bluuebunny/crossref_metadata_2025 huggingface dataset:
Adipose type I interferon signalling protects against metabolic dysfunction
Authors: Wieser Verena , Adolph Timon Erik , Grander Christoph , Grabherr Felix , Enrich Barbara , Moser Patrizia , Moschen Alexander Rupert , Kaser Susanne , Tilg Herbert
Published: December 2016

Objective

Low-grade chronic inflammation emerges as a potent driver of insulin resistance and glucose dysregulation in obesity and associated non-alcoholic fatty liver disease (NAFLD). The liver, subcutaneous fat and the immune system participate in disturbances of metabolism. Type I interferon (IFN) signalling initiated by innate and adaptive immunity modulates inflammatory responses consequent to infection. However, little is known about the role of type I IFN signalling in metabolic diseases and the development of NAFLD.

Design

We determined the impact of type I IFN signalling by tissue-specific deletion of interferon (α and β) receptor 1 (Ifnar1) in hepatocytes (Ifnar1Δhep), adipocytes (Ifnar1Δat), intestinal epithelial cells (Ifnar1ΔIEC) or myelocytes (Ifnar1Δmyel) on glucose metabolism, obesity and hepatic disease in mice exposed to a high-fat or methionine-choline-deficient (MCD) diet. Furthermore, we investigated the expression of type I IFN-regulated genes in patients with obesity undergoing laparoscopic adjustable gastric banding (LAGB).

Results

Long chain fatty acids induce type I IFN responses in murine hepatocytes and macrophages and exposure to a high-fat diet elicited type I IFN-regulated gene expression in the liver of wild-type mice. Hepatocyte-specific, but not adipose tissue-specific deletion of Ifnar1 worsened steatosis and inflammation induced by the MCD diet. In contrast, adipose-specific, but not hepatocyte-specific deletion of Ifnar1 deteriorated metabolic dysregulation induced by a high-fat diet, indicated by increased weight gain, insulin resistance and an impaired glucose tolerance. Abrogated type I IFN signalling in myeloid or intestinal epithelial cells did not modulate susceptibility to metabolic or hepatic disease. Improved metabolic control in patients with obesity after LAGB was associated with increased expression of type I IFN-regulated genes in subcutaneous adipose tissue and liver.

Conclusions

Our study implicates a role for adipose and hepatocyte type I IFN signalling in diet-induced metabolic dysregulation and hepatic disease. Further studies on type I IFN signalling in metabolic diseases are warranted.
Anaplastic lymphoma kinase expression and gene alterations in glioblastoma: correlations with clinical outcome
Authors: Karagkounis George , Stranjalis George , Argyrakos Theodore , Pantelaion Varvara , Mastoris Konstantinos , Rontogianni Dimitra , Komaitis Spyridon , Kalamatianos Theodosis , Sakas Damianos , Tiniakos Dina
Published: December 2016

Aims

To study anaplastic lymphoma kinase (ALK) protein expression and possible underlying gene alterations in glioblastoma (GBM), correlating them with clinical outcome.

Methods

We studied ALK immunohistochemical expression and fluorescent in situ hybridisation (FISH)-detected ALK gene alterations in 51 GBMs (46 isocitrate dehydrogenase-1 (IDH1)R132H-negative and 5 IDH-mutant (IDH1R132H-positive)). We compared two anti-ALK antibodies and immunohistochemical detection systems (5Α4/Nichirei Biosciences, D5F3/Ventana). The results were correlated with tumour cell proliferation and clinical outcome.

Results

Intense granular cytoplasmic ALK immunostaining was observed in 10/51 (19.61%) GBM and correlated with high Ki67 proliferation index; only 1 in 10 ALK-positive cases displayed multiplealkgene signals by FISH. Moderate ALK immunostaining was observed in 21 (41.17%), weak immunostaining in 5 (9.80%) while 15 (29.42%) cases were negative. p53 was expressed in 26/51 GBM (50.9%) (10% cut-off). IDH1R132H-negative GBM showed higher ALK expression compared with IDH-mutant GBM (65.2% vs 20%). ALK overexpression was more common in older patients but did not correlate with other clinicopathological variables or patient overall survival.

Conclusions

ALK overexpression can be identified in up to 70% of GBMs and does not correlate with underlyingalkgene amplification. Despite being more common in rapidly growing, clinically aggressive GBM, ALK overexpression did not show correlation with prognosis in this study.
Examining the potential use and long-term stability of guaiac faecal occult blood test cards for microbial DNA 16S rRNA sequencing
Authors: Taylor Morag , Wood Henry M , Halloran Stephen P , Quirke Philip
Published: December 2016

Aims

With a growing interest in the influence the gut microbiome has on the development of colorectal cancer (CRC), we investigated the feasibility and stability of isolating and typing microbial DNA from guaiac faecal occult blood test (gFOBt) cards. This has the future potential to screen the microbial populations present in confirmed colorectal neoplasia cases with aims to predict the presence and development of CRC.

Methods

Fresh stool samples from three healthy volunteers were applied to gFOBt cards. DNA was extracted from both the cards and fresh stool samples. A series of additional cards were prepared from one volunteer, and extracted at time points between 2 weeks and 3 years. The V4 region of the 16S rRNA gene was amplified and sequenced on an Illumina MiSeq at 2×250 bp read lengths. Data were analysed using QIIME software.

Results

Samples were grouped both by volunteer and by type (fresh or gFOBt), and compared a variety of ways: visual inspection of taxa, α and β diversity, intraclass correlation. In all comparisons, samples grouped by volunteer, and not by sample type. The different time points showed no appreciable differences with increased storage time.

