The Journal of Pathology最新文献

{"title":"Enhanced prostatic Esr1+ luminal epithelial cells in the absence of SRD5A2","authors":"Christina Sharkey,&nbsp;Xingbo Long,&nbsp;Ra'ad Al-Faouri,&nbsp;Douglas Strand,&nbsp;Aria F Olumi,&nbsp;Zongwei Wang","doi":"10.1002/path.6283","DOIUrl":"10.1002/path.6283","url":null,"abstract":"<p>Steroid 5α reductase 2 (SRD5A2) converts testosterone to dihydrotestosterone and is crucial for prostatic development. 5α reductase inhibitors (5ARI) reduce prostate size in benign prostate hyperplasia (BPH) and ameliorate lower urinary tract symptoms secondary to BPH. However, the mechanisms of 5ARI functioning are still not fully understood. Here, we used a <i>Srd5a2</i>^−/− mouse model and employed single-cell RNA sequencing to explore the impact of SRD5A2 absence on prostate cellular heterogeneity. Significant alterations in luminal epithelial cell (LE) populations were observed, alongside an increased proportion and proliferative phenotype of estrogen receptor 1 (ESR1)⁺ LE2 cells, following an SRD5A2-independent ESR1 differentiation trajectory. LE2 cells exhibited enhanced estrogen response gene signatures, suggesting an alternative pathway for prostate growth when SRD5A2 is absent. Human prostate biopsy analysis revealed an inverse correlation between the expressions of SRD5A2 and LE2 markers (ESR1/PKCα), and an inverse correlation between SRD5A2 and the clinical efficiency of 5ARI. These findings provide insights into 5ARI resistance mechanisms and potential alternative therapies for BPH-related lower urinary tract symptoms. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 3","pages":"300-314"},"PeriodicalIF":7.3,"publicationDate":"2024-04-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"From morphology to methylome: epigenetic studies of Müllerian mesonephric-like adenocarcinoma reveal similarities to cervical mesonephric adenocarcinoma†","authors":"Lawrence H Lin,&nbsp;Brooke E Howitt,&nbsp;David L Kolin","doi":"10.1002/path.6285","DOIUrl":"10.1002/path.6285","url":null,"abstract":"<p>Mesonephric adenocarcinomas (MAs) and mesonephric-like adenocarcinomas (MLAs) are rare, aggressive neoplasms that arise in the gynecologic tract and show overlapping morphologic, immunohistochemical, and molecular features. While MAs occur in the cervix and are thought to arise from mesonephric remnants, MLAs occur in the endometrium and ovary and are believed to originate from transdifferentiation of Müllerian lesions. Both MAs and MLAs show a variety of architectural patterns, exhibit frequent expression of GATA3 by immunohistochemistry, and harbor <i>KRAS</i> mutations. In a recent article published in <i>The Journal of Pathology</i>, Kommoss and colleagues used DNA methylation profiling to extend these similarities and showed that MLAs and MAs cluster together based on their epigenetic signatures and are epigenetically distinct from other Müllerian adenocarcinomas. They also showed that MLAs and MAs harbor a high number of global copy number alterations. This study provides evidence that MLAs more closely resemble MAs than Müllerian carcinomas on an epigenetic level. As a result, the authors argue that MLA should be renamed ‘mesonephric-type adenocarcinoma.’ Further research is needed to establish the relationship between these two entities, their etiology, and pathogenesis. