bluuebunny/crossref_metadata_2025 huggingface dataset:
Squamosamide Derivative FLZ Protects Pancreaticβ-Cells from Glucotoxicity by Stimulating Akt-FOXO1 Pathway
Authors: Kong Xiangchen , Zhang Longmei , Hua Xianxin , Ma Xiaosong
Published: June 2015

Chronic hyperglycemia increases apoptosis and reduces glucose-stimulated insulin secretion. Although protective agents have been searched extensively, none has been found so far. Here we tested FLZ, a synthetic derivative of squamosamide from a Chinese herb, as a potential candidate for antiglucotoxicity in INS-1E cells and mouse islets. Chronic culture ofβ-cells in 30 mM glucose caused progressive reduction of cell viability, accompanied with increased apoptosis and reduced insulin secretion. These effects on apoptosis and insulin were reversed by FLZ in a dose-dependent manner. FLZ treatment also increased forkhead box O1 protein phosphorylation and reduced its nuclear location. On the contrary, FLZ increased pancreatic and duodenal homeobox-1 expression and its nuclear localization, an effect mediated by increased p-Akt. Consistently, Akt selective inhibitor MK-2206 completely abolished antiglucotoxicity effect of FLZ. Furthermore, FLZ treatment increased cytosolic ATP/ADP ratio. Taken together, our results suggest that FLZ could be a potential therapeutic agent to treat the hyperglycemia-inducedβ-cell failure.
Procedural Content Graphs for Urban Modeling
Authors: Silva Pedro Brandão , Eisemann Elmar , Bidarra Rafael , Coelho António
Published: June 2015

Massive procedural content creation, for example, for virtual urban environments, is a difficult, yet important challenge. While shape grammars are a popular example of effectiveness in architectural modeling, they have clear limitations regarding readability, manageability, and expressive power when addressing a variety of complex structural designs. Moreover, shape grammars aim at geometry specification and do not facilitate integration with other types of content, such as textures or light sources, which could rather accompany the generation process. We present procedural content graphs, a graph-based solution for procedural generation that addresses all these issues in a visual, flexible, and more expressive manner. Besides integrating handling of diverse types of content, this approach introduces collective entity manipulation as lists, seamlessly providing features such as advanced filtering, grouping, merging, ordering, and aggregation, essentially unavailable in shape grammars. Hereby, separated entities can be easily merged or just analyzed together in order to perform a variety of context-based decisions and operations. The advantages of this approach are illustrated via examples of tasks that are either very cumbersome or simply impossible to express with previous grammar approaches.
The Effect of Visual Feedback on Writing Size in Parkinson’s Disease
Authors: Potgieser Adriaan R. E. , Roosma Elizabeth , Beudel Martijn , de Jong Bauke M.
Published: June 2015

Parkinson’s disease (PD) leads to impairment in multiple cognitive domains. Micrographia is a relatively early PD sign of visuomotor dysfunction, characterized by a global reduction in writing size and a decrement in size during writing. Here we aimed to investigate the effect of withdrawal of visual feedback on writing size in patients with PD. Twenty-five patients with non-tremor-dominant PD without cognitive dysfunction and twenty-five age-matched controls had to write a standard sentence with and without visual feedback. We assessed the effect of withdrawal of visual feedback by measuring vertical word size (i), horizontal length of the sentence (ii), and the summed horizontal word length without interspacing (iii), comparing patients with controls. In both patients and controls, writing was significantly larger without visual feedback. This enlargement did not significantly differ between the groups. Smaller handwriting significantly correlated with increased disease severity. Contrary to previous observations that withdrawal of visual feedback caused increased writing size in specifically PD, we did not find differences between patients and controls. Both groups wrote larger without visual feedback, which adds insight in general neuronal mechanisms underlying the balance between feed-forward and feedback in visuomotor control, mechanisms that also hold for grasping movements.
Evaluation of Genetic Variations in Maize Seedlings Exposed to Electric Field Based on Protein and DNA Markers
Authors: AL-Huqail Asma A. , Abdelhaliem Ekram
Published: June 2015

The current study analyzed proteins and nuclear DNA of electric fields (ELF) exposed and nonexposed maize seedlings for different exposure periods using sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), isozymes, random amplified polymorphic DNA (RAPD), and comet assay, respectively. SDS-PAGE analysis revealed total of 46 polypeptides bands with different molecular weights ranging from 186.20 to 36.00 KDa. It generated distinctive polymorphism value of 84.62%. Leucine-aminopeptidase, peroxidase, and catalase isozymes showed the highest values of polymorphism (100%) based on zymograms number, relative front (Rf), and optical intensity while esterase isozyme generated polymorphism value of 83.33%. Amino acids were analyzed using high-performance liquid chromatography, which revealed the presence of 17 amino acids of variable contents ranging from 22.65% to 28.09%. RAPD revealed that 78 amplified DNA products had highly polymorphism value (95.08%) based on band numbers, with variable sizes ranging from 120 to 992 base pairs and band intensity. Comet assay recorded the highest extent of nuclear DNA damage as percentage of tailed DNA (2.38%) and tail moment unit (5.36) at ELF exposure of maize nuclei for 5 days. The current study concluded that the longer ELF exposing periods had genotoxic stress on macromolecules of maize cells and biomarkers used should be augmented for reliable estimates of genotoxicity after exposure of economic plants to ELF stressors.
Multiple Adjacent Isolated Thoracic Spinous Process Fractures in High-Energy Trauma
Authors: Kirsch Jacob M. , Nathani Amit , Patel Rakesh D.
Published: June 2015

