<?xml version="1.0" encoding="UTF-8"?>
<!DOCTYPE root>
<article xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" xmlns:ali="http://www.niso.org/schemas/ali/1.0/" article-type="other" dtd-version="1.2" xml:lang="en"><front><journal-meta><journal-id journal-id-type="publisher-id">Russian Journal of Biotherapy</journal-id><journal-title-group><journal-title xml:lang="en">Russian Journal of Biotherapy</journal-title><trans-title-group xml:lang="ru"><trans-title>Российский биотерапевтический журнал</trans-title></trans-title-group></journal-title-group><issn publication-format="print">1726-9784</issn><issn publication-format="electronic">1726-9792</issn><publisher><publisher-name xml:lang="en">Publishing House ABV Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="publisher-id">1411</article-id><article-id pub-id-type="doi">10.17650/1726-9784-2023-22-4-10-16</article-id><article-categories><subj-group subj-group-type="toc-heading" xml:lang="en"><subject>REVIEWS</subject></subj-group><subj-group subj-group-type="toc-heading" xml:lang="ru"><subject>ОБЗОРЫ ЛИТЕРАТУРЫ</subject></subj-group><subj-group subj-group-type="article-type"><subject></subject></subj-group></article-categories><title-group><article-title xml:lang="en">Multiparametric immunohistochemical analysis in cancer diagnosis (literary review)</article-title><trans-title-group xml:lang="ru"><trans-title>Многопараметрический иммуногистохимический анализ в диагностике онкологических заболеваний (обзор литературы)</trans-title></trans-title-group></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-8391-040X</contrib-id><name-alternatives><name xml:lang="en"><surname>Nabiev</surname><given-names>I. R.</given-names></name><name xml:lang="ru"><surname>Набиев</surname><given-names>И. Р.</given-names></name></name-alternatives><address><country country="FR">France</country></address><bio xml:lang="en"><p>51 rue Cognacq Jay, 51100 Reims</p><p>bld. 2, 8 Trubetskaya St., 119146 Moscow</p></bio><bio xml:lang="ru"><p>51100 Реймс, ул. Когнак Жэ, 51</p><p>119992 Москва, ул. Трубецкая, 8, стр. 2;</p></bio><email>igor.nabiev@gmail.com</email><xref ref-type="aff" rid="aff1"/><xref ref-type="aff" rid="aff2"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-6688-8423</contrib-id><name-alternatives><name xml:lang="en"><surname>Baryshnikova</surname><given-names>M. A.</given-names></name><name xml:lang="ru"><surname>Барышникова</surname><given-names>М. А.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>24 Kashirskoe Shosse, 115522 Moscow</p></bio><bio xml:lang="ru"><p>115522 Москва, Каширское шоссе, 24</p></bio><xref ref-type="aff" rid="aff3"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0003-4755-5313</contrib-id><name-alternatives><name xml:lang="en"><surname>Sokolova</surname><given-names>Z. A.</given-names></name><name xml:lang="ru"><surname>Соколова</surname><given-names>З. А.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>24 Kashirskoe Shosse, 115522 Moscow</p></bio><bio xml:lang="ru"><p>115522 Москва, Каширское шоссе, 24</p></bio><xref ref-type="aff" rid="aff3"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0001-5321-3753</contrib-id><name-alternatives><name xml:lang="en"><surname>Sokolov</surname><given-names>P. M.</given-names></name><name xml:lang="ru"><surname>Соколов</surname><given-names>П. М.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>bld. 2, 8 Trubetskaya St., 119146 Moscow</p><p>5 Nobelya St., Skolkovo, 121205 Moscow</p></bio><bio xml:lang="ru"><p>119992 Москва, ул. Трубецкая, 8, стр. 2</p><p>121205 Москва, Сколково, ул. Нобеля, 5</p></bio><xref ref-type="aff" rid="aff4"/><xref ref-type="aff" rid="aff5"/></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid">https://orcid.org/0000-0002-1930-5424</contrib-id><name-alternatives><name xml:lang="en"><surname>Karaulov</surname><given-names>A. V.