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"135-138"},"PeriodicalIF":7.3,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6285","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TGF-β3 from fibroblasts promotes necrotising sialometaplasia by suppressing salivary gland cell proliferation and inducing squamous metaplasia","authors":"Shohei Yoshimoto,&nbsp;Naomi Yada,&nbsp;Ayataka Ishikawa,&nbsp;Kenji Kawano,&nbsp;Kou Matsuo,&nbsp;Akimitsu Hiraki,&nbsp;Kazuhiko Okamura","doi":"10.1002/path.6287","DOIUrl":"10.1002/path.6287","url":null,"abstract":"<p>Necrotising sialometaplasia (NSM) is a non-neoplastic lesion mainly arising in the minor salivary glands of the oral cavity. In the clinical features, NSM shows swelling with or without ulceration, and can mimic a malignant disease such as squamous cell carcinoma. Histopathologically, NSM usually shows the lobular architecture that is observed in the salivary glands. Additionally, acinar infarction and squamous metaplasia of salivary ducts and acini are observable. The aetiology of this lesion remains unknown, although it has a characteristic feature that sometimes requires clinical and histopathological differentiation from malignancy. In this study, we investigated upregulated genes in NSM compared with normal salivary glands, and focused on the TGF-β3 (<i>TGFB3</i>) gene. The results of the histopathological studies clarified that fibroblasts surrounding the lesion express TGF-β3. Moreover, <i>in vitro</i> studies using mouse salivary gland organoids revealed that TGF-β3 suppressed salivary gland cell proliferation and induced squamous metaplasia. We demonstrated a possible aetiology of NSM by concluding that increased TGF-β3 expression during wound healing or tissue regeneration played a critical role in cell proliferation and metaplasia. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 3","pages":"338-346"},"PeriodicalIF":7.3,"publicationDate":"2024-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140602999","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Co-targeting BET, CBP, and p300 inhibits neuroendocrine signalling in androgen receptor-null prostate cancer","authors":"Nicholas Choo,&nbsp;Shivakumar Keerthikumar,&nbsp;Susanne Ramm,&nbsp;Daisaku Ashikari,&nbsp;Linda Teng,&nbsp;Birunthi Niranjan,&nbsp;Shelley Hedwards,&nbsp;Laura H Porter,&nbsp;David L Goode,&nbsp;Kaylene J Simpson,&nbsp;Renea A Taylor,&nbsp;Gail P Risbridger,&nbsp;Mitchell G Lawrence","doi":"10.1002/path.6280","DOIUrl":"10.1002/path.6280","url":null,"abstract":"<p>There are diverse phenotypes of castration-resistant prostate cancer, including neuroendocrine disease, that vary in their sensitivity to drug treatment. The efficacy of BET and CBP/p300 inhibitors in prostate cancer is attributed, at least in part, to their ability to decrease androgen receptor (AR) signalling. However, the activity of BET and CBP/p300 inhibitors in prostate cancers that lack the AR is unclear. In this study, we showed that BRD4, CBP, and p300 were co-expressed in AR-positive and AR-null prostate cancer. A combined inhibitor of these three proteins, NEO2734, reduced the growth of both AR-positive and AR-null organoids, as measured by changes in viability, size, and composition. NEO2734 treatment caused consistent transcriptional downregulation of cell cycle pathways. In neuroendocrine models, NEO2734 treatment reduced <i>ASCL1</i> levels and other neuroendocrine markers, and reduced tumour growth <i>in vivo</i>. Collectively, these results show that epigenome-targeted inhibitors cause decreased growth and phenotype-dependent disruption of lineage regulators in neuroendocrine prostate cancer, warranting further development of compounds with this activity in the clinic. © 2024 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"242-256"},"PeriodicalIF":7.3,"publicationDate":"2024-04-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6280","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140592993","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cell division-dependent dissemination following E-cadherin loss underlies initiation of diffuse-type gastric cancer","authors":"Jooske L Monster,&nbsp;Lars JS Kemp,&nbsp;Georg A Busslinger,&nbsp;Marjolein J Vliem,&nbsp;Lucca LM Derks,&nbsp;Annelot AL Staes,&nbsp;Tanya M Bisseling,&nbsp;Hans Clevers,&nbsp;Rachel S van der Post,&nbsp;Martijn Gloerich","doi":"10.1002/path.6277","DOIUrl":"10.1002/path.6277","url":null,"abstract":"<p>Loss of the cell–cell adhesion protein