.##Burk CD,Miller L, Handler SD, Cohen AR. Preoperative history and coagulation screening in children undergoing tonsillectomy. Pediatrics. 1992;89:691-695.##Lee MT, Nardi MA, Hadzi-Nesic J, Karpatkin M. Transient hemorrhagic diathesis associated with and inhibitor of prothrombin with lupus anticoagulant in 1 1/2-year-old girl: report of a case and review of the literature. Am J Hematol. 1996;51:307-314.##https://doi.org/10.1002/(SICI)1096-8652(199604)51:43.0.CO;2-B##Brodeur GM, O'Neill PJ,Willimas JA. Acquired inhibitors of coagulation in nonhemophiliac children. J Pediatr. 1980;96:439-441##Bernini JC, Buchanan GR, Ashcraft J. Hypoprothrombinemia and severe hemorrhage associated with a lupus anticoagulant. J Pediatr. 1993;123:937-939.##Bernstein ML, Salusinsky-Sternbach M, Bellefleur M, Esseltine DW. Thrombotic and hemorrhagic complications in children with the lupus anticoagulant. Am J Dis Child. 1984;138:1132-1135##Schmugge M, Tolle S, Marbet GA, et al. Gingival bleeding, epistaxis and haematoma three days after gastroenteritis: the haemorrhagic lupus anticoagulant syndrome. Eur J Pediatr. 2001;160:43-46.##Vivaldi P, Rossetti G, Galli M, Finazzi G. Severe bleeding due to acquired hypoprothrombinemia-lupus anticoagulant syndrome. Case report and review of literature. Haematologica. 1997;82:345-347.##Humphries JE, Acker MN, Pinkston JE, Ruddy S. Transient lupus anticoagulant associated with prothrombin deficiency: unusual cause of bleeding in a 5-year-old girl. Am J Pediatr Hematol Oncol. 1994;16:372-376##Anderson A, Mohan U, Liesner R. Transient lupus anticoagulant: an unusual cause of bruising in children. Emergency Medicine Journal. 2003;20(5):e6-e.##Knobe K, Tedgård U, Ek T, Sandström P-E, Hillarp A. Lupus anticoagulants in two children-bleeding due to non phospholipid-dependent antiprothrombin antibodies. European journal of pediatrics. 2012;171(9):1383-7.##Bajaj S, Rapaport S, Fierer D, Herbst K, Schwartz D. A mechanism for the hypoprothrombinemia of the acquired hypoprothrombinemia-lupus anticoagulant syndrome. Blood. 1983;61(4):684-92.##https://doi.org/10.1182/blood.V61.4.684.bloodjournal614684##Mingers A, Sutor A. Lupus inhibitors in childhood. Haemostaseologie. 1992;12:101-6.##Manco-Johnson MJ, Nuss R, Key N, et al. Lupus anticoagulant and protein S deficiency in children with postvaricella purpura fulminans or thrombosis. J Pediatr. 1996;128:319-323.##Finazzi G, Brancaccio V, Moia M, et al. Natural history and risk factors for thrombosis in 360 patients with antiphospholipid antibodies: a four-year prospective study from the Italian Registry. Am J Med. 1996;100:530-536.##Galli M, Finazzi G, Norbis F, et al. The risk of thrombosis in patients with lupus anticoagulants is predicted by their specific coagulation profile. Thromb Haemost. 1999;81:695-700.##Talotta R, Robertson ES. Antiphospholipid antibodies and risk of post-COVID-19 vaccination thrombophilia: The straw that breaks the camel's back? Cytokine Growth Factor Rev. 2021;60:52-60.##Ansari K, Ghemtiri E, Hamidipour S, Saberianpour S. Thrombocytopenia and coronavirus: A prognosis and progression of the Coronavirus disease. Iranian Journal of Pediatric Hematology and Oncology. 2022 Apr 10;12(2):134-9.##Gupta D, Chatterjee T, Sharma A, Ganguli P, Das S, Sharma S. Rare case of acquired hemophilia and lupus anticoagulant. Indian J Hematol Blood Transfus. 2014 Sep;30(3):197-200. doi: 10.1007/s12288-012-0204-5. Epub 2012 Oct 9. PMID: 25114408; PMCID: PMC4115089.##Chen, V., Roby, L.C., Wentzel, S. et al. Acquired hemophilia A in the setting of dual anticoagulation therapy and lupus anticoagulant: a case report. J Med Case Reports 16, 177 (2022).##Seidizadeh O, Ahmadinejad M, Homayoun S, Mannucci PM, Peyvandi F. Von Willebrand disease combined with coagulation defects in Iran. Blood Transfus. 2021 Sep;19(5):428-434. doi: 10.2450/2021.0078-21. Epub 2021 May 28. PMID: 34059196; PMCID: PMC8486600## ##

Role of microorganisms in the developmental, prognostic, and therapeutics of gastric cancer 2 2 Gastric cancer (GC) is the most frequent destructive polyp allied to the GIT. It is reported as the foremost oncological complication with a prevalence ranks fifth and mortality ranks fourth worldwide with a survival rate of <25% in five years. In GC, men were observed as 2-3 times more susceptible to incidence and mortality than women. The GC patients experienced a burden of symptoms with multiple co-occurring symptoms including pain, weight loss, depression, fatigue, dysphagia, nausea, vomiting, etc. The risk factors of GC include infection of H. pylori, smoking, obesity, hereditary, high salt, radiation, and the frequent use of medications, etc. The role of genes, long-coding RNAs, metabolomics, machine learning, plant extracts, and nanoparticles has been studied for the progression, diagnosis, and treatment of GC. Due to the progressive stage diagnosis and lack of competent therapy, an imperative requirement is the identification of sensitive and accurate biomarkers towards the initial prognosis and the development of innovative therapeutic approaches. Microorganisms execute a momentous role in human health by contributing to immune system development and accomplishing an extensive range of metabolic functions. The disturbance in the stability of the microbes may stimulate various diseases including cancer. This review focuses on the role of microorganisms in the development, prognosis, and therapy of GC. 272 292 2023/06/212023/08/82023/06/232023/07/102023/06/302023/06/292023/07/6 1402/4/15 2023/08/122023/08/172023/08/222023/08/202023/09/22023/09/182023/09/18 1402/6/27 Sadaf Wajahat Sadaf Wajahat Department of Biosciences, Mohammad Ali Jinnah University, Karachi, Pakistan s.sadaf.wajahat@gmail.com Gastrointestinal tract Microorganisms Progression Diagnosis Treatment. Chen S, Wei Y, Liu H, Gong Y, Zhou Y, Yang H, Tang L. Analysis of Collagen type X alpha 1 (COL10A1) expression and prognostic significance in gastric cancer based on bioinformatics. Bioengineered. 2021;12(1):127-37.