</given-names></name><name xml:lang="ru"><surname>Караулов</surname><given-names>А. В.</given-names></name></name-alternatives><address><country country="RU">Russian Federation</country></address><bio xml:lang="en"><p>bld. 2, 8 Trubetskaya St., 119146 Moscow</p></bio><bio xml:lang="ru"><p>119992 Москва, ул. Трубецкая, 8, стр. 2</p></bio><xref ref-type="aff" rid="aff4"/></contrib></contrib-group><aff-alternatives id="aff1"><aff><institution xml:lang="en">Université de Reims Champagne-Ardenne</institution></aff><aff><institution xml:lang="ru">Университет Реймса Шампань-Арденн</institution></aff></aff-alternatives><aff-alternatives id="aff2"><aff><institution xml:lang="en">Sechenov First Moscow State Medical University (Sechenov University)</institution></aff><aff><institution xml:lang="ru">ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова» Минздрава России&#13;
(Сеченовский Университет)</institution></aff></aff-alternatives><aff-alternatives id="aff3"><aff><institution xml:lang="en">N.N. Blokhin National Medical Research Center of Oncology, Ministry of Health of Russia</institution></aff><aff><institution xml:lang="ru">ФГБУ «Национальный медицинский исследовательский центр онкологии им. Н. Н. Блохина» Минздрава России</institution></aff></aff-alternatives><aff-alternatives id="aff4"><aff><institution xml:lang="en">Sechenov First Moscow State Medical University (Sechenov University)</institution></aff><aff><institution xml:lang="ru">ФГАОУ ВО «Первый Московский государственный медицинский университет им. И. М. Сеченова» Минздрава России (Сеченовский Университет)</institution></aff></aff-alternatives><aff-alternatives id="aff5"><aff><institution xml:lang="en">Life Improvement by Future Technologies (LIFT) Center</institution></aff><aff><institution xml:lang="ru">LIFT (Life Improvement by Future Technologies) Центр</institution></aff></aff-alternatives><pub-date date-type="pub" iso-8601-date="2023-11-23" publication-format="electronic"><day>23</day><month>11</month><year>2023</year></pub-date><volume>22</volume><issue>4</issue><issue-title xml:lang="en"/><issue-title xml:lang="ru"/><fpage>10</fpage><lpage>16</lpage><history><date date-type="received" iso-8601-date="2023-11-22"><day>22</day><month>11</month><year>2023</year></date><date date-type="accepted" iso-8601-date="2023-11-22"><day>22</day><month>11</month><year>2023</year></date></history><permissions><ali:free_to_read xmlns:ali="http://www.niso.org/schemas/ali/1.0/"/></permissions><self-uri xlink:href="https://bioterapevt.abvpress.ru/jour/article/view/1411">https://bioterapevt.abvpress.ru/jour/article/view/1411</self-uri><abstract xml:lang="en"><p><bold>Introduction.</bold> Multiparametric comparative analysis of clinical and molecular genetic biomarkers of malignant tumors has strong diagnostic and prognostic potentials and is a prerequisite for the development of personalized medicine. This approach makes it possible not only to simultaneously detect the expression of several tumor biomarkers, but also to obtain data on their spatial distribution in tissues examined, as well as to estimate the mutual location of tumor cells and tumor microenvironment expressing specific biomarkers. Thus, multiparametric immunohistochemical analysis (IHCA), which allows not only confirming the specific disease, but also carrying out 3D imaging of biopsy specimens and analyzing the spatial organization of tumor tissue, as well as the expression rates of biomarkers at the level of individual cells, opens wide prospects in the diagnosis and treatment of cancer.