{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T23:05:45Z","timestamp":1792191945497,"version":"4.4.0"},"reference-count":41,"publisher":"Public Library of Science (PLoS)","issue":"3","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Horst-J\u00fcrgen-L\u00fchl-Stiftung","award":["19-12-2022"],"award-info":[{"award-number":["19-12-2022"]}]},{"DOI":"10.13039\/501100004543","name":"China Scholarship Council","doi-asserted-by":"publisher","award":["202108430037"],"award-info":[{"award-number":["202108430037"]}],"id":[{"id":"10.13039\/501100004543","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["HE 5825\/9-1"],"award-info":[{"award-number":["HE 5825\/9-1"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:sec id=\"sec001\">\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>Benign prostatic hyperplasia (BPH) includes epithelial, stromal and mixed hyperplasia, but their specific contributions to voiding symptoms and prostate volume (PV) are unknown. Here, we examined relationships of symptoms and PV with stromal and epithelial markers in patients undergoing laser enucleation for BPH.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec002\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Tissues were obtained from holmium or thulium laser enucleation of the prostate (n\u2009=\u2009146 patients). Expressions of the smooth muscle marker calponin-1 (CNN1) and the glandular-epithelial cell marker keratin-19 (KRT19) were assessed by RT-PCR and Western blot, and analyzed for correlation with international prostate symptom score (IPSS), maximum urinary flow rate (Q\n                      <jats:sub>max<\/jats:sub>\n                      ), and PV.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec003\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      The ratio of CNN1\/KRT19 mRNA correlated positively with Q\n                      <jats:sub>max<\/jats:sub>\n                      (r\u2009=\u20090.3809, p\u2009=\u20090.0263), and by trend negatively with IPSS (r\u2009=\u2009\u22120.2161, p\u2009=\u20090.0944). Accordingly, the IPSS increased with keratin protein expression (r\u2009=\u20090.4244, p\u2009=\u20090.0307), while the Q\n                      <jats:sub>max<\/jats:sub>\n                      tended to correlate negatively with keratin expression (r\u2009=\u2009\u22120.2058, p\u2009=\u20090.4999). PV correlated negatively with CNN1 mRNA expression (r\u2009=\u2009\u22120.205, p\u2009=\u20090.0405). The inverse correlation of CNN1 with PV persisted in patients without catheterization (r\u2009=\u2009\u22120.2568, p\u2009=\u20090.0457), but was lacking in catheterized patients after separated analyses.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec id=\"sec004\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      Voiding symptoms in patients undergoing laser enucleation for BPH aggravate with increasing keratin content. Symptoms in patients needing surgery for BPH depend rather on glandular-epithelial hyperplasia, but not on stromal hyperplasia, what might explain why these patients are refractory to treatment with \u03b1\n                      <jats:sub>1<\/jats:sub>\n                      -blockers.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1371\/journal.pone.0345306","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T17:23:22Z","timestamp":1774373002000},"page":"e0345306","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":1,"title":["Voiding symptoms aggravate with decreasing stromal\/epithelial ratio and increasing glandular-epithelial content in patients undergoing laser enucleation for benign prostatic hyperplasia, independently from prostate 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of prostate smooth muscle","volume":"21","author":"E Shapiro","year":"1992","journal-title":"Prostate"},{"issue":"5","key":"pone.0345306.ref017","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1016\/S0022-5347(17)37546-8","article-title":"The relative proportion of stromal and epithelial hyperplasia is related to the development of symptomatic benign prostate hyperplasia","volume":"147","author":"E Shapiro","year":"1992","journal-title":"J Urol"},{"key":"pone.0345306.ref018","first-page":"113","article-title":"Morphometry of benign prostatic hyperplasia during androgen suppressive therapy. Relationships among epithelial content, PSA density, and clinical outcome","volume":"179","author":"A Svindland","year":"1996","journal-title":"Scand J Urol Nephrol Suppl"},{"key":"pone.0345306.ref019","doi-asserted-by":"crossref","first-page":"1181","DOI":"10.2147\/IJGM.S395705","article-title":"The symptoms of benign prostatic hyperplasia patients with stromal-dominated hyperplasia nodules may be associated with prostate fibrosis","volume":"16","author":"Y Cao","year":"2023","journal-title":"Int J Gen Med"},{"issue":"4","key":"pone.0345306.ref020","doi-asserted-by":"crossref","first-page":"486","DOI":"10.1016\/S0090-4295(94)80044-8","article-title":"Morphometry of the prostate: I. Distribution of tissue components in hyperplastic glands","volume":"44","author":"LS Marks","year":"1994","journal-title":"Urology"},{"issue":"3","key":"pone.0345306.ref021","doi-asserted-by":"crossref","first-page":"984","DOI":"10.4103\/jfmpc.jfmpc_1339_23","article-title":"A hospital-based study of prostate biopsy results in Indian males","volume":"13","author":"M Khalid","year":"2024","journal-title":"J Family Med Prim