##Li H, Wang J, Wang W, Wang H, Lv JQ. Effect of miR-26a-5p on gastric cancer cell proliferation, migration, and invasion by targeting COL10A1. European Review for Medical and & Pharmacological Sciences. 2020; 24(3):1186-94.##Sun H, Wang Y, Wang S, Xie Y, Sun K, Li S, Cui W, Wang K. The involvement of collagen family genes in tumor enlargement of gastric cancer. Scientific Reports 2023; 13(1):100.##Zhuo W, Liu Y, Li S, Guo D, Sun Q, Jin J, Rao X, Li M, Sun M, Jiang M, Xu Y, Teng L, Jin Y, Si J, Liu W, Kang Y, Zhou T. Long Noncoding RNA GMAN, Up-regulated in Gastric Cancer Tissues, Is Associated With Metastasis in Patients and Promotes Translation of Ephrin A1 by Competitively Binding GMAN-AS. Gastroenterology. 2019; 156(3):676-91.##Liang M, Huang G, Liu Z, Wang Q, Yu Z, Liu Z, Lin H, Li M, Zhou X, Zheng Y. Elevated levels of hsa_circ_006100 in gastric cancer promote cell growth and metastasis via miR‐195/GPRC5A signalling. Cell Proliferation. 2019;52(5):12661.##Global Cancer Observatory: International Agency for Research on Cancer: World Health Organization, 2020. Cancer Fact Sheet. https://gco.iarc.fr/today/data/factsheets/cancers/7-Stomach-fact-sheet.pdf (accessed 8 January 2023).##Cheng XJ, Lin JC, Tu SP. Etiology and prevention of gastric cancer. Gastrointestinal tumours 2016;3(1):25-36.##Hwang M-A, Won M, Im J-Y, Kang M-J, Kweon D-H, Kim B-K. TNF− α Secreted from Macrophages Increases the Expression of Prometastatic Integrin αV in Gastric Cancer. International Journal of Molecular Sciences. 2023; 24(1):376.##Afzal A, Qayyum MA, Shah MH. Comparative assessment of trace elements in the blood of gastric cancer patients and healthy subjects. Biointerface Research in Applied Chemistry. 2020;11:10824-43.##Shabbir A, Qureshi MA, Khalid AB, Mirza T, Shaikh A, Hasan SM. Gastric adenocarcinoma expressing human epidermal growth factor receptor in South Asian population. Saudi Journal of Gastroenterology. 2018;24(5):289-93.##Yousaf A, Tasneem N, Mustafa A, Fatima R, Nabia N, Khan RA, Abdulbasit H, Abubakar M, Asadullah A, Rizwan R, Baqa-ur-Rehman B. Gastric cancer associated risk factors and prevalence in Pakistan. ASEAN Journal of Science and Engineering. 2021;1(2):73-8.##Zhang Z, Peng L, Yang W, Li B, Hua Y, Luo S. PHF5A facilitates the development and progression of gastric cancer through SKP2-mediated stabilization of FOS. Journal of Translational Medicine. 2023;21(1):1-4.##Pham QT, Taniyama D, Akabane S, Takashima T, Maruyama R, Sekino Y, Sentani K, Yasui W, Oue N. Essential Roles of TDO2 in Gastric Cancer: TDO2 Is Associated with Cancer Progression, Patient Survival, PD-L1 Expression, and Cancer Stem Cells. Pathology. 2023;90(1):44-55.##Ni T, Chu Z, Tao L, Zhao Y, Zhu M, Luo Y, Sunagawa M, Wang H, Liu Y. PTBP1 drives c-Myc-dependent gastric cancer progression and stemness. British Journal of Cancer. 2023;128(6):1005-18.##Li A, Guo Y, Yin Z, Liu X, Xie G. MTA2 is one of 14 Transcription factors predicting recurrence free survival in gastric cancer and promotes cancer progression by targeting MCM5. Journal of Cancer. 2023;14(2):262-74.##An L, Liu Y. ZNF460 mediates epithelial-mesenchymal transition to promote gastric cancer progression by transactivating APOC1 expression. Experimental Cell Research. 2023;422(2):113452.##Ding K, Zhang F, Qi G, Lin M, Chen M, Chen Y, Zheng J, Zhou F. ZFP36L1 Promotes gastric cancer progression via regulating JNK and p38 MAPK signaling pathways. Recent Patents on Anti-Cancer Drug Discovery. 2023;18(1):80-91.##Lin X, Li G, Yan X, Fu W, Ruan J, Ding H, Yu H, Chen X, Lan L, Dai Y, Pan K. Long non-coding RNA BC002811 Promotes Gastric Cancer Metastasis by Regulating SOX2 Binding to the PTEN Promoter. International Journal of Biological Sciences. 2023;19(3):967-80.##Wang S, Qiao C, Li J, Liu S, Li P. LncRNA CASC19 promotes gastric cancer progression through preventing CREB1 protein ubiquitin/proteasome-dependent degradation. Carcinogenesis. 2023;44(3): 209-20.##Dong C, Luan F, Tian W, Duan K, Chen T, Ren J, Li W, Li D, Zhi Q, Zhou J. Identification and validation of crucial lnc-TRIM28-14 and hub genes promoting gastric cancer peritoneal metastasis. BMC Cancer. 2023; 23(1):76.##Mochalski P, Leja M, Ślefarska-Wolak D, Mezmale L, Patsko V, Ager C, Królicka A, Mayhew CA, Shani G, Haick H. Identification of Key Volatile Organic Compounds Released by Gastric Tissues as Potential Non-Invasive Biomarkers for Gastric Cancer. Diagnostics. 2023;13(3):335.##Dong L, Duan X, Bin L, Wang J, Gao Q, Sun X, Xu Y. Evaluation of Fourier transform infrared (FTIR) spectroscopy with multivariate analysis as a novel diagnostic tool for lymph node metastasis in gastric cancer. Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy. 2023;289:122209.##Chu-xuan X, Fei J, Wei-tao S. Plasma markers for gastric cancer diagnosis: a metabolomics-and machine learning-based exploratory study. Chinese Journal of Public Health. 2023;39(2):1-6.##Muhammad JS, Manzoor S, Cui ZG, Khoder G. DNA Methylation-Mediated Overexpression of CXCL1 in Helicobacter pylori-Induced Gastric Cancer: In Silico-and In Vitro-Based Identification of a Potential Biomarker for Carcinogenesis. International Journal of Molecular Sciences. 2023;(1):795.##Zheng P, Liu J. Cost-Effectiveness Analysis of Hp and New Gastric Cancer Screening Scoring System for Screening and Prevention of Gastric Cancer. Current Oncology. 2023;30(1):1132-45.##Wang SS, Guo ZP, Zhao XY. [Diagnostic Value of Serum Pepsinogen Ⅰ/Pepsinogen Ⅱ Combined with Tumor Markers for Helicobacter pylori-Positive Early-Stage Gastric Cancer]. Sichuan da xue xue bao Yi xue ban = Journal of Sichuan University Medical science edition. 2023;54(1):186-91.##Chen X, Liang D, Sun W, Shou X, Shang L, Shen X. Suspended bubble microcapsule delivery systems from droplet microfluidic technology for the local treatment of gastric cancer. Chemical Engineering Journal. 2023;458:141428.##Ahn CR, Kim HI, Kim JE, Ha IJ, Ahn KS, Park J, Kim YW, Baek SH. Ponciri Fructus Immatarus Sensitizes the Apoptotic Effect of Hyperthermia Treatment in AGS Gastric Cancer Cells through ROS-Dependent HSP Suppression. Biomedicines. 2023;11(2):405.