Global Regulator SATB1 Recruits β-Catenin and Regulates TH2 Differentiation in Wnt-Dependent Manner

Chromatin organizer SATB1 and Wnt transducer β-catenin form a complex and regulate expression of GATA3 and TH2 cytokines in Wnt-dependent manner and orchestrate TH2 lineage commitment

An Elastic Interaction-Based Loss Function for Medical Image Segmentation

Deep learning techniques have shown their success in medical image segmentation since they are easy to manipulate and robust to various types of datasets. The commonly used loss functions in the deep segmentation task are pixel-wise loss functions. This results in a bottleneck for these models to achieve high precision for complicated structures in biomedical images. For example, the predicted small blood vessels in retinal images are often disconnected or even missed under the supervision of the pixel-wise losses. This paper addresses this problem by introducing a long-range elastic interaction-based training strategy. In this strategy, convolutional neural network (CNN) learns the target region under the guidance of the elastic interaction energy between the boundary of the predicted region and that of the actual object. Under the supervision of the proposed loss, the boundary of the predicted region is attracted strongly by the object boundary and tends to stay connected. Experimental results show that our method is able to achieve considerable improvements compared to commonly used pixel-wise loss functions (cross entropy and dice Loss) and other recent loss functions on three retinal vessel segmentation datasets, DRIVE, STARE and CHASEDB1

食道扁平上皮癌におきてエンドセリンB受容体の高発現は腫瘍の血管新生と予後に関与する

BACKGROUND:The endothelin axis has been shown to have a pivotal role in several human malignancies. The aim of this study was to clarify the clinical importance of endothelin receptor type B (ETBR) in human oesophageal squamous cell carcinoma (OSCC). METHODS:We evaluated ETBR expression in 107 patients with OSCC by immunohistochemistry. Microvessel density (MVD) and lymphatic vessel density were assessed by CD31 and D2-40 immunostaining, respectively. Furthermore, CD4, CD8, and CD45RO+ tumour-infiltrating lymphocytes (TILs) were immunohistochemically analysed.RESULTS:Sixty-one (57%) cases showed high expression of ETBR. Endothelin receptor type B expression was correlated with several clinicopathological factors including tumour differentiation, tumour depth, and lymph node metastasis. The overall and disease-specific survival rates were significantly lower in patients with high ETBR expression than patients with low expression. Furthermore, multivariate analysis revealed that ETBR status was an independent prognostic factor for patient survival. Mechanistic analysis indicated that MVD was significantly higher in tumour tissues with high ETBR expression compared with those with low expression, suggesting that angiogenesis may be a key mechanism in tumour progression and metastasis of OSCC mediated by ETBR expression. By contrast, there were no significant correlations between TILs and ETBR expression.CONCLUSION: Endothelin receptor type B has a pivotal role in oesophageal cancer and may be therapeutic target for this intractable malignancy.博士（医学）・乙第1336号・平成26年5月28

Redox proteomics of the inflammatory secretome identifies a common set of redoxins and other glutathionylated proteins released in inflammation, influenza virus infection and oxidative stress

Protein cysteines can form transient disulfides with glutathione (GSH), resulting in the production of glutathionylated proteins, and this process is regarded as a mechanism by which the redox state of the cell can regulate protein function. Most studies on redox regulation of immunity have focused on intracellular proteins. In this study we have used redox proteomics to identify those proteins released in glutathionylated form by macrophages stimulated with lipopolysaccharide (LPS) after pre-loading the cells with biotinylated GSH. Of the several proteins identified in the redox secretome, we have selected a number for validation. Proteomic analysis indicated that LPS stimulated the release of peroxiredoxin (PRDX) 1, PRDX2, vimentin (VIM), profilin1 (PFN1) and thioredoxin 1 (TXN1). For PRDX1 and TXN1, we were able to confirm that the released protein is glutathionylated. PRDX1, PRDX2 and TXN1 were also released by the human pulmonary epithelial cell line, A549, infected with influenza virus. The release of the proteins identified was inhibited by the anti-inflammatory glucocorticoid, dexamethasone (DEX), which also inhibited tumor necrosis factor (TNF)-α release, and by thiol antioxidants (N-butanoyl GSH derivative, GSH-C4, and N-acetylcysteine (NAC), which did not affect TNF-α production. The proteins identified could be useful as biomarkers of oxidative stress associated with inflammation, and further studies will be required to investigate if the extracellular forms of these proteins has immunoregulatory functions

