Prenylflavonoids isolated from Macaranga tanarius stimulate odontoblast differentiation of human dental pulp stem cells and tooth root formation via the mitogen-activated protein kinase and protein kinase B pathways.

AIM: To identify odontogenesis-promoting compounds and examine the molecular mechanism underlying enhanced odontoblast differentiation and tooth formation. METHODOLOGY: Five different nymphaeols, nymphaeol B (NB), isonymphaeol B (INB), nymphaeol A (NA), 3'-geranyl-naringenin (GN) and nymphaeol C (NC) were isolated from the fruit of Macaranga tanarius. The cytotoxic effect of nymphaeols on human DPSCs was observed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effect of nymphaeols on odontoblast differentiation was analysed with Alizarin Red S staining and odontoblast marker expression was assessed using real-time polymerase chain reaction and Western blot analysis. The molecular mechanism was investigated with Western blot analysis. In order to examine the effect of INB on dentine formation in the developing tooth germ, INB-soaked beads were placed under the tooth bud explants in the collagen gel; thereafter, the tooth bud explant-bead complexes were implanted into the sub-renal capsules for 3 weeks. Tooth root formation was analysed using micro-computed tomography and histological analysis. Data are presented as mean ± standard error (SEM) values of three independent experiments, and results are compared using a two-tailed Student's t-test. The data were considered to have statistical significance when the P-value was less than 0.05. RESULTS: Three of the compounds, NB, INB, and GN, did not exert a cytotoxic effect on human DPSCs. However, INB was most effective in promoting the deposition of calcium minerals in vitro (P < 0.001) and induced the expression of odontogenic marker genes (P < 0.05). Moreover, this compound strongly induced the phosphorylation of mitogen-activated protein (MAP) kinases and protein kinase B (AKT) (P < 0.05). The inhibition of p38 MAP, c-Jun N-terminal kinase (JNK), and AKT substantially suppressed the INB-induced odontoblast differentiation (P < 0.001). In addition, isonymphaeol B significantly induced the formation of dentine and elongation of the tooth root in vivo (P < 0.05). CONCLUSIONS: Prenylflavonoids, including INB, exerted stimulatory effects on odontoblast differentiation and tooth root and dentine formation via the MAP kinase and AKT signalling pathways. These results suggest that nymphaeols could stimulate the repair processes for dentine defects or injuries.

Correction to: Optimized THP-1 differentiation is required for the detection of responses to weak stimuli.

After the publication of our article [1] we were made aware that in Fig. 2D the images for PMA 2.5 ng/ml and PMA 25 ng/ml are identical.

iNKT cells prevent obesity-induced hepatic steatosis in mice in a C-C chemokine receptor 7-dependent manner.

Non-alcoholic fatty liver disease and non-alcoholic steatohepatitis are characterized by an increase in hepatic triglyceride content with infiltration of immune cells, which can cause steatohepatitis and hepatic insulin resistance. C-C chemokine receptor 7 (CCR7) is primarily expressed in immune cells, and CCR7 deficiency leads to the development of multi-organ autoimmunity, chronic renal disease and autoimmune diabetes. Here, we investigated the effect of CCR7 on hepatic steatosis in a mouse model and its underlying mechanism. Our results demonstrated that body and liver weights were higher in the CCR7-/- mice than in the wild-type (WT) mice when they were fed a high-fat diet. Further, glucose tolerance and insulin sensitivity were markedly diminished in CCR7-/- mice. The number of invariant natural killer T (iNKT) cells was reduced in the livers of the CCR7-/- mice. Moreover, liver inflammation was detected in obese CCR7-/- mice, which was ameliorated by the adoptive transfer of hepatic mononuclear cells from WT mice, but not through the transfer of hepatic mononuclear cells from CD1d-/- or interleukin-10-deficient (IL-10-/-) mice. Overall, these results suggest that CCR7+ mononuclear cells in the liver could regulate obesity-induced hepatic steatosis via induction of IL-10-expressing iNKT cells.