##Carrasco N, Garrido M, Montenegro I, Madrid A, Hartley R, González I, Rubilar M, Villena J, Valenzuela-Valderrama M. Antitumoral Activity of Leptocarpha rivularis Flower Extracts against Gastric Cancer Cells. International Journal of Molecular Sciences. 2023;24(2):1439.##Yu X, Peng W, Wang Y, Xu W, Chen W, Huang L, Xu H, He X, Wang S, Sun Q, Lu W. Palmitic Acid Inhibits the Growth and Metastasis of Gastric Cancer by Blocking the STAT3 Signaling Pathway. Cancers. 2023; 15(2):388.##Li CS, Nguyen TV, Chai OH, Park BH, Lee JS, Kim SM. 3,3′-Diindolylmethane Augments 5-Fluorouracil-InducedGrowth Suppression in Gastric Cancer Cells through Suppression of the Akt/GSK-3β and WNT/Beta-Catenin. Journal of Oncology. 2023;2023:8268955.##Poorshamohammad C, Liu L, Cheng X, Abbas Momtazi-Borojeni A, Chai J. Green synthesis of plant-stabilized Au nanoparticles for the treatment of gastric carcinoma. Arabian Journal of Chemistry. 2023;16(1):104386.##Xu H, Shen X, Li X, Yang X, Chen C, Luo D. The natural product dehydrocurvularin induces apoptosis of gastric cancer cells by activating PARP-1 and caspase-3. Apoptosis. 2023;18:1-4.##Zheng X, Song X, Shao Y, Xu B, Chen L, Zhou Q, Hu W, Zhang D, Wu C, Tao M, Zhu Y, Jiang J. Prognostic role of tumor-infiltrating lymphocytes in gastric cancer: a meta-analysis. Oncotarget. 2017;8(34):57386-98.##Zhang E, He X, Zhang C, Su J, Lu X, Si X, Chen J, Yin D, Han L, De W. A novel long noncoding RNA HOXC-AS3 mediates tumorigenesis of gastric cancer by binding to YBX1. Genome Biology. 2018;19(1):154.##Pereira-Marques J, Ferreira RM, Pinto-Ribeiro I, Figueiredo C. Helicobacter pylori infection, the gastric microbiome and gastric cancer. Advances in Microbiology, Infectious Diseases and Public Health Volume. 2019; 11:195-210.##Gambardella V, Castillo J, Tarazona N, Gimeno-Valiente F, Martínez-Ciarpaglini C, Cabeza-Segura M, Roselló S, Roda D, Huerta M, Cervantes A, Fleitas T. The role of tumor-associated macrophages in gastric cancer development and their potential as a therapeutic target. Cancer Treatment Reviews. 2020;86:102015.##Casamayor M, Morlock R, Maeda H, Ajani J.. Targeted literature review of the global burden of gastric cancer. Ecancermedicalscience. 2018;12:883.##Fitzmaurice C, Allen C, Barber RM, Barregard L, Bhutta ZA, Brenner H, Dicker DJ, Chimed-Orchir O, Dandona R, Dandona L, Fleming T, Forouzanfar MH, Hancock J, Hay RJ, Hunter-Merrill R, Huynh C, Hosgood HD, Johnson CO, Jonas JB, Khubchandani J, Kumar GA, Kutz M, Lan Q, Larson HJ, Liang X, Lim SS, Lopez AD, MacIntyre MF, Marczak L, Marquez N, Mokdad AH, Pinho C, Pourmalek F, Salomon JA, Sanabria JR, Sandar L, Sartorius B, Schwartz SM, Shackelford KA, Shibuya K, Stanaway J, Steiner C, Sun J, Takahashi K, Vollset SE, Vos T, Wagner JA, Wang H, Westerman R, Zeeb H, Zoeckler L, Abd-Allah F, Ahmed MB, Alabed S, Alam NK, Aldhahri SF, Alem G, Alemayohu MA, Ali R, Al-Raddadi R, Amare A, Amoako Y, Artaman A, Asayesh H, Atnafu N, Awasthi A, Saleem HB, Barac A, Bedi N, Bensenor I, Berhane A, Bernabé E, Betsu B, Binagwaho A, Boneya D, Campos-Nonato I, Castañeda-Orjuela C, Catalá-López F, Chiang P, Chibueze C, Chitheer A, Choi JY, Cowie B, Damtew S, das Neves J, Dey S, Dharmaratne S, Dhillon P, Ding E, Driscoll T, Ekwueme D, Endries AY, Farvid M, Farzadfar F, Fernandes J, Fischer F, TT GH, Gebru A, Gopalani S, Hailu A, Horino M, Horita N, Husseini A, Huybrechts I, Inoue M, Islami F, Jakovljevic M, James S, Javanbakht M, Jee SH, Kasaeian A, Kedir MS, Khader YS, Khang YH, Kim D, Leigh J, Linn S, Lunevicius R, El Razek HMA, Malekzadeh R, Malta DC, Marcenes W, Markos D, Melaku YA, Meles KG, Mendoza W, Mengiste DT, Meretoja TJ, Miller TR, Mohammad KA, Mohammadi A, Mohammed S, Moradi-Lakeh M, Nagel G, Nand D, Le Nguyen Q, Nolte S, Ogbo FA, Oladimeji KE, Oren E, Pa M, Park EK, Pereira DM, Plass D, Qorbani M, Radfar A, Rafay A, Rahman M, Rana SM, Søreide K, Satpathy M, Sawhney M, Sepanlou SG, Shaikh MA, She J, Shiue I, Shore HR, Shrime MG, So S, Soneji S, Stathopoulou V, Stroumpoulis K, Sufiyan MB, Sykes BL, Tabarés-Seisdedos R, Tadese F, Tedla BA, Tessema GA, Thakur JS, Tran BX, Ukwaja KN, Uzochukwu BSC, Vlassov VV, Weiderpass E, Wubshet Terefe M, Yebyo HG, Yimam HH, Yonemoto N, Younis MZ, Yu C, Zaidi Z, Zaki MES, Zenebe ZM, Murray CJL, Naghavi M. Global, Regional, and National Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life-years for 32 Cancer Groups, 1990 to 2015: A Systematic Analysis for the Global Burden of Disease Study. JAMA Oncology. 2017;3(4):524-48.##Machlowska J, Baj J, Sitarz M, Maciejewski R, Sitarz R. Gastric cancer: epidemiology, risk factors, classification, genomic characteristics and treatment strategies. International Journal of Molecular Sciences. 2020;21(11):4012.##Ilic M, Ilic I. Epidemiology of stomach cancer. World Journal of Gastroenterology. 2022;28(12):1187-203.##Pernot S, Terme M, Radosevic-Robin N, Castan F, Badoual C, Marcheteau E, Penault-Llorca F, Bouche O, Bennouna J, Francois E, Ghiringhelli F, De La Fouchardiere C, Samalin E, Baptiste Bachet J, Borg C, Boige V, Voron T, Stanbury T, Tartour E, Gourgou S, Malka D, Taieb J. Infiltrating and peripheral immune cell analysis in advanced gastric cancer according to the Lauren classification and its prognostic significance. Gastric Cancer. 2020;23(1):73-81.##Wang Q, Liu G, Hu C. Molecular classification of gastric adenocarcinoma. Gastroenterology Research. 2019; 12(6):275-82.##Tang CT, Zeng L, Yang J, Zeng C, Chen Y. Analysis of the Incidence and Survival of Gastric Cancer Based on the Lauren Classification: A Large Population-Based Study Using SEER. Frontiers in Oncology. 2020;10:1212.##Wang XX, Ding Y, Wang SW, Dong D, Li HL, Chen J, Hu H, Lu C, Tian J, Shan XH. Intratumoral and peritumoral radiomics analysis for preoperative Lauren classification in gastric cancer. Cancer Imaging. 2020; 20(1):83.##https://doi.org/10.1186/s40644-020-00358-3##Usui G, Matsusaka K, Mano Y, Urabe M, Funata S, Fukayama M, Ushiku T, Kaneda A. DNA Methylation and Genetic Aberrations in Gastric Cancer. Digestion. 2021;102(1):25-32.