The interaction of Wnt-11 and signalling cascades in prostate cancer

Prostate cancer (PCa) is the second most common cancer among the male population. Conventional therapies target androgen signalling, which drives tumour growth; however, they provide limited survival benefits for patients. It is essential, therefore, to develop a more specific biomarker than the current gold standard, PSA testing. The Wnt signalling pathway induces expression of target genes through cell surface receptors. A non-canonical member of this family, Wnt-11, is evolutionarily highly conserved and is normally expressed by various cells in the developing embryo, as well as in the heart, liver and skeletal muscle of adult humans. We comprehensively review several cell signalling pathways to explain how they interact with Wnt-11, demonstrating its use as a potential biomarker for PCa. Several studies have shown that the expression of Wnt-11 is associated with gastric, renal and colorectal adenocarcinomas and PCa. Moreover, Wnt-11 affects extracellular matrix composition and cytoskeletal rearrangement, and it is required for proliferation and/or survival during cell differentiation. It was found that PCa cell lines express high levels of Wnt-11, which allows differentiation of the epithelial prostate tumour cells to neuron-like (NE) cells. The NE cells produce additional factors that can cause regression after treatment. Accumulating evidence shows that Wnt-11 could be a potential biomarker in diagnosing PCa. Many studies have shown both non-canonical and canonical Wnts interact with several signalling cascades such as PKC, JNK, NF-κB, Rho, PKA and PI3K. In particular, evidence demonstrates Wnt-11 is involved in the progression of PCa, thus it could have the potential to become both a specific disease marker and an important therapeutic target

Wnt4 Enhances Murine Hematopoietic Progenitor Cell Expansion Through a Planar Cell Polarity-Like Pathway

Background: While the role of canonical (b-catenin-mediated) Wnt signaling in hematolymphopoiesis has been studied extensively, little is known of the potential importance of non-canonical Wnt signals in hematopoietic cells. Wnt4 is one of the Wnt proteins that can elicit non-canonical pathways. We have previously shown that retroviral overexpression of Wnt4 by hematopoietic cells increased thymic cellularity as well as the frequency of early thymic progenitors and bone marrow hematopoietic progenitor cells (HPCs). However, the molecular pathways responsible for its effect in HPCs are not known. Methodology/Principal Findings: Here we report that Wnt4 stimulation resulted in the activation of the small GTPase Rac1 as well as Jnk kinases in an HPC cell line. Jnk activity was necessary, while b-catenin was dispensable, for the Wnt4-mediated expansion of primary fetal liver HPCs in culture. Furthermore, Jnk2-deficient and Wnt4 hemizygous mice presented lower numbers of HPCs in their bone marrow, and Jnk2-deficient HPCs showed increased rates of apoptosis. Wnt4 also improved HPC activity in a competitive reconstitution model in a cell-autonomous, Jnk2-dependent manner. Lastly, we identified Fz6 as a receptor for Wnt4 in immature HPCs and showed that the absence of Wnt4 led to a decreased expression of four polarity complex genes. Conclusions/Significance: Our results establish a functional role for non-canonical Wnt signaling in hematopoiesis throug

Quality of life after patient-initiated vs physician-initiated response to symptom monitoring:the SYMPRO-Lung trial

BackgroundPrevious studies using patient-reported outcomes measures (PROMs) to monitor symptoms during and after (lung) cancer treatment used alerts that were sent to the health-care provider, although an approach in which patients receive alerts could be more clinically feasible. The primary aim of this study was to compare the effect of weekly PROM symptom monitoring via a reactive approach (patient receives alert) or active approach (health-care provider receives alert) with care as usual on health-related quality of life (HRQOL) at 15 weeks after start of treatment in lung cancer patients.MethodsThe SYMPRO–Lung trial is a multicenter randomized controlled trial using a stepped wedge design. Stage I-IV lung cancer patients in the reactive and active groups reported PROM symptoms weekly, which were linked to a common alerting algorithm. HRQOL was measured by the EORTC QLQ-C30 at baseline and after 15 weeks. Linear regression analyses and effect size estimates were used to assess mean QOL–C30 change scores between groups, accounting for confounding.ResultsA total of 515 patients were included (160 active group, 89 reactive group, 266 control group). No differences in HRQOL were observed between the reactive and active group (summary score: unstandardized beta [B] = 0.51, 95% confidence interval [CI] = -3.22 to 4.24, Cohen d effect size [ES] = 0.06; physical functioning: B = 0.25, 95% CI = -5.15 to 4.64, ES = 0.02). The combined intervention groups had statistically and clinically significantly better mean change scores on the summary score (B = 4.85, 95% CI = 1.96 to 7.73, ES = 0.57) and physical functioning (B = 7.00, 95% CI = 2.90 to 11.09, ES = 0.71) compared with the control group.ConclusionsWeekly PRO symptom monitoring statistically and clinically significantly improves HRQOL in lung cancer patients. The logistically less intensive, reactive approach may be a better fit for implementation