The utility of ultrasound superb microvascular imaging for evaluation of breast tumour vascularity: comparison with colour and power Doppler imaging regarding diagnostic performance.

AIM: To investigate the utility of superb microvascular imaging (SMI) for evaluating the vascularity of breast masses in comparison with colour or power Doppler ultrasound (US) and the effect on diagnostic performance. MATERIALS AND METHODS: A total of 191 biopsy-proven masses (99 benign and 92 malignant) in 166 women with greyscale, colour Doppler, power Doppler, and SMI images were enrolled in this retrospective study. Three radiologists analysed the vascular images using a three-factor scoring system to evaluate the number, morphology, and distribution of tumour vessels. They assessed the Breast Imaging-Reporting and Data System categories for greyscale US alone and combinations of greyscale US and each type of vascular US. The Kruskal-Wallis test was performed and the area under the receiver-operating characteristic curve (AUC) measured. On SMI, vascular scores were compared between benign and malignant masses and the optimal cut-off value for the overall score was determined. RESULTS: SMI showed higher vascular scores than colour or power Doppler US and malignant masses had higher scores than benign masses (p<0.001). The diagnostic performance of the combination of greyscale US and SMI was higher than those of greyscale US alone and greyscale and colour or power Doppler US (AUC, 0.815 versus 0.774, 0.789, 0.791; p<0.001). The optimal cut-off value of the overall vascular score was 5 with a sensitivity of 82.3% and a specificity of 65.3% (AUC, 0.808). CONCLUSION: SMI is superior to colour or power Doppler US for characterising the vascularity in breast masses and improving diagnostic performance.

Compliance and persistence with hydroxychloroquine in South Korean patients with systemic lupus erythematosus.

We aimed to analyze compliance and persistence with hydroxychloroquine (HCQ) in real practice and identify risk factors for poor adherence in South Korean patients with systemic lupus erythematosus (SLE). This retrospective longitudinal study evaluated 235 SLE patients in whom oral HCQ was newly started from 2002 to 2016 at a tertiary hospital in South Korea. Compliance was assessed using one-year medication possession ratio (MPR) and non-compliance was defined as a one-year MPR < 0.8. Persistence was determined as the time from HCQ treatment initiation to discontinuation without interruption for ≥56 days. The mean one-year MPR of HCQ was 0.88 and the frequency of non-compliance was 19.9%. During the study period, 115 (48.9%) patients discontinued HCQ and forgetfulness and/or carelessness (73%) were the most common reason for HCQ non-persistence, followed by adverse events (10.4%), unknown factors (10.4%), and pregnancy (6.1%). Median duration until HCQ discontinuation was 55.1 months and the one-year persistence rate to HCQ was 0.8. SLE Disease Activity Index 2000 (SLEDAI-2K) < 6 was a significant risk factor for non-compliance (OR = 2.98, p = 0.001) and non-persistence (HR = 1.55, p = 0.046) with HCQ after adjusting confounding factors. However, HCQ adherence was not associated with the dose of HCQ or concomitant immunosuppressive medications. Our data showed that overall adherence to HCQ in SLE patients was suboptimal in real practice and SLEDAI-2K score < 6 was a risk factor for poor adherence, suggesting the need to improve adherence with HCQ treatment in SLE patients, especially in those with low disease activity.

Bladder stone formation on permanent suture material ten years after laparoscopic high uterosacral ligament suspension.

The present authors describe an uncommon case of iatrogenic bladder stone formation in a patient who underwent surgery for pelvic organ prolapse. A female patient who underwent high uterosacral ligament suspension ten years ago presented with pyuria and irritable bladder symptoms that did not respond to treatment. She had not experienced any specific urinary symptoms during the previous ten years. Patient evaluation revealed bladder stone formation on the non-absorbable suture material used during the previous operation. Cystoscopy during the previous operation did not find the suture material, and the suture knot that was tied extravesically during the operation was found inside the bladder. These strongly suggest delayed migration and rotation of the'suture knot after surgery rather than direct penetration of the bladder during operation. Delayed suture migration is a long-term complication that clinicians should consider in a patient who suffers from recurrent urinary symptoms after pelvic surgery around the bladder.

