bluuebunny/crossref_metadata_2025 huggingface dataset:
Antiviral Activities of Several Oral Traditional Chinese Medicines against Influenza Viruses
Authors: Ma Lin-Lin , Ge Miao , Wang Hui-Qiang , Yin Jin-Qiu , Jiang Jian-Dong , Li Yu-Huan
Published: October 2015

Influenza is still a serious threat to human health with significant morbidity and mortality. The emergence of drug-resistant influenza viruses poses a great challenge to existing antiviral drugs. Traditional Chinese medicines (TCMs) may be an alternative to overcome the challenge. Here, 10 oral proprietary Chinese medicines were selected to evaluate their anti-influenza activities. These drugs exhibit potent inhibitory effects against influenza A H1N1, influenza A H3N2, and influenza B virus. Importantly, they demonstrate potent antiviral activities against drug-resistant strains. In the study of mechanisms, we found that Xiaoqinglong mixture could increase antiviral interferon production by activating p38 MAPK, JNK/SAPK pathway, and relative nuclear transcription factors. Lastly, our studies also indicate that some of these medicines show inhibitory activities against EV71 and CVB strains. In conclusion, the 10 traditional Chinese medicines, as kind of compound combination medicines, show broad-spectrum antiviral activities, possibly also including inhibitory activities against strains resistant to available antiviral drugs.
Alteration of Blood Parameters and Histoarchitecture of Liver and Kidney of Silver Barb after Chronic Exposure to Quinalphos
Authors: Mohammod Mostakim Golam , Zahangir Md. Mahiuddin , Monir Mishu Mahbuba , Rahman Md. Khalilur , Islam M. Sadiqul
Published: October 2015

Quinalphos (QP) is commonly used for pest control in the agricultural fields surrounding freshwater reservoirs. This study was conducted to evaluate the chronic toxicity of this pesticide on blood parameters and some organs of silver barb,Barbonymus gonionotus. Fish were exposed to two sublethal concentrations, 0.47 ppm and 0.94 ppm, of QP for a period of 28 days. All the blood parameters (red blood cell, hematocrit, and hemoglobin) and blood glucose except for white blood cells decreased with increasing concentration of toxicant and become significantly lower (p<0.05) at higher concentration when compared with control. The derived hematological indices of mean corpuscular volume, mean corpuscular hemoglobin, and mean corpuscular hemoglobin concentration were equally altered compared to control. Histoarchitectural changes of liver and kidney were observed after exposure to the QP. Hypertrophy of hepatocytes, mild to severe necrosis, ruptured central vein, and vacuolation were observed in the liver of treated groups. Highly degenerated kidney tubules and hematopoietic tissue, degeneration of renal corpuscle, vacuolization, and necrosis were evident in the kidney of treated groups. In conclusion, chronic exposure to QP at sublethal concentrations induced hematological and histological alterations in silver barb and offers a simple tool to evaluate toxicity derived alterations.
Comparison of the Frequentist MATA Confidence Interval with Bayesian Model-Averaged Confidence Intervals
Authors: Turek Daniel
Published: October 2015

Model averaging is a technique used to account for model uncertainty, in both Bayesian and frequentist multimodel inferences. In this paper, we compare the performance of model-averaged Bayesian credible intervals and frequentist confidence intervals. Frequentist intervals are constructed according to the model-averaged tail area (MATA) methodology. Differences between the Bayesian and frequentist methods are illustrated through an example involving cloud seeding. The coverage performance and interval width of each technique are then studied using simulation. A frequentist MATA interval performs best in the normal linear setting, while Bayesian credible intervals yield the best coverage performance in a lognormal setting. The use of a data-dependent prior probability for models improved the coverage of the model-averaged Bayesian interval, relative to that using uniform model prior probabilities. Data-dependent model prior probabilities are philosophically controversial in Bayesian statistics, and our results suggest that their use is beneficial when model averaging.
Ancient Schwannoma of Ansa Cervicalis: A Rare Clinical Entity and Review of the Literature
Authors: Rath Satyajit , Sasmal Prakash K. , Saha Kaushik , Deep N. , Mishra Pritinanda , Mishra Tushar S. , Sharma Rakesh
Published: October 2015

Ancient schwannoma is an uncommon variant of schwannoma, a benign tumor arising from the nerve sheath. It is reported to arise from any nerves except optic and olfactory. However, only six cases of ancient schwannomas arising from ansa cervicalis nerve have been reported to date in English literature. Proper preoperative evaluation is necessary to rule out other causes of neck mass such as thyroid lesions, lymphadenopathy, and carotid body tumor. We report a case of ancient schwannoma arising from the ansa cervicalis nerve. The origin of the lesion from ansa cervicalis was confirmed by intraoperative finding. Postoperative histopathological examination revealed degenerative changes including pleomorphism, cellular atypia, large nuclei with prominent nucleoli, and paucity of mitotic figures. Periphery of the mass showed nuclear palisading with characteristic verocay bodies. Immunohistochemical evaluation for S-100 showed diffuse positivity of the tumor cells, thereby confirming the diagnosis of schwannoma. We consider that schwannoma of cervical region can have origin from any nerve and should try to identify the origin pre- and intraoperatively. The postoperative complications depend on the nerve of origin and the precision of the surgery performed.
Steroids in Central Retinal Vein Occlusion: Is There a Role in Current Treatment Practice?
Authors: Ashraf Mohammed , Souka Ahmed A. R.
Published: October 2015