Isolated thoracic spinous process fractures involving multiple adjacent vertebral segments are a rare occurrence in the setting of high-energy trauma. These findings should prompt further investigation to exclude other concomitant osseous or ligamentous injuries. Evaluation by computed tomography is often most useful to detect these fractures. Proper treatment of extensive multilevel injury is poorly defined in the literature. In our experience, conservative management consisting of initial bracing with graduated lifting restrictions has produced excellent functional results.
Meeting Report: Inaugural Chemotherapy-Induced Peripheral Neuropathy Symposium, Santa Barbara, CA, February 2015
Authors: Smith Jennifer A. , Benbow Sarah J.
Published: June 2015

Chemotherapy-induced peripheral neuropathy is a common, dose-limiting side effect of cancer treatment. This conference was the first of its kind to bring together a wide range of clinicians, researchers, and industry professionals to address the potential causes, preventions, and treatments for this drug toxicity. Intraepidermal nerve fiber loss, axonal degeneration, immune cell infiltration, alterations in tubulin protein expression and microtubule stability, axonal transport, and mitochondrial dysfunction were addressed as possible mechanisms. Problems with animal models of the disease were discussed, as well as the potential of patient-derived induced sensory neurons to serve as a novel in vitro model. Cancer Res; 75(18); 3696–8. ©2015 AACR.
Genome Analysis of Latin American Cervical Cancer: Frequent Activation of the PIK3CA Pathway
Authors: Lou Hong , Villagran Guillermo , Boland Joseph F. , Im Kate M. , Polo Sarita , Zhou Weiyin , Odey Ushie , Juárez-Torres Eligia , Medina-Martínez Ingrid , Roman-Basaure Edgar , Mitchell Jason , Roberson David , Sawitzke Julie , Garland Lisa , Rodríguez-Herrera Maria , Wells David , Troyer Jennifer , Pinto Francisco Castillo , Bass Sara , Zhang Xijun , Castillo Miriam , Gold Bert , Morales Hesler , Yeager Meredith , Berumen Jaime , Alvirez Enrique , Gharzouzi Eduardo , Dean Michael
Published: June 2015

Purpose: Cervical cancer is one of the most common causes of cancer mortality for women living in poverty, causing more than 28,000 deaths annually in Latin America and 266,000 worldwide. To better understand the molecular basis of the disease, we ascertained blood and tumor samples from Guatemala and Venezuela and performed genomic characterization.

Experimental Design: We performed human papillomavirus (HPV) typing and identified somatically mutated genes using exome and ultra-deep targeted sequencing with confirmation in samples from Mexico. Copy number changes were also assessed in the exome sequence.

Results: Cervical cancer cases in Guatemala and Venezuela have an average age of diagnosis of 50 years and 5.6 children. Analysis of 675 tumors revealed activation of PIK3CA and other PI3K/AKT pathway genes in 31% of squamous carcinomas and 24% of adeno- and adenosquamous tumors, predominantly at two sites (E542K, E545K) in the helical domain of the PIK3CA gene. This distribution of PIK3CA mutations is distinct from most other cancer types and does not result in the in vitro phosphorylation of AKT. Somatic mutations were more frequent in squamous carcinomas diagnosed after the age of 50 years. Frequent gain of chromosome 3q was found, and low PIK3CA mutation fractions in many tumors suggest that PI3K mutation can be a late event in tumor progression.

Conclusions: PI3K pathway mutation is important to cervical carcinogenesis in Latin America. Therapeutic agents that directly target PI3K could play a role in the therapy of this common malignancy. Clin Cancer Res; 21(23); 5360–70. ©2015 AACR.
miR-195 Inhibits Tumor Progression by Targeting RPS6KB1 in Human Prostate Cancer
Authors: Cai Chao , Chen Qing-Biao , Han Zhao-Dong , Zhang Yan-Qiong , He Hui-Chan , Chen Jia-Hong , Chen Yan-Ru , Yang Sheng-Bang , Wu Yong-Ding , Zeng Yan-Ru , Qin Guo-Qiang , Liang Yu-Xiang , Dai Qi-Shan , Jiang Fu-Neng , Wu Shu-lin , Zeng Guo-Hua , Zhong Wei-De , Wu Chin-Lee
Published: June 2015

Purpose: To investigate the involvement of hsa-miRNA-195-5p (miR-195) in progression and prognosis of human prostate cancer.

Experimental Design: qRT-PCR was performed to detect miR-195 expression in both prostate cancer cell lines and clinical tissue samples. Its clinical significance was statistically analyzed. The roles of miR-195 and its candidate target gene, ribosomal protein S6 kinase, 70 kDa, polypeptide 1 (RPS6KB1) in prostate cancer progression were confirmed on the basis of both in vitro and in vivo systems.

Results: miR-195 downregulation in prostate cancer tissues was significantly associated with high Gleason score (P = 0.001), positive metastasis failure (P < 0.001), and biochemical recurrence (BCR, P < 0.001). Survival analysis identified miR-195 as an independent prognostic factor for BCR-free survival of prostate cancer patients (P = 0.022). Then, we confirmed the tumor suppressive role of miR-195 through prostate cancer cell invasion, migration, and apoptosis assays in vitro, along with tumor xenograft growth, angiogenesis, and invasion in vivo according to both gain-of-function and loss-of-function experiments. In addition, RPS6KB1 was identified as a novel direct target of miR-195 through proteomic expression profiling combined with bioinformatic target prediction and luciferase reporter assay. Moreover, the reexpression and knockdown of RPS6KB1 could respectively rescue and imitate the effects induced by miR-195. Importantly, RPS6KB1 expression was closely correlated with aggressive progression and poor prognosis in prostate cancer patients as opposed to miR-195. Furthermore, we identified MMP-9, VEGF, BAD, and E-cadherin as the downstream effectors of miR-195–RPS6KB1 axis.