E-cadherin underlies the development of diffuse-type gastric cancer (DGC), which is characterized by the gradual accumulation of tumor cells originating from the gastric epithelium in the surrounding stroma. How E-cadherin deficiency drives DGC formation remains elusive. Therefore, we investigated the consequences of E-cadherin loss on gastric epithelial organization utilizing a human gastric organoid model and histological analyses of early-stage DGC lesions. E-cadherin depletion from gastric organoids recapitulates DGC initiation, with progressive loss of a single-layered architecture and detachment of individual cells. We found that E-cadherin deficiency in gastric epithelia does not lead to a general loss of epithelial cohesion but disrupts the spindle orientation machinery. This leads to a loss of planar cell division orientation and, consequently, daughter cells are positioned outside of the gastric epithelial layer. Although basally delaminated cells fail to detach and instead reintegrate into the epithelium, apically mispositioned daughter cells can trigger the gradual loss of the single-layered epithelial architecture. This impaired architecture hampers reintegration of mispositioned daughter cells and enables basally delaminated cells to disseminate into the surrounding matrix. Taken together, our findings describe how E-cadherin deficiency disrupts gastric epithelial architecture through displacement of dividing cells and provide new insights in the onset of DGC. © 2024 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"226-241"},"PeriodicalIF":7.3,"publicationDate":"2024-04-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6277","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140593143","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polyketide synthase positive Escherichia coli one-time measurement in stool is not informative of colorectal cancer risk in a screening setting","authors":"Willemijn de Klaver,&nbsp;Meike de Wit,&nbsp;Anne Bolijn,&nbsp;Marianne Tijssen,&nbsp;Pien Delis-van Diemen,&nbsp;Margriet Lemmens,&nbsp;Manon CW Spaander,&nbsp;Evelien Dekker,&nbsp;Monique E van Leerdam,&nbsp;Veerle MH Coupé,&nbsp;Ruben van Boxtel,&nbsp;Hans Clevers,&nbsp;Beatriz Carvalho,&nbsp;Gerrit A Meijer","doi":"10.1002/path.6276","DOIUrl":"10.1002/path.6276","url":null,"abstract":"<p>Environmental factors like the pathogenicity island <i>polyketide synthase positive (pks+) Escherichia coli</i> (<i>E. coli</i>) could have potential for risk stratification in colorectal cancer (CRC) screening. The association between <i>pks+ E. coli</i> measured in fecal immunochemical test (FIT) samples and the detection of advanced neoplasia (AN) at colonoscopy was investigated. Biobanked FIT samples were analyzed for both presence of <i>E. coli</i> and <i>pks+ E. coli</i> and correlated with colonoscopy findings; 5020 CRC screening participants were included. Controls were participants in which no relevant lesion was detected because of FIT-negative results (cut-off ≥15 μg Hb/g feces), a negative colonoscopy, or a colonoscopy during which only a nonadvanced polyp was detected. Cases were participants with AN [CRC, advanced adenoma (AA), or advanced serrated polyp (ASP)]. Existing DNA isolation and quantitative polymerase chain reaction (qPCR) procedures were used for the detection of <i>E. coli</i> and <i>pks+ E. coli</i> in stool. A total of 4542 (90.2%) individuals were <i>E. coli</i> positive, and 1322 (26.2%) were <i>pks+ E. coli</i> positive. The prevalence of <i>E. coli</i> in FIT samples from individuals with AN was 92.9% compared to 89.7% in FIT samples of controls (<i>p</i> = 0.010). The prevalence of <i>pks+ E. coli</i> in FIT samples from individuals with AN (28.6%) and controls (25.9%) was not significantly different (<i>p</i> = 0.13). The prevalences of <i>pks+ E. coli</i> in FIT samples from individuals with CRC, AA, or ASP were 29.6%, 28.3%, and 