##Oue N, Sentani K, Sakamoto N, Uraoka N, Yasui W.. Molecular carcinogenesis of gastric cancer: Lauren classification, mucin phenotype expression, and cancer stem cells. International Journal of Clinical Oncology 2019; 24(7):771-8.##Ramos MF, Pereira MA, Amorim LC, de Mello ES, Faraj SF, Ribeiro U, Hoff PM, Cecconello I, de Castria TB. Gastric cancer molecular classification and adjuvant therapy: Is there a different benefit according to the subtype? Journal of Surgical Oncology. 2020;121(5):804-13.##McLean MH, El-Omar EM. Genetics of gastric cancer. Nature Reviews Gastroenterology & Hepatology. 2014; 11(11):664-74.##Slavin TP, Weitzel JN, Neuhausen SL, Schrader KA, Oliveira C, Karam R. Genetics of gastric cancer: what do we know about the genetic risks? Translational Gastroenterology and Hepatology. 2019;4:55.##Shenoy S. CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management. Cancer Management and Research. 2019;11:10477-86.##Abdi E, Latifi‐Navid S, Zahri S, Yazdanbod A, Pourfarzi F. Risk factors predisposing to cardia gastric adenocarcinoma: Insights and new perspectives. Cancer Medicine. 2019;8(13):6114-26.##Ebrahimi V, Soleimanian A, Ebrahimi T, Azargun R, Yazdani P, Eyvazi S, Tarhriz V. Epigenetic modifications in gastric cancer: Focus on DNA methylation. Gene. 2020;742:144577.##Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric Cancer: Descriptive Epidemiology, Risk Factors, Screening, and Prevention. Cancer Epidemiology, Biomarkers & Prevention. 2014;23(5):700-13.##Arnold M, Park JY, Camargo MC, Lunet N, Forman D, Soerjomataram I. Is gastric cancer becoming a rare disease? A global assessment of predicted incidence trends to 2035. Gut. 2020;69(5):823-9.##Yan L, Chen Y, Chen F, Tao T, Hu Z, Wang J, You J, Wong BCY, Chen J, Ye W. Effect of Helicobacter pylori Eradication on Gastric Cancer Prevention: Updated Report From a Randomized Controlled Trial With 26.5 Years of Follow-up. Gastroenterology. 2022;163(1):154-62.##Choi IJ, Kim CG, Lee JY, Kim Y-I, Kook MC, Park B, Joo J. Family history of gastric cancer and Helicobacter pylori treatment. New England Journal of Medicine. 2020;382(5):427-36.##Butt J, Varga MG, Wang T, Tsugane S, Shimazu T, Zheng W, Abnet CC, Yoo KY, Park SK, Kim J. Jee SH. Smoking, Helicobacter pylori serology, and gastric cancer risk in prospective studies from China, Japan, and Korea. Cancer Prevention Research. 2019;12(10):667-74.##Canale M, Casadei-Gardini A, Ulivi P, Arechederra M, Berasain C, Lollini P-L, Fernández-Barrena MG, Avila MA. Epigenetic mechanisms in gastric cancer: Potential new therapeutic opportunities. International Journal of Molecular Sciences. 2020;21(15):5500.##Gullo I, Grillo F, Mastracci L, Vanoli A, Carneiro F, Saragoni L, Limarzi F, Ferro J, Parente P, Fassan M. Precancerous lesions of the stomach, gastric cancer and hereditary gastric cancer syndromes. Pathologica. 2020;112(3):166-85.##Poorolajal J, Moradi L, Mohammadi Y, Cheraghi Z, Gohari-Ensaf F. Risk factors for stomach cancer: a systematic review and meta-analysis. Epidemiology and Health. 2020;42:2020004.##Bai X, Ding SQ, Zhang XP, Han MH, Dai DQ. Exposure to Commonly Used Drugs and the Risk of Gastric Cancer: An Umbrella Review of Meta-Analyses. Cancers. 2023;15(2):372.##Collatuzzo G, Pelucchi C, Negri E, López‐Carrillo L, Tsugane S, Hidaka A, Shigueaki Hamada G, Hernández‐Ramírez RU, López‐Cervantes M, Malekzadeh R. Porfarzi F. Exploring the interactions between Helicobacter pylori (Hp) infection and other risk factors of gastric cancer: A pooled analysis in the Stomach cancer Pooling (StoP) Project. International Journal of Cancer. 2021;149(6):1228-38.##Miftahussurur M, Waskito LA, Syam AF, Nusi IA, Wibawa IDN, Rezkitha YAA, Siregar G, Yulizal O, Akil F, Uwan WB. Simanjuntak D. Analysis of risks of gastric cancer by gastric mucosa among Indonesian ethnic groups. PLoS ONE. 2019;14(5):e0216670.##Lam BQ, Srivastava R, Morvant J, Shankar S, Srivastava RK. Association of diabetes mellitus and alcohol abuse with cancer: Molecular mechanisms and clinical significance. Cancers. 2021;10(11):3077.##Wu B, Yang D, Yang S, Zhang G. Dietary salt intake and gastric cancer risk: a systematic review and meta-analysis. Frontiers in Nutrition. 2021;8:801228.##Murphy N, Jenab M, Gunter MJ. Adiposity and gastrointestinal cancers: epidemiology, mechanisms and future directions. Nature Reviews Gastroenterology & Hepatology. 2018;15(11):659-70.##Yin J, Wu X, Li S, Li C, Guo Z. Impact of environmental factors on gastric cancer: A review of the scientific evidence, human prevention and adaptation. Journal of Environmental Sciences. 2020;89:65-79.##Guo Y, Cao XS, Zhou MG, Yu B. Gastric microbiota in gastric cancer: Different roles of Helicobacter pylori and other microbes. Frontier in Cellular and Infection Microbiology. 2023;12:1975.##Shah D, Bentrem D. Environmental and genetic risk factors for gastric cancer. Journal of Surgical Oncology. 2022;125(7):1096-103.##Lin Y, Docherty SL, Porter LS, Bailey DE. Symptom experience and self-management for multiple co-occurring symptoms in patients with gastric cancer: A qualitative study. European Journal of Oncology Nursing. 2020;49:101860.##Yu J, Jung J, Park SR, Ryu MH, Park Jh, Kim JH, Yoon SM. Role of palliative radiotherapy in bleeding control in patients with unresectable advanced gastric cancer. BMC Cancer. 2021;21(1):413.##Majewski M, Mertowska P, Mertowski S, Smolak K, Grywalska E, Torres K. Microbiota and the Immune System; Actors in the Gastric Cancer Story. Cancers. 2022;14(15):3832.##Dalhammar K, Kristensson J, Falkenback D, Rasmussen BH, Malmström M. Symptoms, problems and quality of life in patients newly diagnosed with oesophageal and gastric cancer - a comparative study of treatment strategy. BMC Cancer. 2022;22(1):434.##Lin Y. Common and co-occurring symptoms experienced by patients with gastric cancer. Oncology Nursing Society. 2020;47(2):187-202.##Wang FH, Shen L, Li J, Zhou ZW, Liang H, Zhang XT, Tang L, Xin Y, Jin J, Zhang YJ, Yuan XL, Liu TS, Li GX, Wu Q, Xu HM, Ji JF, Li YF, Wang X, Yu S, Liu H, Guan WL, Xu RH. The Chinese Society of Clinical Oncology (CSCO): clinical guidelines for the diagnosis and treatment of gastric cancer. Cancer Communications. 