Epithelial Pattern Research Articles

Reticular Epithelial Edema in a Postkeratoplasty Eye Due to Ripasudil.

A 34-year-old female underwent phacoemulsification with Descemet stripping endothelial keratoplasty (Supplementary Digital Content, Fig. 1A, B, http://links.lww.com/APJO/ A132) under a failed previous therapeutic penetrating keratoplasty. The visual acuity was restored to 20/50. At 2 years postoperative period, she developed raised intraocular pressure of 30 mm Hg despite being on 2 antiglaucoma medications, and hence ripasudil was initiated as an additional antiglaucoma medication. The endothelial cell density was 920 cells/mm.1Figure 1: Slitlamp image (A) and anterior segment optical coherence tomography (B) illustrating reticular edema in superficial cornea after 4 months of ripasudil use.Her intraocular pressure at 1 month of starting ripasudil was 12 mm Hg. Subsequently, 3 months later, she presented with counting finger vision, honeycomb edema in the superficial cornea (Fig. 1). Ripasudil was discontinued and 1 month later, although the epithelial net-like pattern disappeared, the graft was diffusely edematous and failed to recover the clarity until a follow-up of 3 months (Supplementary Digital Content, Fig. 1C, D, http://links.lww.com/APJO/A132) when repeat endothe-lial keratoplasty was planned. Rho kinase inhibitors have gained popularity in the management of glaucoma and corneal endothelial diseases.2 Ripasudil and netarsudil are Rho kinase inhibitors approved for clinical use. Reticular bullous epithelial edema has been reported with the use of 0.02% netarsudil, which improves in some eyes after the medication is discontinued.1 In our patient, similar pattern of edema was noted with 0.4% ripasudil after 4 months of treatment, which failed to resolve on discontinuing ripasudil. The reticular epithelial edema during ripasudil treatment should be distinguished from graft rejection. The medication should be stopped promptly if cornea edema is noted. The likelihood of nonclearance of edema should be explained to the patients.

Corneal Ectasia detection by epithelium pattern standard deviation from optical coherence tomography.

To test the ability of the corneal epithelial pattern standard deviation to distinguish between normal and cases with corneal ectatic condition. Instituto de Olhos Renato Ambrósio, Rio de janeiro, Brazil. Cross-sectional retrospective study. Patients were stratified into four groups based on clinical data and. (Groups 1 and 2 comprised one eye randomly selected from 105 patients with normal corneas (N) and 86 patients with bilateral keratoconus (KC). Groups 3 and 4, respectively comprised 11 ectatic eyes with no surgical treatment for keratoconus (VAE-E) from patients whose fellow eyes (61) presented with normal topographic patterns (VAE-NT). Corneas were scanned using an OCT system (RT Vue) and Scheimpflug corneal tomography (Pentacam), and also had biomechanical assessment through the Corvis ST. Corneal epithelial thickness maps were analyzed and the pattern standard deviation (PSD) value was calculated. The area under the ROC curve analysis was used to evaluate the diagnostic accuracy of the indices. Epithelial PSD was significantly different across the four groups (p<0.0001). The pairwise comparison revealed that the normal group presented significantly lower values than both ectasia groups (KC and VAE-E, p<0.0001) and the VAE-NT group (p=0.0008). There was no significant difference between KC and VAE-E (p=0.4284), while they were significantly higher than the VAE-NT group (p<0.0001 and p=0.0004). Epithelial PSD can be used to detect abnormal epithelial thickness patterns. Corneal epithelial thickness changes could be detected accurately in keratoconus patients, even in the form fruste of the disease.