32.1%, respectively. In conclusion, the prevalence of <i>pks+ E. coli</i> in a screening population was 26.2% and did not differ significantly between individuals with AN and controls. These findings disqualify the straightforward option of using a snapshot measurement of <i>pks+ E. coli</i> in FIT samples as a stratification biomarker for CRC risk. © 2024 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"217-225"},"PeriodicalIF":7.3,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6276","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317470","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Obliteration of portal venules contributes to portal hypertension in biliary cirrhosis","authors":"Shan Shan,&nbsp;Xinyan Zhao,&nbsp;Michelle A Wood-Trageser,&nbsp;Doudou Hu,&nbsp;Liwei Liu,&nbsp;Beining Qi,&nbsp;Jianbo Jian,&nbsp;Ping Wang,&nbsp;Wenjuan Lv,&nbsp;Chunhong Hu","doi":"10.1002/path.6273","DOIUrl":"10.1002/path.6273","url":null,"abstract":"<p>The effects of the obliteration of portal venules (OPV) in cirrhotic portal hypertension are poorly understood. To investigate its contribution to portal hypertension in biliary cirrhosis and its underlying mechanism, we evaluated OPV using two-dimensional (2D) histopathology in liver explants from patients with biliary atresia (BA, <i>n</i> = 63), primary biliary cholangitis (PBC, <i>n</i> = 18), and hepatitis B-related cirrhosis (Hep-B-cirrhosis, <i>n</i> = 35). Then, three-dimensional (3D) OPV was measured by X-ray phase-contrast CT in two parallel models in rats following bile duct ligation (BDL) or carbon tetrachloride (CCl₄) administration, representing biliary cirrhosis and post-necrotic cirrhosis, respectively. The portal pressure was also measured in the two models. Finally, the effects of proliferative bile ducts on OPV were investigated. We found that OPV was significantly more frequent in patients with biliary cirrhosis, including BA (78.57 ± 16.45%) and PBC (60.00 ± 17.15%), than that in Hep-B-cirrhotic patients (29.43 ± 14.94%, <i>p</i> &lt; 0.001). OPV occurred earlier, evidenced by the paired liver biopsy at a Kasai procedure (KP), and was irreversible even after a successful KP in the patients with BA. OPV was also significantly more frequent in the BDL models than in the CCl₄ models, as shown by 2D and 3D quantitative analysis. Portal pressure was significantly higher in the BDL model than that in the CCl₄ model. With the proliferation of bile ducts, portal venules were compressed and irreversibly occluded, contributing to the earlier and higher portal pressure in biliary cirrhosis. OPV, as a pre-sinusoidal component, plays a key role in the pathogenesis of portal hypertension in biliary cirrhosis. The proliferated bile ducts and ductules gradually take up the ‘territory’ originally attributed to portal venules and compress the portal venules, which may lead to OPV in biliary cirrhosis. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"178-189"},"PeriodicalIF":7.3,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Research autopsy programmes in oncology: shared experience from 14 centres across the world","authors":"Tatjana Geukens,&nbsp;Marion Maetens,&nbsp;Jody E Hooper,&nbsp;Steffi Oesterreich,&nbsp;Adrian V Lee,&nbsp;Lori Miller,&nbsp;Jenny M Atkinson,&nbsp;Margaret Rosenzweig,&nbsp;Shannon Puhalla,&nbsp;Heather Thorne,&nbsp;Lisa Devereux,&nbsp;David Bowtell,&nbsp;Sherene Loi,&nbsp;Eliza R Bacon,&nbsp;Kena Ihle,&nbsp;Mihae Song,&nbsp;Lorna Rodriguez-Rodriguez,&nbsp;Alana L Welm,&nbsp;Lisa Gauchay,&nbsp;Rajmohan Murali,&nbsp;Pharto Chanda,&nbsp;Ali Karacay,&nbsp;Cristina Naceur-Lombardelli,&nbsp;Hayley Bridger,&nbsp;Charles Swanton,&nbsp;Mariam Jamal-Hanjani,&nbsp;Lori Kollath,&nbsp;Lawrence True,&nbsp;Colm Morrissey,&nbsp;Meagan Chambers,&nbsp;Arul M Chinnaiyan,&nbsp;Allecia Wilson,&nbsp;Rohit Mehra,&nbsp;Zachery Reichert,&nbsp;Lisa A Carey,&nbsp;Charles M Perou,&nbsp;Erin Kelly,&nbsp;Daichi