Transcriptional repression of cancer stem cell marker CD133 by tumor suppressor p53.

Novel therapeutic strategies are needed to overcome cancer recurrence, metastasis, and resistance to chemo- and radiotherapy. Cancer stem cells (CSCs) are major contributors to the malignant transformation of cells due to their capacity for self-renewal. Although various CSC markers have been identified in several types of tumors, they are primarily used as cancer-prediction markers and for the isolation of CSC populations. CD133, one of the best-characterized CSC markers in distinct solid tumor types, was shown to be correlated with CSC tumor-initiating capacity; however, the regulation of CD133 expression and its function in cancer are poorly understood. Here, we show that CD133 expression is negatively regulated by direct binding of the p53 tumor suppressor protein to a noncanonical p53-binding sequence in the CD133 promoter. Binding of p53 recruits Histone Deacetylase 1 (HDAC1) to the CD133 promoter and subsequently suppresses CD133 expression by reducing histone H3 acetylation. Furthermore, CD133 depletion suppresses tumor cell proliferation, colony formation, and the expression of core stemness transcription factors including NANOG, octamer-binding transcription factor 4 (OCT4), SOX2, and c-MYC. Critically, the anti-proliferative effects of p53 are antagonized by rescue of CD133 expression in a p53 overexpressing cell line, indicating that the tumor suppressive activity of p53 might be mediated by CD133 suppression. Taken together, our results suggest that p53-mediated transcriptional regulation of CD133 is a key underlying mechanism for controlling the growth and tumor-initiating capacity of CSCs and provide a novel perspective on targeting CSCs for cancer therapy.

Predicting Microbial Interactions Using Vector Autoregressive Model with Graph Regularization.

Microbial interactions play important roles on the structure and function of complex microbial communities. With the rapid accumulation of high-throughput metagenomic or 16S rRNA sequencing data, it is possible to infer complex microbial interactions. Co-occurrence patterns of microbial species among multiple samples are often utilized to infer interactions. There are few methods to consider the temporally interacting patterns among microbial species. In this paper, we present a Graph-regularized Vector Autoregressive (GVAR) model to infer causal relationships among microbial entities. The new model has advantage comparing to the original vector autoregressive (VAR) model. Specifically, GVAR can incorporate similarity information for microbial interaction inference--i.e., GVAR assumed that if two species are similar in the previous stage, they tend to have similar influence on the other species in the next stage. We apply the model on a time series dataset of human gut microbiome which was treated with repeated antibiotics. The experimental results indicate that the new approach has better performance than several other VAR-based models and demonstrate its capability of extracting relevant microbial interactions.

Ultrasonography of the optic nerve sheath to assess intracranial pressure changes after ventriculo-peritoneal shunt surgery in children with hydrocephalus: a prospective observational study.

The optic nerve sheath diameter has been verified by various clinical studies as a non-invasive indicator of intracranial hypertension. The aim of this study was to compare the optic nerve sheath diameter before and immediately after ventriculo-peritoneal shunt surgery in children with hydrocephalus. We analysed transorbital ultrasonographic images recorded after induction of anaesthesia and 30 min after shunt insertion in 34 children, measuring the optic nerve sheath diameters using a linear ultrasound probe. The mean (SD) optic nerve sheath diameters were 5.4 (0.6) mm (right) and 5.3 (0.7) mm (left) before surgery and 4.4 (0.5) mm (right) and 4.5 (0.7) mm (left) after surgery (p < 0.0001 for before and after comparisons for both eyes). The technique allows rapid and non-invasive assessment of intracranial pressure to guide appropriate postoperative management.

