{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T12:00:17Z","timestamp":1781092817501,"version":"3.54.1"},"reference-count":62,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,12,29]],"date-time":"2022-12-29T00:00:00Z","timestamp":1672272000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Medical Sciences"],"abstract":"<jats:p>Background: Knowledge about the occurrence of processes such as proliferation, apoptosis and angiogenesis in healthy lung tissues with different bronchial epitheliums is limited, and further exploration can contribute to a better understanding of the physiological renewal of lung tissues. The processes mentioned above occur with the help of important tissue factors; therefore, the aim of the study was to determine the expression of markers Ki-67, nestin, CD34 and vascular endothelial growth factor (VEFG) and detect apoptotic cells in relatively healthy lung tissue. Methods: Samples of relatively healthy lung tissue were obtained from 19 patients and divided into groups of patients with non-changed and patients with metaplastic bronchial epithelium. Tissue samples were examined by hematoxylin and eosin staining. Ki-67, nestin, VEGF and CD34-positive cells were detected by the immunohistochemistry method. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling (TUNEL) assay was carried out to detect apoptotic cells. The number of positive structures was counted semi-quantitatively by microscopy. Results: Ki-67-positive cells were detected in only one case. An occasional to moderate number of nestin-positive structures was found in various tissues of relatively healthy lungs with different bronchial epitheliums. No apoptotic cells were seen in non-changed bronchial epithelium, compared with few apoptotic cells in metaplastic bronchial epithelium. Metaplastic bronchial epithelium contained more VEGF-positive cells than non-changed bronchial epithelium. Samples with non-changed, and metaplastic bronchial epithelium both contained a similar number of CD34-positive structures. Conclusions: Proliferative activity and programmed cell death are not prominent events in normal lung tissue. A moderate number of nestin-positive cells in the alveolar epithelium and cartilage of bronchi with pseudostratified ciliated epithelium suggests a significant role of neuronal origin cells in these structures, to be intensified in metaplastic bronchial epithelium. A practically non-changed number of CD34-positive cells excludes any difference in stimulation of endothelial origin cells between lungs with different types of epithelium, while an increase in VEGF in structures with metaplastic epithelium suggests the presence\/influence of tissue ischemia impact on possible development\/maintenance of metaplasia.<\/jats:p>","DOI":"10.3390\/medsci11010007","type":"journal-article","created":{"date-parts":[[2022,12,30]],"date-time":"2022-12-30T03:31:17Z","timestamp":1672371077000},"page":"7","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Expression of Markers Ki-67, Nestin, VEGF, CD34 and Apoptosis in Relatively Healthy Lung Tissue with Non-Changed and Metaplastic Bronchial Epithelium"],"prefix":"10.3390","volume":"11","author":[{"given":"Kaiva Zile","family":"Zarina","sequence":"first","affiliation":[{"name":"Institute of Anatomy and Anthropology, Riga Stradins University, Kronvalda Boulevard 9, LV-1010 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9804-4666","authenticated-orcid":false,"given":"Mara","family":"Pilmane","sequence":"additional","affiliation":[{"name":"Institute of Anatomy and Anthropology, Riga Stradins University, Kronvalda Boulevard 9, LV-1010 Riga, Latvia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1038\/nm.3642","article-title":"Lung regeneration: Mechanisms, applications and emerging stem cell populations","volume":"20","author":"Kotton","year":"2014","journal-title":"Nat. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1016\/j.canlet.2011.04.002","article-title":"MicroRNA-519d targets MKi67 and suppresses cell growth in the hepatocellular carcinoma cell line QGY-7703","volume":"28","author":"Hou","year":"2011","journal-title":"Cancer Lett."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1007\/s10549-013-2560-8","article-title":"Ki-67 is a prognostic parameter in breast cancer patients: Results of a large population-based cohort of a cancer registry","volume":"139","author":"Inwald","year":"2013","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Sorbye, S.W., Kilvaer, T.K., Valkov, A., Donnem, T., Smeland, E., Al-Shibli, K., Bremnes, R.M., and Busund, L.T. (2012). Prognostic impact of Jab1, p16, p21, p62, Ki67 and Skp2 in soft tissue sarcomas. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0047068"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/2049-6958-7-29","article-title":"Prognostic value of p53 and Ki67 expression in fiberoptic bronchial biopsies of patients with non small cell lung cancer","volume":"7","author":"Ciancio","year":"2012","journal-title":"Multidiscip. Respir. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e13722","DOI":"10.7554\/eLife.13722","article-title":"The cell proliferation antigen Ki-67 organises heterochromatin","volume":"5","author":"Sobecki","year":"2016","journal-title":"eLife"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1546","DOI":"10.7150\/ijbs.33423","article-title":"The Structural Function of Nestin in Cell Body Softening is Correlated with Cancer Cell Metastasis","volume":"15","author":"Yamagishi","year":"2019","journal-title":"Int. J. Biol. Sci."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2162","DOI":"10.1002\/stem.541","article-title":"Nestin is required for the proper self-renewal of neural stem cells","volume":"28","author":"Park","year":"2010","journal-title":"Stem Cells"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"291","DOI":"10.4149\/neo_2010_04_291","article-title":"Nestin expression in human tumors and tumor cell lines","volume":"57","author":"Krupkova","year":"2010","journal-title":"Neoplasma"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"330","DOI":"10.1016\/j.devcel.2014.03.014","article-title":"Vasculature-associated cells expressing nestin in developing bones encompass early cells in the osteoblast and endothelial lineage","volume":"29","author":"Ono","year":"2014","journal-title":"Dev. Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1466","DOI":"10.1038\/cr.2014.149","article-title":"Characterization of Nestin-positive stem Leydig cells as a potential source for the treatment of testicular Leydig cell dysfunction","volume":"24","author":"Jiang","year":"2014","journal-title":"Cell Res."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.ydbio.2006.12.026","article-title":"Nestin-GFP reporter expression defines the quiescent state of skeletal muscle satellite cells","volume":"304","author":"Day","year":"2007","journal-title":"Dev. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1093\/cvr\/cvq105","article-title":"Vascular endothelial growth factors and vascular permeability","volume":"87","author":"Bates","year":"2010","journal-title":"Cardiovasc. Res."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1038\/nm0603-669","article-title":"The biology of VEGF and its receptors","volume":"9","author":"Ferrara","year":"2003","journal-title":"Nat. Med."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Barratt, S.L., Flower, V.A., Pauling, J.D., and Millar, A.B. (2018). VEGF (Vascular Endothelial Growth Factor) and Fibrotic Lung Disease. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19051269"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"479","DOI":"10.1164\/rccm.201603-0568OC","article-title":"Differential Expression of VEGF-Axxx Isoforms Is Critical for Development of Pulmonary Fibrosis","volume":"196","author":"Barratt","year":"2017","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1002\/stem.1661","article-title":"Concise review: Evidence for CD34 as a common marker for diverse progenitors","volume":"32","author":"Sidney","year":"2014","journal-title":"Stem Cells"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1159","DOI":"10.3109\/14653249.2012.729817","article-title":"Is CD34 truly a negative marker for mesenchymal stromal cells?","volume":"14","author":"Lin","year":"2012","journal-title":"Cytotherapy"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"3683","DOI":"10.1242\/jcs.037507","article-title":"Novel functions of the CD34 family","volume":"121","author":"Nielsen","year":"2008","journal-title":"J. Cell Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1080\/10739680902941737","article-title":"CD34 is a key regulator of hematopoietic stem cell trafficking to bone marrow and mast cell progenitor trafficking in the periphery","volume":"16","author":"Nielsen","year":"2009","journal-title":"Microcirculation"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Confalonieri, P., Volpe, M.C., Jacob, J., Maiocchi, S., Salton, F., Ruaro, B., Confalonieri, M., and Braga, L. (2022). Regeneration or Repair? The Role of Alveolar Epithelial Cells in the Pathogenesis of Idiopathic Pulmonary Fibrosis (IPF). Cells, 11.","DOI":"10.3390\/cells11132095"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.molimm.2022.12.002","article-title":"Synergism of TNF-\u03b1 and IFN-\u03b2 triggers human airway epithelial cells death by apoptosis and pyroptosis","volume":"153","author":"Sun","year":"2022","journal-title":"Mol. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/978-1-61779-860-3_5","article-title":"Detection of apoptosis by TUNEL assay","volume":"887","author":"Kyrylkova","year":"2012","journal-title":"Methods Mol. Biol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e110531","DOI":"10.5812\/aapm.110531","article-title":"Pulsed Radiofrequency Increases Nestin and Matrix Metalloproteinase-2 Expression in Porcine Lumbar Dorsal Root Ganglion","volume":"12","author":"Arons","year":"2022","journal-title":"Anesthesiol. Pain Med."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Pilmane, M., Sumerags, D., Jain, N., Jain, S., and Sumeraga, G. (2021). Singer\u2019s Nodules: Investigating the Etiopathogenetic Markers Progressing Their Pathogenesis and Clinical Manifestations. Biology, 10.","DOI":"10.3390\/biology10121268"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"584","DOI":"10.5603\/FM.a2021.0084","article-title":"Morphologic comparison of blood vessels used for coronary artery bypass graft surgery","volume":"81","author":"Garnizone","year":"2022","journal-title":"Folia Morphol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1369\/0022155420923272","article-title":"Induction of High Endothelial Venule-like Vessels in Oral and Cutaneous Lichen Planus: A Comparative Study","volume":"68","author":"Yoshida","year":"2020","journal-title":"J. Histochem. Cytochem. Off. J. Histochem. Soc."