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Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing (IL-11 + ) cells are not fully understood. To characterize IL-11 + cells in vivo, we generate Il11 reporter mice. IL-11 + cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11 + cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11 + fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11 + fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment. The stromal fibroblast population in the colon is composed of heterogeneous and distinct cell subtypes that play a crucial role in the development of colitis and colon cancer. Here the authors generate IL-11 reporter mice and characterize the origin and phenotype of inflammatory IL-11 + fibroblasts in colitis and colon cancer preclinical models.

Gastrointestinal colonization has been considered as the primary source of candidaemia; however, few established mouse models are available that mimic this infection route. We therefore developed a reproducible mouse model of invasive candidiasis initiated by fungal translocation and compared the virulence of six major pathogenic Candida species. The mice were fed a low-protein diet and then inoculated intragastrically with Candida cells. Oral antibiotics and cyclophosphamide were then administered to facilitate colonization and subsequent dissemination of Candida cells. Mice infected with Candida albicans and Candida tropicalis exhibited higher mortality than mice infected with the other four species. Among the less virulent species, stool titres of Candida glabrata and Candida parapsilosis were higher than those of Candida krusei and Candida guilliermondii . The fungal burdens of C. parapsilosis and C. krusei in the livers and kidneys were significantly greater than those of C. guilliermondii . Histopathologically, C. albicans demonstrated the highest pathogenicity to invade into gut mucosa and liver tissues causing marked necrosis. Overall, this model allowed analysis of the virulence traits of Candida strains in individual mice including colonization in the gut, penetration into intestinal mucosa, invasion into blood vessels, and the subsequent dissemination leading to lethal infections.

In triple-negative breast cancer (TNBC), the clinicopathological significance of the expression of a second estrogen receptor, ERβ, remains unclear. Further, although the clinicopathological significance of mutant p53 and androgen receptor (AR) has been investigated in TNBC, they have not been established as therapeutic targets. Experimental studies reported the importance of cross-talk between ERβ and p53 or AR in TNBC. In this study, we immunohistochemically examined ERβ expression in surgical specimens of TNBC obtained from postmenopausal patients who underwent surgery without neoadjuvant therapy and investigated the relationship between ERβ expression and various clinicopathological factors, including clinical outcome, while also considering p53 and AR. No significant difference in clinical outcome was noted according to the ERβ status alone (p = 0.2908). However, the ERβ status did affect the relationship between the clinical outcome and p53 or AR status; p53-positive or AR-positive group exhibited significantly more favorable clinical outcomes than p53-negative or AR-negative group, respectively, in the ERβ-positive group (p53, p = 0.0265; AR, p = 0.0285), but not in the ERβ-negative group (p53, p = 0.7228; AR, p = 0.7734). This may be the result of a functional interaction between ERβ and p53 or AR. The role of ERβ in TNBC will be elucidated in further complex studies considering multiple molecules.

Background The consistency of intracranial meningiomas is an important clinical factor because it affects the success of surgical resection. This study aimed at identifying and quantitatively measuring pathological factors that contribute to the consistency of meningiomas. Furthermore, we investigated the relationship between these factors and preoperative neuroradiological imaging. Methods We analyzed 42 intracranial meningioma specimens, which had been removed at our institution between October 2012 and March 2018. Consistency was measured quantitatively after resection using an industrial stiffness meter. For pathological evaluation, we quantitatively measured the collagen-fiber content through binarization of images of Azan-Mallory-stained section. We assessed calcification and necrosis semi-quantitatively using images acquired of Hematoxylin and Eosin stained samples. The relationship between collagen-fiber content rate and imaging findings was examined. Results The content of collagen fibers significantly positively correlated with meningioma consistency ( p < 0.0001). Collagen-fiber content was significantly higher in low- and iso-intensity regions compared with high-intensity regions on the magnetic resonance T2-weighted images ( p = 0.0148 and p = 0.0394, respectively). Calcification and necrosis showed no correlation with tumor consistency. Conclusions The quantitative hardness of intracranial meningiomas positively correlated with collagen-fiber content; thus, the amount of collagen fibers may be a factor that determines the hardness of intracranial meningiomas. Our results demonstrate that T2-weighted images reflect the collagen-fiber content and are useful for estimating tumor consistency preoperatively and non-invasively.

