bluuebunny/crossref_metadata_2025 huggingface dataset:
Birth of the Canadian Digestive Health Foundation
Authors: Beck Ivan T
Published: March 2016

The Canadian Digestive Disease Foundation, renamed the Canadian Digestive Health Foundation -- Fondation canadienne pour la promotion de la santé digestive -- in December 2001, is the culmination of ongoing efforts by the Canadian Association of Gastroenterology to establish an independent charitable organization. In February 2001, it was officially endorsed as the Foundation for the Canadian Association of Gastroenterology. The initial efforts to establish this Foundation, led by Dr Richard McKenna in 1963, were unsuccessful. In 1991, Glaxo Canada (now GlaxoSmithKline) became a founding donor, and with the four founding physicians -- Drs Ivan T Beck, Richard H Hunt, Suzanne E Lemire and Alan BR Thomson -- the expenses to establish the Foundation were met. A charitable number was obtained in 1995 (0997427-11). The second founding donor was Janssen Canada (now Janssen-Ortho), and public education support came from Astra Canada (now AstraZeneca Canada). The Foundation initially relied on corporate donors, but now approaches physicians, patients and the general public. The objectives of the Foundation are to advance the science of gastroenterology and to provide knowledge of digestive diseases and nutrition to the general public, to enhance the quality of life of persons who are afflicted with these disorders. The major achievements of the Foundation are the provision of one-year operating grants to new investigators, which have allowed them to accumulate early data and subsequently obtain support from other major granting organizations. It also provides Fellowships and studentship support grants, in conjunction with the Canadian Institutes of Health Research and the pharmaceutical industry. The education committee found that there was little research support in this field, considering the large economic burden of digestive disease and the amount of outstanding work done by Canadian researchers. A bilingual Web site, a web-based specialist's discussion program and bilingual pamphlets facilitate public awareness and allow patients to voice concerns.
Hypophosphatemia after Right Hepatectomy for Living Donor Liver Transplantation
Authors: Burak Kelly W , Rosen Charles B , Fidler Jeff L , Hesley Gina K , Nagorney David , Charlton Michael R , Brandhagen David J
Published: March 2016

Hypophosphatemia has been described in patients undergoing right hepatectomy for liver cancer and in living donors for liver transplantation who also received total parenteral nutrition. At the study centre, significant hypophosphatemia (0.36 mmol/L or less) requiring intravenous replacement was seen in two of the first nine living donors for adult-to-adult liver transplantation. To determine the frequency of hypophosphatemia in living donors, the authors obtained phosphate levels on stored serum samples from postoperative days 0, 1, 3 and 7 in all nine patients, none of whom were on total parenteral nutrition. Within the first week, hypophosphatemia developed in 55.6% of patients and phosphate levels returned to normal by day 7 in all nine patients. One patient had normal phosphate levels during the first week, but had profound hypophosphatemia (0.32 mmol/L) on day 14 when he presented with a Staphylococcus aureus infection of a bile collection and significant hypoxemia. The extent of hepatectomy and the rate of liver regeneration, estimated by baseline and postoperative day 7 volumetric computed tomography scans, did not correlate with the development of hypophosphatemia. In conclusion, hypophosphatemia is common in living donors undergoing right hepatectomy and may be associated with complications. All living donors should be monitored for the development of hypophosphatemia during the first two postoperative weeks.
Injection of Botulinum Toxin a to Upper Esophageal Sphincter for Oropharyngeal Dysphagia in Two Patients with Inclusion Body Myositis
Authors: Liu Louis WC , Tarnopolsky Mark , Armstrong David
Published: March 2016

Inclusion body myositis (IBM) is a progressive degenerative skeletal muscle disease leading to weakening and atrophy of both proximal and distal muscles. Dysphagia is reported in up to 86% of IBM patients. Surgical cricopharyngeal myotomy may be effective for cricopharyngeal dysphagia and there is one published report that botulinum toxin A, injected into the cricopharyngeus muscle using a hypopharyngoscope under general anesthesia, relieved IBM-associated dysphagia. This report presents the first documentation of botulinum toxin A injection into the upper esophageal sphincter using a flexible esophagogastroduodenoscope under conscious sedation, to reduce upper esophageal sphincter pressure and successfully alleviate oropharyngeal dysphagia in two IBM patients.
Time to register for the World Congress of Gastroenterology meeting in Montreal: September 10-14, 2005
Authors: Sherman Philip M , Fedorak Richard N , Leddin Desmond
Published: March 2016

By now, you should have received an announcement regarding the World Congress of Gastroenterolgy (WCOG) 2005 meeting in Montreal, Quebec entitled 'Global Goals in Gastroenterology - Expanding Horizons in the 21st Century'. Enclosed with the announcement is a registration form. We have completed and sent in our forms already - and now encourage you to do the same!
Hilar Tumours
Authors: Costamagna Guido , Tringali Andrea , Petruzziello Lucio , Spada Cristiano
Published: March 2016

Tumours that involve the confluence of the bile ducts in the liver hilum provide a major therapeutic challenge. Adequate palliation requires relief of jaundice. Even though jaundice can be relieved if only 30% of the liver is drained, the presence of undrained bile ducts may result in pruritus and a continued risk of cholangitis and hepatic abscess. The biliary anatomy is defined by cholangiography, which today can be performed by magnetic resonance; the stricture is dilated, and plastic or metallic stents are endoscopically inserted over a guidewire. Patients with complex hilar strictures may benefit from the insertion of one or more stents, although there is debate about how many are necessary. The present article provides specific technical details, describes comparative trials of unilateral versus bilateral biliary drainage and explores new techniques that warrant further investigation.
Granulomatous Bronchiolitis with Necrobiotic Pulmonary Nodules in Chrohn's Disease
Authors: Freeman Hugh J , Davis Jennifer E , Prest Marcia E , Lawson Edward J
Published: March 2016