With the current widespread use of anti-VEGFs in the treatment of central retinal vein occlusion (CRVO), the role for steroids has become greatly diminished. Recent large scale randomized control trials (RCTs) have established the efficacy and safety of anti-VEGFs in the treatment of CRVO. Steroids are known to cause elevations in intraocular pressure as well as increase the risk of cataract formation. With that in mind many ophthalmologists are injecting steroids less frequently. This paper aims to review some of the data pertaining to the use of steroids either as a first line monotherapy, adjunct therapy, or an alternative therapy to help answer the question: Is there currently any role for steroids in the management of CRVO?
Carbon Monoxide Inhibits Tenascin‐C Mediated Inflammation via IL‐10 Expression in a Septic Mouse Model
Authors: Uddin Md. Jamal , Li Chun-shi , Joe Yeonsoo , Chen Yingqing , Zhang Qinggao , Ryter Stefan W. , Chung Hun Taeg
Published: October 2015

Tenascin‐C (TN‐C), an extracellular matrix (ECM) glycoprotein, is specifically induced upon tissue injury and infection and during septic conditions. Carbon monoxide (CO) gas is known to exert various anti‐inflammatory effects in various inflammatory diseases. However, the mechanisms underlying the effect of CO on TN‐C‐mediated inflammation are unknown. In the present study, we found that treatment with LPS significantly enhanced TN‐C expression in macrophages. CO gas, or treatment with the CO‐donor compound, CORM‐2, dramatically reduced LPS‐induced expression of TN‐C and proinflammatory cytokines while significantly increased the expression of IL‐10. Treatment with TN‐C siRNA significantly suppressed the effects of LPS on proinflammatory cytokines production. TN‐C siRNA did not affect the CORM‐2‐dependent increase of IL‐10 expression. In cells transfected with IL‐10 siRNA, CORM‐2 had no effect on the LPS‐induced expression of TN‐C and its downstream cytokines. These data suggest that IL‐10 mediates the inhibitory effect of CO on TN‐C and the downstream production of proinflammatory cytokines. Additionally, administration of CORM‐2 dramatically reduced LPS‐induced TN‐C and proinflammatory cytokines production while expression of IL‐10 was significantly increased. In conclusion, CO regulated IL‐10 expression and thus inhibited TN‐C‐mediated inflammation in vitro and in vivo.
Phenolic Compounds fromOlea europaeaL. Possess Antioxidant Activity and Inhibit Carbohydrate Metabolizing EnzymesIn Vitro
Authors: Dekdouk Nadia , Malafronte Nicola , Russo Daniela , Faraone Immacolata , De Tommasi Nunziatina , Ameddah Souad , Severino Lorella , Milella Luigi
Published: October 2015

Phenolic composition and biological activities of fruit extracts from Italian and AlgerianOlea europaeaL. cultivars were studied. Total phenolic and tannin contents were quantified in the extracts. Moreover 14 different phenolic compounds were identified, and their profiles showed remarkable quantitative differences among analysed extracts. Moreover antioxidant and enzymatic inhibition activities were studied. Three complementary assays were used to measure their antioxidant activities and consequently Relative Antioxidant Capacity Index (RACI) was used to compare and easily describe obtained results. Results showed thatChemlal, between Algerian cultivars, andCoratina, among Italian ones, had the highest RACI values. On the other hand all extracts and the most abundant phenolics were tested for their efficiency to inhibitα-amylase andα-glucosidase enzymes.Leccino, among all analysed cultivars, and luteolin, among identified phenolic compounds, were found to be the best inhibitors ofα-amylase andα-glucosidase enzymes. Results demonstrated thatOlea europaeafruit extracts can represent an important natural source with high antioxidant potential and significantα-amylase andα-glucosidase inhibitory effects.
A Random Parameter Model for Continuous-Time Mean-Variance Asset-Liability Management
Authors: Ma Hui-qiang , Wu Meng , Huang Nan-jing
Published: October 2015

We consider a continuous-time mean-variance asset-liability management problem in a market with random market parameters; that is, interest rate, appreciation rates, and volatility rates are considered to be stochastic processes. By using the theories of stochastic linear-quadratic (LQ) optimal control and backward stochastic differential equations (BSDEs), we tackle this problem and derive optimal investment strategies as well as the mean-variance efficient frontier analytically in terms of the solution of BSDEs. We find that the efficient frontier is still a parabola in a market with random parameters. Comparing with the existing results, we also find that the liability does not affect the feasibility of the mean-variance portfolio selection problem. However, in an incomplete market with random parameters, the liability can not be fully hedged.
Effects of Climate Change and Human Activities on Surface Runoff in the Luan River Basin
Authors: Zeng Sidong , Zhan Chesheng , Sun Fubao , Du Hong , Wang Feiyu
Published: October 2015

Quantifying the effects of climate change and human activities on runoff changes is the focus of climate change and hydrological research. This paper presents an integrated method employing the Budyko-based Fu model, hydrological modeling, and climate elasticity approaches to separate the effects of the two driving factors on surface runoff in the Luan River basin, China. The Budyko-based Fu model and the double mass curve method are used to analyze runoff changes during the period 1958~2009. Then two types of hydrological models (the distributed Soil and Water Assessment Tool model and the lumped SIMHYD model) and seven climate elasticity methods (including a nonparametric method and six Budyko-based methods) are applied to estimate the contributions of climate change and human activities to runoff change. The results show that all quantification methods are effective, and the results obtained by the nine methods are generally consistent. During the study period, the effects of climate change on runoff change accounted for 28.3~46.8% while those of human activities contributed with 53.2~71.7%, indicating that both factors have significant effects on the runoff decline in the basin, and that the effects of human activities are relatively stronger than those of climate change.
Melanoma of the Right Foot Simulating Kaposi’s Disease
Authors: Kouassi K. A. , Kassi K. , Kouamé K. , Oussou M. A. , Kouassi I. , Gbery I. P. , Ecra E. J. , Sangare A. , Ahogo C. , Kaloga M. , Yoboue P. , Kanga J. M.
Published: October 2015