Conclusion: The newly identified miR-195–RPS6KB1 axis partially illustrates the molecular mechanism of prostate cancer progression and represents a novel potential therapeutic target for prostate cancer treatment. Clin Cancer Res; 21(21); 4922–34. ©2015 AACR.
Epithelial PD-L2 Expression Marks Barrett's Esophagus and Esophageal Adenocarcinoma
Authors: Derks Sarah , Nason Katie S. , Liao Xiaoyun , Stachler Matthew D. , Liu Kevin X. , Liu Jie Bin , Sicinska Ewa , Goldberg Michael S. , Freeman Gordon J. , Rodig Scott J. , Davison Jon M. , Bass Adam J.
Published: June 2015

Esophageal adenocarcinoma is an increasingly common disease with a dismal 5-year survival rate of 10% to 15%. In the first systematic evaluation of the PD-1 pathway in esophageal adenocarcinoma, we identify expression of PD-L2 in cancer cells in 51.7% of esophageal adenocarcinomas. Epithelial PD-L1 was expressed on only 2% of cases, although PD-L1+ immune cells were observed in 18% of esophageal adenocarcinomas. We also evaluated expression in the precursor lesion of esophageal adenocarcinoma, Barrett's esophagus, which emerges following gastric reflux–induced esophageal inflammation, and found PD-L2 expression in Barrett's esophagus but not in non–Barrett's esophagus esophagitis. Because the progression from squamous esophagitis to Barrett's esophagus is accompanied by a transition from a TH1 to TH2 immune response, we hypothesized that the TH2 cytokines IL4/IL13 could contribute to PD-L2 induction. We confirmed that these cytokines can augment PD-L2 expression in esophageal adenocarcinoma cell lines. These results suggest that the inflammatory environment in Barrett's esophagus and esophageal adenocarcinoma may contribute to the expression of PD-L2. Furthermore, the potential for PD-1 receptor blockade to be effective in esophageal adenocarcinomas with epithelial PD-L2 or immune cell PD-L1 expression should be evaluated in clinical trials. Cancer Immunol Res; 3(10); 1123–9. ©2015 AACR.
Imaging Modalities for Assessment of Treatment Response to Nonsurgical Hepatocellular Carcinoma Therapy: Contrast-Enhanced US, CT, and MRI
Authors: Minami Yasunori , Kudo Masatoshi
Published: June 2015

Tumor response and time to progression have been considered pivotal for surrogate assessment of treatment efficacy for patients with hepatocellular carcinoma (HCC). Recent advancements in imaging modalities such as contrast-enhanced ultrasound (US), computed tomography (CT), and magnetic resonance imaging (MRI) are playing an important role in assessing the therapeutic effects of HCC treatments. According to some HCC clinical guidelines, post-therapeutic evaluation of HCC patients is based exclusively on contrast-enhanced dynamic imaging criteria. The recommended techniques are contrast-enhanced CT or contrast-enhanced MRI. Contrast-enhanced US is employed more in the positive diagnosis of HCC than in post-therapeutic monitoring. Although contrast enhancement is an important finding on imaging, enhancement does not necessarily depict the same phenomenon across modalities. We need to become well acquainted with the characteristics of each modality, including not only contrast-enhanced CT and MRI but also contrast-enhanced US. Many nonsurgical treatment options are now available for unresectable HCC, and accurate assessment of tumor response is essential to achieve favorable outcomes. For the assessment of successful radiofrequency ablation (RFA), the achievement of a sufficient ablation margin as well the absence of tumor vascular enhancement is essential. To evaluate the response to transcatheter arterial chemoembolization (TACE), enhanced tumor shrinkage is relied on as a measure of antitumor activity. Here, we give an overview of the current status of imaging assessment of HCC response to nonsurgical treatments including RFA and TACE.
The Efficacy and Safety of Growth Hormone Therapy in Children with Noonan Syndrome: A Review of the Evidence
Authors: Noonan Jacqueline A. , Kappelgaard Anne-Marie
Published: June 2015

Noonan syndrome is a genetic disorder associated with short stature. We reviewed 15 studies in which growth hormone (GH) therapy was used in children with Noonan syndrome. Data show consistent increases in mean height standard deviation score (SDS), with first-year changes of up to 1.26 SDS. Among studies reporting adult or near-adult height, GH therapy over 5-7 years resulted in adult height SDS from -0.6 to -2.1, with up to 60% of subjects in some studies achieving adult height within 1 SDS of mid-parental height. GH treatment results in an acceleration of bone age, likely reflecting normalization from the retarded bone age common in Noonan syndrome patients at the start of therapy. BMI is not affected by GH treatment, but favorable changes in fat mass and body composition are achievable. Longer-term studies and observational studies suggest a waning of the effect of GH therapy over time, as is seen in other GH-treated conditions, and early initiation of therapy and prepubertal status are important predictors of response. GH treatment does not appear to be associated with adverse cardiac or metabolic effects, and data on malignancy during GH treatment give no cause for concern, although they are limited.
A Bayesian Partitioning Model for the Detection of Multilocus Effects in Case-Control Studies
Authors: Ray Debashree , Li Xiang , Pan Wei , Pankow James S. , Basu Saonli
Published: June 2015