A 37-year-old man with extensive Crohn's disease of the stomach, small and large intestine for almost a decade developed respiratory symptoms and radiological findings suggestive of pneumonia that failed to resolve with antibiotic treatment. Computed tomography scanning of his lungs showed extensive changes with cavitated parenchymal nodules. Histological evaluation of an open lung biopsy showed granulomatous bronchiolitis and pulmonary necrobiosis. Treatment with steroids and immunosuppression resulted in complete resolution of his clinical symptoms of pneumonia and abnormal computed tomography imaging changes. Granulomatous bronchiolitis and necrobiotic nodules may be a manifestation of Crohn's disease in the absence of microbial agents, including mycobacteria or fungal agents. While a multiplicity of complex pulmonary changes may occur in Crohn's disease, their clinical recognition and precise pathological definition may be particularly important if treatment with a biological agent, such as infliximab, is being considered.
Recognizing the Clinical Contraindications to the Use of Oral Sodium Phosphate for Colon Cleansing: A Case Study
Authors: Hookey Lawrence C , Vanner Stephen
Published: March 2016

Oral sodium phosphate has been demonstrated in numerous clinical trials to be an effective and well-tolerated colonic cleansing agent. However, there exists a potential to induce shifts in intravascular volume. The phosphate load often results in hyperphosphatemia, which may precipitate hypocalcemia. A review at the authors' institution identified four patients with adverse events related to oral sodium phosphate. Three of these cases had pre-existing comorbidities that predisposed them to the adverse event, or had received doses higher than that used or recommended in previous trials. Recommendations for relative and absolute contraindications to the use of oral sodium phosphate are described.
Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation: Guidelines on Colon Cancer Screening
Authors: Leddin Desmond , Hunt Richard , Champion Malcolm , Cockeram Alan , Flook Nigel , Gould Michael , Kim Young-In , Love Jonathan , Morgan David , Natsheh Susan , Sadowski Dan ,   for the Canadian Association of Gastroenterology and the Canadian Digestive Health Foundation committee on colon cancer screening
Published: March 2016

Colorectal cancer is the third most prevalent cancer affecting both men and women in Canada. Many of these cancers are preventable, and the Canadian Association of Gastroenterology (CAG) and the Canadian Digestive Health Foundation (CDHF) strongly support the establishment of screening programs for colorectal cancer. These guidelines discuss a number of screening options, listing the advantages and disadvantages of each. Ultimately, the test that is used for screening should be determined by patient preference, current evidence and local resources.
Canadian Association of Gastroenterology Launches Human Resource Planning Initiatives
Authors: Leddin Desmond
Published: March 2016

In 2002, the Canadian Association of Gastroenterology (CAG) conducted a survey of the membership, the results of which were reviewed and developed by the Past Presidents' Council into a long term strategic plan. Survey findings and the resulting strategic plan were published earlier this year in The Canadian Journal of Gastroenterology and can be reviewed on the CAG Web site at http://www.pulsus.com/Gastro/18_01/Pdf/newe_ed.pdf and http://www.pulsus.com/Gastro/18_02/Pdf/newe_ed.pdf. Members repeatedly noted the importance of collecting statistics on gastroenterology in Canada and addressing human resource issues.
A Hybrid Approach for Fast Computation of Multiple Incident Angles Electromagnetic Scattering Problems with Compressive Sensing and Adaptive Cross Approximation
Authors: Wang Guo-hua , Sun Yu-fa
Published: March 2016

A hybrid compressive approach for fast computation of the electromagnetic scattering problems with multiple incident angles is proposed. The compressive sensing (CS) technique is firstly introduced to the method of moment (MoM) to reduce the number of the right-hand sides (RHS), but since the resulting excitation matrix contains linear dependency and has low-rank characteristics, the adaptive cross approximation (ACA) algorithm is used to recompress such excitation matrix, keeping only the necessary physical information. The hybrid compressive approach can reduce the number of the RHS to lower level. In fact, the ratio of the number of the RHS between the compressed excitation matrix and the original excitation matrix in the conventional MoM is close to one to fifteen. Numerical results are presented to validate the efficiency and accuracy of this method, which turns out to be highly efficient and accurate for the solution to multiple incident angles electromagnetic scattering problems.
Electronic Origin of Defect States in Fe-Doped LiNbO3Ferroelectrics
Authors: Noguchi Yuji , Inoue Ryotaro , Miyayama Masaru
Published: March 2016

We investigate the role of Fe in the electronic structure of ferroelectric LiNbO3by density-functional theory calculations. We show that Fe2+on the Li site (Fe2+Li) features a displacement opposite to the direction of spontaneous polarization and acts as a trigger for the bulk photovoltaic (PV) effect. In contrast to Fe3+on the Li site that forms the defect states (1e,a, and 2e) below the conduction band minimum, the reduction from Fe3+to Fe2+accompanied by a lattice relaxation markedly lowers only theastate (dz2) owing to a strong orbital hybridization with Nb-4d. Theastate ofFe2+Liprovides the highest electron-occupied defect state in the middle of the band gap. A reduction treatment of Fe-LN is expected to increase the concentration of Fe2+and therefore to enhance the PV effect under visible light illumination.
Anti-Inflammatory Effects of GLP-1-Based Therapies beyond Glucose Control
Authors: Lee Young-Sun , Jun Hee-Sook
Published: March 2016

