bluuebunny/crossref_metadata_2025 huggingface dataset:
Therapeutic Strategies for Oxidative Stress‐Related Cardiovascular Diseases: Removal of Excess Reactive Oxygen Species in Adult Stem Cells
Authors: Kim Hyunyun , Yun Jisoo , Kwon Sang-Mo
Published: September 2016

Accumulating evidence indicates that acute and chronic uncontrolled overproduction of oxidative stress‐related factors including reactive oxygen species (ROS) causes cardiovascular diseases (CVDs), atherosclerosis, and diabetes. Moreover ROS mediate various signaling pathways underlying vascular inflammation in ischemic tissues. With respect to stem cell‐based therapy, several studies clearly indicate that modulating antioxidant production at cellular levels enhances stem/progenitor cell functionalities, including proliferation, long‐term survival in ischemic tissues, and complete differentiation of transplanted cells into mature vascular cells. Recently emerging therapeutic strategies involving adult stem cells, including endothelial progenitor cells (EPCs), for treating ischemic CVDs have highlighted the need to control intracellular ROS production, because it critically affects the replicative senescence of ex vivo expanded therapeutic cells. Better understanding of the complexity of cellular ROS in stem cell biology might improve cell survival in ischemic tissues and enhance the regenerative potentials of transplanted stem/progenitor cells. In this review, we will discuss the nature and sources of ROS, drug‐based therapeutic strategies for scavenging ROS, and EPC based therapeutic strategies for treating oxidative stress‐related CVDs. Furthermore, we will discuss whether primed EPCs pretreated with natural ROS‐scavenging compounds are crucial and promising therapeutic strategies for vascular repair.
Optimising Health Literacy and Access of Service Provision to Community Dwelling Older People with Diabetes Receiving Home Nursing Support
Authors: Goeman Dianne , Conway Sue , Norman Ralph , Morley Jo , Weerasuriya Rona , Osborne Richard H. , Beauchamp Alison
Published: September 2016

Background. Health literacy is the ability to access, understand, and use information and services for good health. Among people with chronic conditions, health literacy requirements for effective self-management are high. The Optimising Health Literacy and Access (Ophelia) study engaged diverse organisations in the codesign of interventions involving the Health Literacy Questionnaire (HLQ) needs assessment, followed by development and evaluation of interventions addressing identified needs. This study reports the process and outcomes of one of the nine organisations, the Royal District Nursing Service (RDNS). Methods. Participants were home nursing clients with diabetes. The intervention included tailored diabetes self-management education according to preferred learning style, a standardised diabetes education tool, resources, and teach-back method. Results. Needs analysis of 113 quota-sampled clients showed difficulties managing health and finding and appraising health information. The service-wide diabetes education intervention was applied to 24 clients. The intervention was well received by clients and nurses. Positive impacts on clients’ diabetes knowledge and behaviour were seen and nurses reported clear benefits to their practice. Conclusion. A structured method that supports healthcare services to codesign interventions that respond to the health literacy needs of their clients can lead to evidence-informed, sustainable practice changes that support clients to better understand effective diabetes self-management.
Allium cepa Extract and Quercetin Protect Neuronal Cells from Oxidative Stress via PKC‐ε Inactivation/ERK1/2 Activation
Authors: Lee Bo Kyung , Jung Yi-Sook
Published: September 2016

Oxidative stress plays an important role in the pathophysiology of various neurologic disorders. Allium cepa extract (ACE) and their main flavonoid component quercetin (QCT) possess antioxidant activities and protect neurons from oxidative stress. We investigated the underlying molecular mechanisms, particularly those linked to the antioxidant effects of the ACE. Primary cortical neuronal cells derived from mouse embryos were preincubated with ACE or QCT for 30 min and exposed to L‐buthionine sulfoximine for 4~24 h. We found that ACE and QCT significantly decreased neuronal death and the ROS increase induced by L‐buthionine‐S, R‐sulfoximine (BSO) in a concentration‐dependent manner. Furthermore, ACE and QCT activated extracellular signal‐regulated kinase 1/2 (ERK1/2), leading to downregulation of protein kinase C‐ε (PKC‐ε) in BSO‐stimulated neuronal cells. In addition, ACE and QCT decreased the phosphorylated levels of p38 mitogen‐activated protein kinase. Our results provide new insight into the protective mechanism of ACE and QCT against oxidative stress in neuronal cells. The results suggest that the inactivation of PKC‐ε induced by phosphorylating ERK1/2 is responsible for the neuroprotective effect of ACE and QCT against BSO‐induced oxidative stress.
Asymptotic Theory in Model Diagnostic for General Multivariate Spatial Regression
Authors: Somayasa Wayan , Adhi Wibawa Gusti N. , Hamimu La , Ngkoimani La Ode
Published: September 2016