Conclusions

This study has demonstrated that there is good concordance between microbial DNA isolated from fresh stool sample, and from the matched gFOBt card. Samples stored for up to 3 years showed no detrimental effect on measureable microbial DNA. This study has important future implications for investigating microbial influence on CRC development and other pathologies.
Human polyomavirus DNA detection in keratoacanthoma and Spitz naevus: no evidence for a causal role
Authors: Haeggblom Linnea , Franzén Joar , Näsman Anders
Published: December 2016

Keratoacanthomas (KA) and Spitz naevus (SN) are both lesions with unknown aetiology; therefore, the possibility of a viral involvement, more specifically the involvement of human polyomaviruses (HPyV), was investigated. In total, 22 cases of KA and 25 cases of SN were tested for the presence of HPyVs. DNA was extracted and amplified by multiplex PCR and thereafter tested with a multiplex bead-based assay for HPyVs (BKPyV, JCPyV, KIPyV, WUPyV, MCPyV, TSPyV, HPyV6, 7 and 9) and two primate viruses (SV40 and LPyV). HPyV DNA was found in 20 of the 47 lesions. There was no significant difference in HPyV DNA detection frequency between patients diagnosed with KA and patients diagnosed with SN, nor any over-representation of a specific HPyV type in any of the two patient categories. In conclusion, evidence for a specific aetiological role of any of the above tested HPyVs in either KA or SN was not disclosed.
Impact of contaminated household environment on stunting in children aged 12–59 months in Burkina Faso
Authors: Fregonese Federica , Siekmans Kendra , Kouanda Seni , Druetz Thomas , Ly Antarou , Diabaté Souleymane , Haddad Slim
Published: December 2016

Background

Stunting affects 165 million children worldwide, with repercussions on their survival and development. A contaminated environment is likely to contribute to stunting: frequent faecal-oral transmission possibly causes environmental enteropathy, a chronic inflammatory disorder that may contribute to faltering growth in children. This study's objective was to assess the effect of contaminated environment on stunting in Burkina Faso, where stunting prevalence is persistently high.

Methods

Panel study of children aged 1–5 years in Kaya. Household socioeconomic characteristics, food needs and sanitary conditions were measured once, and child growth every year (2011–2014). Using multiple correspondence analysis and 12 questions and observations on water, sanitation, hygiene behaviours, yard cleanliness and animal proximity, we constructed a ‘contaminated environment’ index as a proxy of faecal-oral transmission exposure. Analysis was performed using a generalised structural equation model (SEM), adjusting for repeat observations and hierarchical data.

Results

Stunting (<2 SD height-for-age) prevalence was 29% among 3121 children (median (IQR) age 36 (25–48) months). Environment contamination was widespread, particularly in rural and peri-urban areas, and was associated with stunting (prevalence ratio 1.30; p=0.008), controlling for sex, age, survey year, setting, mother's education, father's occupation, household food security and wealth. This association was significant for children of all ages (1–5 years) and settings. Lower contamination and higher food security had effects of comparable magnitude.

Conclusions

Environment contamination can be at least as influential as nutritional components in the pathway to stunting. There is a rationale for including interventions to reduce environment contamination in stunting prevention programmes.
Latest generation of flat detector CT as a peri-interventional diagnostic tool: a comparative study with multidetector CT
Authors: Leyhe Johanna Rosemarie , Tsogkas Ioannis , Hesse Amélie Carolina , Behme Daniel , Schregel Katharina , Papageorgiou Ismini , Liman Jan , Knauth Michael , Psychogios Marios-Nikos
Published: December 2016

Background and purpose

Flat detector CT (FDCT) has been used as a peri-interventional diagnostic tool in numerous studies with mixed results regarding image quality and detection of intracranial lesions. We compared the diagnostic aspects of the latest generation FDCT with standard multidetector CT (MDCT).

Materials and methods

102 patients were included in our retrospective study. All patients had undergone interventional procedures. FDCT was acquired peri-interventionally and compared with postinterventional MDCT regarding depiction of ventricular/subarachnoidal spaces, detection of intracranial hemorrhage, and delineation of ischemic lesions using an ordinal scale. Ischemic lesions were quantified with the Alberta Stroke Program Early CT Scale (ASPECTS) on both examinations. Two neuroradiologists with varying grades of experience and a medical student scored the anonymized images separately, blinded to the clinical history.

Results

The two methods were of equal diagnostic value regarding evaluation of the ventricular system and the subarachnoidal spaces. Subarachnoidal, intraventricular, and parenchymal hemorrhages were detected with a sensitivity of 95%, 97%, and 100% and specificity of 97%, 100%, and 99%, respectively, using FDCT. Gray–white differentiation was feasible in the majority of FDCT scans, and ischemic lesions were detected with a sensitivity of 71% on FDCT, compared with MDCT scans. The mean difference in ASPECTS values on FDCT and MDCT was 0.5 points (95% CI 0.12 to 0.88).

Conclusions

The latest generation of FDCT is a reliable and accurate tool for the detection of intracranial hemorrhage. Gray–white differentiation is feasible in the supratentorial region.
The crater lake of Copahue volcano (Argentina): geochemical and thermal changes between 1995 and 2015
Authors: Agusto Mariano R. , Caselli Alberto , Daga Romina , Varekamp Johan , Trinelli Alcira , Dos Santos Afonso María , Velez María Laura , Euillades Pablo , Ribeiro Guevara Sergio
Published: December 2016