Glucagon-like peptide-1 (GLP-1) is an incretin hormone mainly secreted from intestinal L cells in response to nutrient ingestion. GLP-1 has beneficial effects for glucose homeostasis by stimulating insulin secretion from pancreatic beta-cells, delaying gastric emptying, decreasing plasma glucagon, reducing food intake, and stimulating glucose disposal. Therefore, GLP-1-based therapies such as GLP-1 receptor agonists and inhibitors of dipeptidyl peptidase-4, which is a GLP-1 inactivating enzyme, have been developed for treatment of type 2 diabetes. In addition to glucose-lowering effects, emerging data suggests that GLP-1-based therapies also show anti-inflammatory effects in chronic inflammatory diseases including type 1 and 2 diabetes, atherosclerosis, neurodegenerative disorders, nonalcoholic steatohepatitis, diabetic nephropathy, asthma, and psoriasis. This review outlines the anti-inflammatory actions of GLP-1-based therapies on diseases associated with chronic inflammationin vivoandin vitro, and their molecular mechanisms of anti-inflammatory action.
Damage Detection of Structures for Ambient Loading Based on Cross Correlation Function Amplitude and SVM
Authors: Huo Lin-sheng , Li Xu , Yang Yeong-Bin , Li Hong-Nan
Published: March 2016

An effective method for the damage detection of skeletal structures which combines the cross correlation function amplitude (CCFA) with the support vector machine (SVM) is presented in this paper. The proposed method consists of two stages. Firstly, the data features are extracted from the CCFA, which, calculated from dynamic responses and as a representation of the modal shapes of the structure, changes when damage occurs on the structure. The data features are then input into the SVM with the one-against-one (OAO) algorithm to classify the damage status of the structure. The simulation data of IASC-ASCE benchmark model and a vibration experiment of truss structure are adopted to verify the feasibility of proposed method. The results show that the proposed method is suitable for the damage identification of skeletal structures with the limited sensors subjected to ambient excitation. As the CCFA based data features are sensitive to damage, the proposed method demonstrates its reliability in the diagnosis of structures with damage, especially for those with minor damage. In addition, the proposed method shows better noise robustness and is more suitable for noisy environments.
Primary Mucosa-Associated Lymphoid Tissue Lymphoma of Thyroid with the Serial Ultrasound Findings
Authors: Jeon Eon Ju , Shon Ho Sang , Jung Eui Dal
Published: March 2016

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) of the thyroid gland is uncommon. Even though its natural history is not well defined, it is known to be indolent course. We present a case of primary MALT thyroid lymphoma with the serial sonographic findings in the patient presenting as the focal nodule. A 45-year-old woman visited our hospital for neck examination. Initially, fine-needle aspiration cytology in the focal hypoechoic lesion in the left thyroid lobe on ultrasound sonography was performed and consistent with Hashimoto’s thyroiditis. However, the results of serial ultrasounds and core-needle biopsy revealed an extranodal marginal zone lymphoma of MALT on 4-year follow-up. Patients with a focal hypoechoic nodule with linear echogenic strands and segmental pattern in the background of Hashimoto’s thyroiditis on ultrasonography should undergo careful surveillance for malignancy. Serial sonographic features in this case are meaningful in the understanding of the natural history of the extranodal marginal zone lymphoma of MALT of the thyroid.
Miniaturization of UWB Antennas on Organic Material
Authors: Nikolaou Symeon , Abbasi Muhammad Ali Babar
Published: March 2016

Three planar, CPW-fed, UWB antennas with increasingly reduced size are presented and the miniaturization method is discussed. The first antenna is a CPW-fed elliptical slot with an uneven U-shaped tuning stub, the second antenna is a cactus shaped monopole, and the third one is a miniaturized version of the cactus shaped monopole antenna. All presented antennas have a simulated and measured return loss below −10 dB over the 3.1 to 10.6 GHz UWB frequency range and mostly omnidirectional radiation patterns. The proposed antennas are fabricated on liquid crystal polymer (LCP). The CPW-fed slot antenna requires an overall board dimension of 38 mm × 40 mm, and the evolved cactus monopole is confined in a 28 mm × 32 mm board, while the final miniaturized cactus monopole is printed on 28 mm × 20 mm board, resulting in a 41% and 63% size reduction, respectively. Using both simulations and measurements, the paper analyzes the response of all three antennas and discusses and demonstrates the effectiveness of the implemented miniaturization method.
Dynamic Friction Parameter Identification Method with LuGre Model for Direct-Drive Rotary Torque Motor
Authors: Wang Xingjian , Lin Siru , Wang Shaoping
Published: March 2016

Attainment of high-performance motion/velocity control objectives for the Direct-Drive Rotary (DDR) torque motor should fully consider practical nonlinearities in controller design, such as dynamic friction. The LuGre model has been widely utilized to describe nonlinear friction behavior; however, parameter identification for the LuGre model remains a challenge. A new dynamic friction parameter identification method for LuGre model is proposed in this study. Static parameters are identified through a series of constant velocity experiments, while dynamic parameters are obtained through a presliding process. Novel evolutionary algorithm (NEA) is utilized to increase identification accuracy. Experimental results gathered from the identification experiments conducted in the study for a practical DDR torque motor control system validate the effectiveness of the proposed method.
Advantages and Limitations of Direct PCR Amplification of Bacterial 16S-rDNA from Resected Heart Tissue or Swabs Followed by Direct Sequencing for Diagnosing Infective Endocarditis: A Retrospective Analysis in the Routine Clinical Setting
Authors: Maneg Daniela , Sponsel Janina , Müller Iris , Lohr Benedikt , Penders John , Madlener Katharina , Hunfeld Klaus-Peter
Published: March 2016