2019;39(1):10.##Wang FH, Zhang XT, Li YF, Tang L, Qu XJ, Ying JE, Zhang J, Sun LY, Lin RB, Qiu H. Wang C. The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of gastric cancer, 2021. Cancer Communications. 2021;41(8):747-95.##Wu D, Zhang P, Ma J, Xu J, Yang L, Xu W, Que H, Chen M, Xu H. Serum biomarker panels for the diagnosis of gastric cancer. Cancer Medicine. 2019;8(4):1576-83.##Niu PH, Zhao LL, Wu HL, Zhao DB, Chen YT. Artificial intelligence in gastric cancer: Application and future perspectives. World Journal of Gastroenterology. 2020;26(36):5408-19.##Zhu Y, Wang QC, Xu MD, Zhang Z, Cheng J, Zhong YS, Zhang YQ, Chen WF, Yao LQ, Zhou PH, Li QL. Application of convolutional neural network in the diagnosis of the invasion depth of gastric cancer based on conventional endoscopy. Gastrointestinal Endoscopy. 2019;89(4):806-15.e1.##Ueyama H, Kato Y, Akazawa Y, Yatagai N, Komori H, Takeda T, Matsumoto K, Ueda K, Matsumoto K, Hojo M. Yao T. Application of artificial intelligence using a convolutional neural network for diagnosis of early gastric cancer based on magnifying endoscopy with narrow‐band imaging. Journal of Gastroenterology and Hepatology. 2021;36(2):482-9.##Horiuchi Y, Hirasawa T, Ishizuka N, Tokai Y, Namikawa K, Yoshimizu S, Ishiyama A, Yoshio T, Tsuchida T, Fujisaki J, Tada T. Performance of a computer-aided diagnosis system in diagnosing early gastric cancer using magnifying endoscopy videos with narrow-band imaging (with videos). Gastrointestinal Endoscopy. 2020;92(4):856-65.e1.##Cai J, Chen Z, Zuo X. circSMARCA5 Functions as a Diagnostic and Prognostic Biomarker for Gastric Cancer. Disease markers. 2019;2019:2473652.##https://doi.org/10.1155/2019/2473652##Ma Y, Xu H, Zhou Z, Tian Y, Du K, Zhang H, Jiang X, Lu J, Niu Y, Tu L, Liu H, Zhu H, Chen P, Liu Y. CFNC, a neocryptolepine derivative, inhibited the growth of gastric cancer AGS cells by inhibiting PI3K/AKT signaling pathway. European Journal of Pharmacology. 2023;938:175408.##Sexton RE, Al Hallak MN, Diab M, Azmi AS. Gastric cancer: a comprehensive review of current and future treatment strategies. Cancer and Metastasis Reviews. 2020;39(4):1179-203.##Jiang H, Shi Z, Wang P, Wang C, Yang L, Du G, Zhang H, Shi B, Jia J, Li Q, Wang H, Li Z. Claudin18.2-Specific Chimeric Antigen Receptor Engineered T Cells for the Treatment of Gastric Cancer. JNCI: Journal of the National Cancer Institute. 2018;111(4):409-18.##Gao Q, Cui L, Huang C, Chen Z, Wang X, Wen S, Zhao Y, Wang M, Shen B, Zhu W. Gastric cancer-derived mesenchymal stem cells promote gastric cancer cell lines migration by modulating CD276 expression. Experimental Cell Research. 2023;422(1):113414.##Zali H, Rezaei-Tavirani M, Azodi M. Gastric cancer: prevention, risk factors and treatment. Gastroenterology and Hepatology from Bed to Bench. 2011;4(4):175-85.##Park JY, von Karsa L, Herrero R. Prevention strategies for gastric cancer: a global perspective. Clinical Endoscopy. 2014;47(6):478-89.##Cheng XJ, Lin JC, Tu SP. Etiology and Prevention of Gastric Cancer. Gastrointestinal Tumors. 2016;3(1):25-36.##Sitarz R, Skierucha M, Mielko J, Offerhaus GJA, Maciejewski R, Polkowski WP. Gastric cancer: epidemiology, prevention, classification, and treatment. Cancer Management and Research. 2018;10:239.##Cuzzuol BR, Vieira ES, Araújo GRL, Apolonio JS, de Carvalho LS, da Silva Junior RT, de Brito BB, de Melo FF. Gastric cancer: a brief review, from risk factors to treatment. Archives of Gastroenterology Research. 2020;1(2):34-9.##Yan L, Chen Y, Chen F, Tao T, Hu Z, Wang J, You J, Wong BC, Chen J, Ye W. Effect of Helicobacter pylori eradication on gastric cancer prevention: updated report from a randomized controlled trial with 26.5 years of follow-up. Gastroenterology. 2022;163(1):154-62. 3.##Kim J, Oh A, Truong H, Laszkowska M, Camargo MC, Abrams J, Hur C. Low sodium diet for gastric cancer prevention in the United States: Results of a Markov model. Cancer Medicine. 2021;10(2):684-92.##Qu YM, Chen A, Zhao X, Wang Z, Guo D, Shao SL, Tao YY, Li QJ, Wang MY, Ma WS. Huntingtin-associated protein 1 is a potential tumor suppressor for gastric cancer. Molecular Biology Reports. 2023;50(2):1517-31.##Gunathilake MN, Lee J, Choi IJ, Kim Y-I, Ahn Y, Park C, Kim J. Association between the relative abundance of gastric microbiota and the risk of gastric cancer: a case-control study. Scientific Reports. 2019;9(1):1-11.##Ogunrinola GA, Oyewale JO, Oshamika OO, Olasehinde GI. The Human Microbiome and Its Impacts on Health. International Journal of Microbiology. 2020;2020:8045646.##Zhang S, Shi D, Li M, Li Y, Wang X, Li W. The relationship between gastric microbiota and gastric disease. Scandinavian Journal of Gastroenterology. 2019;54(4):391-6.##Conti L, Annibale B, Lahner E. Autoimmune Gastritis and Gastric Microbiota. Microorganisms. 2020;8(11):1827.##Koga Y. Microbiota in the stomach and application of probiotics to gastroduodenal diseases. World Journal of Gastroenterology. 2022;28(47):6702-15.##Wen J, Lau HCH, Peppelenbosch M, Yu J. Gastric Microbiota beyond H. pylori: An Emerging Critical Character in Gastric Carcinogenesis. Biomedicines. 2021;9(11):1680.##Stewart OA, Wu F, Chen Y. The role of gastric microbiota in gastric cancer. Gut Microbes. 2020;11(5):1220-30.##Whisner CM, Athena Aktipis C. The Role of the Microbiome in Cancer Initiation and Progression: How Microbes and Cancer Cells Utilize Excess Energy and Promote One Another's Growth. Current Nutrition Reports. 2019;8(1):42-51.##Meng C, Bai C, Brown TD, Hood LE, Tian Q. Human Gut Microbiota and Gastrointestinal Cancer. Genomics, Proteomics & Bioinformatics. 2018;16(1):33-49.##Liu X, Shao L, Liu X, Ji F, Mei Y, Cheng Y, Liu F, Yan C, Li L, Ling Z. Alterations of gastric mucosal microbiota across different stomach microhabitats in a cohort of 276 patients with gastric cancer. EBioMedicine. 2019;40:336-48.##Alipour M. Molecular Mechanism of Helicobacter pylori-Induced Gastric Cancer. Journal of Gastrointestinal Cancer. 2021;52(1):23-30.