Maeda,&nbsp;Akiteru Goto,&nbsp;Janina Kulka,&nbsp;Borbála Székely,&nbsp;A Marcell Szasz,&nbsp;Anna-Mária Tőkés,&nbsp;Wouter Van Den Bogaert,&nbsp;Giuseppe Floris,&nbsp;Christine Desmedt","doi":"10.1002/path.6271","DOIUrl":"10.1002/path.6271","url":null,"abstract":"<p>While there is a great clinical need to understand the biology of metastatic cancer in order to treat it more effectively, research is hampered by limited sample availability. Research autopsy programmes can crucially advance the field through synchronous, extensive, and high-volume sample collection. However, it remains an underused strategy in translational research. Via an extensive questionnaire, we collected information on the study design, enrolment strategy, study conduct, sample and data management, and challenges and opportunities of research autopsy programmes in oncology worldwide. Fourteen programmes participated in this study. Eight programmes operated 24 h/7 days, resulting in a lower median postmortem interval (time between death and start of the autopsy, 4 h) compared with those operating during working hours (9 h). Most programmes (<i>n</i> = 10) succeeded in collecting all samples within a median of 12 h after death. A large number of tumour sites were sampled during each autopsy (median 15.5 per patient). The median number of samples collected per patient was 58, including different processing methods for tumour samples but also non-tumour tissues and liquid biopsies. Unique biological insights derived from these samples included metastatic progression, treatment resistance, disease heterogeneity, tumour dormancy, interactions with the tumour micro-environment, and tumour representation in liquid biopsies. Tumour patient-derived xenograft (PDX) or organoid (PDO) models were additionally established, allowing for drug discovery and treatment sensitivity assays. Apart from the opportunities and achievements, we also present the challenges related with postmortem sample collections and strategies to overcome them, based on the shared experience of these 14 programmes. Through this work, we hope to increase the transparency of postmortem tissue donation, to encourage and aid the creation of new programmes, and to foster collaborations on these unique sample collections. © 2024 The Authors. <i>The Journal of Pathology</i> published by John Wiley &amp; Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"150-165"},"PeriodicalIF":7.3,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/path.6271","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317471","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"UPK3A+ umbrella cell damage mediated by TLR3–NR2F6 triggers programmed destruction of urothelium in Hunner-type interstitial cystitis/painful bladder syndrome","authors":"Liao Peng,&nbsp;Jia-Wei Chen,&nbsp;Yuan-Zhuo Chen,&nbsp;Chi Zhang,&nbsp;Si-Hong Shen,&nbsp;Meng-Zhu Liu,&nbsp;Yang Fan,&nbsp;Shi-Qin Yang,&nbsp;Xiu-Zhen Zhang,&nbsp;Wei Wang,&nbsp;Xiao-Shuai Gao,&nbsp;Xing-Peng Di,&nbsp;Yu-Cheng Ma,&nbsp;Xiao Zeng,&nbsp;Hong Shen,&nbsp;Xi Jin,&nbsp;De-Yi Luo","doi":"10.1002/path.6275","DOIUrl":"10.1002/path.6275","url":null,"abstract":"<p>Urothelial damage and barrier dysfunction emerge as the foremost mechanisms in Hunner-type interstitial cystitis/bladder pain syndrome (HIC). Although treatments aimed at urothelial regeneration and repair have been employed, their therapeutic effectiveness remains limited due to the inadequate understanding of specific cell types involved in damage and the lack of specific molecular targets within these mechanisms. Therefore, we harnessed single-cell RNA sequencing to elucidate the heterogeneity and developmental trajectory of urothelial cells within HIC bladders. Through reclustering, we identified eight distinct clusters of urothelial cells. There was a significant reduction in UPK3A⁺ umbrella cells and a simultaneous increase in progenitor-like pluripotent