Melanoma is a malignant tumor rarely being described in sub-Saharan Africa. We reported an unusual and atypical clinical presentation. It was a 59-year-old patient who was hospitalized for a monomelic black tumor evolving for 10 years. Histopathological examination confirmed the melanocytic origin of this tumor. Paraclinical assessment did not find any visceral metastasis. A partial resection of the tumor was performed. The patient left the hospital against medical consent due to lack of technical facilities. The delay in the consultation and the lack of knowledge of melanoma by doctors and patients might contribute to the severity and the difficulties of its management.
Quantum Sized Zinc Oxide Immobilized on Bentonite Clay and Degradation of C.I. Acid Red 35 in Aqueous under Ultraviolet Light
Authors: Xu Hang , Zhang Dandan , Xu Airong , Wu Fengmin , Cao Renqiang
Published: October 2015

Nano-ZnO supported on bentonite was prepared to form composite photocatalyst by sol-gel method. The photocatalyst was analyzed by X-ray diffraction (XRD), scanning electron microscopy (SEM), and transmission electron microscope (TEM). C.I. Acid Red 35 was used as simulating contaminant to be treated by ultraviolet light synergistic with nano-ZnO/bentonite. The results show that 5.7 nm ZnO particle was acquired and uniformly dispersed on the surface of the bentonite at calcination temperature of 200°C. The removal of C.I. Acid Red 35 could reach 84.9% after 200 min under optimum ZnO/bentonite dosage of 0.6 g L−1. The 60% ZnO content in ZnO/bentonite composite exhibited a great photocatalytic activity to treat C.I. Acid Red 35. The photocatalytic process followed pseudo-first-order kinetics and the best apparent rate constant was 0.00927 min−1with correlation coefficient (R2) of above 0.98.
Recycling of Cooking Oil Waste into Reactive Polyurethane for Blending with Thermoplastic Polyethylene
Authors: Rus Anika Zafiah M. , Salim N. Syamimi M. , Sapiee N. Haiza
Published: October 2015

Driven by the need of growing to a more sustainable and environmentally friendly future, this research is started by mixing in-house produced biorenewable polymers (BP) from waste cooking oil with the standard low density polyethylene (LDPE) and high density polyethylene (HDPE) via melt-mixing at low ratios. These mixtures are then compounded via injection molding to produce tensile samples. By using the quality of individual compounds injected, the parameters obtained for all ratios of LDPE/BP were the same with neat LDPE whereas some adjustments were required for the HDPE/BP compounds. The corresponding mechanical behaviors of each ratio were also examined and the results showed that both tensile strength and strain of the LDPE/BP were better than neat LDPE. On the other hand, increasing the BP content in HDPE/BP will increase the toughness of the compound if compared to neat HDPE. Therefore, not only does the presence of BP provide renewable properties, but it also improves the mechanical properties. Moreover, the processing temperature and composition of BP will both influence the quality and mechanical behavior of the product made. Thus, this study may aid any intention on processing these in-house produced polymers by injection molding.
Design and Analytical Analysis of a Novel DBA Algorithm with Dual-Polling Tables in EPON
Authors: Lai Jiunn-Ru , Huang Hsin-Yi , Chen Wen-Ping , Wang Luke K. , Cho Ming-Yuan
Published: October 2015

Ethernet passive optical network is a point-to-multipoint structure, and an effective media access protocol should be designed for collision avoidance and bandwidth allocation. Most previous researches have aimed to solve the problem using dynamic bandwidth allocation (DBA) algorithms with polling-based schemes. Unfortunately, idle channel time among the polling cycles cannot be overcome efficiently. In this paper, a dual-polling DBA (DP-DBA) algorithm which consists of an interpolling mechanism and an intrapolling mechanism is proposed. The interpolling mechanism helps eliminate the idle time problem while the intrapolling part aggregates the unused bandwidth of the light-loaded users and those due to nondefragmentation of the Ethernet frames of the general users. We also evaluate the performance of the DP-DBA algorithm by a comparison with the interleaved polling with adaptive cycle time (IPACT), the dynamic bandwidth allocation with a modified grant table generation algorithm (DBA2), the Double-Phase Polling (DPP), and the adaptive DBA algorithm with sorting report messages (Sort-DBA) schemes with simulation results. For greater realism with regard to general applications, we also simulate the asymmetric traffic loads at the optical network units (ONUs).The results show that DP-DBA outperforms the other DBA schemes under asymmetric load conditions.
A Comprehensive Survey on Particle Swarm Optimization Algorithm and Its Applications
Authors: Zhang Yudong , Wang Shuihua , Ji Genlin
Published: October 2015

Particle swarm optimization (PSO) is a heuristic global optimization method, proposed originally by Kennedy and Eberhart in 1995. It is now one of the most commonly used optimization techniques. This survey presented a comprehensive investigation of PSO. On one hand, we provided advances with PSO, including its modifications (including quantum-behaved PSO, bare-bones PSO, chaotic PSO, and fuzzy PSO), population topology (as fully connected, von Neumann, ring, star, random, etc.), hybridization (with genetic algorithm, simulated annealing, Tabu search, artificial immune system, ant colony algorithm, artificial bee colony, differential evolution, harmonic search, and biogeography-based optimization), extensions (to multiobjective, constrained, discrete, and binary optimization), theoretical analysis (parameter selection and tuning, and convergence analysis), and parallel implementation (in multicore, multiprocessor, GPU, and cloud computing forms). On the other hand, we offered a survey on applications of PSO to the following eight fields: electrical and electronic engineering, automation control systems, communication theory, operations research, mechanical engineering, fuel and energy, medicine, chemistry, and biology. It is hoped that this survey would be beneficial for the researchers studying PSO algorithms.
Interpolation of Missing Precipitation Data Using Kernel Estimations for Hydrologic Modeling
Authors: Lee Hyojin , Kang Kwangmin
Published: October 2015