The crater lake and associated hydrothermal features of Copahue volcano have been studied intensively over the last 20 years (1995–2015). The geochemical and isotopic compositions of the waters provide insights into the processes occurring in the volcanic–hydrothermal system, the crater lake and the thermal springs. Variations in the temperature and chemical composition of the waters reveal fundamental changes in the system that precede and accompany the magmatic and phreatic eruptive events at Copahue. A conceptual model of the summit system was developed involving the intrusion of slivers of magma in the hot acidic hydrothermal cell, the saturation of waters with secondary minerals leading to reduced permeability, the blocking of fluid pathways by liquid sulphur during heating events and the transport of gas from the magma through the ductile–brittle transition into the hydrothermal system. Geophysical data were integrated with the chemical data to provide new insights into the behaviour of the deep magmatic system that feeds the volcano edifice. Multidisciplinary studies were used to identify precursory signals of eruptive activity to give an early warning of pending volcanic hazards. Several geochemical ratios in river water were identified as potential indicators of upcoming volcanic activity, which could be used in co-operation with the community and local authorities to deal with these volcanic hazards.
Association of serum HMGB2 level with MACE at 1 mo of myocardial infarction: Aggravation of myocardial ischemic injury in rats by HMGB2 via ROS
Authors: Liu Zhu Hui , Dai Dao Peng , Ding Feng Hua , Pan Wen Qi , Fang Yue Hua , Zhang Qi , Li Man , Yang Ping , Wang Xiao Qun , Shen Ying , Wang Ling Jie , Yan Xiao Xiang , He Yu Hu , Yang Ke , Zhang Rui Yan , Shen Wei Feng , Chen Ying , Lu Lin
Published: December 2016

High-mobility group box (HMGB) family is related to inflammatory diseases. We investigated whether serum HMGB2 levels are related to myocardial infarction (MI) severity and major adverse cardiac events (MACE) during MI. We included 432 consecutive patients with ST-segment elevation myocardial infarction and 312 controls. Serum HMGB2 levels were significantly higher in MI patients than in controls. Increased HMGB2 levels were associated with MACE and negatively with ejection fraction in MI patients. HMGB2 was an independent determinant of MACE in logistic regression analysis. HMGB2 protein (10 μg) or saline was injected intramyocardially in MI rats, with or without coadministration of the NADPH oxidase inhibitor apocynin. After 72 h, pathological, echocardiographic, and hemodynamic examinations showed that HMGB2 increased infarct size and worsened cardiac function in MI rats. Moreover, HMGB2 administration enhanced reactive oxygen species (ROS) production, cell apoptosis, inflammation, and autophagosome clearance impairment, which were attenuated by coadministration of apocynin or knock down of receptor for advanced glycation end products (RAGE). In conclusion, increased serum HMGB2 levels are associated with MI severity and MACE at 1 mo. HMGB2 promotes myocardial ischemic injury in rats and hypoxic H9C2 cell damage via ROS provoked by RAGE.

NEW & NOTEWORTHY We demonstrate that serum high-mobility group box 2 is associated with major adverse cardiac events at 1 mo in myocardial infarction patients. Mechanistically, high-mobility group box 2 promotes reactive oxygen species production via receptor for advanced glycation end products signaling in ischemic myocardium, thereby aggravating cell apoptosis, inflammation, and autophagosome clearance impairment. This study reveals that high-mobility group box 2 is a novel factor enhancing ischemic injury in myocardial infarction.
Targeted epigenetic editing of SPDEF reduces mucus production in lung epithelial cells
Authors: Song Juan , Cano-Rodriquez David , Winkle Melanie , Gjaltema Rutger A. F. , Goubert Désirée , Jurkowski Tomasz P. , Heijink Irene H. , Rots Marianne G. , Hylkema Machteld N.
Published: December 2016

Airway mucus hypersecretion contributes to the morbidity and mortality in patients with chronic inflammatory lung diseases. Reducing mucus production is crucial for improving patients’ quality of life. The transcription factor SAM-pointed domain–containing Ets-like factor ( SPDEF) plays a critical role in the regulation of mucus production and, therefore, represents a potential therapeutic target. This study aims to reduce lung epithelial mucus production by targeted silencing SPDEF using the novel strategy, epigenetic editing. Zinc fingers and CRISPR/dCas platforms were engineered to target repressors (KRAB, DNA methyltransferases, histone methyltransferases) to the SPDEF promoter. All constructs were able to effectively suppress both SPDEF mRNA and protein expression, which was accompanied by inhibition of downstream mucus-related genes [anterior gradient 2 ( AGR2), mucin 5AC ( MUC5AC)]. For the histone methyltransferase G9A, and not its mutant or other effectors, the obtained silencing was mitotically stable. These results indicate efficient SPDEF silencing and downregulation of mucus-related gene expression by epigenetic editing, in human lung epithelial cells. This opens avenues for epigenetic editing as a novel therapeutic strategy to induce long-lasting mucus inhibition.
Ginkgo Biloba Ameliorates Subfertility Induced by Testicular Ischemia/Reperfusion Injury in Adult Wistar Rats: A Possible New Mitochondrial Mechanism
Authors: Ahmed Asmaa Ibrahim , Lasheen Noha N. , El-Zawahry Khaled Mohamed
Published: December 2016

Testicular torsion, a surgical emergency, could affect the endocrine and exocrine testicular functions. This study demonstrates histopathological and physiological effects of testicular ischemia/perfusion (I/R) injury and the possible protective effects of Ginkgo biloba treatment. Fifty adult male Wistar rats, 180–200 gm, were randomly divided into sham‐operated, Gingko biloba supplemented, ischemia only, I/R, and Gingko biloba treated I/R groups. Overnight fasted rats were anaesthetized by Pentobarbital; I/R was performed by left testis 720° rotation in I/R and treated I/R groups. Orchiectomy was performed for histopathological studies and detection of mitochondrial NAD+. Determination of free testosterone, FSH, TNF‐α, and IL1‐β in plasma was performed. Plasma‐free testosterone was significantly decreased, while plasma FSH, TNF‐α, IL‐1β, and testicular mitochondrial NAD+ were significantly increased in I/R group compared to control group. These parameters were reversed in Gingko biloba treated I/R group compared to I/R group. I/R caused marked testicular damage and increased APAF‐1 in the apoptotic cells which were reversed by Ginkgo biloba treatment. It could be concluded that I/R caused subfertility induced by apoptosis and oxidative stress manifested by the elevated testicular mitochondrial NAD+, which is considered a new possible mechanism. Also, testicular injury could be reduced by Gingko biloba administration alone.
[18F]FDG Uptake in the Aortic Wall Smooth Muscle of Atherosclerotic Plaques in the Simian Atherosclerosis Model
Authors: Iwaki Takayuki , Mizuma Hiroshi , Hokamura Kazuya , Onoe Hirotaka , Umemura Kazuo
Published: December 2016