We establish an asymptotic approach for checking the appropriateness of an assumed multivariate spatial regression model by considering the set-indexed partial sums process of the least squares residuals of the vector of observations. In this work, we assume that the components of the observation, whose mean is generated by a certain basis, are correlated. By this reason we need more effort in deriving the results. To get the limit process we apply the multivariate analog of the well-known Prohorov’s theorem. To test the hypothesis we define tests which are given by Kolmogorov-Smirnov (KS) and Cramér-von Mises (CvM) functionals of the partial sums processes. The calibration of the probability distribution of the tests is conducted by proposing bootstrap resampling technique based on the residuals. We studied the finite sample size performance of the KS and CvM tests by simulation. The application of the proposed test procedure to real data is also discussed.
A Unique Case of Mycophenolate Induced Colitis after 10 Years of Use
Authors: Goyal Abhinav , Salahuddin Moiz , Govil Yogesh
Published: September 2016

A 31-year-old female with a history of lupus nephritis on Hydroxychloroquine, Prednisone, and Mycophenolate Mofetil (MMF) for 10 years presented to the hospital for ankle swelling. On day four, she started to have severe, nonbloody, watery diarrhea with abdominal distension and tenderness. Stool PCR was negative forC. difficile.CT abdomen/pelvis showed gaseous distension of the colon without any obstruction. Flexible sigmoidoscopy revealed a normal looking mucosa. Histopathology showed crypt atrophy and increased crypt apoptosis, consistent with MMF colitis. The diarrhea resolved three days after stopping MMF. Although generally well tolerated, diarrhea is a common side effect of MMF. Most cases occur in the first six months of starting MMF. This case is unique because it describes MMF colitis in lupus after more than 10 years. Thus, MMF colitis should be considered as a differential in patients taking it, regardless of the duration of use.
Proteomic Biomarkers Panel: New Insights in Chronic Kidney Disease
Authors: Mihai Simona , Codrici Elena , Popescu Ionela Daniela , Enciu Ana-Maria , Rusu Elena , Zilisteanu Diana , Albulescu Radu , Anton Gabriela , Tanase Cristiana
Published: September 2016

Chronic kidney disease, despite being a “silent epidemic” disease, represents one of the main causes of mortality in general population, along with cardiovascular disease, which is the leading cause of poor prognosis for these patients. The specific objective of our study was to characterize the relationship between the inflammatory status, the bone disorders markers, and kidney failure in chronic kidney disease patient stages 2–4, in order to design a novel biomarker panel that improves early disease diagnosis and therapeutic response, thus being further integrated into clinical applications. A panel of proteomic biomarkers, assessed by xMAP array, which includes mediators of inflammation (IL-6, TNF-α) and mineral and bone disorder biomarkers (OPG, OPN, OCN, FGF-23, and Fetuin-A), was found to be more relevant than a single biomarker to detect early CKD stages. The association between inflammatory cytokines and bone disorders markers, IL-6, TNF-α, OPN, OPG, and FGF-23, reflects the severity of vascular changes in CKD and predicts disease progression. Proteomic xMAP analyses shed light on a new approach to clinical evaluation for CKD staging and prognosis.
Complex Laparoscopic Myomectomy with Severe Adhesions Performed with Proper Preventive Measures and Power Morcellation Provides a Safe Choice in Certain Infertility Cases
Authors: Alfaro-Alfaro Jaime , Flores-Manzur María de los Ángeles , Nevarez-Bernal Roberto , Ayala-Yáñez Rodrigo
Published: September 2016