Temporally and spatially regulated collagen XVIII isoforms are involved in ureteric tree development via the TSP1-like domain

Collagen XVIII (ColXVIII) is a component of the extracellular matrix implicated in embryogenesis and control of tissue homoeostasis. We now provide evidence that ColXVIII has a specific role in renal branching morphogenesis as observed in analyses of total and isoform-specific knockout embryos and mice. The expression of the short and the two longer isoforms differ temporally and spatially during renal development. The lack of ColXVIII or its specific isoforms lead to congenital defects in the 3D patterning of the ureteric tree where the short isoform plays a prominent role. Moreover, the ex vivo data suggests that ColXVIII is involved in the kidney epithelial tree patterning via its N-terminal domains, and especially the Thrombospondin-1-like domain common to all isoforms. This morphogenetic function likely involves integrins expressed in the ureteric epithelium. Altogether, the results point to an important role for ColXVIII in the matrix-integrin-mediated functions regulating renal development.

A Clinicopathological Study with Risk-Stratified Staging of Pediatric Hepatoblastoma: A 5-Year Experience from a Tertiary Cancer Center.

Hepatoblastoma encompasses 1% of pediatric malignancies and is the most common liver malignancy in children. Ninety percent of cases are younger than 5 years of age. Clinical and pathological risk stratification forms a crucial role in determining the treatment strategy. This study aimed to assess the clinicopathological profile of hepatoblastoma with risk stratification and follow-up in children. A retrospective evaluation was performed on all pediatric patients diagnosed as hepatoblastoma between 2016 and 2020 in our institution. Clinical, radiological, biochemical, pathological, and treatment data were analyzed. Cases were stratified based on the SIOPEL protocol and compared with the outcome. The median age of all children was 1 year, the male-to-female ratio was 2.3:1, and elevated α-fetoprotein (AFP) was observed in all cases. SIOPEL risk stratification showed that 50% of children were at high risk. The histopathological types were fetal (30%), embryonal (20%), and macrotrabecular (5%) patterns under epithelial type and mixed epithelial and mesenchymal type (45%) with 1 case showing teratoid features. During the follow-up period, 6 out of the 7 children who died, belonged to the high-risk SIOPEL category, and 5 presented a mixed epithelial and mesenchymal pattern. Our study found a significant correlation between clinicopathological data, histopathological patterns, and outcomes. Accordingly, histopathological patterns could be considered one of the criteria for risk stratification. Histopathological risk stratification indicators (such as SIOPEL and PRETEXT) have strong prognostic and predictive outcomes; hence, our study emphasizes such parameters to aid oncologists.

Dysregulated Polycomb Repressive Complex 2 contributes to chronic obstructive pulmonary disease by rewiring stem cell fate.

Aberrant lung cell differentiation is a hallmark of many lung diseases including chronic obstructive pulmonary disease (COPD). The EZH2-containing Polycomb Repressive Complex 2 (PRC2) regulates embryonic lung stem cell fate, but its role in adult lung is obscure. Histological analysis of patient tissues revealed that loss of PRC2 activity was correlated with aberrant bronchiolar cell differentiation in COPD lung. Histological and single-cell RNA-sequencing analyses showed that loss of EZH2 in mouse lung organoids led to lowered self-renewal capability, increased squamous morphological development, and marked shifts in progenitor cell populations. Evaluation of invivo models revealed that heterozygosity of Ezh2 in mice with ovalbumin-induced lung inflammation led to epithelial cell differentiation patterns similar to those in COPD lung. We also identified cystathionine-β-synthase as a possible upstream factor for PRC2 destabilization. Our findings suggest that PRC2 is integral to facilitating proper lung stem cell differentiation in humans and mice.

Hearing loss in mice with disruption of auditory epithelial patterning in the cochlea.