Deletion of Osr2 Partially Rescues Tooth Development in Runx2 Mutant Mice.

Tooth organogenesis depends on genetically programmed sequential and reciprocal inductive interactions between the dental epithelium and neural crest-derived mesenchyme. Previous studies showed that the Msx1 and Runx2 transcription factors are required for activation of odontogenic signals, including Bmp4 and Fgf3, in the early tooth mesenchyme to drive tooth morphogenesis through the bud-to-cap transition and that Runx2 acts downstream of Msx1 to activate Fgf3 expression. Recent studies identified Osr2 as a repressor of tooth development and showed that inactivation of Osr2 rescued molar tooth morphogenesis in the Msx1(-/-) mutant mice as well as in mice with neural crest-specific inactivation of Bmp4. Here we show that Runx2 expression is expanded in the tooth bud mesenchyme in Osr2(-/-) mutant mouse embryos and is partially restored in the tooth mesenchyme in Msx1(-/-)Osr2(-/-) mutants in comparison with Msx1(-/-) and wild-type embryos. Whereas mandibular molar development arrested at the bud stage and maxillary molar development arrested at the bud-to-cap transition in Runx2(-/-) mutant mice, both mandibular and maxillary molar tooth germs progressed to the early bell stage, with rescued expression of Msx1 and Bmp4 in the dental papilla as well as expression of Bmp4, p21, and Shh in the primary enamel knot in the Osr2(-/-)Runx2(-/-) compound mutants. In contrast to the Msx1(-/-)Osr2(-/-) compound mutants, which exhibit nearly normal first molar morphogenesis, the Osr2(-/-)Runx2(-/-) compound mutant embryos failed to activate the expression of Fgf3 and Fgf10 in the dental papilla and exhibited significant deficit in cell proliferation in both the dental epithelium and mesenchyme in comparison with the control embryos. These data indicate that Runx2 synergizes with Msx1 to drive tooth morphogenesis through the bud-to-cap transition and that Runx2 controls continued tooth growth and morphogenesis beyond the cap stage through activation of Fgf3 and Fgf10 expression in the dental papilla.

Selecting protein families for environmental features based on manifold regularization.

Recently, statistics and machine learning have been developed to identify functional or taxonomic features of environmental features or physiological status. Important proteins (or other functional and taxonomic entities) to environmental features can be potentially used as biosensors. A major challenge is how the distribution of protein and gene functions embodies the adaption of microbial communities across environments and host habitats. In this paper, we propose a novel regularization method for linear regression to adapt the challenge. The approach is inspired by local linear embedding (LLE) and we call it a manifold-constrained regularization for linear regression (McRe). The novel regularization procedure also has potential to be used in solving other linear systems. We demonstrate the efficiency and the performance of the approach in both simulation and real data.

Comparison of dimensional reduction methods for detecting and visualizing novel patterns in human and marine microbiome.

Using metagenomics to detect the global structure of microbial community remains a significant challenge. The structure of a microbial community and its functions are complicated because of not only the complex interactions among microbes but also their interactions with confounding environmental factors. Recently dimension reduction methods have been employed extensively to investigate the complex structure embedded in metagenomic profiles which summarize the abundance of functional or taxonomic categorizations in metagenomic studies. However, metagenomic profiles are not necessary to meet the "Assumption of Linearity" behind these methods. Therefore it is worth to investigate whether nonlinear methods are appropriate methods which can be utilized in metagenomic analysis. In this paper, we compare the applications of several methods, including two linear methods (Principle component analysis and nonnegative matrix factorization) and a nonlinear manifold learning method--Isomap on visualizing and analyzing metagenomic profiles. These methods are applied and compared on a taxonomic profile from 33 human gut metagenomes and a large-scale Pfam profile which are derived from 45 metagenomes in Global Ocean Sampling expedition. We find that all three methods can discover interesting structures of the taxonomic profile from human gut. Furthermore, Isomap identified a novel nonlinear structure of protein families. The relationships among the identified nonlinear components and environmental factors of global ocean are explored. The results indicate that nonlinear methods could be a complementary technique to current linear methods in analyzing metagenomic dataset.