Background: Genome-wide association studies (GWASs) have identified hundreds of genetic variants associated with complex diseases, but these variants appear to explain very little of the disease heritability. The typical single-locus association analysis in a GWAS fails to detect variants with small effect sizes and to capture higher-order interaction among these variants. Multilocus association analysis provides a powerful alternative by jointly modeling the variants within a gene or a pathway and by reducing the burden of multiple hypothesis testing in a GWAS. Methods: Here, we propose a powerful and flexible dimension reduction approach to model multilocus association. We use a Bayesian partitioning model which clusters SNPs according to their direction of association, models higher-order interactions using a flexible scoring scheme and uses posterior marginal probabilities to detect association between the SNP set and the disease. Results: We illustrate our method using extensive simulation studies and applying it to detect multilocus interaction in Atherosclerosis Risk in Communities (ARIC) GWAS with type 2 diabetes. Conclusion: We demonstrate that our approach has better power to detect multilocus interactions than several existing approaches. When applied to the ARIC study dataset with 9,328 individuals to study gene-based associations for type 2 diabetes, our method identified some novel variants not detected by conventional single-locus association analyses.
Effect of Corticosteroids on Facial Function after Cerebellopontine Angle Tumor Removal: A Double-Blind Study versus Placebo
Authors: Bozorg Grayeli Alexis , Ferrary Evelyne , Tubach Florence , Bernat Isabelle , Deguine Olivier , Darrouzet Vincent , Robier Alain , Zaouche Sandra , Dubreuil Christian , Marx Mathieu , Kalamarides Michel , Fraysse Bernard , Sterkers Olivier
Published: June 2015

The aim of this study was to assess the effect of corticosteroids administered intra- and postoperatively on the occurrence of facial palsy after a cerebellopontine angle (CPA) tumor resection, and to investigate pre- and intraoperative prognostic factors. A multicenter, prospective, randomized, double-blind and versus-placebo study was conducted between 2006 and 2010. Three hundred and ten patients operated on for a CPA tumor (96% vestibular schwannomas, 4% miscellaneous) were included by five participating centers. The population was stratified into patients with small (≤15 mm CPA on axial MRI views) and large tumors. In each group, patients were randomized to receive corticosteroid (1 mg/kg/day i.v. methylprednisolone intraoperatively and at postoperative days 1-5) or placebo. Steroids did not affect the facial function at postoperative days 1, 8 and 30 in patients with small or large tumors as evaluated by House and Brackmann grading.
Atopic Dermatitis: Global Epidemiology and Risk Factors
Authors: Nutten Sophie
Published: June 2015

Atopic dermatitis (AD) is a chronic inflammatory skin disease posing a significant burden on health-care resources and patients' quality of life. It is a complex disease with a wide spectrum of clinical presentations and combinations of symptoms. AD affects up to 20% of children and up to 3% of adults; recent data show that its prevalence is still increasing, especially in low-income countries. First manifestations of AD usually appear early in life and often precede other allergic diseases such as asthma or allergic rhinitis. Individuals affected by AD usually have genetically determined risk factors affecting the skin barrier function or the immune system. However, genetic mutations alone might not be enough to cause clinical manifestations of AD, and it is merely the interaction of a dysfunctional epidermal barrier in genetically predisposed individuals with harmful effects of environmental agents which leads to the development of the disease. AD has been described as an allergic skin disease, but today, the contribution of allergic reactions to the initiation of AD is challenged, and it is proposed that allergy is rather a consequence of AD in subjects with a concomitant underlying atopic constitution. Treatment at best achieves symptom control rather than cure; there is thus a strong need to identify alternatives for disease prevention.
The Impact of Atopic Dermatitis on Quality of Life
Authors: Lifschitz Carlos
Published: June 2015

Approximately 5-20% of children worldwide suffer from atopic dermatitis (AD), a kind of dermatitis characterized as an inflammatory, relapsing, noncontagious and itchy skin disorder. Children often develop AD during their first year of life. An increased rate of sensitization to both food and aeroallergens has been shown to coexist in patients with AD. Sensitization to well-known allergens such as cow's milk protein can occur on average in 50% of children with AD. In general, quality of life (QoL) is perceived as the quality of an individual's daily life, that is, an assessment of their well-being or lack thereof. QoL is a broad concept that includes such things as standard of living, community, and family life. Patients with skin diseases experience a wide range of symptoms ranging from trivial problems to major handicaps which affect their lives. The misery of living with AD cannot be overstated for it may have a profoundly negative effect on the health-related QoL of children and their families in many cases. Physicians taking care of children with AD should consult parents on how their child's illness has impacted their lifestyle and recommend professional intervention if deemed necessary.
The Bile Acid Receptor TGR5 and Liver Regeneration
Authors: Jourdainne Valeska , Péan Noémie , Doignon Isabelle , Humbert Lydie , Rainteau Dominique , Tordjmann Thierry
Published: June 2015

Background: Most of the literature on the bile acid (BA) membrane receptor TGR5 is dedicated to its potential role in the metabolic syndrome, through its regulatory impact on energy expenditure, insulin and GLP-1 secretion, and inflammatory processes. While the receptor was cloned in 2002, very little data are available on TGR5 functions in the normal and diseased liver. However, TGR5 is highly expressed in Kupffer cells and liver endothelial cells, and is particularly enriched in the biliary tract [cholangiocytes and gallbladder (GB) smooth muscle cells]. We recently demonstrated that TGR5 has a crucial protective impact on the liver in case of BA overload, including after partial hepatectomy. Key Messages: TGR5-KO mice after PH exhibited periportal bile infarcts, excessive hepatic inflammation and defective adaptation of biliary composition (bicarbonate and chloride). Most importantly, TGR5-KO mice had a more hydrophobic BA pool, with more secondary BA than WT animals, suggesting that TGR5-KO bile may be harmful for the liver, mainly in situations of BA overload. As GB is both the tissue displaying the highest level of TGR5 expression and a crucial physiological site for the regulation of BA pool hydrophobicity by reducing secondary BA, we investigated whether TGR5 may control BA pool composition through an impact on GB. Preliminary data suggest that in the absence of TGR5, reduced GB filling dampens the cholecystohepatic shunt, resulting in more secondary BA, more hydrophobic BA pool and extensive liver injury in case of BA overload. Conclusions: In the setting of BA overload, TGR5 is protective of the liver through the regulation of not only secretory and inflammatory processes, but also through the control of BA pool composition, at least in part by targeting the GB. Thereby, TGR5 appears to be crucial for protecting the regenerating liver from BA overload.
Gut Microbiota, Cirrhosis, and Alcohol Regulate Bile Acid Metabolism in the Gut
Authors: Ridlon Jason M. , Kang Dae-Joong , Hylemon Phillip B. , Bajaj Jasmohan S.
Published: June 2015