Atherosclerosis is a self-sustaining inflammatory fibroproliferative disease that progresses in discrete stages and involves a number of cell types and effector molecules. Recently, [18F]fluoro-2-deoxy-D-glucose- ([18F]FDG-) positron emission tomography (PET) has been suggested as a tool to evaluate atherosclerotic plaques by detecting accumulated macrophages associated with inflammation progress. However, at the cellular level, it remains unknown whether only macrophages exhibit high uptake of [18F]FDG. To identify the cellular origin of [18F]FDG uptake in atherosclerotic plaques, we developed a simian atherosclerosis model and performed PET and ex vivo macro- and micro-autoradiography (ARG). Increased [18F]FDG uptake in the aortic wall was observed in high-cholesterol diet-treated monkeys and WHHL rabbits. Macro-ARG of [18F]FDG in aortic sections showed that [18F]FDG was accumulated in the media and intima in the simian model as similar to that in WHHL rabbits. Combined analysis of micro-ARG with immunohistochemistry in the simian atherosclerosis model revealed that most cellular [18F]FDG uptake observed in the media was derived not only from the infiltrated macrophages in atherosclerotic plaques but also from the smooth muscle cells (SMCs) of the aortic wall in atherosclerotic lesions.
A Novel Model of the Ideal Point Method Coupled with Objective and Subjective Weighting Method for Evaluation of Surrounding Rock Stability
Authors: Wang Yingchao , Zhao Ning , Jing Hongwen , Meng Bo , Yin Xin
Published: December 2016

The classification of surrounding rock stability is the critical problem in tunneling engineering. In order to decrease engineering disasters, the surrounding rock stability should be accurately evaluated. The ideal point method is applied to the classification of surrounding rock stability. Considering the complexity of surrounding rock classification, some factors such as rock uniaxial compressive strengthen, integrality coefficient of rock mass, the angle between tunnel axis and the main joint, joints condition, and seepage measurement of groundwater are selected as evaluation indices. The weight coefficients of these evaluation indices are determined by the objective and subjective weighting method, consisting with the delphi method and the information entropy theory. The objective and subjective weighting method is exact and reliable to determine the weights of evaluation indices, considering not only the expert’s experiences, but also objectivity of the field test data. A new composite model is established for evaluating the surrounding rock stability based on the ideal point method and the objective and subjective weighting method. The present model is applied to Beigu mountain tunnel in Jiangsu province, China. The result is in good agreement with practical situation of surrounding rock, which proves that the ideal point method used to classify the surrounding rock in tunnels is reasonable and effective. The present model is simple and has very strong operability, which possesses a good prospect of engineering application.
Signaling Pathways in Cardiac Myocyte Apoptosis
Authors: Xia Peng , Liu Yuening , Cheng Zhaokang
Published: December 2016

Cardiovascular diseases, the number 1 cause of death worldwide, are frequently associated with apoptotic death of cardiac myocytes. Since cardiomyocyte apoptosis is a highly regulated process, pharmacological intervention of apoptosis pathways may represent a promising therapeutic strategy for a number of cardiovascular diseases and disorders including myocardial infarction, ischemia/reperfusion injury, chemotherapy cardiotoxicity, and end-stage heart failure. Despite rapid growth of our knowledge in apoptosis signaling pathways, a clinically applicable treatment targeting this cellular process is currently unavailable. To help identify potential innovative directions for future research, it is necessary to have a full understanding of the apoptotic pathways currently known to be functional in cardiac myocytes. Here, we summarize recent progress in the regulation of cardiomyocyte apoptosis by multiple signaling molecules and pathways, with a focus on the involvement of these pathways in the pathogenesis of heart disease. In addition, we provide an update regarding bench to bedside translation of this knowledge and discuss unanswered questions that need further investigation.
Postocclusive Hyperemia Measured with Laser Doppler Flowmetry and Transcutaneous Oxygen Tension in the Diagnosis of Primary Raynaud’s Phenomenon: A Prospective, Controlled Study
Authors: Maga Paweł , Henry Brandon Michael , Kmiotek Elizabeth K. , Gregorczyk-Maga Iwona , Kaczmarczyk Paweł , Tomaszewski Krzysztof A. , Niżankowski Rafał
Published: December 2016

The aim of this study was to measure the sensitivity and specificity of transcutaneous oxygen tension and postocclusive hyperemia testing using laser Doppler flowmetry in patients with primary Raynaud’s phenomenon. One hundred patients and one hundred controls were included in the study. Baseline microvascular blood flow and then time to peak flow following occlusion were measured using laser Doppler flowmetry. Afterwards, the transcutaneous oxygen tension was recorded. The sensitivities of baseline microvascular blood flow, postocclusive time to peak flow, and transcutaneous oxygen tension were 79%, 79%, and 77%, respectively. The postocclusive time peak flow had a superior specificity of 90% and area under the curve of 0.92 as compared to 66% and 0.80 for baseline microvascular flow and 64% and 0.76 for transcutaneous oxygen tension. Time to postocclusive peak blood flow measured by laser Doppler flowmetry is a highly accurate test for differentiating patients with primary Raynaud’s phenomenon from healthy controls.
Gastric Cancer Cell Proliferation and Survival Is Enabled by a Cyclophilin B/STAT3/miR-520d-5p Signaling Feedback Loop
Authors: Li Ting , Guo Hanqing , Zhao Xiaodi , Jin Jiang , Zhang Lifeng , Li Hong , Lu Yuanyuan , Nie Yongzhan , Wu Kaichun , Shi Yongquan , Fan Daiming
Published: December 2016

