Suppression of STAT3 and HIF-1 Alpha Mediates Anti-Angiogenic Activity of Betulinic Acid in Hypoxic PC-3 Prostate Cancer Cells

Background: Signal transducer and activator of transcription 3 (STAT3) is a transcription factor that regulates various cellular processes such as cell survival, angiogenesis and proliferation. In the present study, we examined that betulinic acid (BA), a triterpene from the bark of white birch, had the inhibitory effects on hypoxia-mediated activation of STAT3 in androgen independent human prostate cancer PC-3 cells. Methodology/Principal Findings: BA inhibited the protein expression and the transcriptional activities of hypoxia-inducible factor-1a (HIF-1a) under hypoxic condition. Consistently, BA blocked hypoxia-induced phosphorylation, DNA binding activity and nuclear accumulation of STAT3. In addition, BA significantly reduced cellular and secreted levels of vascular endothelial growth factor (VEGF), a critical angiogenic factor and a target gene of STAT3 induced under hypoxia. Furthermore, BA prevented in vitro capillary tube formation in human umbilical vein endothelial cells (HUVECs) maintained in conditioned medium of hypoxic PC-3 cells, implying anti-angiogenic activity of BA under hypoxic condition. Of note, chromatin immunoprecipitation (ChiP) assay revealed that BA inhibited binding of HIF-1a and STAT3 to VEGF promoter. Furthermore, silencing STAT3 using siRNA transfection effectively enhanced the reduced VEGF production induced by BA treatment under hypoxia. Conclusions/Significance: Taken together, our results suggest that BA has anti-angiogenic activity by disturbing th

Interleukin-2 induces the in vitro maturation of human pluripotent stem cell-derived intestinal organoids.

Human pluripotent stem cell (hPSC)-derived intestinal organoids (hIOs) form 3D structures organized into crypt and villus domains, making them an excellent in vitro model system for studying human intestinal development and disease. However, hPSC-derived hIOs still require in vivo maturation to fully recapitulate adult intestine, with the mechanism of maturation remaining elusive. Here, we show that the co-culture with human T lymphocytes induce the in vitro maturation of hIOs, and identify STAT3-activating interleukin-2 (IL-2) as the major factor inducing maturation. hIOs exposed to IL-2 closely mimic the adult intestinal epithelium and have comparable expression levels of mature intestinal markers, as well as increased intestine-specific functional activities. Even after in vivo engraftment, in vitro-matured hIOs retain their maturation status. The results of our study demonstrate that STAT3 signaling can induce the maturation of hIOs in vitro, thereby circumventing the need for animal models and in vivo maturation

Kikuchi-Fujimoto disease mimicking malignant lymphoma with 2-[F]fluoro-2-deoxy-D-glucose PET/CT in children

PurposeKikuchi-Fujimoto disease (KFD) is a benign disease, which is characterized by a cervical lymphadenopathy with fever, and it often mimics malignant lymphoma (ML). 2-[18F]fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) is a powerful imaging modality for the diagnosis, staging and monitoring of ML, with the limitations including the nonspecific FDG uptake in infectious or inflammatory processes. This study compared clinical manifestations and PET/CT findings between KFD and ML patients.MethodsWe retrospectively reviewed the medical records of 23 patients with KFD and 33 patients with ML, diagnosed histopathologically, between January 2000 and May 2013 at the Department of Pediatrics, Yeungnam University Medical Center. Among them, we analyzed the clinical manifestations, laboratory findings and characteristics, and the amount of 18F-FDG uptake between 8 KFD and 9 ML patients who had 18F-FDG PET/CT.ResultsThe 18F-FDG PET/CT maximum standardized uptake values (SUVmax) ranged from 8.3 to 22.5 (mean, 12.0) in KFDs, and from 5.8 to 34.3 (mean, 15.9) in MLs. There were no significant differences in SUVmax between KFDs and MLs. 18F-FDG PET/CT with ML patients showed hot uptakes in the extranodal organs, such as bone marrow, small bowel, thymus, kidney, orbit and pleura. However, none of the KFD cases showed extranodal uptake (P<0.001). 18F-FDG PET/CT findings of KFD with nodal involvement only were indistinguishable from those of ML.ConclusionPatients who had extranodal involvement on PET/CT were more likely to have malignancy than KFD

Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study

Background : Multiple epiphyseal dysplasia (MED) is a relatively common skeletal dysplasia mainly involving the epiphyses of the long bones. However, it is a genetically heterogeneous group of diseases sharing certain aspects of the radiologic phenotype. In surveys conducted in East Asia, MATN3 was the most common causative gene, followed by COMP. In this study, the authors compared clinical manifestation of MED patients caused by MATN3 and COMP gene mutations, as well as subsequent orthopaedic interventions. Methods : Fifty nine molecularly-confirmed MED patients were subjects of this study. The MATN3 gene mutation group comprised of 37 patients (9 female, 28 male). The COMP gene mutation consisted of 22 cases (15 females, 7 males). Medical records and radiographs were reviewed, and questionnaire surveys or telephone interviews were conducted. Results : At the first presentation, the mean age was 8.8 ± 2.8 years (mean ± standard deviation) in the MATN3 group, and 8.5 ± 3.5 years in the COMP group (p = 0.670). The height in the COMP group was significantly shorter than those in the MATN3 group (p < 0.001). Gait abnormality at the first visit (p = 0.041) and the lastest follow-up (p = 0.037) were statistically significant difference. Hip pain (p = 0.084), limitation of daily activity (p = 0.075) at the latest follow-up tended to be more frequent in the COMP group. Hip dysplasia was more common in the COMP group, having significantly larger acetabular angle (p = 0.037), smaller center-edge angle (p = 0.002), severe Stulberg classification (p < 0.001), and smaller femoral head coverage (p < 0.001). Conclusions : Clinical manifestations of MED caused by MATN3 were milder than manifestations of the COMP mutation group. These differences in clinical manifestation and prognosis justify molecular differentiation between the two genotypes.This study was supported by a grant from the SNUH Research Fund (No. 04-2013-0640).Peer Reviewe

Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study

Background : Multiple epiphyseal dysplasia (MED) is a relatively common skeletal dysplasia mainly involving the epiphyses of the long bones. However, it is a genetically heterogeneous group of diseases sharing certain aspects of the radiologic phenotype. In surveys conducted in East Asia, MATN3 was the most common causative gene, followed by COMP. In this study, the authors compared clinical manifestation of MED patients caused by MATN3 and COMP gene mutations, as well as subsequent orthopaedic interventions. Methods : Fifty nine molecularly-confirmed MED patients were subjects of this study. The MATN3 gene mutation group comprised of 37 patients (9 female, 28 male). The COMP gene mutation consisted of 22 cases (15 females, 7 males). Medical records and radiographs were reviewed, and questionnaire surveys or telephone interviews were conducted. Results : At the first presentation, the mean age was 8.8 ± 2.8 years (mean ± standard deviation) in the MATN3 group, and 8.5 ± 3.5 years in the COMP group (p = 0.670). The height in the COMP group was significantly shorter than those in the MATN3 group (p < 0.001). Gait abnormality at the first visit (p = 0.041) and the lastest follow-up (p = 0.037) were statistically significant difference. Hip pain (p = 0.084), limitation of daily activity (p = 0.075) at the latest follow-up tended to be more frequent in the COMP group. Hip dysplasia was more common in the COMP group, having significantly larger acetabular angle (p = 0.037), smaller center-edge angle (p = 0.002), severe Stulberg classification (p < 0.001), and smaller femoral head coverage (p < 0.001). Conclusions : Clinical manifestations of MED caused by MATN3 were milder than manifestations of the COMP mutation group. These differences in clinical manifestation and prognosis justify molecular differentiation between the two genotypes.This study was supported by a grant from the SNUH Research Fund (No. 04-2013-0640).Peer Reviewe

Comparison of orthopaedic manifestations of multiple epiphyseal dysplasia caused by MATN3 versus COMP mutations: a case control study

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited.Abstract Background Multiple epiphyseal dysplasia (MED) is a relatively common skeletal dysplasia mainly involving the epiphyses of the long bones. However, it is a genetically heterogeneous group of diseases sharing certain aspects of the radiologic phenotype. In surveys conducted in East Asia, MATN3 was the most common causative gene, followed by COMP. In this study, the authors compared clinical manifestation of MED patients caused by MATN3 and COMP gene mutations, as well as subsequent orthopaedic interventions. Methods Fifty nine molecularly-confirmed MED patients were subjects of this study. The MATN3 gene mutation group comprised of 37 patients (9 female, 28 male). The COMP gene mutation consisted of 22 cases (15 females, 7 males). Medical records and radiographs were reviewed, and questionnaire surveys or telephone interviews were conducted. Results At the first presentation, the mean age was 8.8 ± 2.8 years (mean ± standard deviation) in the MATN3 group, and 8.5 ± 3.5 years in the COMP group (p = 0.670). The height in the COMP group was significantly shorter than those in the MATN3 group (p < 0.001). Gait abnormality at the first visit (p = 0.041) and the lastest follow-up (p = 0.037) were statistically significant difference. Hip pain (p = 0.084), limitation of daily activity (p = 0.075) at the latest follow-up tended to be more frequent in the COMP group. Hip dysplasia was more common in the COMP group, having significantly larger acetabular angle (p = 0.037), smaller center-edge angle (p = 0.002), severe Stulberg classification (p < 0.001), and smaller femoral head coverage (p < 0.001). Conclusions Clinical manifestations of MED caused by MATN3 were milder than manifestations of the COMP mutation group. These differences in clinical manifestation and prognosis justify molecular differentiation between the two genotypes