Search

Background: Intratympanic and intravenous gadolinium administration is used to visualise endolymphatic hydrops. Aims/objectives: The goal of this study was to compare the image quality between intratympanic (IT-method) and intravenous (IV-method) gadolinium administration using three-dimensional inversion recovery with real reconstruction (3D real IR) sequences. Materials and methods: A number of 152 patients with Meniere's disease were included. The 3D real IR sequence was performed 24 h after IT administration or 4 h after IV administration. The detection rate of endolymphatic hydrops, signal-to-noise ratio (SNR), and contrast-to-noise ratio (CNR) of the two methods were compared. Specifically, the average image scores of the two methods were evaluated by two radiologists. Results: The SNRROI and CNRs of the IT-method were higher than those of the IV-method, whereas no significant difference between the IT-method and IV-method with regard to the SNRB was found. The average image scores were 3.49 ± 0.12 and 3.30 ± 0.12 for the IT-method and IV-method, respectively (p = .229). No statistically significant difference was found between two methods in terms of the detection rate of endolymphatic hydrops. Conclusions and significance: IT-method images can display endolymphatic hydrops more precisely than IV-method images. The IV-method can be used as an alternative to the IT-method in clinical applications to some extent.

Previous literatures reported insulin-like growth factor-2 messenger RNA-binding protein 3 (IGF2BP3) is a poor prognostic marker for colorectal cancer (CRC) patients. However, basic research on the effect and biological role of IGF2BP3 in CRC was still scare. Real-time quantitative polymerase chain reaction and western blot analysis were used to examine IGF2BP3 expression level in tumors and paired normal tissues from CRC patients. Tissue microarrays with 192 CRC patients were subjected to immunohistochemical staining to analyze the prognostic value of IGF2BP3. Proliferation assays, migration assays, and xenograft tumor formation in nude mice were performed to assess the biological role of IGF2BP3 in CRC cells. IGF2BP3 expression was significantly upregulated in tumor tissues compared with the matched normal tissues both in messenger RNA and protein level and was associated with worse prognosis. IGF2BP3 knockdown made cell cycle arrest to impair the proliferation ability of CRC cells and further inhibited the xenograft tumor growth in nude mice, also inhibited the migration ability of CRC cells via inducing epithelial-mesenchymal transition. Therefore, the research demonstrated that increased IGF2BP3 expression promoted the aggressive phenotypes of CRC cells. Targeted IGF2BP3 could be a novel and effective gene therapy for CRC patients to make a better prognosis.

The basal cell compartment in many epithelial tissues is generally believed to serve as an important pool of stem cells. However, basal cells are heterogenous and the stem cell subpopulation within basal cells is not well elucidated. Here we uncover that the core epithelial-to-mesenchymal transition (EMT) inducer Zeb1 is expressed in a prostate basal cell subpopulation. The Zeb1+ prostate epithelial cells are multipotent prostate basal stem cells (PBSCs) that can self-renew and generate functional prostatic glandular structures at the single-cell level. Genetic ablation studies reveal an indispensable role for Zeb1 in prostate basal cell development. Utilizing unbiased single-cell transcriptomic analysis of over 9000 mouse prostate basal cells, we confirm the existence of the Zeb1+ basal cell subset. Moreover, Zeb1+ epithelial cells can be detected in mouse and human prostate tumors. Identification of the PBSC and its transcriptome profile is crucial to advance our understanding of prostate development and tumorigenesis., Heterogeneous populations of basal cells in the prostate epithelium contain stem cells. Here the authors show that Zeb1 marks a pool of prostate epithelial stem cells that self-renew, generate prostate glandular structures with all 3 epithelial cell types and are required for prostate basal cell development.

Objectives Epigenetic modifiers were important players in the development of haematological malignancies and sensitivity to therapy. Mutations of SET domain‐containing 2 (SETD2), a methyltransferase that catalyses the trimethylation of histone 3 on lysine 36 (H3K36me3), were found in various myeloid malignancies. However, the detailed mechanisms through which SETD2 confers chronic myeloid leukaemia progression and resistance to therapy targeting on BCR‐ABL remain unclear. Materials and methods The level of SETD2 in imatinib‐sensitive and imatinib‐resistant chronic myeloid leukaemia (CML) cells was examined by immunoblotting and quantitative real‐time PCR. We analysed CD34+CD38− leukaemic stem cells by flow cytometry and colony formation assays upon SETD2 knockdown or overexpression. The impact of SETD2 expression alterations or small‐molecule inhibitor JIB‐04 targeting H3K36me3 loss on imatinib sensitivity was assessed by IC50, cell apoptosis and proliferation assays. Finally, RNA sequencing and ChIP‐quantitative PCR were performed to verify putative downstream targets. Results SETD2 was found to act as a tumour suppressor in CML. The novel oncogenic targets MYCN and ERG were shown to be the direct downstream targets of SETD2, where their overexpression induced by SETD2 knockdown caused imatinib insensitivity and leukaemic stem cell enrichment in CML cell lines. Treatment with JIB‐04, an inhibitor that restores H3K36me3 levels through blockade of its demethylation, successfully improved the cell imatinib sensitivity and enhanced the chemotherapeutic effect. Conclusions Our study not only emphasizes the regulatory mechanism of SETD2 in CML, but also provides promising therapeutic strategies for overcoming the imatinib resistance in patients with CML.