</p><p><bold>Aim.</bold> Systematizing data on the potential of multiparametric IHCA for cancer diagnosis and development of the personalized approach to cancer therapy.</p><p><bold>Results.</bold> Multiparametric IHCA allows estimating the heterogeneity of the tumor at the level of molecular subtypes, as well as the heterogeneity of the tumor microenvironment. These data make it possible to predict tumor development, determine its metastatic potential, and select an effective strategy for individual therapy.</p><p><bold>Conclusion.</bold> This review analyzes the use of multiparametric IHCA for the detection of malignant tumors and shows its high potential for the differentiation of tumors and the study of tumor microenvironment. This ensures effective selection of the therapeutic strategy and accurate assessment of the response to therapy.</p></abstract><trans-abstract xml:lang="ru"><p><bold>Введение.</bold> Многопараметрический сравнительный анализ клинических и молекулярно-генетических биомаркеров злокачественных новообразований обладает мощным диагностическим и прогностическим потенциалом и является необходимой предпосылкой для развития персонализированной медицины. Данный подход позволяет не только одновременно выявить экспрессию определенных биомаркеров опухоли, но и получить данные об их пространственном распределении в исследуемых тканях, а также оценить взаимное расположение клеток опухоли и ее микроокружения, экспрессирующих те или иные биомаркеры. Таким образом, многопараметрический иммуногистохимический анализ, позволяющий не только подтвердить наличие определенной нозологии, но и провести 3D-визуализацию биоптатов, изучить пространственную организацию опухолевой ткани и уровни экспрессии биомаркеров на уровне единичных клеток, может открыть широкие перспективы в диагностике и лечении онкологических заболеваний.</p><p><bold>Цель исследования</bold> – систематизировать данные о возможностях многопараметрического иммуногистохимического анализа для диагностики и развития персонализированного подхода к терапии онкологических заболеваний.</p><p><bold>Результаты.</bold> Многопараметрический иммуногистохимический анализ дает возможность оценивать гетерогенность опухолей на уровне молекулярных подтипов, а также гетерогенность опухолевого микроокружения, таким образом позволяет прогнозировать развитие опухоли, определить ее метастатический потенциал, а также выбрать эффективную стратегию для подбора индивидуальной терапии.</p><p><bold>Заключение.</bold> В настоящем обзоре проанализированы результаты использования многопараметрического иммуногистохимического анализа для детекции онкологических заболеваний, показан высокий потенциал этого метода для дифференциации онкологических нозологий и исследования микроокружения опухолей, что позволяет эффективно выбрать терапевтическую стратегию и оценить ответ опухоли на терапию.</p></trans-abstract><kwd-group xml:lang="en"><kwd>multiparametric detection</kwd><kwd>immunohistochemical analysis</kwd><kwd>immunofluorescence</kwd><kwd>cancer biomarkers</kwd><kwd>tumor microenvironment</kwd></kwd-group><kwd-group xml:lang="ru"><kwd>многопараметрическая детекция</kwd><kwd>иммуногистохимический анализ</kwd><kwd>иммунофлуоресценция</kwd><kwd>биомаркеры рака</kwd><kwd>микроокружение опухоли</kwd></kwd-group><funding-group><funding-statement xml:lang="en">This work was supported by the Ministry of Science and Higher Education of the Russian Federation through the grant № 075-15-2021-937.</funding-statement><funding-statement xml:lang="ru">Данная работа была поддержана грантом № 075-15-2021-937 Министерства науки и высшего образования Российской Федерации.