Infective endocarditis (IE) is a life-threatening disease that is associated with high morbidity and mortality. Its long-term prognosis strongly depends on a timely and optimized antibiotic treatment. Therefore, identification of the causative pathogen is crucial and currently based on blood cultures followed by characterization and susceptibility testing of the isolate. However, antibiotic treatment starting prior to blood sampling or IE caused by fastidious or intracellular microorganisms may cause negative culture results. Here we investigate the additional diagnostic value of broad-range PCR in combination with direct sequencing on resected heart tissue or swabs in patients with tissue or swab culture-negative IE in a routine clinical setting. Sensitivity, specificity, and positive and negative predictive values of broad-range PCR from diagnostic material in our patients were 33.3%, 76.9%, 90.9%, and 14.3%, respectively. We identified a total of 20 patients (21.5%) with tissue or culture-negative IE who profited by the additional application of broad-range PCR. We conclude that broad-range PCR on resected heart tissue or swabs is an important complementary diagnostic approach. It should be seen as an indispensable new tool for both the therapeutic and diagnostic management of culture-negative IE and we thus propose its possible inclusion in Duke’s diagnostic classification scheme.
Pre- and Postcopulatory Traits ofSalvatorMale Lizards in Allopatry and Sympatry
Authors: Naretto Sergio , Blengini Cecilia S. , Cardozo Gabriela , Chiaraviglio Margarita
Published: March 2016

The reproductive traits of males are under influence of sexual pressures before and after copulation. The strength of sexual selection varies across populations because they undergo varying competition for mating opportunities. Besides intraspecific pressures, individuals seem to be subjected to pressures driven by interspecific interactions in sympatry. Lizards may vary their reproductive strategies through varying sexual characters, body size, gonadal investment, and sperm traits. We evaluated the reproductive traits, involved in pre- and postcopulatory competition, in allopatric and sympatric populations ofSalvatorlizards. We observed a spatial gradient of male competition among populations, with the following order: allopatric zone ofS. rufescens; sympatric zone; and allopatric zone ofS. merianae. Accordingly, variation in secondary sexual character, the relative testis mass, and the length of sperm component was observed between allopatry and sympatry in each species, suggesting differences in the investment of reproductive traits. However, we found that these twoSalvatorspecies did not differ in secondary sexual characters in sympatry. Interestingly, the trade-off between testes and muscle varied differently from allopatry to sympatry between theseSalvatorspecies, suggesting that the influence of social context on reproductive traits investment would affect lizard species differently.
Cooperation Dynamics on Mobile Crowd Networks of Device-to-Device Communications
Authors: Deng Yong , Wei Guiyi , Xie Mande , Shao Jun
Published: March 2016

The explosive use of smart devices enabled the emergence of collective resource sharing among mobile individuals. Mobile users need to cooperate with each other to improve the whole network’s quality of service. By modeling the cooperative behaviors in a mobile crowd into an evolutionary Prisoner’s dilemma game, we investigate the relationships between cooperation rate and some main influence factors, including crowd density, communication range, temptation to defect, and mobility attributes. Using evolutionary game theory, our analysis on the cooperative behaviors of mobile takes a deep insight into the cooperation promotion in a dynamical network with selfish autonomous users. The experiment results show that mobile user’s features, including speed, moving probability, and reaction radius, have an obvious influence on the formation of a cooperative mobile social network. We also found some optimal status when the crowd’s cooperation rate reaches the best. These findings are important if we want to establish a mobile social network with a good performance.
Nationality, Gender, Age, and Body Mass Index Influences on Vitamin D Concentration among Elderly Patients and Young Iraqi and Jordanian in Jordan
Authors: Al-Horani Hanan , Abu Dayyih Wael , Mallah Eyad , Hamad Mohammed , Mima Mohammad , Awad Riad , Arafat Tawfiq
Published: March 2016

Vitamin D is necessary for maintaining and regulating calcium levels; thus, insufficiency of vitamin D increases the risk of many chronic diseases. This study aimed to examine vitamin D levels among Jordanian and Iraqi volunteers and find the relation between vitamin D level and lipid profile patients. Vitamin D levels were evaluated using enzyme-linked immunosorbent assay. For young healthy group subjects, vitamin D levels were 20.60 ± 5.94 ng/mL for Jordanian and 27.59 ± 7.74 ng/mL for Iraqi. Vitamin D concentrations for young males and females were 25.82 ± 8.33 ng/mL and 21.95 ± 6.39 ng/mL, respectively. Females wearing hijab were 20.87 ± 6.45 ng/mL, while uncovered females were 23.55 ± 6.04 ng/mL. For >40 years Iraqi subjects, vitamin D level for healthy was 29.78 ± 9.49 ng/mL and 23.88 ± 7.93 ng/mL for hyperlipidemic subjects. Vitamin D levels for overweight and obese healthy groups were significantly higher (P<0.050) than those for the hyperlipidemic patients groups. Vitamin D levels for males were significantly higher than females and were significantly higher for healthy than those hyperlipidemic Iraqi patients. These findings showed that vitamin D levels are affected by age, nationality, gender, and health statues and highlight the importance of vitamin D supplementation for groups with low levels particularly old, hijab wearing females, and hyperlipidemic groups.
Cooperative Beamforming for Physical-Layer Security in Power-Constrained Wireless Sensor Networks with Partial Relay Selection
Authors: Qian Mujun , Liu Chen , Zou Yulong
Published: March 2016