Laparoscopic myomectomy offers a real benefit to infertile patients with uterine fibroids and peritoneal adhesions. The procedure requires a skilled surgeon and laparoscopy technique to minimize adhesion formation and other proven benefits. Restrictions arise since this procedure requires power morcellation for fibroid tissue extraction. Two years ago, the Food and Drug Administration in the United States of America (FDA) issued the alert on power morcellation for uterine leiomyomas, addressing the risk of malignant cell spreading within the abdominal cavity (actual risk assessment from 1 in 360 to 1 in 7400 cases). We review a 30-year-old female, without previous gestations, hypermenorrhea, intermenstrual bleeding, and chronic pelvic pain. Transvaginal ultrasound reports multiple fibroids in the right portion of a bicornuate uterus. Relevant history includes open myomectomy 6 years before and a complicated appendectomy, developing peritonitis within a year. Laparoscopy revealed multiple adhesions blocking uterine access, a bicornuate uterus, and myomas in the expected site. Myomectomy was performed utilizing power morcellation with good results. FDA recommendations have diminished this procedure’s selection, converting many to open variants. This particular case was technically challenging, requiring morcellation, and safety device deployment was impossible, yet the infertility issue was properly addressed. Patient evaluation, safety measures, and laparoscopy benefits may outweigh the risks in particular cases as this one.
A Systematised Review of Primary School Whole Class Child Obesity Interventions: Effectiveness, Characteristics, and Strategies
Authors: Brown Elise C. , Buchan Duncan S. , Baker Julien S. , Wyatt Frank B. , Bocalini Danilo S. , Kilgore Lon
Published: September 2016

Background. A systematised review was conducted to examine the effectiveness of school-based interventions that focus on changing dietary intake and physical activity levels to reduce childhood obesity.Methods. Multiple databases were searched for randomised and nonrandomised interventions from 2007 to 2016 in full-time elementary schools, which were delivered to the whole class, included dietary and physical activity components, involved both sexes, were written in English, and used body mass index (BMI) as an outcome.Results. The database search produced 8,866 titles from which 78 were deemed relevant and assessed for inclusion resulting in 15 studies meeting all inclusion criteria. From these 15 studies, 9 yielded a reduction or stabilisation in BMI or BMIz-score in the entire intervention group and/or subgroups. Programmes lasting between 6 and 12 months that involve multiple environmental, educational, and physical strategies appear to be most likely to result in BMI or BMIz-score improvement. Moderators most likely influencing an improvement in BMI included increased physical activity, decreased sugar sweetened beverages intake, and increased fruit intake.Conclusions. School-based interventions may be an effective means for child obesity prevention. The identification of consistent elements used in school-based interventions that have demonstrated effectiveness may aid in preventing child obesity.
On the Limit Cycles for Continuous and Discontinuous Cubic Differential Systems
Authors: Jiang Ziguo
Published: September 2016

We study the number of limit cycles for the quadratic polynomial differential systemsx˙=-y+x2,y˙=x+xyhaving an isochronous center with continuous and discontinuous cubic polynomial perturbations. Using the averaging theory of first order, we obtain that 3 limit cycles bifurcate from the periodic orbits of the isochronous center with continuous perturbations and at least 7 limit cycles bifurcate from the periodic orbits of the isochronous center with discontinuous perturbations. Moreover, this work shows that the discontinuous systems have at least 4 more limit cycles surrounding the origin than the continuous ones.
Optimality Conditions for Nondifferentiable Multiobjective Semi-Infinite Programming Problems
Authors: Barilla D. , Caristi G. , Puglisi A.
Published: September 2016

We have considered a multiobjective semi-infinite programming problem with a feasible set defined by inequality constraints. First we studied a Fritz-John type necessary condition. Then, we introduced two constraint qualifications and derive the weak and strong Karush-Kuhn-Tucker (KKT in brief) types necessary conditions for an efficient solution of the considered problem. Finally an extension of a Caristi-Ferrara-Stefanescu result for the (Φ,ρ)-invexity is proved, and some sufficient conditions are presented under this weak assumption. All results are given in terms of Clark subdifferential.
Real‐Time Analysis of Endogenous Wnt Signalling in 3D Mesenchymal Stromal Cells
Authors: Saleh Fatima , Carstairs Alice , Etheridge S. Leah , Genever Paul
Published: September 2016