The understanding of the complex role of the bile acid-gut microbiome axis in health and disease processes is evolving rapidly. Our focus revolves around the interaction of the gut microbiota with liver diseases, especially cirrhosis. The bile acid pool size has recently been shown to be a function of microbial metabolism of bile acid, and regulation of the microbiota by bile acids is important in the development and progression of several liver diseases. Humans produce a large, conjugated hydrophilic bile acid pool, maintained through positive-feedback antagonism of farnesoid X receptor (FXR) in the intestine and liver. Microbes use bile acids, and via FXR signaling this results in a smaller, unconjugated hydrophobic bile acid pool. This equilibrium is critical to maintain health. The challenge is to examine the manifold functions of gut bile acids as modulators of antibiotic, probiotic, and disease progression in cirrhosis, metabolic syndrome, and alcohol use. Recent studies have shown potential mechanisms explaining how perturbations in the microbiome affect bile acid pool size and composition. With advancing liver disease and cirrhosis, there is dysbiosis in the fecal, ileal, and colonic mucosa, in addition to a decrease in bile acid concentration in the intestine due to the liver problems. This results in a dramatic shift toward the Firmicutes, particularly Clostridium cluster XIVa, and increasing production of deoxycholic acid. Alcohol intake speeds up these processes in the subjects with and without cirrhosis without significant FXR feedback. Taken together, these pathways can impact intestinal and systemic inflammation while worsening dysbiosis. The interaction between bile acids, alcohol, cirrhosis, and dysbiosis is an important relationship that influences intestinal and systemic inflammation, which in turn determines progression of the overall disease process. These interactions and the impact of commonly used therapies for liver disease can provide insight into the pathogenesis of inflammation in humans.
Stimulation of Apical Sodium-Dependent Bile Acid Transporter Expands the Bile Acid Pool and Generates Bile Acids with Positive Feedback Properties
Authors: Rudling Mats , Bonde Ylva
Published: June 2015

Background: Bile acid synthesis has been considered a prototype for how a physiological process is controlled by end product feedback inhibition. By this feedback inhibition, bile acid concentrations are kept within safe ranges. However, careful examination of published rodent data strongly suggests that bile acid synthesis is also under potent positive feedback control by hydrophilic bile acids. Key Messages: Current concepts on the regulation of bile acid synthesis are derived from mouse models. Recent data have shown that mice have farnesoid X receptor (FXR) antagonistic bile acids capable of quenching responses elicited by FXR agonistic bile acids. This is important to recognize to understand the regulation of bile acid synthesis in the mouse, and in particular to clarify if mouse model findings are valid also in the human situation. Conclusions: In addition to classic end product feedback inhibition, regulation of bile acid synthesis in the mouse largely appears also to be driven by changes in hepatic levels of murine bile acids such as α- and β-muricholic acids. This has not been previously recognized. Stimulated bile acid synthesis or induction of the apical sodium-dependent bile acid transporter in the intestine, increase the availability of chenodeoxycholic acid in the liver, thereby promoting hepatic conversion of this bile acid into muricholic acids. Recognition of these mechanisms is essential for understanding the regulation of bile acid synthesis in the mouse, and for our awareness of important species differences in the regulation of bile acid synthesis in mice and humans.
Impact of Inhibiting Ileal Apical versus Basolateral Bile Acid Transport on Cholesterol Metabolism and Atherosclerosis in Mice
Authors: Dawson Paul A.
Published: June 2015

Background: Bile acid sequestrants have been used for many years to treat hypercholesterolemia by increasing hepatic conversion of cholesterol to bile acids, thereby inducing hepatic LDL receptor expression and clearance of apoB-containing particles. In order to further understand the underlying molecular mechanisms linking gut-liver signaling and cholesterol homeostasis, mouse models defective in ileal apical membrane bile acid transport (Asbt-null) and ileal basolateral membrane bile acid transport (Ostα-null) were studied under basal and hypercholesterolemic conditions. Key Messages: Hepatic conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism and a major mechanism for cholesterol elimination. Blocking ileal apical membrane bile acid transport (Asbt-null mice) increases fecal bile acid excretion, hepatic Cyp7a1 expression, and the relative proportion of taurocholate in the bile acid pool, but decreases ileal FGF15 expression, bile acid pool size, and hepatic cholesterol content. In contrast, blocking ileal basolateral membrane bile acid transport (Ostα-null mice) increases ileal FGF15 expression, reduces hepatic Cyp7a1 expression, and increases the proportion of tauro-β-muricholic acid in the bile acid pool. In the hypercholesterolemic apoE-null background, plasma cholesterol levels and measurements of atherosclerosis were reduced in Asbt/apoE-null mice, but not in Ostα/apoE-null mice. Conclusions: Blocking the intestinal absorption of bile acids at the apical versus basolateral membrane differentially affects bile acid and cholesterol metabolism, including the development of hypercholesterolemia-associated atherosclerosis. The molecular mechanism likely involves an altered regulation of ileal FGF15 expression.
Sodium Taurocholate Cotransporting Polypeptide Acts as a Receptor for Hepatitis B and D Virus
Authors: Yan Huan , Li Wenhui
Published: June 2015