In the cochlear auditory epithelia, sensory hair and supporting cells are arranged in a checkerboard-like mosaic pattern, which is conserved across a wide range of species. The cell adhesion molecules nectin-1 and nectin-3 are required for this pattern formation. The checkerboard-like pattern is thought to be necessary for auditory function, but has never been examined. Here, we showed the significance of checkerboard-like cellular pattern in the survival and function of sensory hair cells in the cochlear auditory epithelia of nectin-3 knockout (KO) mice. Nectin-3 KO mice showed progressive hearing loss associated with degeneration of aberrantly attached hair cells via apoptosis. Apoptotic hair cell death was due to the disorganization of tight junctions between the hair cells. Our study revealed that the checkerboard-like cellular pattern in the auditory epithelium provides a structural basis for ensuring the survival of cochlear hair cells and hearing function.

Systematic detection of keratoconus in OCT: corneal and epithelial thickness maps.

To detect keratoconus (KC) only by analyzing the corneal and epithelial map parameters and patterns in optical coherence tomography (OCT). Tertiary care refractive surgery center. Retrospective data collection. Corneal and epithelial thickness maps of normal, manifest, and subclinical keratoconic eyes (according to the Belin-Ambrosio display, Pentacam) were evaluated using spectral-domain OCT (Zeiss Cirrus 5000 HD). A new 2-step decision tree was developed based on previous studies with another OCT device. In the first step, if at least 1 of the 4 independent parameters (pachymetry minimum, pachymetry minimum-median, pachymetry superonasal-inferotemporal, and epithelial superonasal-inferotemporal) overruns the cutoff values, the eye was suspicious for KC. In the second step, if the epithelial map showed concentric thinning and the thinnest point of the cornea and epithelium is coincident, the eye was classified as keratoconic. 172 manifest keratoconic eyes (108 patients), 21 subclinical keratoconic eyes (20 patients), and 172 normal eyes (90 age-matched participants) were included in this study. Step 1 captured 100% of manifest and subclinical keratoconic eyes. Step 2 ruled out all suspicious but normal cases and, falsely, 2 subclinical keratoconic eyes. Our 2-step decision tree reached 100% specificity, 100% sensitivity in manifest KC, and 90.4% sensitivity in subclinical KC. Pachymetric and epithelial map parameters and patterns in OCT can be used in the diagnosis of KC, including subclinical cases, yielding a high level of agreement with the commonly used diagnostic reference, the Belin-Ambrosio display. Further improvements by refining our algorithm and including an automated evaluation in the software are desirable.

Abstract B022: The adaptor protein FRS2beta fashions a cytokine-rich inflammatory microenvironment that is associated with DCIS and promotes breast cancer carcinogenesis

Abstract Although it is commonly held that pro-inflammatory changes precede the onset of breast cancer, the underlying mechanisms remain obscure. Here, we report that FRS2beta, an adaptor protein with a highly restricted epithelial expression pattern, mediates the pro-inflammatory changes that alter the stroma in premalignant mammary tissues. We posit that these changes, which include lesions of ductal carcinoma in situ (DCIS), precede disease onset. In the MMTV-ErbB2 mouse model of mammary carcinoma, FRS2beta-deficiency markedly attenuated tumorigenesis. Importantly, tumor cells derived from MMTV-ErbB2 mice failed to generate tumors when grafted in the FRS2beta-deficient premalignant tissues. We found that the co-localization of FRS2beta and the NEMO subunit of the IkappaB kinase (IKK) complex in early endosomes activated nuclear factor-kappaB (NFkappaB), a master regulator of inflammation. Moreover, the inhibition of NFkappaB-induced cytokines CXC chemokine ligand (CXCL)12 and insulin-like growth factor (IGF1) abrogated tumorigenesis. In line with this, human breast cancer tissues that express higher levels of FRS2beta contain more stroma. The elucidation of the FRS2beta-NFkappaB axis uncovers a hitherto unknown molecular link between the pro-inflammatory changes in the DCIS and the disease onset. Citation Format: Noriko Gotoh. The adaptor protein FRS2beta fashions a cytokine-rich inflammatory microenvironment that is associated with DCIS and promotes breast cancer carcinogenesis [abstract]. In: Proceedings of the AACR Special Conference on Rethinking DCIS: An Opportunity for Prevention?; 2022 Sep 8-11; Philadelphia, PA. Philadelphia (PA): AACR; Can Prev Res 2022;15(12 Suppl_1): Abstract nr B022.