},{"key":"ref_28","first-page":"69","article-title":"Statistics corner: A guide to appropriate use of correlation coefficient in medical research","volume":"24","author":"Mukaka","year":"2012","journal-title":"Malawi Med. J."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1164\/rccm.200607-1062OC","article-title":"NHLBI Severe Asthma Research Program (SARP). Epithelial cell proliferation contributes to airway remodeling in severe asthma","volume":"176","author":"Cohen","year":"2007","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Rigden, H.M., Alias, A., Havelock, T., O\u2019Donnell, R., Djukanovic, R., Davies, D.E., and Wilson, S.J. (2016). Squamous Metaplasia Is Increased in the Bronchial Epithelium of Smokers with Chronic Obstructive Pulmonary Disease. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0156009"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1046\/j.1365-2222.2003.01686.x","article-title":"Proliferation and inflammation in bronchial epithelium after allergen in atopic asthmatics","volume":"33","author":"Ricciardolo","year":"2003","journal-title":"Clin. Exp. Allergy"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2425","DOI":"10.1158\/1055-9965.EPI-07-0220","article-title":"Bronchial epithelial Ki-67 index is related to histology, smoking, and gender, but not lung cancer or chronic obstructive pulmonary disease","volume":"16","author":"Miller","year":"2007","journal-title":"Cancer Epidemiol. Biomark. Prev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1136\/thx.2005.052191","article-title":"Surveillance for the detection of early lung cancer in patients with bronchial dysplasia","volume":"62","author":"Banerjee","year":"2007","journal-title":"Thorax"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1038\/modpathol.3800553","article-title":"Histological types and significance of bronchial epithelial dysplasia","volume":"19","author":"Wang","year":"2006","journal-title":"Mod. Pathol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1038\/nrc.2017.68","article-title":"Metaplasia: Tissue injury adaptation and a precursor to the dysplasia-cancer sequence","volume":"17","author":"Giroux","year":"2017","journal-title":"Nat. Rev. Cancer"},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"Pilmane, M., Sidhoma, E., Akota, I., and Kazoka, D. (2019). Characterization of Cytokines and Proliferation Marker Ki67 in Cleft Affected Lip Tissue. Medicina, 55.","DOI":"10.3390\/medicina55090518"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1016\/j.prp.2017.03.003","article-title":"J\u00fanior. Immunohistochemical expression of p16, Ki-67 and p53 in cervical lesions\u2014A systematic review","volume":"213","author":"Silva","year":"2017","journal-title":"Pathol. Res. Pract."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1111\/j.1365-2559.2005.02200.x","article-title":"Ki67 expression in different epithelial types in columnar lined oesophagus indicates varying levels of expanded and aberrant proliferative patterns","volume":"47","author":"Olvera","year":"2005","journal-title":"Histopathology"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"214","DOI":"10.1513\/pats.200504-031AC","article-title":"Apoptosis and epithelial injury in the lungs","volume":"2","author":"Martin","year":"2005","journal-title":"Proc. Am. Thorac. Soc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1949","DOI":"10.1016\/S0002-9440(10)63755-8","article-title":"Differential response of human lung epithelial cells to fas-induced apoptosis","volume":"164","author":"Nakamura","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1136\/ard.59.12.959","article-title":"Apoptosis in normal and osteoarthritic human articular cartilage","volume":"59","author":"Harmand","year":"2000","journal-title":"Ann. Rheum. Dis."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Jaramillo-Rangel, G., Ch\u00e1vez-Briones, M.D., Ancer-Arellano, A., and Ortega-Mart\u00ednez, M. (2021). Nestin-Expressing Cells in the Lung: The Bad and the Good Parts. Cells, 10.","DOI":"10.3390\/cells10123413"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"151","DOI":"10.4067\/S0717-95022014000100026","article-title":"Nestin-positive Stem Cells Participate in Chondrocyte Renewal in Healthy Adult Lung Cartilage","volume":"32","year":"2014","journal-title":"Int. J. Morphol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1002\/cbin.10031","article-title":"Evidence of chondrocyte turnover in lung cartilage, with the probable participation of nestin-positive cells","volume":"37","year":"2013","journal-title":"Cell Biol. Int."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2679","DOI":"10.1111\/jcmm.12653","article-title":"Detection of a novel stem cell probably involved in normal turnover of the lung airway epithelium","volume":"19","year":"2015","journal-title":"J. Cell Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2003721","DOI":"10.1183\/13993003.03721-2020","article-title":"Nestin promotes pulmonary fibrosis via facilitating recycling of TGF-\u03b2 receptor I","volume":"59","author":"Wang","year":"2022","journal-title":"Eur. Respir. J."