Tumor metastasis is the major cause of death for prostate cancer (PCa) patients. However, the treatment options for metastatic PCa are very limited. Epithelial-mesenchymal transition (EMT) has been reported to be an indispensable step for tumor metastasis and is suggested to associate with acquisition of cancer stem cell (CSC) attributes. We propose that small-molecule compounds that can reverse EMT or induce mesenchymal-epithelial transition (MET) of PCa cells may serve as drug candidates for anti-metastasis therapy. Methods: The promoters of CDH1 and VIM genes were sub-cloned to drive the expression of firefly and renilla luciferase reporter in a lentiviral vector. Mesenchymal-like PCa cells were infected with the luciferase reporter lentivirus and subjected to drug screening from a 1274 approved small-molecule drug library for the identification of agents to reverse EMT. The dosage-dependent effect of candidate compounds was confirmed by luciferase reporter assay and immunoblotting. Wound-healing assay, sphere formation, transwell migration assay, and in vivo intracardiac and orthotopic tumor xenograft experiments were used to evaluate the mobility, metastasis and tumor initiating capacity of PCa cells upon treatment. Possible downstream signaling pathways affected by the candidate compound treatment were analyzed by RNA sequencing and immunoblotting. Results: Drug screening identified Amlexanox, a drug used for recurrent aphthous ulcers, as a strong agent to reverse EMT. Amlexanox induced significant suppression of cell mobility, invasion, serial sphere formation and in vivo metastasis and tumor initiating capacity of PCa cells. Amlexanox treatment led to downregulation of the IKK-ɛ/ TBK1/ NF-κB signaling pathway. The effect of Amlexanox on EMT reversion and cell mobility inhibition can be mimicked by other IKK-ɛ/TBK1 inhibitors and rescued by reconstitution of dominant active NF-κB. Conclusions: Amlexanox can sufficiently suppress PCa metastasis by reversing EMT through downregulating the IKK-ɛ/TBK1/NF-κB signaling axis.

Cell polarity and correct mitotic spindle positioning are essential for the maintenance of a proper prostate epithelial architecture, and disruption of the two biological features occurs at early stages in prostate tumorigenesis. However, whether and how these two epithelial attributes are connected in vivo is largely unknown. We herein report that conditional genetic deletion of E-cadherin, a key component of adherens junctions, in a mouse model results in loss of prostate luminal cell polarity and randomization of spindle orientations. Critically, E-cadherin ablation causes prostatic hyperplasia which progresses to invasive adenocarcinoma. Mechanistically, E-cadherin and the spindle positioning determinant LGN interacts with the PDZ domain of cell polarity protein SCRIB and form a ternary protein complex to bridge cell polarity and cell division orientation. These findings provide a novel mechanism by which E-cadherin acts an anchor to maintain prostate epithelial integrity and to prevent carcinogenesis in vivo., Author summary Luminal cells are the most abundant type of the prostate epithelial cells. Most prostate cancers also display a luminal phenotype. Horizontal cell division of luminal cells allows the surface expansion of the secretory prostate lumen and meanwhile maintains the monolayer and polarized epithelial architecture. Disruption of the epithelial integrity and appearance of multilayer epithelia are early events in prostate adenocarcinoma development. However, the molecular mechanism that ensures the horizontal division in luminal cells remains largely unknown. Here, we generated a genetically engineered mouse model in which E-cadherin, a key component of the adherens junction that serves to connect the lateral plasma membrane of neighboring epithelial cells, was knocked out in the prostate luminal cells. E-cadherin deletion leads to loss of cell polarity and disoriented cell division, which subsequently causes dysregulated cell proliferation and strongly predisposes mice for prostate tumorigenesis. Importantly, we revealed that E-cadherin acts as an anchor to recruit cell polarity protein SCRIB and spindle positioning determinant LGN to the lateral cell membrane, thereby ensure a proper alignment of the cell division plane. All these findings uncover a novel mechanism by which E-cadherin links cell polarity and spindle orientation to keep prostate epithelial integrity and prevent carcinogenesis.

Background: A positive circumferential resection margin (CRM) may result in local recurrence (LR), but the significance remains controversial. We attempted to utilize the lymphocyte ratio (LYMR), neutrophil–lymphocyte ratio (NLR), tumor-infiltrating lymphocyte (TIL) count, and their combinations (TIL–LYMR/TIL–NLR) in predicting LR after rectal resection. Methods: Patients with rectal cancer who underwent curative resection between January 2016 and December 2018 were enrolled. Biopsy samples and data from the blood tests of 124 patients with rectal cancer who underwent curative resection were retrospectively obtained. Patients were divided into 2 groups: LR group and non-local recurrence (nLR) group. CD8 + TILs were immunostained using an antibody against CD8. The density of TILs was defined as the number of positive CD8 lymphocytes per square millimeter and was then graded as either high or low (cutoff = 80/mm2). The count of LYMR and NLR was also graded as either high or low. The associations between TILs, LYMR, NLR, and their combinations (TIL–LYMR/TIL–NLR) were evaluated. Results: With a median follow-up of 24.4 months, TIL–LYMR showed a positive correlation with LR (P = .001), but not with the CD8 + TIL count (P = .215) or TIL-NLR count (P = .638). Among inflammatory and immune markers variables, univariate analysis revealed that gender, CD8 + TIL count, and TIL-NLR count were associated with anastomotic leakage (P = .001, P = .014, and P = .036, respectively). In multivariate analysis, TIL–LYMR remained an independent predictor of LR (OR = 8.918, CI = 1.124–70.747, P = .038). We also showed that gender associated with anastomotic leakage in rectal cancer (OR 5.429; 95% CI 1.885–15.637; P = .002). Conclusion: In this study, our data indicate that absence of CD8 + T-cell infiltration in CRM may influence LR. These parameters may help identify LR provide additional information for therapeutic decision-making.