Topological Distribution of Wound Stiffness Modulates Wound-Induced Hair Follicle Neogenesis.

In the large full-thickness mouse skin regeneration model, wound-induced hair neogenesis (WIHN) occurs in the wound center. This implies a spatial regulation of hair regeneration. The role of mechanotransduction during tissue regeneration is poorly understood. Here, we created wounds with equal area but different shapes to understand if perturbing mechanical forces change the area and quantity of de novo hair regeneration. Atomic force microscopy of wound stiffness demonstrated a stiffness gradient across the wound with the wound center softer than the margin. Reducing mechanotransduction signals using FAK or myosin II inhibitors significantly increased WIHN and, conversely, enhancing these signals with an actin stabilizer reduced WIHN. Here, α-SMA was downregulated in FAK inhibitor-treated wounds and lowered wound stiffness. Wound center epithelial cells exhibited a spherical morphology relative to wound margin cells. Differential gene expression analysis of FAK inhibitor-treated wound RNAseq data showed that cytoskeleton-, integrin-, and matrix-associated genes were downregulated, while hair follicular neogenesis, cell proliferation, and cell signaling genes were upregulated. Immunohistochemistry staining showed that FAK inhibition increased pSTAT3 nuclear staining in the regenerative wound center, implying enhanced signaling for hair follicular neogenesis. These findings suggest that controlling wound stiffness modulates tissue regeneration encompassing epithelial competence, tissue patterning, and regeneration during wound healing.

Single-cell transcriptomics reveals common epithelial response patterns in human acute kidney injury

BackgroundAcute kidney injury (AKI) occurs frequently in critically ill patients and is associated with adverse outcomes. Cellular mechanisms underlying AKI and kidney cell responses to injury remain incompletely understood.MethodsWe performed single-nuclei transcriptomics, bulk transcriptomics, molecular imaging studies, and conventional histology on kidney tissues from 8 individuals with severe AKI (stage 2 or 3 according to Kidney Disease: Improving Global Outcomes (KDIGO) criteria). Specimens were obtained within 1–2 h after individuals had succumbed to critical illness associated with respiratory infections, with 4 of 8 individuals diagnosed with COVID-19. Control kidney tissues were obtained post-mortem or after nephrectomy from individuals without AKI.ResultsHigh-depth single cell-resolved gene expression data of human kidneys affected by AKI revealed enrichment of novel injury-associated cell states within the major cell types of the tubular epithelium, in particular in proximal tubules, thick ascending limbs, and distal convoluted tubules. Four distinct, hierarchically interconnected injured cell states were distinguishable and characterized by transcriptome patterns associated with oxidative stress, hypoxia, interferon response, and epithelial-to-mesenchymal transition, respectively. Transcriptome differences between individuals with AKI were driven primarily by the cell type-specific abundance of these four injury subtypes rather than by private molecular responses. AKI-associated changes in gene expression between individuals with and without COVID-19 were similar.ConclusionsThe study provides an extensive resource of the cell type-specific transcriptomic responses associated with critical illness-associated AKI in humans, highlighting recurrent disease-associated signatures and inter-individual heterogeneity. Personalized molecular disease assessment in human AKI may foster the development of tailored therapies.

PI3K signaling specifies proximal-distal fate by driving a developmental gene regulatory network in SOX9+ mouse lung progenitors.