Wnt signalling has been implicated in the regulation of stem cell self‐renewal and differentiation; however, the majority of in vitro studies are carried out using monolayer 2D culture techniques. Here, we used mesenchymal stromal cell (MSC) EGFP reporter lines responsive to Wnt pathway activation in a 3D spheroid culture system to mimic better the in vivo environment. Endogenous Wnt signalling was then investigated under basal conditions and when MSCs were induced to undergo osteogenic and adipogenic differentiation. Interestingly, endogenous Wnt signalling was only active during 3D differentiation whereas 2D cultures showed no EGFP expression throughout an extended differentiation time‐course. Furthermore, exogenous Wnt signalling in 3D adipogenic conditions inhibited differentiation compared to unstimulated controls. In addition, suppressing Wnt signalling by Dkk‐1 restored and facilitated adipogenic differentiation in MSC spheroids. Our findings indicate that endogenous Wnt signalling is active and can be tracked in 3D MSC cultures where it may act as a molecular switch in adipogenesis. The identification of the signalling pathways that regulate MSCs in a 3D in vivo‐like environment will advance our understanding of the molecular mechanisms that control MSC fate.
Capitalizing Resolving Power of Density Gradient Ultracentrifugation by Freezing and Precisely Slicing Centrifuged Solution: Enabling Identification of Complex Proteins from Mitochondria by Matrix Assisted Laser Desorption/Ionization Time-of-Flight Mass Spectrometry
Authors: Yu Haiqing , Lu Joann J. , Rao Wei , Liu Shaorong
Published: September 2016

Density gradient centrifugation is widely utilized for various high purity sample preparations, and density gradient ultracentrifugation (DGU) is often used for more resolution-demanding purification of organelles and protein complexes. Accurately locating different isopycnic layers and precisely extracting solutions from these layers play a critical role in achieving high-resolution DGU separations. In this technique note, we develop a DGU procedure by freezing the solution rapidly (but gently) after centrifugation to fix the resolved layers and by slicing the frozen solution to fractionate the sample. Because the thickness of each slice can be controlled to be as thin as 10 micrometers, we retain virtually all the resolution produced by DGU. To demonstrate the effectiveness of this method, we fractionate complex V from HeLa mitochondria using a conventional technique and this freezing-slicing (F-S) method. The comparison indicates that our F-S method can reduce complex V layer thicknesses by ~40%. After fractionation, we analyze complex V proteins directly on a matrix assisted laser desorption/ionization, time-of-flight mass spectrometer. Twelve out of fifteen subunits of complex V are positively identified. Our method provides a practical protocol to identify proteins from complexes, which is useful to investigate biomolecular complexes and pathways in various conditions and cell types.
Natural Language Processing Based Instrument for Classification of Free Text Medical Records
Authors: Khachidze Manana , Tsintsadze Magda , Archuadze Maia
Published: September 2016

According to the Ministry of Labor, Health and Social Affairs of Georgia a new health management system has to be introduced in the nearest future. In this context arises the problem of structuring and classifying documents containing all the history of medical services provided. The present work introduces the instrument for classification of medical records based on the Georgian language. It is the first attempt of such classification of the Georgian language based medical records. On the whole 24.855 examination records have been studied. The documents were classified into three main groups (ultrasonography, endoscopy, and X-ray) and 13 subgroups using two well-known methods: Support Vector Machine (SVM) andK-Nearest Neighbor (KNN). The results obtained demonstrated that both machine learning methods performed successfully, with a little supremacy of SVM. In the process of classification a “shrink” method, based on features selection, was introduced and applied. At the first stage of classification the results of the “shrink” case were better; however, on the second stage of classification into subclasses 23% of all documents could not be linked to only one definite individual subclass (liver or binary system) due to common features characterizing these subclasses. The overall results of the study were successful.
Synthesis, Structural Elucidation, and Antibacterial Evaluation of Some New Molecules Derived from Coumarin, 1,3,4-Oxadiazole, and Acetamide
Authors: Rasool Shahid , Aziz-ur-Rehman  , Abbasi Muhammad Athar , Siddiqui Sabahat Zahra , Shah Syed Adnan Ali , Hassan Sidra , Ahmad Irshad
Published: September 2016