cells (PPCs) within the HIC bladder. Pseudotime analysis of the urothelial cells in the HIC bladder revealed that cells faced challenges in differentiating into UPK3A⁺ umbrella cells, while PPCs exhibited substantial proliferation to compensate for the loss of UPK3A⁺ umbrella cells. The urothelium in HIC remains unrepaired, despite the substantial proliferation of PPCs. Thus, we propose that inhibiting the pivotal signaling pathways responsible for the injury to UPK3A⁺ umbrella cells is paramount for restoring the urothelial barrier and alleviating lower urinary tract symptoms in HIC patients. Subsequently, we identified key molecular pathways (TLR3 and NR2F6) associated with the injury of UPK3A⁺ umbrella cells in HIC urothelium. Finally, we conducted <i>in vitro</i> and <i>in vivo</i> experiments to confirm the potential of the TLR3–NR2F6 axis as a promising therapeutic target for HIC. These findings hold the potential to inhibit urothelial injury, providing promising clues for early diagnosis and functional bladder self-repair strategies for HIC patients. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"203-216"},"PeriodicalIF":7.3,"publicationDate":"2024-03-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140317472","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Automated tumor immunophenotyping predicts clinical benefit from anti-PD-L1 immunotherapy","authors":"Xiao Li,&nbsp;Jeffrey Eastham,&nbsp;Jennifer M Giltnane,&nbsp;Wei Zou,&nbsp;Andries Zijlstra,&nbsp;Evgeniy Tabatsky,&nbsp;Romain Banchereau,&nbsp;Ching-Wei Chang,&nbsp;Barzin Y Nabet,&nbsp;Namrata S Patil,&nbsp;Luciana Molinero,&nbsp;Steve Chui,&nbsp;Maureen Harryman,&nbsp;Shari Lau,&nbsp;Linda Rangell,&nbsp;Yannick Waumans,&nbsp;Mark Kockx,&nbsp;Darya Orlova,&nbsp;Hartmut Koeppen","doi":"10.1002/path.6274","DOIUrl":"10.1002/path.6274","url":null,"abstract":"<p>Cancer immunotherapy has transformed the clinical approach to patients with malignancies, as profound benefits can be seen in a subset of patients. To identify this subset, biomarker analyses increasingly focus on phenotypic and functional evaluation of the tumor microenvironment to determine if density, spatial distribution, and cellular composition of immune cell infiltrates can provide prognostic and/or predictive information. Attempts have been made to develop standardized methods to evaluate immune infiltrates in the routine assessment of certain tumor types; however, broad adoption of this approach in clinical decision-making is still missing. We developed approaches to categorize solid tumors into ‘desert’, ‘excluded’, and ‘inflamed’ types according to the spatial distribution of CD8+ immune effector cells to determine the prognostic and/or predictive implications of such labels. To overcome the limitations of this subjective approach, we incrementally developed four automated analysis pipelines of increasing granularity and complexity for density and pattern assessment of immune effector cells. We show that categorization based on ‘manual’ observation is predictive for clinical benefit from anti-programmed death ligand 1 therapy in two large cohorts of patients with non-small cell lung cancer or triple-negative breast cancer. For the automated analysis we demonstrate that a combined approach outperforms individual pipelines and successfully relates spatial features to pathologist-based readouts and the patient's response to therapy. Our findings suggest that tumor immunophenotype generated by automated analysis pipelines should be evaluated further as potential predictive biomarkers for cancer immunotherapy. © 2024 The Pathological Society of Great Britain and Ireland.</p>","PeriodicalId":232,"journal":{"name":"The Journal of Pathology","volume":"263 2","pages":"190-202"},"PeriodicalIF":7.3,"publicationDate":"2024-03-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140205988","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}