The tips of the developing respiratory buds are home to important progenitor cells marked by the expression of SOX9 and ID2. Early in embryonic development (prior to E13.5), SOX9+progenitors are multipotent, generating both airway and alveolar epithelium, but are selective progenitors of alveolar epithelial cells later in development. Transcription factors, including Sox9, Etv5, Irx, Mycn, and Foxp1/2 interact in complex gene regulatory networks to control proliferation and differentiation of SOX9+progenitors. Molecular mechanisms by which these transcription factors and other signaling pathways control chromatin state to establish and maintain cell-type identity are not well-defined. Herein, we analyze paired gene expression (RNA-Seq) and chromatin accessibility (ATAC-Seq) data from SOX9+ epithelial progenitor cells (EPCs) during embryonic development in Mus musculus. Widespread changes in chromatin accessibility were observed between E11.5 and E16.5, particularly at distal cis-regulatory elements (e.g. enhancers). Gene regulatory network (GRN) inference identified a common SOX9+ progenitor GRN, implicating phosphoinositide 3-kinase (PI3K) signaling in the developmental regulation of SOX9+ progenitor cells. Consistent with this model, conditional ablation of PI3K signaling in the developing lung epithelium in mouse resulted in an expansion of the SOX9+ EPC population and impaired airway epithelial cell differentiation. These data demonstrate that PI3K signaling is required for epithelial patterning during lung organogenesis, and emphasize the combinatorial power of paired RNA and ATAC seq in defining regulatory networks in development.

DENTINOGENIC GHOST CELL TUMOR WITH FOCAL FEATURES SUGGESTING GHOST CELL ODONTOGENIC CARCINOMA: A CHALLENGING DIAGNOSIS

Dentinogenic ghost cell tumor and ghost cell odontogenic carcinoma form a spectrum of rare benign and malignant odontogenic neoplasms, respectively. A 24-year-old White woman complained of a painful enlargement and dental mobility in the maxilla for approximately 1 year. An intraoral examination showed a 3 × 3 cm firm exophytic mass in the left molar region. Tomographic sections showed a well-defined hypodense expansion with hyperdense foci inside invading the maxillary sinus. Microscopically, incisional sections showed a predominantly solid basaloid epithelium presenting atypical features, mitotic activity, ghost cells, positivity for p53, and high Ki-67 labeling, suggesting malignancy. Partial maxillectomy was performed. Surprisingly, the surgical specimen presented an important variation of the epithelial pattern and lacked any sign of malignancy, with abundant ghost cells and dentinoid, confirming the diagnosis of dentinogenic ghost cell tumor. A strict regular follow-up was done with no signs of recurrence or metastasis over 2 years.

Corneal Epithelium Asymmetry in Children With Atopy: The Effect of Hand Dominance.

PurposeTo evaluate the effect of eye rubbing on the epithelial thickness profile in tomographically normal corneas by AS-OCT and to compare right and left eyes in right-handed children.MethodsThirty right-handed boys (mean age 11.2 years) with ocular allergy and history of eye rubbing were evaluated using Scheimpflug (Pentacam HR, Oculus Wetzlar, Germany) and anterior segment optical coherence tomography. Epithelial thickness (ET) and full corneal thickness (CT) parameters were compared between right and left eyes with a non-parametric Mann–Whitney test. A p-value lower than 0.05 was considered for statistical significance.ResultsNo eyes had topometric nor tomographic criteria for keratoconus. The min-max ET was lower in right eyes (−2.8 µm vs −3.5; p = 0.02). The difference between inferior and superior (I-S) octants was lower in right eyes (1.1 µm vs 1.9 µm; p = 0.03) as a result of inferotemporal thinning. The highest ET difference was registered between nasal and temporal octants and was more pronounced in the right eyes (2 µm vs 3.1 µm; p < 0.001).ConclusionAS-OCT analyses reveal different epithelial thickness patterns between the eyes in young atopic patients, likely eye rubbers. Inferior and temporal epithelial thickness seem to be more affected by thinning in the eye on the side of the dominant hand.