Because of the reported biological activities of coumarin, 1,3,4-oxadiazole, and acetamides, some new compounds incorporating these moieties were synthesized and evaluated for their biological potential against Gram-positive and Gram-negative bacteria. In the present work, 4-chlororesorcinol (1) and ethyl acetoacetate (2) were mixed in a strong acidic medium to synthesize 6-chloro-7-hydroxy-4-methyl-2-oxo-2H-chromene (3) which was subjected to the intermolecular cyclization after consecutive three steps to synthesize 5-[(6-chloro-4-methyl-2-oxo-2H-chromen-7-yl)oxy]methyl-1,3,4-oxadiazol-2-thiol (6). A series of acetamoyl electrophiles, 8a–o, were synthesized from aralkyl/alkyl/aryl amines, 7a–o, in an aqueous basic medium. The final compounds, 9a–o, were synthesized by the reaction of compounds 6 and 8a–o in DMF/NaH. The synthesized compounds were structurally elucidated by spectral data analysis of IR, 1H-NMR, and EIMS. The most of the synthesized compounds remained moderate to excellent antibacterial agents. The molecules, 9e, 9j, and 9k, were the most efficient ones against all the five bacterial strains taken into account.
Properties of Flavonoids Isolated from the Bark of Eysenhardtia polystachya and Their Effect on Oxidative Stress in Streptozotocin‐Induced Diabetes Mellitus in Mice
Authors: Perez-Gutierrez Rosa Martha , Garcia-Campoy Abraham Heriberto , Muñiz-Ramirez Alethia
Published: September 2016

Six new flavonoids 2′,4′‐dihydroxychalcone‐6′‐O‐β‐d‐glucopyranoside (1), α,3,2′,4′‐tetrahydroxy‐4‐methoxy‐dihydrochalcone‐3′‐C‐β‐glucopyranosy‐6′‐O‐β‐d‐glucopyranoside (2), 7‐hydroxy‐5,8′‐dimethoxy‐6′α‐l‐rhamnopyranosyl‐8‐(3‐phenyl‐trans‐acryloyl)‐1‐benzopyran‐2‐one (3), 6′7‐dihydroxy‐5,8‐dimethoxy‐8(3‐phenyl‐trans‐acryloyl)‐1‐benzopyran‐2‐one (4), 9‐hydroxy‐3,8‐dimethoxy‐4‐prenylpterocarpan (5), and α,4,4′‐trihydroxydihydrochalcone‐2′‐O‐β‐d‐glucopyranoside (6) were isolated from bark of Eysenhardtia polystachya. Antidiabetic activity of compounds 1–5 in terms of their cellular antioxidant and free radical scavenging and also in streptozotocin‐ (STZ‐) induced diabetic mice was evaluated on liver transaminases, lipid peroxidation, total bilirubin, total protein, superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (CSH‐Px), and glutathione reductase (GSH). Results indicated that 1–5 scavenged 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH), hydroxyl ( ∙OH), nitric oxide radicals (NO∙), superoxide anion radical (), radical cation (ABTS∙+), and hydrogen peroxide (H2O2) radical, and protection against H2O2 induced BSA damage was also observed. Furthermore, 1–5 showed ability to decrease the oxidative stress in H9c2 cell. Diabetic mice present high levels of lipid peroxide, total protein, SGPT, SGOT, ALP, and TB. However, treatment of STZ‐induced diabetes in mice with 1–5 reduced levels of these enzymes leading to protector effect of liver. In addition, with treatment with 1–5, increases in radical scavenging enzymes of CSH‐Px, SOD, GSH, and CAT have also been observed in diabetic mice. The antioxidant properties of compounds 1–5 are a promising strategy for ameliorating therapeutic effects by avoiding disorders in the normal redox reactions in healthy cells which consequently could alleviate complications of diabetes.
Physicochemical Characterization of Alginate Beads Containing Sugars and Biopolymers
Authors: Aguirre Calvo Tatiana , Santagapita Patricio
Published: September 2016

Alginate hydrogels are suitable for the encapsulation of a great variety of biomolecules. Several alternatives to the conventional alginate formulation are being studied for a broad range of biotechnological applications; among them the addition of sugars and biopolymers arises as a good and economic strategy. Sugars (trehalose and β-cyclodextrin), a cationic biopolymer (chitosan), an anionic biopolymer (pectin), and neutral gums (Arabic, guar, espina corona, and vinal gums) provided different characteristics to the beads. Here we discuss the influence of beads composition on several physicochemical properties, such as size and shape, analyzed through digital image analysis besides both water content and activity. The results showed that the addition of a second biopolymer, β-CD, or trehalose provoked more compact beads, but the fact that they were compact not necessarily implies a concomitant increase in their circularity. Espina corona beads showed the highest circularity value, being useful for applications which require a controlled and high circularity, assuring quality control. Beads with trehalose showed lower water content than the rest of the system, followed by those containing galactomannans (espina corona, vinal, and guar gums), revealing polymer structure effects. A complete characterization of the beads was performed by FT-IR, assigning the characteristics bands to each individual component.
Lie Subalgebras of the Matrix Quantum Pseudodifferential Operators
Authors: Batistelli Karina , Boyallian Carina
Published: September 2016