Precipitation is the main factor that drives hydrologic modeling; therefore, missing precipitation data can cause malfunctions in hydrologic modeling. Although interpolation of missing precipitation data is recognized as an important research topic, only a few methods follow a regression approach. In this study, daily precipitation data were interpolated using five different kernel functions, namely, Epanechnikov, Quartic, Triweight, Tricube, and Cosine, to estimate missing precipitation data. This study also presents an assessment that compares estimation of missing precipitation data throughKth nearest neighborhood (KNN) regression to the five different kernel estimations and their performance in simulating streamflow using the Soil Water Assessment Tool (SWAT) hydrologic model. The results show that the kernel approaches provide higher quality interpolation of precipitation data compared with theKNN regression approach, in terms of both statistical data assessment and hydrologic modeling performance.
Kinetic Profiles of Inflammatory Mediators in the Conjunctival Sac Fluid of Patients upon Photorefractive Keratectomy
Authors: Tisato Veronica , Perri Paolo , Rimondi Erika , Melloni Elisabetta , Lamberti Giuseppe , Milani Daniela , Secchiero Paola , Zauli Giorgio
Published: October 2015

Photorefractive keratectomy (PRK) represents a therapeutic option to remodel corneal stroma and to compensate refractive errors, which involves inflammatory and/or regenerative processes. In this context, the modulation of cytokines/chemokines in the conjunctival sac fluid and their role in the maintenance of the corneal microenvironment during the healing process upon refractive procedures has not been deeply investigated. In this study, serial samples of conjunctival sac fluid of patients (n = 25) undergoing PRK were harvested before and at different time points after surgery. The levels of 29 cytokines/chemokines/growth factors involved in inflammatory/immune processes were measured with a multiplex array system. The results have firstly highlighted the different pattern of cytokine expression between the microenvironment at the anterior surface of the eye and the systemic circulation. More importantly, the kinetic of modulation of cytokines/chemokines at the conjunctival level following PRK revealed that while the majority of cytokines/chemokines showed a significant decrease, MCP‐1 emerged in light of its pronounced and significant increase soon after PRK and during the follow‐up. This methodological approach has highlighted the role of MCP‐1 in the healing process following PRK and has shown a potential for the identification of expression/modulation of soluble factors for biomarker profiling in ocular surface diseases.
Angle at the Medial Border: The Spinovertebra Angle and Its Significance
Authors: Oladipo G. S. , Aigbogun E. O. , Akani G. L.
Published: October 2015

Background. The evolution from quadrupedalism to bipedalism has adjusted the balance of the upper limb to extensive movement at the shoulder. The scapular angles provide the point of attachment and control to various muscles and have been associated with the different movements of the shoulder girdle and joint. This has made the morphometric and anthropometric study of scapula a subject of extensive investigation. Aim. In the present study, the angle at the medial border was measured in the South-Southern Nigerian population and an anatomical name was ascribed to the angle. Method. The study was conducted on 173 scapulae (75 right and 98 left) obtained from various Anatomy Department of South-Sothern Nigerian Universities. The angle at medial border was obtained by pinning the edge of the superior and inferior angles, the lined traced out, and the angle measured using a protractor. SPSS version 20 was used to analyse the data. t-test was used to determine mean angular difference in the sides. Result. The mean ± SD of the medial angle was observed to be 136.88 ± 7.70° (R = 138.13 ± 7.06° : L = 135.92 ± 8.05°). Statistical analysis using the Z-test for mean difference showed the medial angle was found to be higher in the right side of the scapula (mean difference of 2.214 ± 1.152°), but the observed difference was not statistically significant (P > 0.05). The above findings have adjusted the scapula from three to four angles (lateral, superior, inferior, and medial) formed from four borders (lateral, superior, inferior, and superomedial and inferomedial). The medial angle because of its anatomical location was named “spinovertebral” angle, owing to its position at the scapulae spine, and located in medial proximity to the vertebra column. Conclusion. The medial angle (now referred to as the spinovertebral angle) of the right side of the scapula is wider than the left. The representation of the spinovertebral angle is very important, as the directional attachment of the levator scapulae may be altered if it increases or decreases greatly hence resulting in stiffness of the neck. At this point, it could be postulated that the scapular is quadrangular rather than triangular.
Correlation of BRAF Mutation Status in Circulating-Free DNA and Tumor and Association with Clinical Outcome across Four BRAFi and MEKi Clinical Trials
Authors: Santiago-Walker Ademi , Gagnon Robert , Mazumdar Jolly , Casey Michelle , Long Georgina V. , Schadendorf Dirk , Flaherty Keith , Kefford Richard , Hauschild Axel , Hwu Patrick , Haney Patricia , O'Hagan Anne , Carver Jennifer , Goodman Vicki , Legos Jeffrey , Martin Anne-Marie
Published: October 2015

Purpose: Tumor-derived circulating cell–free DNA (cfDNA) is a potential alternative source from which to derive tumor mutation status. cfDNA data from four clinical studies of the BRAF inhibitor (BRAFi) dabrafenib or the MEK inhibitor (MEKi) trametinib were analyzed to determine the association between BRAF mutation status in cfDNA and tumor tissue, and the association of BRAF cfDNA mutation status with baseline factors and clinical outcome.