Abstract 2117: IFN-γ signaling in myeloid cells regulates pancreatic cancer growth and progression

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by low survival, early metastasis, and rapidly emerging resistance to therapy. Interferon gamma (IFN-γ) signaling pathway is one of the key regulators of the tumor microenvironment in numerous cancer settings and its possible key role in myeloid cells is suggested. Here we investigated the IFN-y signaling in myeloid cells during PDAC development, progression, and metastasis using mice with conditional ablation of IFNgR2 in myeloid cells (IFNgR2-Delta-Mye). We performed an orthotopical injection of cells derived from conditional murine pancreatic model (Pdx1Cre-Kras-P53, or “KPC” cells) into IFNgR2-LysMCre (IFNgR2-Delta-Mye) mice. Ablation of IFN-γ signaling in myeloid cells led to a higher tumor burden compared to controls. Subsequent RNA sequence analysis demonstrated that IFN-γR2 deficiency in myeloid cells resulted in increased TGFβ1 gene expression as well as changes in metabolic and growth factor pathways in macrophages isolated from tumor tissue. Immunofluorescent analysis demonstrated that IFN-γR2 deletion in myeloid cells led to changes in cancer cell differentiation, resulting in a loss of characteristic epithelial histological pattern and shifting it towards more aggressive phenotype, possible via TGFβ1 dependent mechanism. Using murine model of liver metastasis, we found that loss of IFN-γR2 in myeloid cells leads to increased metastatic outgrowth of PDAC KPC cells. This effect was partially dependent on the gut microbiota, as shown by “separated and co-housed mice” experiments. Deficiency of IFN-γR2 in myeloid cells resulted in increased recruitment and infiltration of monocytes in normal and tumor/metastatic liver tissues. Our data identifies myeloid cell type specific IFN-γ signaling pathway as an important regulator of pancreatic cancer progression and metastasis, that can be potentially exploited as a novel immunooncology target. Citation Format: Elena Ivleva, Natalia Andreeva, Sergei Grivennikov. IFN-γ signaling in myeloid cells regulates pancreatic cancer growth and progression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2117.

Orthokeratinized odontogenic cysts: A clinicopathologic study of 159 cases and molecular evidence for the absence of PTCH1 mutations.

Orthokeratinized odontogenic cyst (OOC), a newly designated entity of odontogenic cysts, is an intraosseous jaw cyst that is entirely or predominantly lined by orthokeratinized squamous epithelium. The aim of this study was to report a large series of OOC to substantiate its clinicopathologic profiles and to investigate PTCH1 mutations in OOCs. The clinicopathologic features of 167 OOCs from 159 patients were analyzed and the immunohistochemical expression of markers related to cell differentiation and proliferation was evaluated. Furthermore, PTCH1 mutations were analyzed in 14 fresh samples of OOC. OOCs occurred mostly in the third and fourth decades (60.4%) with a male predilection (66.7%). The lesions developed more often in the mandible than maxilla, primarily in the posterior mandible and ramus. Eight patients (5.0%) showed multiple locations of either bilateral posterior mandible (n=6) or both the maxilla and mandible. Radiographically, the majority of OOCs (91.2%) showed a well-demarcated, unilocular radiolucency with 14 multilocular cases (8.8%). A follow-up of 131 patients (123 treated by enucleation with or without marsupialization and eight by peripheral ostectomy) revealed no recurrence during an average period of 4.56 years after surgery. Immunohistochemistry indicated lower proliferative activity and a varying epithelial differentiation pattern in OOC compared with odontogenic keratocysts (OKC). No PTCH1 mutation was detected, except for three known single nucleotide polymorphisms. The clinicopathological and molecular differences between OOC and OKC justified their separation, and unlike OKCs, OOCs did not harbor PTCH1 mutations, suggesting different pathogenesis underlying these two jaw cysts.