Care"},{"issue":"4","key":"pone.0345306.ref022","doi-asserted-by":"crossref","first-page":"159","DOI":"10.1111\/pin.13312","article-title":"Does benign prostate hyperplasia histopathological variation impact disease-specific clinical outcomes after transurethral resection?","volume":"73","author":"B Berk","year":"2023","journal-title":"Pathol Int"},{"issue":"2","key":"pone.0345306.ref023","first-page":"104","article-title":"Salient and co-morbid features in benign prostatic hyperplasia: a histopathological study of the prostate","volume":"1","author":"G Shakya","year":"2003","journal-title":"Kathmandu Univ Med J (KUMJ)"},{"issue":"1","key":"pone.0345306.ref024","doi-asserted-by":"crossref","first-page":"22","DOI":"10.5144\/0256-4947.1998.22","article-title":"Benign disorders of the prostate: A histopathological study","volume":"18","author":"JT Anim","year":"1998","journal-title":"Ann Saudi Med"},{"issue":"7","key":"pone.0345306.ref025","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1038\/s41419-018-0744-1","article-title":"M2 macrophage-mediated interleukin-4 signalling induces myofibroblast phenotype during the progression of benign prostatic hyperplasia","volume":"9","author":"J Sheng","year":"2018","journal-title":"Cell Death Dis"},{"issue":"4","key":"pone.0345306.ref026","doi-asserted-by":"crossref","first-page":"650","DOI":"10.1016\/S0090-4295(96)00329-9","article-title":"Histopathologic characterization of hereditary benign prostatic hyperplasia","volume":"48","author":"CB Doehring","year":"1996","journal-title":"Urology"},{"issue":"3","key":"pone.0345306.ref027","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1002\/(SICI)1097-0045(19971101)33:3<177::AID-PROS5>3.0.CO;2-G","article-title":"Morphometric analysis of pediatric and nonhyperplastic prostate glands: evidence that BPH is not a unique stromal process","volume":"33","author":"E Shapiro","year":"1997","journal-title":"Prostate"},{"issue":"5","key":"pone.0345306.ref028","doi-asserted-by":"crossref","first-page":"751","DOI":"10.1016\/S0090-4295(96)00254-3","article-title":"Limitations of transition zone needle biopsy findings in the prediction of transition zone cancer and tissue composition of benign nodular hyperplasia","volume":"48","author":"J McNeal","year":"1996","journal-title":"Urology"},{"issue":"1","key":"pone.0345306.ref029","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1007\/BF00303075","article-title":"Keratin expression: a measure of phenotypic modulation of human prostatic epithelial cells by growth inhibitory factors","volume":"277","author":"DM Peehl","year":"1994","journal-title":"Cell Tissue Res"},{"issue":"3","key":"pone.0345306.ref030","doi-asserted-by":"crossref","first-page":"332","DOI":"10.1159\/000480835","article-title":"Changes in keratin expression during the development of benign prostatic hyperplasia","volume":"32","author":"Y Xue","year":"1997","journal-title":"Eur Urol"},{"issue":"7","key":"pone.0345306.ref031","doi-asserted-by":"crossref","first-page":"932","DOI":"10.1046\/j.1464-410x.2000.00606.x","article-title":"Phenotypic and genotypic characterization of commonly used human prostatic cell lines","volume":"85","author":"S Mitchell","year":"2000","journal-title":"BJU Int"},{"issue":"4","key":"pone.0345306.ref032","article-title":"P21-activated kinase inhibitors FRAX486 and IPA3: Inhibition of prostate stromal cell growth and effects on smooth muscle contraction in the human prostate","volume":"11","author":"Y Wang","year":"2016","journal-title":"PLoS One"},{"issue":"11","key":"pone.0345306.ref033","doi-asserted-by":"crossref","first-page":"2905","DOI":"10.1111\/bph.13099","article-title":"Inhibition of prostate smooth muscle contraction and prostate stromal cell growth by the inhibitors of Rac, NSC23766 and EHT1864","volume":"172","author":"Y Wang","year":"2015","journal-title":"Br J Pharmacol"},{"issue":"1","key":"pone.0345306.ref034","doi-asserted-by":"crossref","DOI":"10.1152\/ajprenal.00125.2017","article-title":"Inhibition of smooth muscle contraction and ARF6 activity by the inhibitor for cytohesin GEFs, secinH3, in the human prostate","volume":"314","author":"A Herlemann","year":"2018","journal-title":"Am J Physiol Renal Physiol"},{"issue":"23","key":"pone.0345306.ref035","doi-asserted-by":"crossref","first-page":"3342","DOI":"10.1111\/bph.13623","article-title":"Smooth muscle contraction and growth of stromal cells in the human prostate are both inhibited by the Src family kinase inhibitors, AZM475271 and PP2","volume":"173","author":"Y Wang","year":"2016","journal-title":"Br J Pharmacol"},{"key":"pone.0345306.ref036","doi-asserted-by":"crossref","first-page":"734","DOI":"10.3389\/fphys.2018.00734","article-title":"Inhibition of prostate smooth muscle contraction by inhibitors of polo-like Kinases","volume":"9","author":"M Hennenberg","year":"2018","journal-title":"Front Physiol"},{"issue":"11","key":"pone.0345306.ref037","doi-asserted-by":"crossref","first-page":"2077","DOI":"10.1111\/bph.14201","article-title":"Inhibition of human prostate smooth muscle contraction by the LIM kinase inhibitors, SR7826 and LIMKi3","volume":"175","author":"Q Yu","year":"2018","journal-title":"Br J Pharmacol"},{"issue":"11","key":"pone.0345306.ref038","doi-asserted-by":"crossref","first-page":"831","DOI":"10.1002\/pros.23998","article-title":"Inhibition of neurogenic and thromboxane A2 -induced human prostate smooth muscle contraction by the integrin \u03b12\u03b21 inhibitor 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