Experimental Design: Patients with BRAF V600 mutation–positive melanoma were enrolled in each study after central confirmation of BRAF status in tumor using a PCR-based assay. BRAF mutation status in cfDNA from patient plasma collected at baseline, 732 of 836 (88%) enrolled patients in total, was determined.

Results: BRAF mutations were detectable in cfDNA in 76% and 81% of patients with BRAF V600E/V600K–positive tumors, respectively. Patients negative for BRAF mutations in cfDNA had longer progression-free survival (PFS) and overall survival in each of the four studies, compared with patients with detectable cfDNA BRAF mutations. The presence of BRAF-mutant cfDNA was an independent prognostic factor for PFS after multivariate adjustment for baseline factors in three of four studies. Patients negative for BRAF mutation–positive cfDNA in plasma had higher response rates to dabrafenib and trametinib.

Conclusions: BRAF mutations in cfDNA are detectable in >75% of late-stage melanoma patients with BRAF mutation–positive tumors. The lack of circulating, BRAF mutation–positive cfDNA is clinically significant for metastatic melanoma patients, and may be a prognostic marker for better disease outcome. Clin Cancer Res; 22(3); 567–74. ©2015 AACR.
Nivolumab in Resected and Unresectable Metastatic Melanoma: Characteristics of Immune-Related Adverse Events and Association with Outcomes
Authors: Freeman-Keller Morganna , Kim Youngchul , Cronin Heather , Richards Allison , Gibney Geoffrey , Weber Jeffrey S.
Published: October 2015

Purpose: Retrospective analysis of irAEs in melanoma patients treated with nivolumab.

Experimental Design: Data were pooled from 148 patients (33 resected, 115 unresectable) treated with nivolumab plus peptide vaccine or nivolumab alone every 2 weeks for 12 weeks. Patients with stable disease or regression received an additional 12-week cycle, then nivolumab alone every 12 weeks for up to 2 additional years. Frequency, grade, and characteristics of immune-related adverse events (irAE) were analyzed. A 12-week landmark survival analysis using a multivariate time-dependent Cox proportional hazard model assessed difference in overall survival (OS) in the presence or absence of irAEs.

Results: IrAEs of any grade were observed in 68.2% of patients (101 of 148). Grade III/IV irAEs were infrequent: 3 (2%) had grade III rash, 2 (1.35%) had asymptomatic grade III elevation in amylase/lipase, and 2 (1.35%) had grade III colitis. A statistically significant OS difference was noted among patients with any grade of irAE versus those without (P ≤ 0.001), and OS benefit was noted in patients who reported three or more irAE events (P ≤ 0.001). Subset analyses showed statistically significant OS differences with rash [P = 0.001; HR, 0.423; 95% confidence interval (CI), 0.243–0.735] and vitiligo (P = 0.012; HR, 0.184; 95% CI, 0.036–0.94). Rash and vitiligo also correlated with statistically significant OS differences in patients with metastatic disease (P = 0.004 and P = 0.028, respectively). No significant survival differences were seen with other irAEs (endocrinopathies, colitis, or pneumonitis).

Conclusions: Cutaneous irAEs are associated with improved survival in melanoma patients treated with nivolumab, and clinical benefit should be validated in larger prospective analyses. Clin Cancer Res; 22(4); 886–94. ©2015 AACR.
Exposure and Tumor Fn14 Expression as Determinants of Pharmacodynamics of the Anti-TWEAK Monoclonal Antibody RG7212 in Patients with Fn14-Positive Solid Tumors
Authors: Meulendijks Didier , Lassen Ulrik N. , Siu Lillian L. , Huitema Alwin D.R. , Karanikas Vaios , Mau-Sorensen Morten , Jonker Derek J. , Hansen Aaron R. , Simcox Mary E. , Schostack Kathleen J. , Bottino Dean , Zhong Hua , Roessler Markus , Vega-Harring Suzana M. , Jarutat Tiantom , Geho David , Wang Karen , DeMario Mark , Goss Glenwood D. , Schellens Jan H.M.
Published: October 2015

Purpose: The TWEAK–Fn14 pathway represents a novel anticancer target that is being actively investigated. Understanding the relationship between pharmacokinetics of anti-TWEAK therapeutics and tumor pharmacodynamics is critical. We investigated exposure-response relationships of RG7212, an anti-TWEAK mAb, in patients with Fn14-expressing tumors.

Experimental Design: Patients with Fn14-positive tumors (IHC≥1+) treated in a phase I first-in-human study with ascending doses of RG7212 were the basis for this analysis. Pharmacokinetics of RG7212 and dynamics of TWEAK were determined, as were changes in tumor TWEAK–Fn14 signaling in paired pre- and posttreatment tumor biopsies. The objectives of the analysis were to define exposure-response relationships and the relationship between pretreatment tumor Fn14 expression and pharmacodynamic effect. Associations between changes in TWEAK–Fn14 signaling and clinical outcome were explored.

Results: Thirty-six patients were included in the analysis. RG7212 reduced plasma TWEAK to undetectable levels at all observed RG7212 exposures. In contrast, reductions in tumor Fn14 and TRAF1 protein expression were observed only at higher exposure (≥300 mg*h/mL). Significant reductions in tumor Ki-67 expression and early changes in serum concentrations of CCL-2 and MMP-9 were observed exclusively in patients with higher drug exposure who had high pretreatment tumor Fn14 expression. Pretreatment tumor Fn14 expression was not associated with outcome, but a trend toward longer time on study was observed with high versus low RG7212 exposure.