Molecular links between inflammation and cancer remain obscure despite their great pathogenic significance. The JAK2/STAT3 pathway activated by IL6 and other proinflammatory cytokines has garnered attention as a pivotal link in cancer pathogenesis, but the basis for its activation in cancer cells is not understood. Here we report that an IL6-triggered feedback loop involving STAT3-mediated suppression of miR-520d-5p and upregulation of its downstream target cyclophilin B (CypB) regulate the growth and survival of gastric cancer cells. In clinical specimens of gastric cancer, we documented increased expression of CypB and activation of STAT3. Mechanistic investigations identified miR-520d-5p as a regulator of CypB mRNA levels. This signaling axis regulated gastric cancer growth by modulating phosphorylation of STAT3. Furthermore, miR-520d-5p was identified as a direct STAT3 target and IL6-mediated inhibition of miR-520d-5p relied upon STAT3 activity. Our findings define a positive feedback loop that drives gastric carcinogenesis as influenced by H. pylori infections that involve proinflammatory IL6 stimulation. Cancer Res; 77(5); 1227–40. ©2016 AACR.
The Natural Diterpenoid Isoforretin A Inhibits Thioredoxin-1 and Triggers Potent ROS-Mediated Antitumor Effects
Authors: Sun Xiaoyan , Wang Weiguang , Chen Jiao , Cai Xueting , Yang Jie , Yang Yang , Yan Huaijiang , Cheng Xiaolan , Ye Juan , Lu Wuguang , Hu Chunping , Sun Handong , Pu Jianxin , Cao Peng
Published: December 2016

Aberrant expression of thioredoxin 1 (Trx1) plays an important role in cancer initiation and progression and has gained attention as an anticancer drug target. Here we report that the recently discovered natural diterpenoid isoforretin A (IsoA) significantly inhibits Trx1 activity and mediates anticancer effects in multiple preclinical settings. The inhibitory effect of IsoA was antagonized by free radical scavengers polyethylene glycol-catalase, polyethylene glycol superoxide dismutase, thiol-based antioxidants N-acetylcysteine and glutathione. Mass spectrometry analysis revealed that the mechanism of action was based on direct conjugation of IsoA to the Cys32/Cys35 residues of Trx1. This conjugation event attenuated reversible thiol reduction of Trx1, leading to ROS accumulation and a broader degradation of thiol redox homeostasis in cancer cells. Extending these in vitro findings, we documented that IsoA administration inhibited the growth of HepG2 tumors in a murine xenograft model of hepatocellular carcinoma. Taken together, our findings highlight IsoA as a potent bioactive inhibitor of Trx1 and a candidate anticancer natural product. Cancer Res; 77(4); 926–36. ©2016 AACR.
Wnt5a Drives an Invasive Phenotype in Human Glioblastoma Stem-like Cells
Authors: Binda Elena , Visioli Alberto , Giani Fabrizio , Trivieri Nadia , Palumbo Orazio , Restelli Silvia , Dezi Fabio , Mazza Tommaso , Fusilli Caterina , Legnani Federico , Carella Massimo , Di Meco Francesco , Duggal Rohit , Vescovi Angelo L.
Published: December 2016

Brain invasion by glioblastoma determines prognosis, recurrence, and lethality in patients, but no master factor coordinating the invasive properties of glioblastoma has been identified. Here we report evidence favoring such a role for the noncanonical WNT family member Wnt5a. We found the most invasive gliomas to be characterized by Wnt5a overexpression, which correlated with poor prognosis and also discriminated infiltrating mesenchymal glioblastoma from poorly motile proneural and classical glioblastoma. Indeed, Wnt5a overexpression associated with tumor-promoting stem-like characteristics (TPC) in defining the character of highly infiltrating mesenchymal glioblastoma cells (Wnt5aHigh). Inhibiting Wnt5a in mesenchymal glioblastoma TPC suppressed their infiltrating capability. Conversely, enforcing high levels of Wnt5a activated an infiltrative, mesenchymal-like program in classical glioblastoma TPC and Wnt5aLow mesenchymal TPC. In intracranial mouse xenograft models of glioblastoma, inhibiting Wnt5a activity blocked brain invasion and increased host survival. Overall, our results highlight Wnt5a as a master regulator of brain invasion, specifically TPC, and they provide a therapeutic rationale to target it in patients with glioblastoma. Cancer Res; 77(4); 996–1007. ©2016 AACR.
A Novel Mouse Model to Study Image-Guided, Radiation-Induced Intestinal Injury and Preclinical Screening of Radioprotectors
Authors: Verginadis Ioannis I. , Kanade Rahul , Bell Brett , Koduri Sravya , Ben-Josef Edgar , Koumenis Constantinos
Published: December 2016