</funding-statement></funding-group></article-meta></front><body></body><back><ref-list><ref id="B1"><label>1.</label><citation-alternatives><mixed-citation xml:lang="en">1. Füzéry A.K., Levin J., Chan M.M., Chan D.W. Translation of proteomic biomarkers into FDA approved cancer diagnostics: Issues and challenges. Clin Proteomics 2013;10(1):13. DOI: 10.1186/1559-0275-10-13</mixed-citation><mixed-citation xml:lang="ru">Füzéry A.K., Levin J., Chan M.M., Chan D.W. Translation of proteomic biomarkers into FDA approved cancer diagnostics: Issues and challenges. Clin Proteomics 2013;10(1):13. DOI: 10.1186/1559-0275-10-13</mixed-citation></citation-alternatives></ref><ref id="B2"><label>2.</label><citation-alternatives><mixed-citation xml:lang="en">2. Landegren U., Hammond M. Cancer diagnostics based on plasma protein biomarkers: Hard times but great expectations. Mol Oncol 2021;15(6):1715–26. DOI: 10.1002/1878-0261.12809</mixed-citation><mixed-citation xml:lang="ru">Landegren U., Hammond M. Cancer diagnostics based on plasma protein biomarkers: Hard times but great expectations. Mol Oncol 2021;15(6):1715–26. DOI: 10.1002/1878-0261.12809</mixed-citation></citation-alternatives></ref><ref id="B3"><label>3.</label><citation-alternatives><mixed-citation xml:lang="en">3. Poore G.D., Kopylova E., Zhu Q. et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 2020;579(7800):567–74. DOI: 10.1038/s41586-020-2095-1</mixed-citation><mixed-citation xml:lang="ru">Poore G.D., Kopylova E., Zhu Q. et al. Microbiome analyses of blood and tissues suggest cancer diagnostic approach. Nature 2020;579(7800):567–74. DOI: 10.1038/s41586-020-2095-1</mixed-citation></citation-alternatives></ref><ref id="B4"><label>4.</label><citation-alternatives><mixed-citation xml:lang="en">4. Álvez M.B., Edfors F., von Feilitzen K. et al. Next generation pancancer blood proteome profiling using proximity extension assay. Nat Commun 2023;14(1):4308. DOI: 10.1038/s41467-023-39765-y</mixed-citation><mixed-citation xml:lang="ru">Álvez M.B., Edfors F., von Feilitzen K. et al. Next generation pancancer blood proteome profiling using proximity extension assay. Nat Commun 2023;14(1):4308. DOI: 10.1038/s41467-023-39765-y</mixed-citation></citation-alternatives></ref><ref id="B5"><label>5.</label><citation-alternatives><mixed-citation xml:lang="en">5. Sheng W., Zhang C., Mohiuddin T.M. et al. Multiplex immunofluorescence: A powerful tool in cancer immunotherapy. Int J Mol Sci 2023;24(4):3086. DOI: 10.3390/ijms24043086</mixed-citation><mixed-citation xml:lang="ru">Sheng W., Zhang C., Mohiuddin T.M. et al. Multiplex immunofluorescence: A powerful tool in cancer immunotherapy. Int J Mol Sci 2023;24(4):3086. DOI: 10.3390/ijms24043086</mixed-citation></citation-alternatives></ref><ref id="B6"><label>6.</label><citation-alternatives><mixed-citation xml:lang="en">6. Cheung A.M., Wang D., Liu K. et al. Quantitative single-cell analysis of immunofluorescence protein multiplex images illustrates biomarker spatial heterogeneity within breast cancer subtypes. Breast Cancer Res 2021;23(1):114. DOI: 10.1186/s13058-021-01475-y</mixed-citation><mixed-citation xml:lang="ru">Cheung A.M., Wang D., Liu K. et al. Quantitative single-cell analysis of immunofluorescence protein multiplex images illustrates biomarker spatial heterogeneity within breast cancer subtypes. Breast Cancer Res 2021;23(1):114. DOI: 10.1186/s13058-021-01475-y</mixed-citation></citation-alternatives></ref><ref id="B7"><label>7.