Cell clusters containing intestinal stem cells, line the zebrafish intestine intervillus pocket

SummaryIn the mammalian intestine, stem cells (ISCs) replicate in basal crypts, translocate along the villus, and undergo cell death. This pattern of renewal occurs in the zebrafish intestine in which villi are elongated into villar ridges (VR) separated by intervillus pockets (IVP) but lack the infolded crypts. To understand how epithelial dynamics is maintained without crypts, we investigated the origin of epithelial lineage patterns derived from ISCs in the IVP of chimeric and zebrabow recombinant intestines. We found that the VR epithelium and IVP express the same recombinant colors when expression is under the control of ISC marker promoter prmt1. The expression originates from cell clusters that line the IVP and contain epithelial cells including Prmt1-labeled cells. Our data suggest that Prmt1 is a zebrafish ISC marker and the ISCs reside within basal cell clusters that are functionally analogous to crypts.

Estrogen receptor expression is modulated in human and mouse prostate epithelial cells during cancer progression

Substantial data posit estrogen receptors (ERs) as promising targets for prostate cancer (PCa) therapeutics. However, the trials on assessing the chemo-preventive or therapeutic potential of ER targeting drugs or selective estrogen receptor modulators (SERMs) have not yet established their clinical benefits. This could be ascribed to a possible modulation in the ER expression during PCa progression. Further it is warranted to test various ER targeting drugs in appropriate preclinical models that simulate human ER expression pattern during PCa progression. The study was undertaken to revisit the existing data on the epithelial ER expression pattern in human cancerous prostates and experimentally determine whether these patterns are replicated in TRAMP (Transgenic Adenocarcinoma of Mouse Prostate) mice, a model for human PCa. Estradiol (E2) binding to the plasma membrane of the epithelial cells and its modulation during the PCa progression in TRAMP were also investigated.A reassessment of the existing data revealed a trend towards downregulation in the epithelial expression of wild-type ESR1 transcripts in high-grade PCa, compared to non-cancerous prostate in humans. Next, epithelial cell-enriched populations from TRAMP prostates (TP) displaying low-grade prostatic intraepithelial neoplasia (LGPIN), high-grade PIN (HGPIN), HGPIN with well-differentiated carcinoma (PIN + WDC), WDC (equivalent to grade 2/3 human PCa), and poorly-differentiated carcinoma (PDC-equivalent to grade 4/5 human PCa) revealed significantly higher Esr1 and Esr2 levels in HGPIN and significantly reduced levels in WDC, compared to respective age-matched control prostates. These patterns for the nuclear ERs were similar to the trend shown by E2 binding to the plasma membrane of the epithelial cells during PCa progression in TRAMP. E2 binding to epithelial cells (EpCAM+), though significantly higher in TPs displaying LGPIN, decreased significantly as the disease progressed to WDC. The study highlights a reduction in the epithelial ESR level with the PCa progression and this pattern was evident in both humans and TRAMP. These observations may have major implications in refining PCa therapeutics targeting ER.

Corneal Epithelial Thickness Mapping in the Diagnosis of Ocular Surface Disorders Involving the Corneal Epithelium: A Comparative Study.