We give a complete description of the anti-involutions that preserve the principal gradation of the algebra of matrix quantum pseudodifferential operators and we describe the Lie subalgebras of their minus fixed points.
Molecular Identification and Traceability of Illegal Trading inLignobrycon myersi(Teleostei: Characiformes), a Threatened Brazilian Fish Species, Using DNA Barcode
Authors: Rodrigues Alexandre dos Santos , Brandão José Henrique Souza Galdino , Bitencourt Jamille de Araújo , Jucá-Chagas Ricardo , Sampaio Iracilda , Schneider Horácio , Affonso Paulo Roberto Antunes de Mello
Published: September 2016

Lignobrycon myersiis a threatened freshwater fish species and endemic of a few coastal rivers in northeastern Brazil. Even though the Brazilian laws prohibit the fisheries of threatened species,L. myersiis occasionally found in street markets, being highly appreciated by local population. In order to provide a reliable DNA barcode dataset forL. myersi, we compared mitochondrial sequences of cytochrome c oxidase subunit I (COI) from fresh, frozen, and salt-preserved specimens. Phylogenetically related species (Triportheusspp.) and other fish species (Astyanax fasciatus) commonly mixed withL. myersiin street markets were also included to test the efficiency of molecular identification. In spite of the differences in conservation processes and advanced deterioration of some commercial samples, high-quality COI sequences were obtained and effective in discriminatingL. myersispecimens. In addition, while populations from Contas and Almada River basins seem to comprise a single evolutionary lineage, the specimens from Cachoeira River were genetically differentiated, indicating population structuring. Therefore, DNA barcoding has proved to be useful to trace the illegal trading ofL. myersiand to manage threatened populations, which should focus on conservation of distinct genetic stocks and mitigation on human impacts along their range.
A Small-Molecule Antagonist of HIF2α Is Efficacious in Preclinical Models of Renal Cell Carcinoma
Authors: Wallace Eli M. , Rizzi James P. , Han Guangzhou , Wehn Paul M. , Cao Zhaodan , Du Xinlin , Cheng Tzuling , Czerwinski Robert M. , Dixon Darryl D. , Goggin Barry S. , Grina Jonas A. , Halfmann Megan M. , Maddie Melissa A. , Olive Sarah R. , Schlachter Stephen T. , Tan Huiling , Wang Bin , Wang Keshi , Xie Shanhai , Xu Rui , Yang Hanbiao , Josey John A.
Published: September 2016

More than 90% of clear cell renal cell carcinomas (ccRCC) exhibit inactivation of the von Hippel–Lindau (pVHL) tumor suppressor, establishing it as the major underlying cause of this malignancy. pVHL inactivation results in stabilization of the hypoxia-inducible transcription factors, HIF1α and HIF2α, leading to expression of a genetic program essential for the initiation and progression of ccRCC. Herein, we describe the potent, selective, and orally active small-molecule inhibitor PT2385 as a specific antagonist of HIF2α that allosterically blocks its dimerization with the HIF1α/2α transcriptional dimerization partner ARNT/HIF1β. PT2385 inhibited the expression of HIF2α-dependent genes, including VEGF-A, PAI-1, and cyclin D1 in ccRCC cell lines and tumor xenografts. Treatment of tumor-bearing mice with PT2385 caused dramatic tumor regressions, validating HIF2α as a pivotal oncogenic driver in ccRCC. Notably, unlike other anticancer agents that inhibit VEGF receptor signaling, PT2385 exhibited no adverse effect on cardiovascular performance. Thus, PT2385 represents a novel class of therapeutics for the treatment of RCC with potent preclincal efficacy as well as improved tolerability relative to current agents that target the VEGF pathway. Cancer Res; 76(18); 5491–500. ©2016 AACR.
Cytidine Deaminase Deficiency Reveals New Therapeutic Opportunities against Cancer
Authors: Mameri Hamza , Bièche Ivan , Meseure Didier , Marangoni Elisabetta , Buhagiar-Labarchède Géraldine , Nicolas André , Vacher Sophie , Onclercq-Delic Rosine , Rajapakse Vinodh , Varma Sudhir , Reinhold William C. , Pommier Yves , Amor-Guéret Mounira
Published: September 2016