##Baj J, Korona-Głowniak I, Forma A, Maani A, Sitarz E, Rahnama-Hezavah M, Radzikowska E, Portincasa P. Mechanisms of the Epithelial-Mesenchymal Transition and Tumor Microenvironment in Helicobacter pylori-Induced Gastric Cancer. 2020;9(4):1055.##Dong Z, Chen B, Pan H, Wang D, Liu M, Yang Y, Zou M, Yang J, Xiao K, Zhao R, Zheng X, Zhang L, Zhang Y. Detection of Microbial 16S rRNA Gene in the Serum of Patients With Gastric Cancer. Frontiers in Oncology. 2019;9:608.##Yang L, Li A, Wang Y, Zhang Y. Intratumoral microbiota: roles in cancer initiation, development and therapeutic efficacy. Signal Transduction and Targeted Therapy. 2023;8(1):35.##Wang M, Yang G, Tian Y, Zhang Q, Liu Z, Xin Y. The role of the gut microbiota in gastric cancer: the immunoregulation and immunotherapy. Frontiers in Immunology. 2023;14:1183331.##Liu W, Zhang Q, Zhang Y, Sun L, Xiao H, Luo B. Epstein-Barr Virus Regulates Endothelin-1 Expression through the ERK/FOXO1 Pathway in EBV-Associated Gastric Cancer. Microbiology Spectrum. 2023;11(1):00898-22.##Xu S, Xiang C, Wu J, Teng Y, Wu Z, Wang R, Lu B, Zhan Z, Wu H, Zhang J. Tongue Coating Bacteria as a Potential Stable Biomarker for Gastric Cancer Independent of Lifestyle. Digestive Diseases and Sciences. 2021;66(9):2964-80.##Park JY, Kang CS, Seo HC, Shin JC, Kym SM, Park YS, Shin TS, Kim JG, Kim YK. Bacteria-Derived Extracellular Vesicles in Urine as a Novel Biomarker for Gastric Cancer: Integration of Liquid Biopsy and Metagenome Analysis. Cancers. 2021;13(18):4687.##Wu J, Zhang C, Xu S, Xiang C, Wang R, Yang D, Lu B, Shi L, Tong R, Teng Y, Dong W, Zhang J. Fecal Microbiome Alteration May Be a Potential Marker for Gastric Cancer. Disease Markers. 2020;2020:3461315.##Yu D, Yang J, Jin M, Zhou B, Shi L, Zhao L, Zhang J, Lin Z, Ren J, Liu L, Zhang T, Liu H. Fecal Streptococcus Alteration Is Associated with Gastric Cancer Occurrence and Liver Metastasis. MBio 2021;12(6):02994-21.##Zhang C, Hu A, Li J, Zhang F, Zhong P, Li Y, Li Y. Combined Non-Invasive Prediction and New Biomarkers of Oral and Fecal Microbiota in Patients With Gastric and Colorectal Cancer. Frontiers in Cellular and Infection Microbiology. 2022;12:830648.##Hu YL, Pang W, Huang Y, Zhang Y, Zhang CJ. The Gastric Microbiome Is Perturbed in Advanced Gastric Adenocarcinoma Identified Through Shotgun Metagenomics. Frontiers in Cellular and Infection Microbiology. 2018;8:433.##Chen WD, Zhang X, Zhang MJ, Zhang YP, Shang ZQ, Xin YW, Zhang Y. Salivary Fusobacterium nucleatum serves as a potential diagnostic biomarker for gastric cancer. World Journal of Gastroenterology. 2022;28(30):4120-32.##Song L, Song M, Camargo MC, Van Duine J, Williams S, Chung Y, Kim KM, Lissowska J, Sivins A, Gao W, Karthikeyan K, Park J, Leja M, Cohen JI, LaBaer J, Qiu J, Rabkin CS. Identification of anti-Epstein-Barr virus (EBV) antibody signature in EBV-associated gastric carcinoma. Gastric Cancer. 2021;24(4):858-67.##Rommasi F. Bacterial-Based Methods for Cancer Treatment: What We Know and Where We Are. Oncology and Therapy. 2022;10(1):23-54.##Yang J, Zhou X, Liu X, Ling Z, Ji F. Role of the Gastric Microbiome in Gastric Cancer: From Carcinogenesis to Treatment. Frontiers in Microbiology. 2021;12:641322.##Song S, Vuai MS, Zhong M. The role of bacteria in cancer therapy - enemies in the past, but allies at present. Infectious Agents and Cancer. 2018;13(1):9.##Baindara P, Mandal SM. Bacteria and bacterial anticancer agents as a promising alternative for cancer therapeutics. Biochimie. 2020;177:164-89.##Duan X, Chen P, Xu X, Han M, Li J. Role of Gastric Microorganisms Other than Helicobacter pylori in the Development and Treatment of Gastric Diseases. BioMed Research International. 2022;2022:6263423.##Yarmohammadi M, Yadegar A, Ebrahimi MT, Zali MR. Effects of a Potential Probiotic Strain Lactobacillus gasseri ATCC 33323 on Helicobacter pylori-Induced Inflammatory Response and Gene Expression in Coinfected Gastric Epithelial Cells. Probiotics and Antimicrobial Proteins. 2021;13(3):751-64.##Takeda S, Igoshi K, Tsend-Ayush C, Oyunsuren T, Sakata R, Koga Y, Arima Y, Takeshita M. Lactobacillus paracasei strain 06TCa19 suppresses inflammatory chemokine induced by Helicobacter pylori in human gastric epithelial cells. Human Cell. 2017;30(4):258-66.##Shen S, Ren F, Qin H, Bukhari I, Yang J, Gao D, Ouwehand AC, Lehtinen MJ, Zheng P, Mi Y. Lactobacillus acidophilus NCFM and Lactiplantibacillus plantarum Lp-115 inhibit Helicobacter pylori colonization and gastric inflammation in a murine model. Frontiers in Cellular and Infection Microbiology. 2023;13:196084.##Rasouli BS, Ghadimi-Darsajini A, Nekouian R, Iragian GR. In vitro activity of probiotic Lactobacillus reuteri against gastric cancer progression by downregulation of urokinase plasminogen activator/urokinase plasminogen activator receptor gene expression. Journal of Cancer Research and Therapeutics. 2017;13(2):246-51.##Pakbin B, Pishkhan Dibazar S, Allahyari S, Javadi M, Farasat A, Darzi S. Probiotic Saccharomyces cerevisiae var. boulardii supernatant inhibits survivin gene expression and induces apoptosis in human gastric cancer cells. Food Science & Nutrition. 2021;9(2):692-700.##Maleki-Kakelar H, Dehghani J, Barzegari A, Barar J, Shirmohamadi M, Sadeghi J, Omidi Y. Lactobacillus plantarum induces apoptosis in gastric cancer cells via modulation of signaling pathways in Helicobacter pylori. BioImpacts: BI. 2020;10(2):65-72.##Pan ST, Li ZL, He ZX, Qiu JX, Zhou SF. Molecular mechanisms for tumour resistance to chemotherapy. Clinical and Experimental Pharmacology and Physiology. 2016;43(8):723-37.##Amjad MT, Chidharla A, Kasi A. Cancer Chemotherapy. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2022, PMID: 33232037.##Tegels JJ, De Maat MF, Hulsewé KW, Hoofwijk AG, Stoot JH. Improving the outcomes in gastric cancer surgery. World Journal of Gastroenterology. 2014;20(38):13692-704.##Majeed H, Gupta V. Adverse Effects Of Radiation Therapy. In: StatPearls. StatPearls Publishing, Treasure Island (FL); 2022, PMID: 33085406.