We investigate the physical-layer security of a wireless sensor network comprised of a source-destination pair, multiple decode-and-forward (DF) relays, and an eavesdropper. When the relays forward the source signal to the destination, they should dissipate certain power for driving their physical circuits (e.g., amplifiers and filters), in addition to the transmit power required for emitting radio signals. However, no existing work considers the circuit power when exploiting relays for enhancing the wireless security against eavesdropping. We thus propose the relay-selection based cooperative beamforming framework, where partial relays are selected to forward the source signal in a beamforming manner. We present two relay-selection strategies, namely, the exponential-complexity exhaustive search and linear-complexity relay ordering. For comparison purposes, we also evaluate the conventional all-relay based and best-relay based beamforming schemes, where all relays or only the best one is selected to assist the source-destination transmission. It is shown that the proposed beamforming schemes significantly outperform the conventional all-relay and best-relay based beamforming schemes in terms of secrecy capacity. Additionally, the relay-ordering based beamforming scheme almost achieves the same secrecy capacity as the exhaustive-search method, but with a reduced computational complexity.
Polysome Profiling Links Translational Control to the Radioresponse of Glioblastoma Stem-like Cells
Authors: Wahba Amy , Rath Barbara H. , Bisht Kheem , Camphausen Kevin , Tofilon Philip J.
Published: March 2016

Changes in polysome-bound mRNA (translatome) are correlated closely with changes in the proteome in cells. Therefore, to better understand the processes mediating the response of glioblastoma to ionizing radiation (IR), we used polysome profiling to define the IR-induced translatomes of a set of human glioblastoma stem-like cell (GSC) lines. Although cell line specificity accounted for the largest proportion of genes within each translatome, there were also genes that were common to the GSC lines. In particular, analyses of the IR-induced common translatome identified components of the DNA damage response, consistent with a role for the translational control of gene expression in cellular radioresponse. Moreover, translatome analyses suggested that IR enhanced cap-dependent translation processes, an effect corroborated by the finding of increased eIF4F–cap complex formation detected after irradiation in all GSC lines. Translatome analyses also predicted that Golgi function was affected by IR. Accordingly, Golgi dispersal was detected after irradiation of each of the GSC lines. In addition to the common responses seen, translatome analyses predicted cell line–specific changes in mitochondria, as substantiated by changes in mitochondrial mass and DNA content. Together, these results suggest that analysis of radiation-induced translatomes can provide new molecular insights concerning the radiation response of cancer cells. More specifically, they suggest that the translational control of gene expression may provide a source of molecular targets for glioblastoma radiosensitization. Cancer Res; 76(10); 3078–87. ©2016 AACR.
Long-Lasting Complete Responses in Patients with Metastatic Melanoma after Adoptive Cell Therapy with Tumor-Infiltrating Lymphocytes and an Attenuated IL2 Regimen
Authors: Andersen Rikke , Donia Marco , Ellebaek Eva , Borch Troels Holz , Kongsted Per , Iversen Trine Zeeberg , Hölmich Lisbet Rosenkrantz , Hendel Helle Westergren , Met Özcan , Andersen Mads Hald , thor Straten Per , Svane Inge Marie
Published: March 2016

Purpose: Adoptive cell transfer therapy (ACT) based on autologous tumor-infiltrating lymphocytes (TIL) has achieved impressive clinical results in several phase I and II trials performed outside of Europe. Although transient, the toxicities associated with high-dose (HD) bolus IL2 classically administered together with TILs are severe. To further scrutinize whether similar results can be achieved with lower doses of IL2, we have carried out a phase I/II trial of TIL transfer after classical lymphodepleting chemotherapy followed by an attenuated IL2 regimen.

Experimental Design: Twenty-five patients with progressive treatment-refractory metastatic melanoma, good clinical performance, age < 70 years, and at least one resectable metastasis were eligible. TIL infusion was preceded by standard lymphodepleting chemotherapy and followed by attenuated doses of IL2 administered in an intravenous, continuous decrescendo regimen (ClinicalTrials.gov Identifier: NCT00937625).

Results: Classical IL2-related toxicities were observed but patients were manageable in a general oncology ward without the need for intervention from the intensive care unit. RECIST 1.0 evaluation displayed three complete responses and seven partial responses (ORR 42%). Median overall survival was 21.8 months. Tumor regression was associated with a higher absolute number of infused tumor-reactive T cells. Moreover, induction and persistence of antimelanoma T-cell responses in the peripheral blood was strongly correlated to clinical response to treatment.

Conclusions: TIL-ACT with a reduced IL2 decrescendo regimen results in long-lasting complete responses in patients with treatment-refractory melanoma. Larger randomized trials are needed to elucidate whether clinical efficacy is comparable with TIL-ACT followed by HD bolus IL2. Clin Cancer Res; 22(15); 3734–45. ©2016 AACR.
Myeloma Cell Dynamics in Response to Treatment Supports a Model of Hierarchical Differentiation and Clonal Evolution
Authors: Tang Min , Zhao Rui , van de Velde Helgi , Tross Jennifer G. , Mitsiades Constantine , Viselli Suzanne , Neuwirth Rachel , Esseltine Dixie-Lee , Anderson Kenneth , Ghobrial Irene M. , San Miguel Jesús F. , Richardson Paul G. , Tomasson Michael H. , Michor Franziska
Published: March 2016

Purpose: Since the pioneering work of Salmon and Durie, quantitative measures of tumor burden in multiple myeloma have been used to make clinical predictions and model tumor growth. However, such quantitative analyses have not yet been performed on large datasets from trials using modern chemotherapy regimens.