Background Tumor budding is known predictors of lymph node metastasis from esophageal squamous cell carcinoma. However, it is not easy to detect such small cell clusters on hematoxylin–eosin (HE) staining. Therefore, we evaluated tumor budding using immunohistochemistry (IHC) for epithelial cell markers. Method We analyzed tumor budding in 50 cases of superficial esophageal squamous cell carcinoma. We evaluated the impact of clinicopathological factors and tumor budding to predict lymph node metastasis. A total of 565 tumor sections were assessed using HE staining and IHC for cytokeratin 5/6. Results Based on receiver operating characteristic curves, the cut-off values for high-grade tumor budding evaluated using HE staining or IHC were 2 and 11, respectively. High-grade tumor budding evaluated using HE staining ( P  = 0.007) and IHC ( P  ≤ 0.001) were significantly correlated with lymph node metastasis. For tumors with pT1a-MM to pT1b-SM1, high-grade tumor budding evaluated using IHC was correlated with lymph node metastasis ( P  = 0.050). Conclusions Tumor budding was significantly associated with lymph node metastasis. The optimal cut-off values of tumor budding on HE staining and tumor budding on IHC were 2 and 11, respectively. Even though both tumor budding on HE staining and tumor budding on IHC were significantly associated with lymph node metastasis, tumor budding on IHC tend to be more associated with lymph node metastasis.

Vulvovaginal candidiasis is a common superficial candidiasis; however, a host's immunological mechanism against vaginal Candida infection remains unknown. In this study, we aimed to elucidate the effect of iNKT cell activation on vulvovaginal candidiasis. Using a vulvovaginal candidiasis model with estrogenized mice, we evaluated the fungal burden and number of leukocyte infiltrations in the vaginal lavage of wild-type C57BL/6J mice after Candida albicans inoculation. One day before C. albicans inoculation, α-galactosylceramide (the α-GalCer group) or sterile phosphate-buffered saline (the sham group) was intraperitoneally injected into the mice. We also evaluated the level of antimicrobial peptide S100A8 in the vaginal lavage and analyzed the correlation between S100A8 concentration and the number of vaginal leukocyte infiltrations. Moreover, the number of uterine and vaginal immune cells were evaluated using flow cytometry. The number of vaginal leukocyte infiltrations was significantly higher in the α-GalCer group than in the sham group 3 days after C. albicans inoculation. In addition, the fungal burden was significantly lower in the α-GalCer group than the sham group at 7 days after inoculation. In the analysis of S100A8 concentration of vaginal lavage, there were no significant differences between these two groups, although S100A8 concentration and the number of vaginal leukocyte infiltrations were positively correlated in the α-GalCer group. Moreover, the number of vaginal iNKT cells, NK cells and CD8+ T-cells was significantly higher in the α-GalCer group 3 days after inoculation. α-GalCer-stimulated iNKT cells likely play a protective role against vulvovaginal candidiasis.

AimsL-type amino acid transporter 1 (LAT1) is a major Na+-independent neutral amino acid transporter, forming a complex with CD98hc. The aim of this study is to investigate the significance of LAT1 and CD98hc in invasive breast cancer.MethodsLAT1 and CD98hc expression was immunohistochemically assessed in 280 invasive breast cancers and analysed for association with clinicopathological features.ResultsHigh levels of LAT1 and CD98hc were observed in triple-negative breast cancers (TNBCs) possessing negative immunoreactivity with oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2, compared with non-TNBCs (NTNBCs), and were associated with lymph-node metastasis and higher nuclear grade. The high-LAT1-expression group showed a poor prognosis in NTNBC and TNBC, however, high-CD98hc-expression group showed a poor prognosis only in NTNBC. LAT1 and CD98hc expression could be the prognostic factors in univariate analyses, but not in multivariate analyses. Further, we found that invasive tumour components showed higher LAT1 and CD98hc expression than non-invasive tumour components.ConclusionsLAT1 and CD98hc may possess prognostic values in invasive breast cancer. LAT1 may be linked with cancer cell activities and disease progression in breast cancer.