</label><citation-alternatives><mixed-citation xml:lang="en">7. Yagnik G., Liu Z., Rothschild K.J., Lim M.J. Highly multiplexed immunohistochemical MALDI-MS imaging of biomarkers in tissues. J Am Soc Mass Spectrom 2021;32(4):977–88. DOI: 10.1021/jasms.0c00473</mixed-citation><mixed-citation xml:lang="ru">Yagnik G., Liu Z., Rothschild K.J., Lim M.J. Highly multiplexed immunohistochemical MALDI-MS imaging of biomarkers in tissues. J Am Soc Mass Spectrom 2021;32(4):977–88. DOI: 10.1021/jasms.0c00473</mixed-citation></citation-alternatives></ref><ref id="B8"><label>8.</label><citation-alternatives><mixed-citation xml:lang="en">8. Abdullahi Sidi F., Bingham V., Craig S.G. et al. PD-L1 multiplex and quantitative image analysis for molecular diagnostics. Cancers (Basel) 2020;13(1):29. DOI: 10.3390/cancers13010029</mixed-citation><mixed-citation xml:lang="ru">Abdullahi Sidi F., Bingham V., Craig S.G. et al. PD-L1 multiplex and quantitative image analysis for molecular diagnostics. Cancers (Basel) 2020;13(1):29. DOI: 10.3390/cancers13010029</mixed-citation></citation-alternatives></ref><ref id="B9"><label>9.</label><citation-alternatives><mixed-citation xml:lang="en">9. Sanchez K., Kim I., Chun B. et al. Multiplex immunofluorescence to measure dynamic changes in tumorinfiltrating lymphocytes and PD-L1 in early-stage breast cancer. Breast Cancer Res 2021;23(1):2. DOI: 10.1186/s13058-020-01378-4</mixed-citation><mixed-citation xml:lang="ru">Sanchez K., Kim I., Chun B. et al. Multiplex immunofluorescence to measure dynamic changes in tumorinfiltrating lymphocytes and PD-L1 in early-stage breast cancer. Breast Cancer Res 2021;23(1):2. DOI: 10.1186/s13058-020-01378-4</mixed-citation></citation-alternatives></ref><ref id="B10"><label>10.</label><citation-alternatives><mixed-citation xml:lang="en">10. Mezheyeuski A., Micke P., Martín-Bernabé A. et al. The immune landscape of colorectal cancer. Cancers (Basel) 2021;13(21): 5545. DOI: 10.3390/cancers13215545</mixed-citation><mixed-citation xml:lang="ru">Mezheyeuski A., Micke P., Martín-Bernabé A. et al. The immune landscape of colorectal cancer. Cancers (Basel) 2021;13(21): 5545. DOI: 10.3390/cancers13215545</mixed-citation></citation-alternatives></ref><ref id="B11"><label>11.</label><citation-alternatives><mixed-citation xml:lang="en">11. Zhang W., Song Z.J., Zhang B.Y. et al. Multiplex immunohistochemistry indicates biomarkers in colorectal cancer. Neoplasma 2021;68(6):1272–82. DOI: 10.4149/neo_2021_210312N324</mixed-citation><mixed-citation xml:lang="ru">Zhang W., Song Z.J., Zhang B.Y. et al. Multiplex immunohistochemistry indicates biomarkers in colorectal cancer. Neoplasma 2021;68(6):1272–82. DOI: 10.4149/neo_2021_210312N324</mixed-citation></citation-alternatives></ref><ref id="B12"><label>12.</label><citation-alternatives><mixed-citation xml:lang="en">12. Tsujikawa T., Kumar S., Borkar R.N. et al. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep 2017;19(1):203–17. DOI: 10.1016/j.celrep.2017.03.037</mixed-citation><mixed-citation xml:lang="ru">Tsujikawa T., Kumar S., Borkar R.N. et al. Quantitative multiplex immunohistochemistry reveals myeloid-inflamed tumor-immune complexity associated with poor prognosis. Cell Rep 2017;19(1):203–17. DOI: 10.1016/j.celrep.2017.03.037</mixed-citation></citation-alternatives></ref><ref id="B13"><label>13.</label><citation-alternatives><mixed-citation xml:lang="en">13. Yagi Y., Aly R.G., Tabata K. et al. Three-dimensional histologic, immunohistochemical, and multiplex immunofluorescence analyses of dynamic vessel co-option of spread through air spaces in lung adenocarcinoma. J Thorac Oncol 2020;15(4):589–600. DOI: 10.1016/j.jtho.2019.12.112</mixed-citation><mixed-citation xml:lang="ru">Yagi Y., Aly R.G., Tabata K. et al. Three-dimensional histologic, immunohistochemical, and multiplex immunofluorescence analyses of dynamic vessel co-option of spread through air spaces in lung adenocarcinoma. J Thorac Oncol 2020;15(4):589–600. DOI: 10.1016/j.jtho.2019.12.112</mixed-citation></citation-alternatives></ref><ref id="B14"><label>14.