Experimental Design: We analyzed a large set of tumor response data from three randomized controlled trials of bortezomib-based chemotherapy regimens (total sample size n = 1,469 patients) to establish and validate a novel mathematical model of multiple myeloma cell dynamics.

Results: Treatment dynamics in newly diagnosed patients were most consistent with a model postulating two tumor cell subpopulations, "progenitor cells" and "differentiated cells." Differential treatment responses were observed with significant tumoricidal effects on differentiated cells and less clear effects on progenitor cells. We validated this model using a second trial of newly diagnosed patients and a third trial of refractory patients. When applying our model to data of relapsed patients, we found that a hybrid model incorporating both a differentiation hierarchy and clonal evolution best explains the response patterns.

Conclusions: The clinical data, together with mathematical modeling, suggest that bortezomib-based therapy exerts a selection pressure on myeloma cells that can shape the disease phenotype, thereby generating further inter-patient variability. This model may be a useful tool for improving our understanding of disease biology and the response to chemotherapy regimens. Clin Cancer Res; 22(16); 4206–14. ©2016 AACR.
Neoantigen: A Long March toward Cancer Immunotherapy
Authors: Liu Yang
Published: March 2016

Somatic mutations in cancer give rise to neoantigens. Technology revolutions in cancer genomics and immunology have made it possible to rapidly identify neoantigens for cancer vaccines. Leisegang and colleagues report that it is practical to rapidly identify neoantigens for adoptive T-cell therapy in a mouse tumor model. Clin Cancer Res; 22(11); 2602–4. ©2016 AACR.

See related article by Leisegang et al., p. 2734
Targeting GLI1 Suppresses Cell Growth and Enhances Chemosensitivity in CD34+ Enriched Acute Myeloid Leukemia Progenitor Cells
Authors: Long Bing , Wang Le-Xun , Zheng Fei-Meng , Lai Shu-Ping , Xu Duo-Rong , Hu Yuan , Lin Dong-Jun , Zhang Xiang-Zhong , Dong Lin , Long Zi-Jie , Tong Xiu-Zhen , Liu Quentin
Published: March 2016

Background/Aims: Resistance of leukemia stem cells (LSCs) to chemotherapy in patients with acute myeloid leukemia (AML) causes relapse of disease. Hedgehog (Hh) signaling plays a critical role in the maintenance and differentiation of cancer stem cells. Yet its role in AML remains controversial. The purpose of the present study is to investigate the role of GLI1, the transcriptional activator of Hh signaling, in AML progenitor cells and to explore the anti-AML effects of GLI small-molecule inhibitor GANT61. Methods: The expression of GLI1 mRNA and protein were examined in AML progenitor cells and normal cells. The proliferation, colony formation, apoptosis and differentiation of AML progenitor cells were also analyzed in the presence of GANT61. Results: Kasumi-1 and KG1a cells, containing more CD34+ cells, expressed higher level of GLI1 compared to U937 and NB4 cells with fewer CD34+ cells. Consistently, a positive correlation between the protein levels of GLI1 and CD34 was validated in the bone marrow mononuclear cells (BMMC) of AML patients tested. GANT61 inhibited the proliferation and colony formation in AML cell lines. Importantly, GANT61 induced apoptosis in CD34+ enriched Kasumi-1 and KG1a cells, whereas it induced differentiation in U937 and NB4 cells. Furthermore, GANT61 enhanced the cytotoxicity of cytarabine (Ara-c) in primary CD34+ AML cells, indicating that inhibition of GLI1 could be a promising strategy to enhance chemosensitivity. Conclusions: The present findings suggested that Hh signaling was activated in AML progenitor cells. GLI1 acted as a potential target for AML therapy.
Somatostatin Reduces the Acute Lung Injury of Mice via Increasing the Affinity of Glucocorticoid Receptor
Authors: Zhao Yan , Zhang Min , Xiong Ren-Ping , Chen Xing-Yun , Li Ping , Ning Ya-Lei , Yang Nan , Peng Yan , Zhou Yuan-Guo
Published: March 2016

Background/Aims: Although it has been reported that somatostatin (SOM) upregulated the level of 90-kD heat shock protein (Hsp90), which participates in the inflammatory regulation by its client proteins, such as glucocorticoid receptor (GR), it remains unclear if it has a protective role against acute lung injury (ALI). Methods: ALI model was established by the injection of oleic acid (OA) into the tail vein of mice. Lung injury was assessed by histological analysis, lung water content and arterial blood gases. The levels of Hsp90 and GR, the binding capacity and the affinity of GR were examined. Results: It was showed that pretreatment with SOM significantly increased Hsp90 levels and alleviated lung injuries in OA-injected mice. Furthermore, SOM increased the GR expression and improved the affinity of the GR in animals with lung injury. However, little alteration was found in the maximum binding capacity of the GR in mice with or without SOM. Conclusion: The data indicate SOM exerts a protective effect by increasing Hsp90 abundant and further enhancing the affinity of the GR. The beneficial effects of SOM treatment provide a new strategy for modulation of GR efficiency and alleviation of acute lung injury.
Inhibitory Effects of Resveratrol on the Human Alveolar Rhabdomyosarcoma Cell Line PLA-802 through Inhibition of the TGF-β1/Smad Signaling Pathway
Authors: Yang Hui , Yuan Ye , Luo Cheng , He Haixia , Zhou Yuanda
Published: March 2016