##Ding B, Lou W, Xu L, Li R, Fan W. Analysis the prognostic values of solute carrier (SLC) family 39 genes in gastric cancer. American Journal of Translational Research. 2019;11(1):486-98.##Li Y, Zheng D, Wang F, Xu Y, Yu H, Zhang H. Expression of Demethylase Genes, FTO and ALKBH1, Is Associated with Prognosis of Gastric Cancer. Digestive Diseases and Sciences. 2019;64(6):1503-13.##Hao S, Lv J, Yang Q, Wang A, Li Z, Guo Y, Zhang G. Identification of Key Genes and Circular RNAs in Human Gastric Cancer. Medical Science Monitor: International Medical Journal of Experimental and Clinical Research. 2019;25:2488-504.##Basati G, Mohammadpour H, Emami Razavi A. Association of High Expression Levels of SOX2, NANOG, and OCT4 in Gastric Cancer Tumor Tissues with Progression and Poor Prognosis. Journal of Gastrointestinal Cancer. 2020;51(1):41-7.##Cai H, Jing C, Chang X, Ding D, Han T, Yang J, Lu Z, Hu X, Liu Z, Wang J, Shang L, Wu S, Meng P, Lin L, Zhao J, Nie M, Yin K. Mutational landscape of gastric cancer and clinical application of genomic profiling based on target next-generation sequencing. Journal of Translational Medicine. 2019;17(1):189.##Chong X, Peng R, Sun Y, Zhang L, Zhang Z. Identification of key genes in gastric cancer by bioinformatics analysis. BioMed Research International. 2020;2020:7658230.##Liu M, Yao B, Gui T, Guo C, Wu X, Li J, Ma L, Deng Y, Xu P, Wang Y, Yang D, Li Q, Zeng X, Li X, Hu R, Ge J, Yu Z, Chen Y, Chen B, Ju J, Zhao Q. PRMT5-dependent transcriptional repression of c-Myc target genes promotes gastric cancer progression. Theranostics. 2020;10(10):4437-52.##Janjigian YY, Shitara K, Moehler MH, Garrido M, Gallardo C, Shen L, Yamaguchi K, Wyrwicz L, Skoczylas T, Bragagnoli ASC, Liu T, Tehfe M, Elimova E, Maya REB, Cleary JM, Karamouzis M, Soleymani S, Lei M, Amaya-Chanaga C, Ajani JA. Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 3-year follow-up from CheckMate 649. Journal of Clinical Oncology. 2023;41(16):4025-4025.##Chung HC, Bang Y-J, S Fuchs C, Qin S-K, Satoh T, Shitara K, Tabernero J, Van Cutsem E, Alsina M, Cao ZA, Lu J. First-line pembrolizumab/placebo plus trastuzumab and chemotherapy in HER2-positive advanced gastric cancer: KEYNOTE-811. Future Oncology. 2021;17(5):491-501.##Chen W, Shi K, Liu J, Yang P, Han R, Pan M, Yuan L, Fang C, Yu Y, Qian Z. Sustained co-delivery of 5-fluorouracil and cis-platinum via biodegradable thermo-sensitive hydrogel for intraoperative synergistic combination chemotherapy of gastric cancer. Bioactive Materials. 2023;23:1-15.##https://doi.org/10.1016/j.bioactmat.2022.10.004##Lee Ck, Rha SY, Kim HS, Jung M, Kang B, Che J, Kwon WS, Park S, Bae WK, Koo DH, Shin SJ, Kim H, Jeung HC, Zang DY, Lee SK, Nam CM, Chung HC. A single arm phase Ib/II trial of first-line pembrolizumab, trastuzumab and chemotherapy for advanced HER2-positive gastric cancer. Nature Communications. 2022;13(1):6002.##He L, Chen H, Qi Q, Wu N, Wang Y, Chen M, Feng Q, Dong B, Jin R, Jiang L. Schisandrin B suppresses gastric cancer cell growth and enhances the efficacy of chemotherapy drug 5-FU in vitro and in vivo. European Journal of Pharmacology. 2022;920:174823.##Shitara K, Bang YJ, Iwasa S, Sugimoto N, Ryu M-H, Sakai D, Chung HC, Kawakami H, Yabusaki H, Lee J. Saito K. Trastuzumab deruxtecan in previously treated HER2-positive gastric cancer. New England Journal of Medicine. 2020;382(25):2419-30.##Muro K, Bang YJ, Shankaran V, Geva R, Catenacci DVT, Gupta S, Eder JP, Berger R, Gonzalez EJ, Ray A, Dolled-Filhart M, Emancipator K, Pathiraja K, Lunceford JK, Cheng JD, Koshiji M, Chung HC. Relationship between PD-L1 expression and clinical outcomes in patients (Pts) with advanced gastric cancer treated with the anti-PD-1 monoclonal antibody pembrolizumab (Pembro; MK-3475) in KEYNOTE-012. Journal of Clinical Oncology. 2015;33(3):3-3##Bang YJ, Kang YK, Catenacci DV, Muro K, Fuchs CS, Geva R, Hara H, Golan T, Garrido M, Jalal SI, Borg C, Doi T, Yoon HH, Savage MJ, Wang J, Dalal RP, Shah S, Wainberg ZA, Chung HC. Pembrolizumab alone or in combination with chemotherapy as first-line therapy for patients with advanced gastric or gastroesophageal junction adenocarcinoma: results from the phase II nonrandomized KEYNOTE-059 study. Gastric Cancer. 2019;22(4):828-37.##Deng L, Zhao L, Liu L, Huang H. Systemic investigation of inetetamab in combination with small molecules to treat HER2-overexpressing breast and gastric cancers. Open Life Sciences. 2023;18(1):20220535.##Mezynski MJ, Farrelly AM, Cremona M, Carr A, Morgan C, Workman J, Armstrong P, McAuley J, Madden S, Fay J, Sheehan KM, Kay EW, Holohan C, Elamin Y, Rafee S, Morris PG, Breathnach O, Grogan L, Hennessy BT, Toomey S. Targeting the PI3K and MAPK pathways to improve response to HER2-targeted therapies in HER2-positive gastric cancer. Journal of Translational Medicine. 2021;19(1):184.##Shin SH, Park SS, Ju EJ, Park J, Ko EJ, Hwang JJ, Suh YA, Jang SJ, Lee JS, Ko BK. Kim KT. Establishment of a patient-derived xenograft for development of personalized HER2-targeting therapy in gastric cancer. Anticancer Research. 2018;38(1):287-93.##Guo Y, Zhang Y, Gerhard M, Gao JJ, Mejias-Luque R, Zhang L, Vieth M, Ma JL, Bajbouj M, Suchanek S, Liu WD, Ulm K, Quante M, Li ZX, Zhou T, Schmid R, Classen M, Li WQ, You WC, Pan KF. Effect of Helicobacter pylori on gastrointestinal microbiota: a population-based study in Linqu, a high-risk area of gastric cancer. Gut. 2020;69(9):1598.##Chiang TH, Chang WJ, Chen SLS, Yen AMF, Fann JCY, Chiu SYH, Chen YR, Chuang SL, Shieh CF, Liu CY, Chiu HM, Chiang H, Shun CT, Lin MW, Wu MS, Lin JT, Chan CC, Graham DY, Chen HH, Lee YC. Mass eradication of Helicobacter pylori to reduce gastric cancer incidence and mortality: a long-term cohort study on Matsu Islands. Gut. 2021;70(2):243.##Huang W, Wen F, Ruan S, Gu P, Gu S, Song S, Zhou J, Li Y, Liu J, Shu P. Integrating HPLC-Q-TOF-MS/MS, network pharmacology and experimental validation to decipher the chemical substances and mechanism of modified Gui-shao-liu-jun-zi decoction against gastric cancer. Journal of Traditional and Complementary Medicine. 2023;13(3):245-262.