Influence of enzyme and transporter polymorphisms on trough imatinib concentration and clinical response in chronic myeloid leukemia patients.

BACKGROUND: This study explored the impact of genetic polymorphisms in cytochrome P450 (CYP) enzymes and transporters on the plasma trough concentration of imatinib mesylate (IM) and clinical response in chronic myeloid leukemia (CML). PATIENTS AND METHODS: In total, 82 patients with CML who had been administered 400 mg IM daily for over 6 months were genotyped for 11 single-nucleotide polymorphisms in nine genes (CYP3A4, CYP3A5, CYP2C9, CYP2C19, CYP2D6, ABCB1, SLC22A1, SLC22A2 and ABCG2) using blood samples. The trough imatinib concentration and clinical responses were assessed 6 months after the initiation of IM therapy. RESULTS: The CC, CA and AA genotypes in ABCG2 421C>A gave significantly different frequencies for the major molecular response (MMR) (P = 0.02). However, no significant differences were found between the genotypes of the CYP enzymes and transporters identified in this study and the imatinib plasma trough concentrations and clinical response frequencies, except for the correlation of ABCG2 with MMR. CONCLUSIONS: The results of the present study may indicate that the ABCG 421C>A genetic polymorphism influences the MMR of imatinib in patients with CML.

Exploiting the functional and taxonomic structure of genomic data by probabilistic topic modeling.

In this paper, we present a method that enable both homology-based approach and composition-based approach to further study the functional core (i.e., microbial core and gene core, correspondingly). In the proposed method, the identification of major functionality groups is achieved by generative topic modeling, which is able to extract useful information from unlabeled data. We first show that generative topic model can be used to model the taxon abundance information obtained by homology-based approach and study the microbial core. The model considers each sample as a "document," which has a mixture of functional groups, while each functional group (also known as a "latent topic") is a weight mixture of species. Therefore, estimating the generative topic model for taxon abundance data will uncover the distribution over latent functions (latent topic) in each sample. Second, we show that, generative topic model can also be used to study the genome-level composition of "N-mer" features (DNA subreads obtained by composition-based approaches). The model consider each genome as a mixture of latten genetic patterns (latent topics), while each functional pattern is a weighted mixture of the "N-mer" features, thus the existence of core genomes can be indicated by a set of common N-mer features. After studying the mutual information between latent topics and gene regions, we provide an explanation of the functional roles of uncovered latten genetic patterns. The experimental results demonstrate the effectiveness of proposed method.

Compensation scheme for complementary and alternative medicine use in asbestos-related diseases in New South Wales, Australia.

WHAT IS KNOWN AND OBJECTIVE: Asbestos use has resulted in a high global incidence rate of asbestos-related diseases (ARDs). These diseases require high costs of compensation and medical expense, although definite cures have yet to be found. Complementary and alternative medicine (CAM) has been used as a means to attenuate symptoms of ARDs. Our objective is to describe the compensation scheme for CAM use for a population with ARDs in New South Wales (NSW), Australia. COMMENT: Expenses of CAM have conditionally been compensated by the workers compensation dust-diseases board (DDB) to a population with ARDs. The DDB approves patients` claim for the use of CAM if it is justifiable and related to compensable ARDs. To obtain the DDB`s approval for the CAM cost, a written recommendation letter by the treating medical doctors is required that justifies the use of CAM and that this option does not pose any adverse effects on the compensated patients. WHAT IS NEW AND CONCLUSION: The use of CAM in a subject with ARDs does not have significant benefits of overall survival but does somewhat improve quality of life. However, awareness of the provisions of the compensation scheme for CAM use in a population with ARDs should be carefully informed and also emphasized any side effects on progress of ARDs.

Dynamic biclustering of microarray data by multi-objective immune optimization.