Radiation is an important treatment modality for gastrointestinal tumors, but intestinal injury is a common side effect. Here we describe a physiologically relevant model for studying the molecular determinants of radiation-induced intestinal damage and testing novel radioprotectors. The model employs a radiopaque marker implanted into the surface of the mouse jejunum, serving as a fiducial marker for precise radiation targeting. Mice were imaged with Cone-Beam CT (CBCT) and irradiated (IR) to the marked area using the Small Animal Radiation Research Platform (SARRP). IR-induced damage was acute but reversible and largely restricted to the area of the marker, leaving the surrounding tissues intact. Although whole gut irradiation with these doses caused lethal GI syndrome, focal (5 mm) radiation of the intestine did not cause any weight loss or lethality. However, fibrosis and collagen deposition 4 months post-IR indicated chronic intestinal damage. A separate cohort of mice was treated daily with curcumin, a clinically tested radioprotector, prior to and post-IR. Curcumin-treated mice showed significant decreases in both local and systemic inflammatory cytokine levels and in fibrosis, suggesting it is an effective radioprotector of the intestine. Our results indicate that this model, which emulates clinically relevant intestinal radiation-induced injury, can be used to assess radioprotectors prior to testing in the clinic. Cancer Res; 77(4); 908–17. ©2016 AACR.
Antitumor Activity of RXDX-105 in Multiple Cancer Types with RET Rearrangements or Mutations
Authors: Li Gang G. , Somwar Romel , Joseph James , Smith Roger S. , Hayashi Takuo , Martin Leenus , Franovic Aleksandra , Schairer Anni , Martin Eric , Riely Gregory J. , Harris Jason , Yan Shunqi , Wei Ge , Oliver Jennifer W. , Patel Rupal , Multani Pratik , Ladanyi Marc , Drilon Alexander
Published: December 2016

Purpose: While multikinase inhibitors with RET activity are active in RET-rearranged thyroid and lung cancers, objective response rates are relatively low and toxicity can be substantial. The development of novel RET inhibitors with improved potency and/or reduced toxicity is thus an unmet need. RXDX-105 is a small molecule kinase inhibitor that potently inhibits RET. The purpose of the preclinical and clinical studies was to evaluate the potential of RXDX-105 as an effective therapy for cancers driven by RET alterations.

Experimental design: The RET-inhibitory activity of RXDX-105 was assessed by biochemical and cellular assays, followed by in vivo tumor growth inhibition studies in cell line– and patient-derived xenograft models. Antitumor activity in patients was assessed by imaging and Response Evaluation Criteria in Solid Tumors (RECIST).

Results: Biochemically, RXDX-105 inhibited wild-type RET, CCDC6-RET, NCOA4-RET, PRKAR1A-RET, and RET M918T with low to subnanomolar activity while sparing VEGFR2/KDR and VEGFR1/FLT. RXDX-105 treatment resulted in dose-dependent inhibition of proliferation of CCDC6-RET–rearranged and RET C634W-mutant cell lines and inhibition of downstream signaling pathways. Significant tumor growth inhibition in CCDC6-RET, NCOA4-RET, and KIF5B-RET–containing xenografts was observed, with the concomitant inhibition of p-ERK, p-AKT, and p-PLCγ. Additionally, a patient with advanced RET-rearranged lung cancer had a rapid and sustained response to RXDX-105 in both intracranial and extracranial disease.

Conclusions: These data support the inclusion of patients bearing RET alterations in ongoing and future molecularly enriched clinical trials to explore RXDX-105 efficacy across a variety of tumor types. Clin Cancer Res; 23(12); 2981–90. ©2016 AACR.
CX3CR1-dependent endothelial margination modulates Ly6Chigh monocyte systemic deployment upon inflammation in mice
Authors: Hamon Pauline , Loyher Pierre-Louis , Baudesson de Chanville Camille , Licata Fabrice , Combadière Christophe , Boissonnas Alexandre
Published: December 2016

Key Points

Blood monocytes are distributed between a marginated and a circulating pool. CX3CR1 regulates inflammatory monocyte residence into the blood vasculature during inflammation.
The Global Asthma Network rationale and methods for Phase I global surveillance: prevalence, severity, management and risk factors
Authors: Ellwood Philippa , Asher M. Innes , Billo Nils E. , Bissell Karen , Chiang Chen-Yuan , Ellwood Eamon M. , El-Sony Asma , García-Marcos Luis , Mallol Javier , Marks Guy B. , Pearce Neil E. , Strachan David P.
Published: December 2016

The Global Asthma Network (GAN), established in 2012, followed the International Study of Asthma and Allergies in Childhood (ISAAC). ISAAC Phase One involved over 700 000 adolescents and children from 156 centres in 56 countries; it found marked worldwide variation in symptom prevalence of asthma, rhinitis and eczema that was not explained by the current understanding of these diseases; ISAAC Phase Three involved over 1 187 496 adolescents and children (237 centres in 98 countries). It found that asthma symptom prevalence was increasing in many locations especially in low- and middle-income countries where severity was also high, and identified several environmental factors that required further investigation.

GAN Phase I, described in this article, builds on the ISAAC findings by collecting further information on asthma, rhinitis and eczema prevalence, severity, diagnoses, asthma emergency room visits, hospital admissions, management and use of asthma essential medicines. The subjects will be the same age groups as ISAAC, and their parents. In this first global monitoring of asthma in children and adults since 2003, further evidence will be obtained to understand asthma, management practices and risk factors, leading to further recognition that asthma is an important non-communicable disease and to reduce its global burden.
A genetically encoded biosensor for visualizing hypoxia responsesin vivo
Authors: Misra Tvisha , Baccino-Calace Martin , Meyenhofer Felix , Rodriguez-Crespo David , Akarsu Hatice , Armenta-Calderón Ricardo , Gorr Thomas A. , Frei Christian , Cantera Rafael , Egger Boris , Luschnig Stefan
Published: December 2016