Purpose: One of the main challenges in cancer therapy is the identification of molecular mechanisms mediating resistance or sensitivity to treatment. Cytidine deaminase (CDA) was reported to be downregulated in cells derived from patients with Bloom syndrome, a genetic disease associated with a strong predisposition to a wide range of cancers. The purpose of this study was to determine whether CDA deficiency could be associated with tumors from the general population and could constitute a predictive marker of susceptibility to antitumor drugs.

Experimental Design: We analyzed CDA expression in silico, in large datasets for cancer cell lines and tumors and in various cancer cell lines and primary tumor tissues using IHC, PDXs, qRT-PCR, and Western blotting. We also studied the mechanism underlying CDA silencing and searched for molecules that might target specifically CDA-deficient tumor cells using in silico analysis coupled to classical cellular experimental approaches.

Results: We found that CDA expression is downregulated in about 60% of cancer cells and tissues. We demonstrate that DNA methylation is a prevalent mechanism of CDA silencing in tumors. Finally, we show that CDA-deficient tumor cells can be specifically targeted with epigenetic treatments and with the anticancer drug aminoflavone.

Conclusions: CDA expression status identifies new subgroups of cancers, and CDA deficiency appears to be a novel and relevant predictive marker of susceptibility to antitumor drugs, opening up new possibilities for treating cancer. Clin Cancer Res; 23(8); 2116–26. ©2016 AACR.
Phase I Study of the Anti-CD22 Antibody–Drug Conjugate Pinatuzumab Vedotin with/without Rituximab in Patients with Relapsed/Refractory B-cell Non-Hodgkin Lymphoma
Authors: Advani Ranjana H. , Lebovic Daniel , Chen Andy , Brunvand Mark , Goy Andre , Chang Julie E. , Hochberg Ephraim , Yalamanchili Sreeni , Kahn Robert , Lu Dan , Agarwal Priya , Dere Randall C. , Hsieh Hsin-Ju , Jones Surai , Chu Yu-Waye , Cheson Bruce D.
Published: September 2016

Purpose: Pinatuzumab vedotin is an antibody–drug conjugate with the potent antimicrotubule agent monomethyl auristatin E (MMAE) conjugated to an anti-CD22 antibody via a protease-cleavable linker. This phase I study determined its recommended phase II dose (RP2D) and evaluated its safety, tolerability, and antitumor activity alone and with rituximab in relapsed/refractory (r/r) non-Hodgkin lymphoma (NHL) and chronic lymphocytic leukemia (CLL).

Experimental Design: Patients received escalating doses of pinatuzumab vedotin every 21 days. Clinical activity at the RP2D alone or with rituximab was evaluated in r/r diffuse large B-cell lymphoma (DLBCL) and r/r indolent NHL (iNHL) patients.

Results: Seventy-five patients received single-agent pinatuzumab vedotin. The RP2D was 2.4 mg/kg, based on dose-limiting toxicities (DLT) of grade 4 neutropenia >7 days in 1 of 3 patients and grade 4 neutropenia <7 days in 2 of 3 patients treated at 3.2 mg/kg (maximum assessed dose). No DLTs occurred at 2.4 mg/kg. At the RP2D, neutropenia was the most common grade ≥3 adverse event. Peripheral neuropathy–related grade ≥2 adverse events most frequently resulted in treatment discontinuation. Rituximab cotreatment did not impact safety, tolerability, or pharmacokinetics of pinatuzumab vedotin. Unconjugated MMAE exposure was much lower than antibody-conjugated MMAE exposure, without accumulation with repeat dosing. At the RP2D, objective responses were observed in DLBCL (9/25) and iNHL (7/14) patients; 2 of 8 patients treated with pinatuzumab vedotin (RP2D) and rituximab had complete responses. CLL patients showed no objective responses.