BACKGROUND: Newly microarray technologies yield large-scale datasets. The microarray datasets are usually presented in 2D matrices, where rows represent genes and columns represent experimental conditions. Systematic analysis of those datasets provides the increasing amount of information, which is urgently needed in the post-genomic era. Biclustering, which is a technique developed to allow simultaneous clustering of rows and columns of a dataset, might be useful to extract more accurate information from those datasets. Biclustering requires the optimization of two conflicting objectives (residue and volume), and a multi-objective artificial immune system capable of performing a multi-population search. As a heuristic search technique, artificial immune systems (AISs) can be considered a new computational paradigm inspired by the immunological system of vertebrates and designed to solve a wide range of optimization problems. During biclustering several objectives in conflict with each other have to be optimized simultaneously, so multi-objective optimization model is suitable for solving biclustering problem. RESULTS: Based on dynamic population, this paper proposes a novel dynamic multi-objective immune optimization biclustering (DMOIOB) algorithm to mine coherent patterns from microarray data. Experimental results on two common and public datasets of gene expression profiles show that our approach can effectively find significant localized structures related to sets of genes that show consistent expression patterns across subsets of experimental conditions. The mined patterns present a significant biological relevance in terms of related biological processes, components and molecular functions in a species-independent manner. CONCLUSIONS: The proposed DMOIOB algorithm is an efficient tool to analyze large microarray datasets. It achieves a good diversity and rapid convergence.

Parovarian tumors of borderline malignancy.

The incidence of a parovarian tumor is 10-20% of all uterine adnexal masses, however, it is benign in most cases, and a borderline or malignant tumor is extremely rare. The classification of disease stage and treatment is still controversial owing to its scarcity. We have managed one mucinous and two serous cystadenomas of borderline malignancy originating from paraovarian cysts in our institute over ten year. We report and discuss the cases herein.

Unexpected synchronous follicular lymphoma of paraaortic and pelvic lymph nodes in a patient with endometrial carcinoma: a case report.

BACKGROUND: Multiple neoplasms in a patient occur rarely. There has only been one case report about synchronous endometrial carcinoma and follicular lymphoma of the paraaortic and pelvic lymph node (LN) until now. CASE REPORT: The patient was 64 years old and had vaginal spotting for four months. She was diagnosed with endometrioid endometrial carcinoma by endometrial biopsy. In intraoperative inspection, the whole paraaortic and pelvic LN had formed into a massive tumor bundle following the aorta and iliac vessels. The diagnosis was endometrial carcinoma FIGO Stage IB with synchronous follicular lymphoma Stage III. We performed adjuvant chemotherapy and radiotherapy. Currently, the patient has no evidence of recurrence for either carcinoma. CONCLUSION: Lymph node dissection was included in the staging and debulking operation of the endometrial carcinoma. An inaccurate result of the frozen section can not rule out metastasis of endometrial carcinoma and surgeons can fall into a dilemma regarding treatment.

Borderline mucinous tumor arising in a paratubal cyst: a case report.

BACKGROUND: Paratubal borderline tumors (PBTs) are found incidentally at frozen section or permanant pathology, and are extremely rare. We describe the first case of a paratubal borderline mucinous tumor (PBMT). CASE REPORT: A 20-year-old woman was referred with a complex right adnexal mass on pelvic sonogram. She underwent laparoscopic paratubal cyst enucleation. We used an endobag for cyst extraction. Cyst rupture or tearing of the endobag in the laparoscopic field was absent. Frozen section analysis was reported as a borderline mucinous tumor of low malignant potential. Currently, she has had no evidence of disease recurrence after a laparoscopic fertility-sparing staging procedure. CONCLUSION: A proper preoperative differential diagnosis of an adnexal mass is difficult. Thus, laparoscopy is needed in large or symptomatic cysts. Although growth, torsion and malignancy are rare in paratubal cysts, the possibility of tumor seeding should be excluded with use of an endobag.