},{"key":"ref_47","first-page":"9811905","article-title":"Hypoxia-Induced Nestin Regulates Viability and Metabolism of Lung Cancer by Targeting Transcriptional Factor Nrf2, STAT3, and SOX2","volume":"12","author":"Liu","year":"2022","journal-title":"Comput. Intell. Neurosci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1016\/j.yjmcc.2020.09.005","article-title":"Nestin represents a potential marker of pulmonary vascular remodeling in pulmonary arterial hypertension associated with congenital heart disease","volume":"149","author":"Zhou","year":"2020","journal-title":"J. Mol. Cell Cardiol."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Bhagwani, A.R., Hultman, S., Farkas, D., Moncayo, R., Dandamudi, K., Zadu, A.K., Cool, C.D., and Farkas, L. (2019). Endothelial cells are a source of Nestin expression in Pulmonary Arterial Hypertension. PloS ONE, 14.","DOI":"10.1371\/journal.pone.0213890"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1449","DOI":"10.1183\/09031936.02.00089802","article-title":"Vascular endothelial growth factor mRNA and protein expression in airway epithelial cell lines in vitro","volume":"20","author":"Koyama","year":"2002","journal-title":"Eur. Respir. J."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"L209-21","DOI":"10.1152\/ajplung.00185.2005","article-title":"Vascular endothelial growth factor in the lung","volume":"290","author":"Voelkel","year":"2006","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"621","DOI":"10.1136\/thx.2005.040204","article-title":"Vascular endothelial growth factor (VEGF) in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS): Paradox or paradigm?","volume":"61","author":"Medford","year":"2006","journal-title":"Thorax"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1002\/cphy.c170015","article-title":"Physiological Role of Vascular Endothelial Growth Factors as Homeostatic Regulators","volume":"8","author":"Bates","year":"2018","journal-title":"Compr. Physiol."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Peach, C.J., Mignone, V.W., Arruda, M.A., Alcobia, D.C., Hill, S.J., Kilpatrick, L.E., and Woolard, J. (2018). Molecular Pharmacology of VEGF-A Isoforms: Binding and Signalling at VEGFR2. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19041264"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"L768","DOI":"10.1152\/ajplung.00353.2009","article-title":"VEGF in the lung: A role for novel isoforms","volume":"298","author":"Varet","year":"2010","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"L371","DOI":"10.1152\/ajplung.2000.279.2.L371","article-title":"Expression and regulation of vascular endothelial growth factor in human pulmonary epithelial cells","volume":"279","author":"Boussat","year":"2000","journal-title":"Am. J. Physiol. Lung Cell Mol. Physiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"915","DOI":"10.1002\/iub.234","article-title":"Structure and function of VEGF receptors","volume":"61","author":"Stuttfeld","year":"2009","journal-title":"IUBMB Life"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1274","DOI":"10.1378\/chest.11-1710","article-title":"Cardiac asthma: Transforming growth factor-\u03b2 from the failing heart leads to squamous metaplasia in human airway cells and in the murine lung","volume":"142","author":"Tanabe","year":"2012","journal-title":"Chest"},{"key":"ref_59","first-page":"446","article-title":"Impairment of vascularization of the surface covering epithelium induces ischemia and promotes malignization: A new hypothesis of a possible mechanism of cancer pathogenesis","volume":"17","author":"Karseladze","year":"2015","journal-title":"Clin. Transl. Oncol. Off. Publ. Fed. Span. Oncol. Soc. Natl. Cancer Inst. Mex."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1369\/jhc.4A6514.2005","article-title":"Immunohistochemical expression of endothelial markers CD31, CD34, von Willebrand factor, and Fli-1 in normal human tissues","volume":"54","author":"Pusztaszeri","year":"2006","journal-title":"J. Histochem. Cytochem."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1159\/000065997","article-title":"Expression of CD34 in pulmonary endothelial cells in vivo","volume":"70","author":"Nesslinger","year":"2002","journal-title":"Pathobiology"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1165\/rcmb.2016-0386OC","article-title":"Loss of Vascular CD34 Results in Increased Sensitivity to Lung Injury","volume":"57","author":"Lo","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."}],"container-title":["Medical Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3271\/11\/1\/7\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:55:28Z","timestamp":1760147728000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3271\/11\/1\/7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,12,29]]},"references-count":62,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,3]]}},"alternative-id":["medsci11010007"],"URL":"https:\/\/doi.org\/10.3390\/medsci11010007","relation":{},"ISSN":["2076-3271"],"issn-type":[{"value":"2076-3271","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,12,29]]}}}