While anti-tumor activity of resveratrol has been demonstrated for many cancers, little is known about its effects on soft tissue sarcoma. Overexpression of TGF-β1, a protein inhibited by resveratrol, is a well-known feature of the rhabdomyosarcoma (RMS), a type of soft tissue sarcoma. In the present study, we examined the effects of resveratrol on the human alveolar RMS (ARMS) cell line PLA-802. Cultured PLA-802 cells were treated with different concentrations of resveratrol at distinct time points and changes in their growth, cell cycle progression and TGF-β1 signaling were assessed. MTT assay showed a decrease in the viability of PLA-802 cells treated with resveratrol (p < 0.05). Cell cycle analysis using flow cytometry revealed that resveratrol induced a significant decrease in the number of cells in S phase and an increase in the number of cells in G1 phase (p < 0.05). Furthermore, expression of TGF-β1 and its downstream factor Smad4 mRNA and protein, assessed by RT-PCR and Western blot, were inhibited by resveratrol in a concentration- and time-dependent manner. Immunofluorescent staining results confirmed these changes in expression and showed that co-localization of TGF-β1 with Smad4 was gradually decreased by resveratrol. Together, our results suggest that resveratrol may inhibit cell proliferation and cell cycle progression in PLA-802 cells through inhibiting activity of the TGF-β1 signaling pathway. Our findings highlight the therapeutic potential of resveratrol for suppressing the tumorigenicity of human ARMS.
Epigenetic Regulations of GABAergic Neurotransmission: Relevance for Neurological Disorders and Epigenetic Therapy
Authors: Shrestha Shikshya , Offer Steven M.
Published: March 2016

The GABAergic neurotransmission is a highly conserved system that has been attributed to various regulatory events. There has been a notable number of studies on the importance of GABAergic neurotransmission, both excitatory and inhibitory, in neurogenesis and central nervous system development including its control of neuronal cell proliferation and migration, synaptogenesis, dendrite formation and branching, and new neuronal cell integration in the adult brain. There has been remarkable progress in understanding the epigenetic regulations of GABAergic genes and their aberrant expressions in various neurological disorders such as autism spectrum disorder, Rett's syndrome, schizophrenia and PWS. The roles of histone modifications, chromatin looping and gene methylation have been implicated in altered regulations of key genes in the GABAergic pathway. Taken together, they affect the functioning of GABAergic neurotransmission and disrupt various events in brain development. Here, we focus on the role of GABAergic neurotransmission in brain development and on how various genetic and epigenetic events regulate the GABAergic genes in pre- and postnatal brain. We also discuss how these regulatory mechanisms contribute to the pathogenesis of neurological disorders and, therefore, can be used in the development of potential epigenetic therapy for these diseases.
A Case of Uveal Colobomas Showing Marked Left-Right Difference in Diabetic Retinopathy
Authors: Moriya Takeshi , Ochi Ryosuke , Imagawa Yukihiro , Sato Bumpei , Morishita Seita , Tonari Masahiro , Fukumoto Masanori , Suzuki Hiroyuki , Kobayashi Takatoshi , Kida Teruyo , Ikeda Tsunehiko
Published: March 2016

Purpose: Congenital uveal colobomas, including inferior iris and choroidal colobomas, are associated with microcornea and microphthalmia and often show left-right differences (laterality). The purpose of this study was to report a case of choroidal coloboma associated with left-right differences in diabetic retinopathy (DR). Case: This study reports a 59-year-old male with bilateral iris and choroidal colobomas. The colobomatous area in the patient's right eye extended to the macula, and his right eye had been amblyopic since birth. The colobomatous area in his left eye was less extensive and did not involve the macula. Examination of the patient's left eye revealed multiple hemorrhages and hard exudates in the macula due to DR, but examination of his right eye showed almost no changes in DR, thus revealing a marked left-right difference. Optical coherence tomography showed more extensive retinal thinning in the patient's right eye than in his left eye. Fluorescein fundus angiography revealed a retinal nonperfusion area only in the left eye, and panretinal photocoagulation was subsequently performed. Conclusion: Our findings show that the reason for the left-right difference in DR was attributed to the more severe choroidal coloboma and retinal thinning in the patient's right eye compared to his left eye, thus reducing oxygen demand, as is also seen in eyes with severe myopia.
Low-Frequency Ultrasound Enhances Paclitaxel Efficacy in EMT6 Subcutaneous Tumors in Balb/c Mice
Authors: Liu Zhao-Yang , Weng Chun-Xiao , Chen Wei , Zhao Hua-Ye , Li Tao
Published: March 2016

Background: The objective of this study was to explore the effects of 30 kHz ultrasound on the efficacy of paclitaxel in subcutaneous breast tumors in Balb/c mice in vivo. Materials and Methods: 40 Balb/c female mice were divided into 5 groups: model control group, paclitaxel intraperitoneal (ip) group (20 mg/kg, ip, at 3 day intervals for a total of 3 doses (q3d×3)), paclitaxel intratumoral (it) group (20 mg/kg, it, q3d×3), paclitaxel intraperitoneal (20 mg/kg, ip, q3d×3) combined with low-frequency ultrasound (LFU) group, and paclitaxel intratumoral (20 mg/kg, it, q3d×3) combined with LFU group. Ultrasound parameters were 30 kHz, 200 MW intensity, 15 min, q3d×3. The antitumoral effect was determined by examining the tumor weight in subcutaneously inoculated EMT6 breast carcinoma models in Balb/c mice. All subcutaneous tumors were examined using high performance liquid chromatography (HPLC) upon completion of the experiments. Drug concentrations in the subcutaneous tumors were also analyzed using HPLC. Finally, paraffin sections of the subcutaneous tumors were made, and after hematoxylin and eosin staining, the tumor morphology was examined under a light microscope. Results: LFU combined with paclitaxel significantly restrained tumor growth in transplanted subcutaneous EMT6 tumors in Balb/c mice, and this effect correlated with increased local concentrations of paclitaxel in the tumors. Body weight measurement did not reveal significant adverse effects on the Balb/c mice during the study. Conclusion: LFU combined with paclitaxel has a significant synergistic effect in the treatment of breast cancer.
Neutralisation of factor VIII inhibitors by anti-idiotypes isolated from phage-displayed libraries
Authors: Schmidt Anja , Brettschneider Kerstin , Kahle Jörg , Orlowski Aleksander , Becker-Peters Karin , Stichel Diana , Schulze Jörg , Braner Markus , Tampé Robert , Schwabe Dirk , Königs Christoph
Published: March 2016