Cells experience different oxygen concentrations depending on location, organismal developmental stage, and physiological or pathological conditions. Responses to reduced oxygen levels (hypoxia) rely on the conserved Hypoxia-Inducible Factor 1 (HIF-1). Understanding the developmental and tissue-specific responses to changing oxygen levels has been limited by the lack of adequate tools for monitoring HIF-1 in vivo. To visualise and analyse HIF-1 dynamics in Drosophila, we used a hypoxia biosensor consisting of GFP fused to the oxygen-dependent degradation domain (ODD) of the HIF-1 homologue Sima. GFP-ODD responds to changing oxygen levels and to genetic manipulations of the hypoxia pathway, reflecting oxygen-dependent regulation of HIF-1 at the single-cell level. Ratiometric imaging of GFP-ODD and a red-fluorescent reference protein reveals tissue-specific differences in the cellular hypoxic status at ambient normoxia. Strikingly, cells in the larval brain show distinct hypoxic states that correlate with the distribution and relative densities of respiratory tubes. We present a set of genetic and image analysis tools that enable new approaches to map hypoxic microenvironments, to probe effects of perturbations on hypoxic signalling, and to identify new regulators of the hypoxia response.
A polycycstin-type transient receptor potential (Trp) channel that is activated by ATP
Authors: Traynor David , Kay Robert R.
Published: December 2016

ATP and ADP are ancient extra-cellular signalling molecules that in Dictyostelium amoebae cause rapid, transient increases in cytosolic calcium due to an influx through the plasma membrane. This response is independent of hetero-trimeric G-proteins, the putative IP3 receptor IplA and all P2X channels. We show, unexpectedly, that it is abolished in mutants of the polycystin-type transient receptor potential channel, TrpP. Responses to the chemoattractants cyclic-AMP and folic acid are unaffected in TrpP mutants. We report that the DIF morphogens, cyclic-di-GMP, GABA, glutamate and adenosine all induce strong cytoplasmic calcium responses, likewise independently of TrpP. Thus TrpP is dedicated to purinergic signalling. ATP treatment causes cell blebbing within seconds but this does not require TrpP, implicating a separate purinergic receptor. We could detect no effect of ATP on chemotaxis and TrpP mutants grow, chemotax and develop almost normally in standard conditions. No gating ligand is known for the human homologue of TrpP, polycystin-2, which causes polycystic kidney disease. Our results now show that TrpP mediates purinergic signalling in Dictyostelium and is directly or indirectly gated by ATP.
A feedback mechanism between phospholipase D and deadenylase PARN for the shortening of eukaryotic poly(A) mRNA tails that is deregulated in cancer cells
Authors: Miller Taylor E. , Gomez-Cambronero Julian
Published: December 2016

The removal of mRNA transcripts poly(A) tails by 3-5 exonucleases is the rate-limiting step in mRNA decay in eukaryotes. Known cellular deadenylases are, the CCR4-NOT and PAN complexes, and poly(A)-specific ribonuclease (PARN). The physiological roles and regulation for PARN is beginning to be elucidated. Since phospholipase D (PLD2 isoform) gene expression is upregulated in breast cancer cells and PARN is downregulated, we examined whether a signaling connection existed between these two enzymes. Silencing PARN with siRNA led to an increase in PLD2 protein and overexpression of PARN did the opposite. Overexpression of PLD2, however, led to an increase in PARN expression. Thus, PARN downregulates PLD2 whereas PLD2 upregulates PARN. Co-expression of both PARN and PLD2 mimicked this pattern in non-cancerous cells (COS-7 fibroblasts) but, surprisingly, not in breast cancer MCF-7 cells, where PARN switches from inhibition to activation of PLD2 gene and protein expression. Between 30 and 300 nM phosphatidic acid (PA), the product of PLD enzymatic reaction, added exogenously to culture cells had a stabilizing role of both PARN and PLD2 mRNA decay. PA in combination with PLD2 overexpression increased PARN in vitro deadenylase activity. Lastly, by immunofluorescence microscopy, we observed an intracellular co-localization of PA-loaded vesicles (0.1-1 nm) and PARN. In summary, we report for the first time the involvement of a phospholipase (PLD2) and PA in mediating PARN-induced eukaryotic mRNA decay and the crosstalk between the two enzymes that is deregulated in breast cancer cells.
A developmental transcriptomic analysis ofPax1andPax9in embryonic intervertebral disc development
Authors: Sivakamasundari V. , Kraus Petra , Sun Wenjie , Hu Xiaoming , Lim Siew Lan , Prabhakar Shyam , Lufkin Thomas
Published: December 2016

Pax1 and Pax9 play redundant, synergistic functions in the patterning and differentiation of the sclerotomal cells that give rise to the vertebral bodies and intervertebral discs (IVD) of the axial skeleton. They are conserved in mice and humans, whereby mutations/deficiency of human PAX1/PAX9 have been associated with kyphoscoliosis. By combining cell-type specific transcriptome and ChIP-sequencing data, we identified the roles of Pax1/Pax9 in cell proliferation, cartilage development and collagen fibrillogenesis, which are vital in early IVD morphogenesis. Pax1 is up-regulated in the absence of Pax9, while Pax9 is unaffected by the loss of Pax1/Pax9. We identified the targets compensated by a single- or double-copy of Pax9. They positively regulate many of the cartilage genes known to be regulated by Sox5/Sox6/Sox9 and are connected to Sox5/Sox6 by a negative feedback loop. Pax1/Pax9 are intertwined with BMP and TGF-B pathways and we propose they initiate expression of chondrogenic genes during early IVD differentiation and subsequently become restricted to the outer annulus by the negative feedback mechanism. Our findings highlight how early IVD development is regulated spatio-temporally and have implications for understanding kyphoscoliosis.
Predator stress-induced immunosuppression: trade-off, immune redistribution or immune reconfiguration?
Authors: Adamo Shelley A. , Easy Russell H. , Kovalko Ilya , MacDonald Jenna , McKeen Ashleigh , Swanburg Taylor , Turnbull Kurtis F. , Reeve Catherine
Published: December 2016