Candida auris is an emerging fungal species, and several reports have recently identified C. auris in patients with vulvovaginal candidiasis (VVC), although few studies have investigated the relationship between C. auris and VVC or the associated host factors. Our study, using the VVC mouse model, confirmed persistent vaginal colonization by C. auris , especially clades I, III, and IV, along with reduced neutrophil infiltration and lower S100A8 secretion under interleukin-17A-deficient conditions. In addition, in vitro assays demonstrated enhanced C. auris adhesion to vaginal epithelial cells, especially microaerobic conditions imitating human vaginal microenvironments. Our findings suggest that C. auris exhibits strong vaginal tropism, and IL-17A plays a critical role in controlling C. auris -associated VVC.

BackgroundA combination of positron emission tomography and computed tomography (PET/CT) is an important modality for the diagnosis of carcinoma. Metabolic tumor volume (MTV) and total lesion glycolysis (TLG) have been reported as metabolic parameters in PET/CT since the late 1990s, and they are expected to be useful in diagnosing diverse cancers and as prognostic biomarkers. We evaluated the potential of these parameters in the prognosis of colorectal cancer (CRC) by comparing them with conventional parameters, including the maximum standardized uptake value (SUVmax). We enrolled 84 patients who underwent surgery for CRC without distal metastasis between April 2015 and April 2019. SUVmax, MTV, and TLG were measured by 18F-fluorodeoxyglucose (FDG)-PET/CT. To find an optimal threshold value related to prognosis, the volume of interest in the primary carcinoma was measured at fixed relative and absolute thresholds based on SUVmax (30%, 40%, and 50%; 2.5, 3.0, and 3.5, respectively), tumor-to-liver standardized uptake ratios, TLR (1.0, 1.5, and 2.0), and SUV normalized to lean body mass, SUL (2.0, 2.5, and 3.0). After classifying the patients into two groups according to pathological N stage, the optimal threshold values of all metabolic parameters were compared between groups using a non-parametric comparison test.ResultThe most suitable thresholds for MTV were a SUVmax of 3.5 and a TLR 2.0. TLG with a SUVmax value of 40% showed the most significant difference. The MTV standard uptake ratio of 2.0 was significantly associated with pathological N stage.ConclusionOur results suggest that an MTV TLR 2.0 on PET/CT reflects pathological N stage in local patients with CRC.

Introduction: Triple-negative breast cancer (TNBC), which lacks expression of estrogen receptor (ER), progesterone receptor (PgR), and epidermal growth factor receptor 2 (HER2), currently has no effective hormonal or molecular target therapy. Objective and Methods: To elucidate the role of the mammalian target of rapamycin (mTOR) signaling pathway in TNBC, the expression of molecules involved in mTOR signaling including mTOR, phosphorylated (p)-mTOR, p-4EBP1, GLUT1, GLUT3, HIF-1α, and Ki67 was investigated by immunohistochemistry in 35 TNBC and 81 non-TNBC cases. Results: Expression of p-mTOR, the activated form of mTOR, but not unphosphorylated mTOR, was significantly higher in non-TNBC cases than in TNBC cases. Expression of p-4EBP1, GLUT1, and GLUT3 was higher in TNBC cases than in non-TNBC cases. When the localization of p-mTOR was classified as nuclear, perinuclear, or cytoplasmic, nuclear localization of p-mTOR was observed more frequently in TNBC than in non-TNBC cases and was correlated with the expression of GLUT1 and GLUT3, which was related to proliferation activity examined with Ki67. Conclusions: mTOR signaling regulates cell proliferation in some cases of TNBC and may be a potential target of molecular therapy for TNBC.