Purpose:The purpose of this study was to analyze the role of corneal epithelial thickness (ET) mapping provided by spectral domain optical coherence tomography in the diagnosis of ocular surface disorders (OSDs) involving the corneal epithelium.Design:This was a retrospective comparative study.Methods:Institutional settings are as follows. Study population includes 303 eyes with an OSD and 55 normal eyes (controls). Observation procedures include spectral domain optical coherence tomography with epithelial mapping in the central 6 mm. Main outcome measures include ET map classification (normal, doughnut, spoke-wheel, localized/diffuse, and thinning/thickening patterns) and ET data and statistics (minimum, maximum, and SD). A quantitative threshold was determined with receiver operating curves to distinguish pathological from normal corneas. Sensitivity and specificity of classification and quantitative data were calculated using all eyes to assess the ability to distinguish corneas with a given corneal disorder from other conditions.Results:Classification of full agreement between 3 readers was obtained in 75.4% to 99.4% of cases. Main OSD features were keratoconus (135 eyes), doughnut pattern (sensitivity/specificity = 56/94%), and max–min ET ≥ 13 μm (84/43%); limbal deficiency (56 eyes), spoke-wheel pattern (66/98%), and max–min ET ≥ 14 μm (91/59%); epithelial basement membrane dystrophy (55 eyes), inferior thickening pattern (55/92%), and central ET > 56 μm (53/81%); dry eye (21 eyes), superior thinning pattern (67/88%), and minimal ET ≤ 44 μm (86/48%); pterygium (10 eyes), nasal thickening pattern (100/86%), and nasal ET > 56 μm (80/71%); and in situ carcinoma (11 eyes), max ET > 60 μm (91/60%), and ET SD >5 μm (100/58%).Conclusions:The epithelial map pattern recognition combined with quantitative analysis of ET is relevant for the diagnosis of OSDs and for distinguishing various OSDs from each other. Deep learning analysis of big data could lead to the fully automated diagnosis of these disorders.

Epithelial cells-enriched lncRNA SNHG8 regulates chromatin condensation by binding to Histone H1s.

Linker histone H1 proteins contain many variants in mammalian and can stabilize the condensed state of chromatin by binding to nucleosomes and promoting a more inaccessible structure of DNA. However, it is poorly understood how the binding of histone H1s to chromatin DNA is regulated. Screened as one of a collection of epithelial cells-enriched long non-coding RNAs (lncRNAs), here we found that small nucleolar RNA host gene 8 (SNHG8) is a chromatin-localized lncRNA and presents strong interaction and phase separation with histone H1 variants. Moreover, SNHG8 presents stronger ability to bind H1s than linker DNA, and outcompetes linker DNA for H1 binding. Consequently, loss of SNHG8 increases the amount of H1s that bind to chromatin, promotes chromatin condensation, and induces an epithelial differentiation-associated gene expression pattern. Collectively, our results propose that the highly abundant SNHG8 in epithelial cells keeps histone H1 variants out of nucleosome and its loss contributes to epithelial cell differentiation.

Coexistence of superficial carcinogenesis of resident epithelium besides neuroendocrine neoplasm of the digestive tract.

Background & AimsMixed neuroendocrine–non‐neuroendocrine neoplasm (MiNEN) is a rare neuroendocrine neoplasm (NEN) comprising dual neuroendocrine and non‐neuroendocrine components. Although the coexistence pattern of neuroendocrine and non‐neuroendocrine components in definitive MiNEN is thought to overlap, there may be a coexistent pattern of both components, such as superficial carcinoma adjacent to NEN. The present study evaluated the histopathological findings of the coexistence pattern of superficial carcinomas adjacent to NENs in the esophagogastrointestinal tract.MethodsFrom 2000 to 2019, 35 serial NEN resections of the esophagus (n = 9), stomach (n = 3), and large intestine (n = 23), respectively, were performed at Gunma University Hospital. Borderline areas between NEN and resident superficial epithelium were observed in the 35 serial NEN cases as well as two additional cases from affiliated hospitals.ResultsAmong the 35 serial NEN samples, squamous cell carcinomatous/dysplastic components were identified 77.8% (7/9 cases) of esophageal NENs, and adenocarcinomatous areas were seen in 66.7% (2/3 cases) of gastric NENs and 26% (6/23 cases) of colorectal NENs. Thus, all superficial carcinomatous components adjacent to NENs were observed as squamous cell carcinoma/dysplasia in esophagus and adenocarcinoma in stomach and large intestine, which showed histological characteristics as the resident epithelial pattern in each organ.ConclusionsThese findings suggested a potential “paratransformation” or “bystander effect” in resident epithelium by NENs. Thus, “bystander carcinogenesis” could be a pathogenic mechanism of resident epithelium transformation adjacent to NENs in the esophagogastrointestinal tract.