</label><citation-alternatives><mixed-citation xml:lang="en">14. Eliyatkın N., Yalçın E., Zengel B. et al. Molecular classification of breast carcinoma: From traditional, old-fashioned way to a new age, and a new way. J Breast Health 2015;11(2):59–66. DOI: 10.5152/tjbh.2015.1669</mixed-citation><mixed-citation xml:lang="ru">Eliyatkın N., Yalçın E., Zengel B. et al. Molecular classification of breast carcinoma: From traditional, old-fashioned way to a new age, and a new way. J Breast Health 2015;11(2):59–66. DOI: 10.5152/tjbh.2015.1669</mixed-citation></citation-alternatives></ref><ref id="B15"><label>15.</label><citation-alternatives><mixed-citation xml:lang="en">15. Upadhaya S., Neftelinov S.T., Hodge J., Campbell J. Challenges and opportunities in the PD1/PDL1 inhibitor clinical trial landscape. Nat Rev Drug Discov 2022;21(7):482–3. DOI: 10.1038/d41573-022-00030-4</mixed-citation><mixed-citation xml:lang="ru">Upadhaya S., Neftelinov S.T., Hodge J., Campbell J. Challenges and opportunities in the PD1/PDL1 inhibitor clinical trial landscape. Nat Rev Drug Discov 2022;21(7):482–3. DOI: 10.1038/d41573-022-00030-4</mixed-citation></citation-alternatives></ref><ref id="B16"><label>16.</label><citation-alternatives><mixed-citation xml:lang="en">16. Lu S., Stein J.E., Rimm D.L. et al. Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade: A systematic review and meta-analysis. JAMA Oncol 2019;5(8):1195–204. DOI: 10.1001/jamaoncol.2019.1549</mixed-citation><mixed-citation xml:lang="ru">Lu S., Stein J.E., Rimm D.L. et al. Comparison of biomarker modalities for predicting response to PD-1/PD-L1 checkpoint blockade: A systematic review and meta-analysis. JAMA Oncol 2019;5(8):1195–204. DOI: 10.1001/jamaoncol.2019.1549</mixed-citation></citation-alternatives></ref><ref id="B17"><label>17.</label><citation-alternatives><mixed-citation xml:lang="en">17. Schmid P., Cortes J., Pusztai L. et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382(9):810–21. DOI: 10.1056/NEJMoa1910549</mixed-citation><mixed-citation xml:lang="ru">Schmid P., Cortes J., Pusztai L. et al. Pembrolizumab for early triple-negative breast cancer. N Engl J Med 2020;382(9):810–21. DOI: 10.1056/NEJMoa1910549</mixed-citation></citation-alternatives></ref><ref id="B18"><label>18.</label><citation-alternatives><mixed-citation xml:lang="en">18. Pagès F., Mlecnik B., Marliot F. et al. International validation of the consensus Immunoscore for the classification of colon cancer: A prognostic and accuracy study. Lancet 2018;391(10135):2128–39. DOI: 10.1016/S0140-6736(18)30789-X</mixed-citation><mixed-citation xml:lang="ru">Pagès F., Mlecnik B., Marliot F. et al. International validation of the consensus Immunoscore for the classification of colon cancer: A prognostic and accuracy study. Lancet 2018;391(10135):2128–39. DOI: 10.1016/S0140-6736(18)30789-X</mixed-citation></citation-alternatives></ref><ref id="B19"><label>19.</label><citation-alternatives><mixed-citation xml:lang="en">19. Ghahremani P., Li Y., Kaufman A. et al. Deep learning-inferred multiplex immunofluorescence for immunohistochemical image quantification. Nat Mach Intell 2022;4(4):401–12. DOI: 10.1038/s42256-022-00471-x</mixed-citation><mixed-citation xml:lang="ru">Ghahremani P., Li Y., Kaufman A. et al. Deep learning-inferred multiplex immunofluorescence for immunohistochemical image quantification. Nat Mach Intell 2022;4(4):401–12. DOI: 10.1038/s42256-022-00471-x</mixed-citation></citation-alternatives></ref></ref-list></back></article>