Infection of hepatitis B virus (HBV) remains a major public health problem worldwide. Understanding the viral infection and developing antivirals against HBV have been hampered by the lack of convenient culture systems and animal models for the infection. Sodium taurocholate cotransporting polypeptide (NTCP), a key bile acid transporter expressed in liver, was recently identified as a critical receptor for viral entry of HBV and its satellite virus hepatitis D virus (HDV). This finding enabled a reliable cell culture system for the viruses. Detailed studies have shown that NTCP is the major determinant for the species specificity of HBV and HDV at entry level. NTCP is responsible for most sodium-dependent bile salt uptake in liver. The molecular determinant critical for HBV/HDV infection overlaps with that for bile acids transporting on NTCP. We evaluated bile acids as potential antivirals for HBV and HDV infection, and developed bile acid derivatives that effectively block taurocholate transporting as well as viral infections. The discovery that NTCP acts as a receptor for HBV has opens a new door for future studies towards the ultimate goal of curative treatment of HBV infection.
Aggressive Pituitary Tumors
Authors: Chatzellis Eleftherios , Alexandraki Krystallenia I. , Androulakis Ioannis I. , Kaltsas Gregory
Published: June 2015

Pituitary adenomas are common intracranial tumors that are mainly considered as benign. Rarely, these tumors can exhibit an aggressive behavior, characterized by gross invasion of the surrounding tissues, resistance to conventional treatment leading to early and frequent recurrences. Even more rarely, pituitary tumors can give rise to cerebrospinal or systemic metastases qualifying as pituitary carcinomas according to the latest WHO definition. In the same classification, a subset of tumors with relatively distinct histopathological features was identified and defined as atypical adenomas designated to follow a more aggressive clinical course. This classification, although clinically useful, does not provide an accurate correlation between histopathological findings and the clinical behavior of these tumors, neither is it adequate to convey the precise features of ‘aggressive' tumors. Thus, ‘aggressive' pituitary adenomas need to be properly defined with clinical, radiological, histological and molecular markers in order to identify patients at increased risk of early recurrence or subsequent tumor progression. At present, no single marker or classification system of pituitary tumor aggressiveness exists, and clinically useful information in the literature is insufficient to guide diagnostic and therapeutic decisions. Treatment of patients with aggressive pituitary tumors is challenging since conventional treatments often fail, necessitating multiple surgical procedures with additional radiotherapy. Although traditional chemotherapy applied in other neuroendocrine tumors has not been shown to be efficacious, newer agents, particularly temozolomide, have shown promising results and are currently used despite the lack of data from a randomized prospective trial. Molecular targeted therapies such as mTOR and epidermal growth factor inhibitors have also been applied and might prove to be useful in the management of these patients. In the present review, we provide information regarding the epidemiology and clinical, histopathological and molecular features of aggressive pituitary tumors using recent employed definitions. In addition, we review currently employed therapeutic means providing a therapeutic algorithm and highlight the need to identify more specific disease-related and prognostic markers and the necessity for central registration of these tumors.
In vitro Induction of Residual Caries Lesions in Dentin: Comparative Mineral Loss and Nano-Hardness Analysis
Authors: Schwendicke Falk , Eggers Kerrin , Meyer-Lueckel Hendrik , Dörfer Christof , Kovalev Alexander , Gorb Stanislav , Paris Sebastian
Published: June 2015

Artificially inducing dentinal lesions mimicking those remaining after selective excavation should allow to investigate the effects and limits of such selective excavation, for example regarding the mechanical properties of treated teeth or the remineralisation of sealed residual lesions. Such analyses might otherwise be limited by the variability of natural lesions or ethical and practical concerns. This study compared different demineralisation protocols for their suitability to induce lesions similar to natural residual caries. Twelve natural deep lesions were excavated until leathery dentin remained, and analysed for their mineral loss (ΔZ), lesion depth (LD), mineral loss ratio (R), the slope of the mineral gradient and their nano-hardness profile. Artificial lesions were induced using four different demineralisation protocols (acetic acid pH = 4.95; 0.1 M lactic acid gel pH = 5.0; 0.5 M ethylenediaminetetraacetic acid pH = 7.2; Streptococcus mutans biofilms) and their depths monitored over different demineralisation times. Lesions with depths most according to those of natural lesions were analysed using transversal microradiography. Lesions induced by acetic acid solution did not significantly differ with regards to LD, ΔZ, R and mineral profile. Seven dentin specimens were subsequently submitted to a moderately acidic (pH = 5.3) methylhydroxydiphosphonate-buffered acetate solution for 12 weeks. Natural and artificial residual lesions were similarly deep (mean ± SD: LD = 626 ± 212 and 563 ± 88 µm), demineralised (R = 19.5 ± 4.7 and 29.8 ± 4.1%), showed a flat and continuous mineral gradient (slope = 0.10 ± 0.05 and 0.13 ± 0.06 vol%/µm) and did not significantly differ regarding their nano-hardness profile. The described protocol induces lesions with mineral content and mechanical properties similar to natural residual lesions.
Anti-Inflammatory Effects of Tanshinone IIA on Atherosclerostic Vessels of Ovariectomized ApoE-/- Mice are Mediated by Estrogen Receptor Activation and Through the ERK Signaling Pathway
Authors: Liu Xin , Guo Chun-Yu , Ma Xiao-Juan , Wu Cai-Feng , Zhang Ying , Sun Ming-Yue , Pan Yu-Ting , Yin Hui-Jun
Published: June 2015