Conclusions: RG7212 reduced tumor TWEAK–Fn14 signaling in a systemic exposure-dependent manner. In addition to higher exposure, relatively high Fn14 expression might be required for pharmacodynamic effect of anti-TWEAK monoclonal antibodies. Clin Cancer Res; 22(4); 858–67. ©2015 AACR.
Sonic Hedgehog Signaling Drives Mitochondrial Fragmentation by Suppressing Mitofusins in Cerebellar Granule Neuron Precursors and Medulloblastoma
Authors: Malhotra Anshu , Dey Abhinav , Prasad Niyathi , Kenney Anna Marie
Published: October 2015

Sonic hedgehog (Shh) signaling is closely coupled with bioenergetics of medulloblastoma, the most common malignant pediatric brain tumor. Shh-associated medulloblastoma arises from cerebellar granule neuron precursors (CGNP), a neural progenitor whose developmental expansion requires signaling by Shh, a ligand secreted by the neighboring Purkinje neurons. Previous observations show that Shh signaling inhibits fatty acid oxidation although driving increased fatty acid synthesis. Proliferating CGNPs and mouse Shh medulloblastomas feature high levels of glycolytic enzymes in vivo and in vitro. Because both of these metabolic processes are closely linked to mitochondrial bioenergetics, the role of Shh signaling in mitochondrial biogenesis was investigated. This report uncovers a surprising decrease in mitochondrial membrane potential (MMP) and overall ATP production in CGNPs exposed to Shh, consistent with increased glycolysis resulting in high intracellular acidity, leading to mitochondrial fragmentation. Ultrastructural examination of mitochondria revealed a spherical shape in Shh-treated cells, in contrast to the elongated appearance in vehicle-treated postmitotic cells. Expression of mitofusin 1 and 2 was reduced in these cells, although their ectopic expression restored the MMP to the nonproliferating state and the morphology to a fused, interconnected state. Mouse Shh medulloblastoma cells featured drastically impaired mitochondrial morphology, restoration of which by ectopic mitofusin expression was also associated with a decrease in the expression of Cyclin D2 protein, a marker for proliferation.

Implications: This report exposes a novel role for Shh in regulating mitochondrial dynamics and rescue of the metabolic profile of tumor cells to that of nontransformed, nonproliferating cells and represents a potential avenue for development of medulloblastoma therapeutics. Mol Cancer Res; 14(1); 114–24. ©2015 AACR.
Evidence Suggesting Complement Activation and Haemolysis at Core Temperature in Patients with Cold Autoimmune Haemolytic Anaemia
Authors: Bartolmäs Thilo , Yürek Salih , Balola Abdelwahab Hassan Ahmed , Mayer Beate , Salama Abdulgabar
Published: October 2015

Background: It is unclear why haemolysis may somewhat persist in patients with cold autoimmune haemolytic anaemia (cAIHA) at 37 °C (core temperature). Methods: Seven patients with cAIHA were included in this study. Serological testing was performed using standard techniques. Bound autoantibodies (aab) on patients' RBCs were analysed by the direct antiglobulin test (DAT), dual antiglobulin test (DDAT) and flow cytometry (FC) using pre-warmed RBCs (37 °C). Temperature-dependent complement binding was determined by incubation of patients' serum samples with group O RBCs and fresh serum complement. Results: The DAT was strongly positive with anti-C3d in all cases, independent of season and outside temperature. Haemolysis usually improved during warm periods of time, but decompensated following febrile infections, and persisted throughout the year, though exposure to the cold was strictly avoided. In addition, trace amounts of IgM aab were infrequently detectable on patients' RBCs even at 37 °C, and complement activation was demonstrated following incubation of RBCs with the causative aab at 37 °C. Conclusions: Binding of trace amounts of IgM aab at 37 °C may provide an explanation for the durable C3d-positive DAT and haemolysis in patients with cAIHA.
Treatment Options for Primary Autoimmune Hemolytic Anemia: A Short Comprehensive Review
Authors: Salama Abdulgabar
Published: October 2015

Until now, treatment of primary autoimmune hemolytic anemia of the warm type (wAIHA) is primarily based on immunosuppression. However, many patients do not respond adequately to treatment, and treated patients may develop severe side effects due to uncontrolled, mixed and/or long-lasting immunosuppression. Unfortunately, the newly used therapeutic monoclonal antibodies are unspecific and remain frequently ineffective. Thus, development of a specific therapy for AIHA is necessary. The ideal therapy would be the identification and elimination of the causative origin of autoimmunization and/or the correction or reprogramming of the dysregulated immune components. Blood transfusion is the most rapidly effective measure for patients who develop or may develop hypoxic anemia. Although some effort has been made to guide physicians on how to adequately treat patients with AIHA, a number of individual aspects should be considered prior to treatment. Based on my serological and clinical experience and the analysis of evidence-based studies, we remain far from any optimized therapeutic measures for all AIHA patients. Today, the old standard therapy using controlled steroid administration, with or without azathioprine or cyclophosphamide, is, when complemented with erythropoiesis-stimulating agents, still the most effective therapy in wAIHA. Rituximab or other monoclonal antibodies may be used instead of splenectomy in therapy-refractory patients.
Leuprolide Acetate Inhibits Spinal Cord Inflammatory Response in Experimental Autoimmune Encephalomyelitis by Suppressing NF-κB Activation
Authors: Guzmán-Soto Irene , Salinas Eva , Quintanar J. Luis
Published: October 2015