Following replacement therapy with coagulation factor VIII (FVIII), up to 30 % of haemophilia A patients develop FVIII-specific inhibitory antibodies (FVIII inhibitors). Immune tolerance induction (ITI) is not always successful, resulting in a need for alternative treatments for FVIII inhibitor-positive patients. As tolerance induction in the course of ITI appears to involve the formation of anti-idiotypes specific for anti-FVIII antibodies, such anti-idiotypes might be used to restore haemostasis in haemophilia A patients with FVIII inhibitors. We isolated antiidiotypic antibody fragments (scFvs) binding to murine FVIII inhibitors 2-76 and 2-77 from phage-displayed libraries. FVIII inhibitor/anti-idiotype interactions were very specific as no cross-reactivity with other FVIII inhibitors or isotype controls was observed. ScFvs blocked binding of FVIII inhibitors to FVIII and neutralised their cognate inhibitors in vitro and a monoclonal mouse model. In addition, scFv JkH5 specific for FVIII inhibitor 2-76 stained 2-76-producing hybridoma cells. JkH5 residues R52 and Y226, located in complementary determining regions, were identified as crucial for the JkH5/2-76 interaction using JkH5 alanine mutants. SPR spectroscopy revealed that JkH5 interacts with FVIII inhibitor 2-76 with nanomolar affinity. Thus, FVIII inhibitorspecific, high-affinity anti-idiotypes can be isolated from phagedisplayed libraries and neutralise their respective inhibitors. Furthermore, we show that anti-idiotypic scFvs might be utilised to specifically target inhibitor-specific B cells. Hence, a pool of anti-idiotypes could enable the reestablishment of haemostasis in the presence of FVIII inhibitors in patients or even allow the depletion of inhibitors by targeting inhibitor-specific B cell populations.
Arterial Tortuosity: An Imaging Biomarker of Childhood Stroke Pathogenesis?
Authors: Wei Felix , Diedrich Karl T. , Fullerton Heather J. , deVeber Gabrielle , Wintermark Max , Hodge Jacquie , Kirton Adam , Dowling MM , Benedict SL , Bernard TJ , Fox CK , Friedman NR , Lo WD , Ichord RN , Tan MA , Mackay MT , Hernandez Chavez MI , Humphreys P , Jordan LC , Sultan SM , Rivkin MJ , Rafay MF , Titomanlio L , Kovacevic GS , Yager JY , Amlie-Lefond C , Dlamini N , Condie J , Yeh EA , Kneen R , Bjornson BH , Pergami P , Zou LP , Elbers J , Abdalla A , Chan AK , Farooq O , Lim MJ , Carpenter JL , Pavlakis S , Wong VCN , Forsyth R
Published: March 2016

Background and Purpose—

Arteriopathy is the leading cause of childhood arterial ischemic stroke. Mechanisms are poorly understood but may include inherent abnormalities of arterial structure. Extracranial dissection is associated with connective tissue disorders in adult stroke. Focal cerebral arteriopathy is a common syndrome where pathophysiology is unknown but may include intracranial dissection or transient cerebral arteriopathy. We aimed to quantify cerebral arterial tortuosity in childhood arterial ischemic stroke, hypothesizing increased tortuosity in dissection.

Methods—

Children (1 month to 18 years) with arterial ischemic stroke were recruited within the Vascular Effects of Infection in Pediatric Stroke (VIPS) study with controls from the Calgary Pediatric Stroke Program. Objective, multi-investigator review defined diagnostic categories. A validated imaging software method calculated the mean arterial tortuosity of the major cerebral arteries using 3-dimensional time-of-flight magnetic resonance angiographic source images. Tortuosity of unaffected vessels was compared between children with dissection, transient cerebral arteriopathy, meningitis, moyamoya, cardioembolic strokes, and controls (ANOVA and post hoc Tukey). Trauma-related versus spontaneous dissection was compared (Student
t
test).

Results—

One hundred fifteen children were studied (median, 6.8 years; 43% women). Age and sex were similar across groups. Tortuosity means and variances were consistent with validation studies. Tortuosity in controls (1.346±0.074; n=15) was comparable with moyamoya (1.324±0.038; n=15;
P
=0.998), meningitis (1.348±0.052; n=11;
P
=0.989), and cardioembolic (1.379±0.056; n=27;
P
=0.190) cases. Tortuosity was higher in both extracranial dissection (1.404±0.084; n=22;
P
=0.021) and transient cerebral arteriopathy (1.390±0.040; n=27;
P
=0.001) children. Tortuosity was not different between traumatic versus spontaneous dissections (
P
=0.70).

Conclusions—

In children with dissection and transient cerebral arteriopathy, cerebral arteries demonstrate increased tortuosity. Quantified arterial tortuosity may represent a clinically relevant imaging biomarker of vascular biology in pediatric stroke.