Aims: Estrogen plays a protective role in atherosclerosis. Our preliminary work demonstrated that the active conformation of Tanshinone IIA(TanIIA) is similar to the 17ß-estradiol and it can bind to the estrogen receptor. Here, we hypothesized that Tanshinone IIA might have anti-inflammatory and anti-oxidative effects in atherosclerosis, mediated through estrogen receptor activation. Methods: Subjects for this study were 120 apoE-/- female mice and 20 C57/BL female mice. The apoE-/- mice were ovariectomized (OVX) and the C57/BL mice were sham ovariectomized. The sham OVX mice were maintained on a normal diet (NOR) group. The OVX apoE-/- mice were fed a high fat diet and randomly divided into 6 groups: Model (MOD) group which was fed a high fat diet only, E2 group were given estrogen (E2) 0.13mg/kg/d; E2+ICI group were given E2:0.13mg/kg/d and ICI182780:65mg/kg/m; TLD group (TanIIA low dose) were given TanIIA: 30mg/kg/d; THD group (TanIIA high dose) were given TanIIA:60mg/kg/d; and TLD+ICI group were given TanIIA 30mg/kg/d and ICI182780 65mg/kg/m. After three months of treatment, the aorta and the blood of the mice from each group was collected. The aorta were used for testing the lipid deposition by using hematoxylin and eosin(HE) and oil red O staining and for testing the expression of p-ERK1/2 by Western blot. The blood was used for testing the serum cholesterol, superoxide dismutase (SOD), methane dicarboxylic aldehyde (MDA), nuclear factor kappa (NF-κB), soluble intercellular cell adhesion molecule-1 (sICAM-1), activating protein-1 (AP-1), E-selectin and 17ß-estradiol in serum. Results: Tanshinone IIA significantly reduced the lipid deposition in aorta, decreased the levels of total cholesterol (TC), triglyceride (TG), low density lipoprotein (LDL), very low density lipoprotein (VLDL), MDA, NF-κB, sICAM-1, AP-1, and E-selectin in serum but increased the levels of high density lipoprotein (HDL) and SOD in serum. Tanshinone IIA also suppressed the expression of p-ERK1/2. Tanshinone IIA had no effect of level of serum 17ß-estradiol levels. All of the effects of Tanshinone IIA were similar to estrogen and were inhibited by the estrogen receptor antagonist ICI182780. Conclusion: Tanshinone IIA may play an anti-inflammatory and anti-oxidative stress role in OVX atherosclerotic apoE-/- mice by activating the estrogen receptor through the ERK signaling pathway. Therefore, Tanshinone IIA, as a phytoestrogen, could be used for estrogen replacement therapy for cardiovascular disease of postmenopausal women.
FBXL5 Inhibits Metastasis of Gastric Cancer Through Suppressing Snail1
Authors: Wu Weidong , Ding Honghua , Cao Jun , Zhang Weihao
Published: June 2015

Background/Aims: The Snail family of transcription factors controls epithelial to mesenchymal transition (EMT), a process associated with tumorigenesis originated from epithelial cells. Snail1 is a member from Snail family and upregulation of Snail1 has been detected in gastric cancer (GC), suggesting a potential role of Snail1 in GC metastasis. We have recently reported that FBXL5 regulates cortactin by inducing its ubiquitylation and subsequent proteasomal degradation, resulting in inhibition of metastasis of GC. However, a role of FBXL4 in regulation of other EMT-associated proteins is not unknown. Methods: The levels of FBXL5 and Snail1 as well as their relationship were determined in GC specimen. Co-immunoprecipitation (IP) was performed to detect the interaction between Snail1 and FBXL5 in GC cells. The effects on Snail1 by FBXL5 were examined by overexpression of depletion of FBXL5 in GC cells. The invasiveness of the FBXL5-modified GC cells was examined in both scratch wound healing assay and transwell matrix penetration assay. Results: FBXL5 also physiologically interacted with Snail1. FBXL5 inhibited Snail1 to suppress GC cell invasiveness. Conclusion: FBXL5 negatively regulates several EMT-enhancing factors. FBXL5 is an attractive novel target for inhibiting invasion and metastasis of GC cells.
Cinnamaldehyde Derivative (CB-PIC) Sensitizes Chemo-Resistant Cancer Cells to Drug-Induced Apoptosis via Suppression of MDR1 and its Upstream STAT3 and AKT Signalling
Authors: Xi Jianzhong , Yun Miyong , Lee Duckgue , Park Moon-Nyeo , Kim Eun-Ok , Sohn Eun Jung , Kwon Byung-Mog
Published: June 2015

Background/Aims: Our group reported that cinnamaldehyde derivative, (E)-4-((2-(3-oxopop-1-enyl)phenoxy)methyl)pyridinium malonic acid (CB-PIC) induced apoptosis in hypoxic SW620 colorectal cancer cells via activation of AMP-activated protein kinase (AMPK) and extracellular signal regulated kinase (ERK). Herein, sensitizing effect of CB-PIC was investigated in resistant cancer cells such as paclitaxel (PT) resistant lung cancer cells (H460/PT), and Adriamycin (Adr) resistant breast cancer (MCF7/Adr) and colon cancer (HCT15/cos) cells. Methods: Various drug resistant cell lines were treated with CB-PIC, and the signalling pathway and functional assay were explored by Western blot, Rhodamine assay, FACS, RT-PCR and MTT assay. Results: We found that CB-PIC effectively exerted cytotoxicity, increased sub G1 population and the cleaved form of poly (ADP-ribose) polymerase (PARP) and caspase 9 in drug resistant cancer cells. Furthermore, CB-PIC sensitized resistant cancer cells to adriamycin via downregulation of survival proteins such as survivin, Bcl-xL and Bcl-2, along with MDR1 suppression leading to accumulation of drug in the intracellular region. Of note, CB-PIC transcriptionally decreased MDR1 expression via suppression of STAT3 and AKT signalling in three resistant cancer cells with highly expressed P-glycoprotein. Nonetheless, CB-PIC did not affect transport activity of P-glycoprotein in a short time efflux assay, while epigallocatechin gallate (EGCG) accumulated Rhodamine 123 into intracellular region of cell by direct inhibition of MDR1 transport activity. Conclusions: These data demonstrate that CB-PIC suppresses the P-glycoprotein expression through inhibition of STAT3 and AKT signalling to overcome drug resistance in chemo-resistant cancer cells as a potent chemotherapeutic sensitizer.
MiR-429 Determines Poor Outcome and Inhibits Pancreatic Ductal Adenocarcinoma Growth by Targeting TBK1
Authors: Song Bin , Zheng Kailian , Ma Hongyun , Liu Anan , Jing Wei , Shao Chenghao , Li Gang , Jin Gang
Published: June 2015