Although predator exposure increases the risk of wound infections, it typically induces immunosuppression. A number of non-mutually exclusive hypotheses have been put forward to explain this immunosuppression, including: trade-offs between the immune system and other systems required for anti-predator behaviour, redistribution of immune resources towards mechanisms needed to defend against wound infections, and reconfiguration of the immune system to optimize defense under the physiological state of fight-or-flight readiness. We tested the ability of each hypothesis to explain the effects of chronic predator stress on the immune system of the caterpillar Manduca sexta. Predator stress induced defensive behaviours, reduced weight gain, increased development time and increased the concentration of the stress neurohormone octopamine. It had no significant effect on: hemocyte number, melanization rate, phenoloxidase activity, lysozyme-like activity, or nodule production. Predator stress reduced hemolymph glutathione concentrations. It also increased constitutive expression of the antimicrobial peptide attacin-1 but reduced attacin-1 expression in response to an immune challenge. These results best fit the immune reconfiguration hypothesis, although the other hypotheses are also consistent with some results. Interpreting stress related changes in immune function may require an examination at the level of the whole organism.
Extremal graph on normalized Laplacian spectral radius and energy
Authors: Das Kinkar , SUN SHAOWEI
Published: December 2016

Let $G=(V,\,E)$ be a simple graph of order $n$ and the normalized Laplacian eigenvalues $\rho_1\geq \rho_2\geq \cdots\geq\rho_{n-1}\geq \rho_n=0$. The normalized Laplacian energy (or Randi\'c energy) of $G$ without any isolated vertex is defined as $$RE(G)=\sum_{i=1}^{n}|\rho_i-1|.$$ In this paper, a lower bound on $\rho_1$ of connected graph $G$ ($G$ is not isomorphic to complete graph) is given and the extremal graphs (that is, the second minimal normalized Laplacian spectral radius of connected graphs) are characterized. Moreover, Nordhaus-Gaddum type results for $\rho_1$ are obtained. Recently, Gutman et al.~gave a conjecture on Randi\'c energy of connected graph [I. Gutman, B. Furtula, \c{S}. B. Bozkurt, On Randi\'c energy, Linear Algebra Appl. 442 (2014) 50--57]. Here this conjecture for starlike trees is proven.
UHF and X Band Electro-Magnetic Shielding of Advanced Devices by Some Polymer–Composites
Authors: Sahu K. R , De Udayan
Published: December 2016

Electro-magnetic interference (EMI) affects delicate electronic devices and living beings. Composites of a polymeric binder with fine metallic turnings (copper and brass), powders of conducting inorganic compounds (suitably fired cadmium oxide), ferroelectric powders (BaTiO3 and orthorhombic PbNb2O6), and with their combinations have been prepared as cloth-like sheets, and characterized in a Vector Network Analyzer (VNA) with respect to EMI shielding and reflection capabilities. Input power (Pin) for the EMI shield (above-mentioned test materials), the reflected power (Prefl) and the transmitted power (Pout) have been measured by the VNA as a function of EM wave frequency in two technically important frequency bands - in 700 MHz to 3 GHz part of the ultra-high frequency (UHF) band and in the X-band, covering 8 to 12 GHz. From the measured data, Shielding Effectiveness in dB unit = 10 log (Pout / Pin) and Reflection Effectiveness in dB = 10 log (Prefl / Pin) have been calculated and studied for all the samples, with the results presented and discussed. In particular, our substitution of expensive metal powders by fine metallic turnings, available as waste from mechanical workshops, reduces the cost of polymer-metal composites substantially, retaining high shielding i.e. low transmission (down to -33dB in 08 to 12 GHz range).
Synthesis and Characterization of Sintered AZ91D Magnesium Matrix Composites Reinforced with Red Mud particles
Authors: Rajamani D , Tamilarasan A. , Esakki Balasubramanian , Ananthakumar K
Published: December 2016

Magnesium AZ91D alloy is reinforced with red mud particles, is the by-product of alumina which is extracted from refining of bauxite throughbayer process to fabricate low cost novel composite by powder metallurgy technique. Reinforcement ratio was varied from 0% to 15% whereas size of the particles were kept as 30µm.The microstructure and mechanical properties such as density and microhardness of the composite were evaluated. Microstructural characterization of the sintered composite revealed a near uniform distribution of the red mud particulates with magnesium alloy metal matrix.The test results indicated that the increase in weight % of red mud particles significantly enhances the mechanical propertiesof the composite.
Surface Protection of Steel by Adsorption of Milletia Pinnata Extract
Authors: Sukumaran Monikandon , Devarayan Kesavan
Published: December 2016

Steel corrosion inhibition in acidic and alkaline medium by ethanolic extract of Milletia pinnata is described in this study. The inhibitive behavior of the inhibitor is evaluated by weight loss measurements, adsorption isotherms, and thermochemical parameters. The inhibitor exhibited a maximum of 87% and 90.5% inhibition efficiency against steel corrosion in 0.5 M NaOH and 1.0 M H2SO4, respectively. The weight loss linearly fit to Langmuir adsorption isotherm with correlation coefficient value close to unity. The thermochemical parameters indicated for predominant physical adsorption of the inhibitor molecules on the steel surface.
The future of core surgical training
Authors: Vig Stella , Allum Bill
Published: December 2016

Recent surveys suggest a review is needed.
Expanding role of the internet in the orthopaedic outpatient setting
Authors: Thorne E , Mackenzie PD , Wilson Matthew
Published: December 2016

How feasible are 'virtual' follow-ups really?
The facts and fiction of breaking into the United States
Authors: Taylor James , Galvez Daniel , Atallah Chady , Safar Bashar
Published: December 2016

Advice for international medical graduates on applying to surgical training programmes in the US from one such Stateside success story.
Treasures from the Collections
Authors: Pearson Sarah
Published: December 2016

Transplanting of Teeth by Thomas Rowlandson