##Daniyal M, Liu Y, Yang Y, Xiao F, Fan J, Yu H, Qiu Y, Liu B, Wang W, Yuhui Q. Anti‐gastric cancer activity and mechanism of natural compound "Heilaohulignan C" isolated from kadsura coccinea. 2021;35(7):3977-87.##Zhong L, Yang B, Zhang Z, Wang J, Wang X, Guo Y, Huang W, Wang Q, Cai G, Xia F, Zhou S, Ma S, Nie Y, Lei J, Li M, Liu P, Deng W, Liu Y, Han F, Wang J. Targeting autophagy peptidase ATG4B with a novel natural product inhibitor Azalomycin F4a for advanced gastric cancer. Cell Death & Disease. 2022;13(2):161.##Wang H, Luo Y, Hu Y, Feng X, Feng J, Chu Z, Ou S, Dai X, Wang X, Liu Y. Triptonoterpene, a Natural Product from Celastrus orbiculatus Thunb, Has Biological Activity against the Metastasis of Gastric Cancer Cells. Molecules. 2022;27(22):8005.##Peng X, Shi J, Zhao Z, Tong R, Zhang X, Zhong L. Emetine, a small molecule natural product, displays potent anti-gastric cancer activity via regulation of multiple signaling pathways. Cancer Chemotherapy and Pharmacology. 2023;91(4):303-15.##Dai D, Yang Y, Yu J, Dang T, Qin W, Teng L, Ye J, Jiang H. Interactions between gastric microbiota and metabolites in gastric cancer. Cell Death & Disease. 2021;12(12):1104.##Hsieh YY, Tung SY, Pan HY, Yen CW, Xu HW, Lin YJ, Deng YF, Hsu WT, Wu CS, Li C. Increased abundance of Clostridium and Fusobacterium in gastric microbiota of patients with gastric cancer in Taiwan. Scientific Reports. 2018;8(1):1-11.##Li TH, Qin Y, Sham PC, Lau KS, Chu KM, Leung WK. Alterations in Gastric Microbiota After H. Pylori Eradication and in Different Histological Stages of Gastric Carcinogenesis. Scientific Reports. 2017;7(1):44935.##Chen XH, Wang A, Chu AN, Gong YH, Yuan Y. Mucosa-Associated Microbiota in Gastric Cancer Tissues Compared With Non-cancer Tissues.Frontiers in Microbiology. 2019;10:1261.##Qi Yf, Sun Jn, Ren Lf, Cao Xl, Dong Jh, Tao K, Guan Xm, Cui Yn, Su W. Intestinal Microbiota Is Altered in Patients with Gastric Cancer from Shanxi Province, China. Digestive Diseases and Sciences. 2019;64(5):1193-203.##Hansen A, Johannesen TB, Spiegelhauer M, Kupcinskas J, Urba M, Skieceviciene J, Jonaitis L, Frandsen T, Kupcinskas L, Fuursted K. Andersen LP. Distinct composition and distribution of the gastric mycobiota observed between dyspeptic and gastric cancer patients evaluated from gastric biopsies. Microbial Health Dis. 2020;2:340.##Wang Z, Gao X, Zeng R, Wu Q, Sun H, Wu W, Zhang X, Sun G, Yan B, Wu L, Ren R, Guo M, Peng L, Yang Y. Changes of the Gastric Mucosal Microbiome Associated With Histological Stages of Gastric Carcinogenesis. Frontiers in Microbiology. 2020;11:997.## ##

Guideline for the diagnosis and treatment of diabetes mellitus in patients with transfusion-dependent thalassemia 2 2 Thalassemia major hemoglobinopathy requires regular blood transfusions, often leading to iron overload due to repeated transfusions and increased intestinal iron absorption. The association between thalassemia major and metabolic complications, including diabetes and metabolic syndrome, has been recognized due to iron overload, insulin secretion impairment, insulin resistance, hepatic dysfunction, and other endocrine complications. These hormonal imbalances can also influence glucose metabolism and contribute to the development of metabolic syndrome. It's essential for individuals with thalassemia major to undergo regular monitoring of their glucose metabolism, including periodic assessments of fasting blood glucose, oral glucose tolerance tests, and measurement of Fructosamine. Early detection and management of diabetes and metabolic syndrome in thalassemia major patients are crucial to minimize complications and optimize overall health. Medical management may involve a combination of regular blood transfusions, iron chelation therapy to reduce iron overload, lifestyle modifications such as a healthy diet and physical activity, and, if needed, pharmacological interventions for glycemic control. Close collaboration between hematologists and endocrinologists is often necessary to provide comprehensive care for individuals with thalassemia major and metabolic complications.  293 303 2023/06/212023/08/82023/06/232023/07/102023/06/302023/06/292023/07/62023/07/26 1402/5/4 2023/08/122023/08/172023/08/222023/08/202023/09/22023/09/182023/09/182023/09/21 1402/6/30 Mohammad E. Khamseh Mohammad E. Khamseh Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran. m.e.khamseh@gmail.com Mojtaba Malek Mojtaba Malek Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran. malekmoj@yahoo.com Nahid Hashemi-madani Nahid Hashemi-madani Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran. nahid.hashemimadani@gmail.com Fariba Ghassemi Fariba Ghassemi Pediatric Growth and Development Research Center, Iran University of medical sciences, Tehran-Iran fariba.ghasemi@yahoo.com Neda Rahimian Neda Rahimian Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran. rahimian.n@iums.ac.ir Amir Ziaee Amir Ziaee Pediatric Growth and Development Research Center, Iran University of medical sciences, Tehran-Iran aziaee1963@yahoo.com Mohammad Reza Foroughi-Gilvaee Mohammad Reza Foroughi-Gilvaee Pediatric Growth and Development Research Center, Iran University of medical sciences, Tehran-Iran emad.foroughi95@gmail.com Pooya Faranoush Pooya Faranoush Pediatric Growth and Development Research Center, Iran University of medical sciences, Tehran-Iran pooya1375@yahoo.com Negin Sadighnia Negin Sadighnia Pediatric Growth and Development Research Center, Iran University of medical sciences, Tehran-Iran negin_sadighnia@yahoo.com Ali Elahinia Ali Elahinia Pediatric Growth and Development Research Center, Iran University of medical sciences, Tehran-Iran elahinia.ali75@gmail.com Mohammad Reza Rezvany Mohammad Reza Rezvany Pediatric Growth and Development Research Center, Iran University of medical sciences, Tehran-Iran rezvani.mr@iums.ac.ir Vahid Saeedi Vahid Saeedi Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran. Mohammad Faranoush Mohammad Faranoush Pediatric Growth and Development Research Center, Iran University of medical sciences, Tehran-Iran faranoush47@gmail.com Thalassemia Blood transfusion Diabetes ## ##