Background: Pancreatic ductal adenocarcinoma (PDAC) ranks fourth on the list of cancer-related causes of death and its prognosis has not improved significantly over the past decades. Deregulation or dysfunction of miRNAs contribute to cancer development. Previous data indicates that miR-429 is involved in the pathogenesis of PDAC. However, the role of miR-429 in PDAC remained unknown. Methods: MiR-429 levels in sample tissues of 78 patients and in PANC1 and SW1990 cell lines were quantified by real-time PCR. MiR-429 expression was modulated using specific pre- and anti-miRNAs and cell growth was assayed by MTT analysis. Bioinformatics prediction of the miR-429 putative target genes was performed and luciferase assays confirmed TBK1 as a direct target gene. TBK1 levels in PDAC tissues were analyzed by immunohistochemistry. Results: MiR-429 was remarkably decreased in PDAC tissues and cell lines. Lower miR-429 expression in PDAC tissues significantly correlated with shorter survival of PDAC patients. Overexpression of miR-429 inhibited PDAC cell lines growth in vitro and vice versa. TBK1 was found to be the direct target gene of miR-429. Higher TBK1 protein level in PDAC tissues correlated with shorter survival of PDAC patients. Overexpression of TBK1 partly restored cell proliferation. Conclusions: Low level of miR-429 and high level of TBK1 in PDAC promoted PDAC cells growth which might be related to the low survival rate of PDAC patients. MiR-429 play its role in PDAC by targeting TBK1.
Traditional Chinese Medicine Baicalin Suppresses mESCs Proliferation through Inhibition of miR-294 Expression
Authors: Wang Jian , Masika Jacob , Zhou Jianxia , Wang Jun , Zhu Minjie , Luo Hongyan , Hu Xinwu , Zhang Liangpin , Tang Ming , Gao Linlin , Hescheler Jürgen , Liang Huamin
Published: June 2015

Background: Traditional Chinese herbal medicines (TCMs) have been widely used against a broad spectrum of biological activities, including influencing the cardiac differentiation from mouse embryonic stem cells (mESCs). However, their effects and mechanisms of action on ESCs proliferation remain to be determined. The present study aimed to determine the effect of three TCMs, baicalin, ginsenoside Rg1, and puerarin, on mESCs proliferation and to elucidate the possible mechanism of their action. Methods: Cell proliferation was examined with a cell proliferation assay Cell Counting Kit-8 (CCK-8), propidium iodide (PI) staining was used to visualize cell cycle. The mRNA expression level of c-myc, c-fos, c-jun, GAPDH and microRNAs were measured by quantitative real time RT-PCR. Results: We found that baicalin 50 μM suppressed the proliferation of mESCs as observations in more cells in G1 phase and less cells in either S phase or G2/M phase. Moreover, baicalin suppressed the expressions of c-jun and c-fos in mESCs and down-regulated the expression of miR-294. Overexpression of miR-294 in mESCs significantly reversed the effects of baicalin both on mESC proliferation and c-fos/c-jun expression. Conclusions: Baicalin down-regulation of miR-294 may be its key mechanism of action in decreasing mESCs proliferation.
Long Non Coding RNA-UCA1 Contributes to Cardiomyocyte Apoptosis by Suppression of p27 Expression
Authors: Liu Youbin , Zhou Daliang , Li Guangnan , Ming Xing , Tu Ying feng , Tian Jinwei , Lu Huimin , Yu Bo
Published: June 2015

Background/Aims: Urothelial carcinoma-associated 1 (UCA1) is a recently identified long non coding RNA (lncRNA). However, few studies have explored its role in cardiomyocytes after focal cardiac ischemia reperfusion injury (CIR). Methods: Rat CIR models were established using ligation of the Lower Anterior Descending artery (LAD). Cell apoptosis and reactive oxygen species (ROS) production in cardiac tissues were explored using immunohistochemistry and DHE staining. lncRNA expression patterns were detected using microarray and validated by qPCR. Cell viability and apoptosis were examined using MTT assay and flow cytometry. Results: CIR significantly induced cell apoptosis and ROS production in the rat model. The results of microarray demonstrated the reduced expression of UCA1, which was validated by qPCR. Follow-up experiments showed that UCA1 was involved in H2O2-induced cell apoptosis. We further showed that UCA1 negatively correlated with the expression of p27. Moreover, overexpression of p27 could induce primary cardiomyocyte apoptosis. Conclusions: Reduction of UCA1 levels plays a pro-apoptotic role in primary cardiomyocytes partially through stimulation of p27 protein expression. These results are in agreement with the observed levels of UCA1, p27 and apoptosis after cardiac I/R injury, suggesting that UCA1 might have an important role during I/R injury.