Objective: Recent findings have shown that gonadotropin-releasing hormone (GnRH) administration in an animal model of multiple sclerosis (experimental autoimmune encephalomyelitis, EAE) improves clinical signs of locomotion. The present study was designed to determine whether the administration of the synthetic analog of GnRH, leuprolide acetate (LA) - besides its effects on clinical signs of locomotion - also has an effect on the activation/expression levels of molecular markers of EAE, namely transcription nuclear factor (NF)-κB and the proinflammatory cytokines IL-1ß, IL-17A, IL-23 and TNF-a. Methods: EAE spinal cords were collected from control and LA-administered rats. Lumbar sections were processed at four different time points during the course of the disease to analyze NF-κB activation by chemiluminescent Western blot, and during the EAE recovery phase to evaluate proinflammatory cytokine levels by quantitative real-time PCR. Results: It was found that LA administration to EAE rats promoted a significant reduction of NF-κB activation during the course of the disease and also decreased the mRNA expression levels of the proinflammatory cytokines IL-1ß, IL-17A and TNF-a in the EAE recovery phase; both effects are consistent with the decrease in the severity of clinical signs of locomotion induced by the treatment. Conclusion: LA causes a reduction in the severity of locomotor activity, as well as in the activation of NF-κB and the number of proinflammatory markers in rats with EAE. These results suggest the use of this agonist as a potential therapeutic approach for multiple sclerosis.
A Novel Organ Culture Model of Mouse Intervertebral Disc Tissues
Authors: Yan Zhengjian , Yin Liangjun , Wang Zhongliang , Ye Jixing , Zhang Zhonglin , Li Ruifang , Denduluri Sahitya K. , Wang Jing , Wei Qiang , Zhao Lianggong , Lu Shun , Wang Xin , Tang Shengli , Shi Lewis L. , Lee Michael J. , He Tong-Chuan , Deng Zhong-Liang
Published: October 2015

The intervertebral disc (IVD) is a fibrocartilaginous joint between two vertebral bodies. An IVD unit consists of a gelatinous central nucleus pulposus, encased by the annulus fibrosus, which is sandwiched between cartilaginous endplates (EPs). The IVD homeostasis can be disrupted by injuries, ageing and/or genetic predispositions, leading to degenerative disc disorders and subsequent lower back pain. The complex structure and distinct characteristics of IVDs warrant the establishment of robust in vitro IVD organ culture for studying the etiology and treatment of disc degeneration. Here, we isolate mouse lumbar IVDs and culture the minimal IVD units in submersion or suspension medium supplemented with 2% bovine serum or 10% fetal bovine serum (FBS). We find the minimal IVD units remain healthy for up to 14 days when cultured in submersion culture supplemented with 10% FBS. New bone formation in the EPs of the cultured IVDs can be assessed with calcein labeling. Furthermore, the cultured IVDs can be effectively transduced by recombinant adenovirus, and transgene expression lasts for 2 weeks. Thus, our findings demonstrate that the optimized IVD organ culture system can be used to study IVD biology and screen for biological factors that may prevent, alleviate and/or treat disc degeneration.
Coexistence of Hidradenitis Suppurativa with Autoimmune Thyroiditis: Report of Three Cases
Authors: González-López Marcos A. , Blanco Ricardo , Mata Cristina , López-Escobar María , Lacalle Marina , Consuegra Germana , González-Vela M. Carmen , González-Gay Miguel A.
Published: October 2015

Hidradenitis suppurativa (HS) is a chronic, relapsing inflammatory skin disease affecting terminal hair follicles in apocrine-gland-bearing skin. The pathogenesis of HS is still unknown, although increasing evidence suggests that the immune system plays an important role. Herein we describe 3 patients with HS coexisting with autoimmune (Hashimoto's) thyroiditis (AT). To our knowledge, the co-occurrence of these two diseases has not previously been described. The coexistence of HS with autoimmune disorders, such as AT, may support the hypothesis on dysregulation of the immune system's function as implicated in the pathogenesis of HS. Based on our findings, we feel that an assessment of thyroid function and antithyroid antibodies should be performed in patients with HS.
Functional Outcome of Hemorrhagic Transformation after Thrombolysis for Ischemic Stroke: A Prospective Study
Authors: Annan Mariam , Gaudron Marie , Cottier Jean-Philippe , Cazals Xavier , Dejobert Maelle , Corcia Philippe , Bertrand Philippe , Mondon Karl , de Toffol Bertrand , Debiais Séverine
Published: October 2015

Background/Aims: Hemorrhagic transformation (HT) is usually taken into account when symptomatic, but the role of asymptomatic HT is not well known. The aim of our study was to evaluate the link between HT after thrombolysis for ischemic stroke and functional outcome at 3 months, with particular emphasis on asymptomatic HT. Methods: Our study was performed prospectively between June 2012 and June 2013 in the Stroke Unit of the University Hospital Center of Tours (France). All patients treated with intravenous thrombolysis were consecutively included. HT was classified on susceptibility-weighted imaging (SWI) with 3-tesla MRI at 7 ± 3 days after treatment. We evaluated functional outcome at 3 months using the modified Rankin Scale (mRS). Dependency was defined as an mRS score of ≥3. Results: After 1 year, 128 patients had received thrombolytic therapy for ischemic stroke, of whom 90 patients underwent both 3-tesla MRI and SWI at day 7. Fifty-two had HT, including 8 symptomatic cases. At 3 months, 68% of those patients were dependent compared to 31% of patients without HT [OR 4.6 (1.9-11.4), p = 0.001]. In asymptomatic HT, the rate was 62% [OR 3.5 (1.4-8.9), p = 0.007], but did not reach significance after adjustment for stroke severity. Discussion: Our study found no statistically significant effect of HT on outcome after adjustment for initial stroke severity. However, the innocuousness of HT is not certain, and only few studies have already highlighted the increased risk of dependency. Using 3-tesla MRI with SWI allows us to increase the detection rate of small hemorrhage. Conclusion: HT after thrombolysis is very frequent on SWI, but the initial stroke severity is an important predictor to assess the role of HT for patient outcome.
Detection of Cortical Microbleeds in Postmortem Brains of Patients with Lewy Body Dementia: A 7.0-Tesla Magnetic Resonance Imaging Study with Neuropathological Correlates
Authors: De Reuck Jacques L. , Auger Florent , Durieux Nicolas , Cordonnier Charlotte , Deramecourt Vincent , Lebert Florence , Leys Didier , Pasquier Florence , Maurage Claude-Alain , Bordet Regis
Published: October 2015

Background: It is unclear whether associated cerebrovascular pathology contributes to the clinical spectrum of Lewy body dementia (LBD). Summary: The present postmortem 7.0-tesla MRI study investigates the anatomical distribution of cortical microbleeds (CoMBs) in LBD brains with and without associated Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA). CoMBs predominated in the frontal section of the LBD brains and were associated to severe white matter lesions. No differences were observed when LBD brains with and without AD and CAA were compared. Key Messages: In LBD, there is a specific distribution of CoMBs that is different from that in other neurodegenerative diseases. The increase of frontal CoMBs is not due to the frequently associated AD and CAA features but due to the LBD itself.
Toward a Preoperative Classification of Lymph Node Metastases in Patients with Small Intestinal Neuroendocrine Tumors in the Era of Intestinal-Sparing Surgery
Authors: Lardière-Deguelte Sophie , de Mestier Louis , Appéré François , Vullierme Marie-Pierre , Zappa Magaly , Hoeffel Christine , Noaves Marleny , Brixi Hedia , Hentic Olivia , Ruszniewski Philippe , Cadiot Guillaume , Panis Yves , Kianmanesh Reza
Published: October 2015

Introduction: In patients with small intestinal neuroendocrine tumors (siNETs), surgical resection of the primary tumor and associated mesenteric lymph nodes (LNs) is recommended, but is not well standardized and can be risky in patients with superior mesenteric vessel involvement. Objective: We aimed to evaluate the correlation between the length of resected small bowel and the number of removed LNs, and to propose a preoperative morphological classification of siNET-associated LNs. Methods: The records of patients operated on for siNETs at two expert centers between August 2005 and November 2013 were analyzed. Two specialist radiologists reviewed the preoperative imaging and classified mesenteric LNs into five stages according to their proximity to the trunk and/or branches of the superior mesenteric artery. Results: 72 patients were included. The mean number of removed LNs was 12 ± 15 and the length of removed small intestine was 53 ± 43 cm. No correlation existed between the length of small bowel resection and the number of removed LNs. Overall, 9 (12%), 13 (18%), 36 (50%), 14 (19%) and 0 patients were classified into LN stages 0, I, II, III and IV. The correlation rate between the two observers was 0.98. Patients with LN stage III (hardly resectable) had more removed LNs than those with LN stages 0, I or II (easily removable). Conclusion: Optimal lymphadenectomy is not always associated with extended small bowel resection. In the era of small bowel-sparing surgery, the preoperative classification of mesenteric LNs could help to standardize the surgical management of patients with siNETs.
BRCA2 gene mutations and coagulation-associated biomarkers
Authors: Acosta Daniel , Santos-Sancho Juana María , Modrego Javier , Caldés Trinidad , Hoya Miguel de la , Díaz-Rubio Eduardo , Díaz-Millán Isabel , Heras Natalia de las , Zalba Luis Alfonso Rico , Lahera Vicente , Melander Olle , Perez-Segura Pedro , Zamorano-León José J , López Farré Antonio
Published: October 2015

Thromboembolic events are the second cause of death in cancer patients, although the mechanisms underlying this increased thromboembolic risk remain unclear. The aims of this study were to examine whether BRCA2 gene mutations may modify the circulating levels of thrombocoagulation biomarkers and whether breast cancer development may influence changes in such circulating biomarkers. The study was performed in 25 women with mutations in the BRCA2 gene (n=12 breast cancer, n=13 breast cancer-free) and in 13 BRCA2 nonmutant controls. Results revealed that plasma levels of fibrinogen gamma chain isotypes 2 and 3, haptoglobin isotypes 4 and 5, serotransferrin isotypes 3 and 4 and convertase C3/C5 isotypes 4 and 5 were significantly higher in BRCA2 mutation carriers compared to controls. However, plasma levels of vitamin D binding protein isotype 1 and alpha1-antitrypsin isotypes 2, 3 and 4 were significantly decreased in BRCA2 mutation carriers compared to controls. Plasma expression of PF4 and P-selectin was significantly higher in BRCA2 mutations carriers than in controls. BRCA2 truncated mutations conserving a binding region for RAD51 were associated with increased plasma levels of alpha1-antitrypsin isotypes 3 and 4 with respect to women showing BRCA2 mutations that loss the binding RD51 region to BRCA2. Only plasma levels of vitamin D binding protein isotypes 1 and 3 were significantly reduced and alpha 1-antitrypsin isotype 1 was increased in cancer-free BRCA2 mutation carriers compared to BRCA2 mutation carriers with breast cancer. The presence of BRCA2 mutations is associated with increased plasma levels of thrombo-coagulating-related proteins, which are independent to breast cancer development.