Conclusions: The RP2D of pinatuzumab vedotin alone and with rituximab was 2.4 mg/kg, which was well tolerated, with encouraging clinical activity in r/r NHL. Clin Cancer Res; 23(5); 1167–76. ©2016 AACR.
Detection of Therapeutically Targetable Driver and Resistance Mutations in Lung Cancer Patients by Next-Generation Sequencing of Cell-Free Circulating Tumor DNA
Authors: Thompson Jeffrey C. , Yee Stephanie S. , Troxel Andrea B. , Savitch Samantha L. , Fan Ryan , Balli David , Lieberman David B. , Morrissette Jennifer D. , Evans Tracey L. , Bauml Joshua , Aggarwal Charu , Kosteva John A. , Alley Evan , Ciunci Christine , Cohen Roger B. , Bagley Stephen , Stonehouse-Lee Susan , Sherry Victoria E. , Gilbert Elizabeth , Langer Corey , Vachani Anil , Carpenter Erica L.
Published: September 2016

Purpose: The expanding number of targeted therapeutics for non–small cell lung cancer (NSCLC) necessitates real-time tumor genotyping, yet tissue biopsies are difficult to perform serially and often yield inadequate DNA for next-generation sequencing (NGS). We evaluated the feasibility of using cell-free circulating tumor DNA (ctDNA) NGS as a complement or alternative to tissue NGS.

Experimental Design: A total of 112 plasma samples obtained from a consecutive study of 102 prospectively enrolled patients with advanced NSCLC were subjected to ultra-deep sequencing of up to 70 genes and matched with tissue samples, when possible.

Results: We detected 275 alterations in 45 genes, and at least one alteration in the ctDNA for 86 of 102 patients (84%), with EGFR variants being most common. ctDNA NGS detected 50 driver and 12 resistance mutations, and mutations in 22 additional genes for which experimental therapies, including clinical trials, are available. Although ctDNA NGS was completed for 102 consecutive patients, tissue sequencing was only successful for 50 patients (49%). Actionable EGFR mutations were detected in 24 tissue and 19 ctDNA samples, yielding concordance of 79%, with a shorter time interval between tissue and blood collection associated with increased concordance (P = 0.038). ctDNA sequencing identified eight patients harboring a resistance mutation who developed progressive disease while on targeted therapy, and for whom tissue sequencing was not possible.

Conclusions: Therapeutically targetable driver and resistance mutations can be detected by ctDNA NGS, even when tissue is unavailable, thus allowing more accurate diagnosis, improved patient management, and serial sampling to monitor disease progression and clonal evolution. Clin Cancer Res; 22(23); 5772–82. ©2016 AACR.
High-Risk Premenopausal Luminal A Breast Cancer Patients Derive no Benefit from Adjuvant Cyclophosphamide-based Chemotherapy: Results from the DBCG77B Clinical Trial
Authors: Nielsen Torsten O. , Jensen Maj-Brit , Burugu Samantha , Gao Dongxia , Jørgensen Charlotte L. Tykjaer , Balslev Eva , Ejlertsen Bent
Published: September 2016

Purpose: Luminal A breast cancers have better prognosis than other molecular subtypes. Luminal A cancers may also be insensitive to adjuvant chemotherapy, although there is little high-level evidence to confirm this concept. The primary hypothesis in this formal prospective–retrospective analysis was to assess interaction between subtype (Luminal A vs. other) and treatment (chemotherapy vs. not) for the primary endpoint (10-year invasive disease-free survival) of a breast cancer trial randomizing women to adjuvant chemotherapy, analyzed in multivariate Cox proportional hazards models using the Wald interaction test.

Experimental Design: The Danish Breast Cancer Cooperative Group 77B clinical trial randomized 1,072 premenopausal women to no systematic treatment (control), levamisole, cyclophosphamide, or cyclophosphamide–methotrexate–fluorouracil arms. All arms included radiotherapy but no endocrine therapy. Researchers with no access to clinical data performed intrinsic subtype analysis on tissue microarrays using published immunohistochemical methods based on estrogen receptor, progesterone receptor, HER2, Ki67, and basal markers.

Results: Patients (n = 709) had tissue available; chemotherapy benefit in these patients was similar to the original trial (HR, 0.56). Immunohistochemistry classified 165 as Luminal A, 319 Luminal B, 58 HER2-enriched, and 82 core basal (among 91 triple-negative). Patients with Luminal A breast tumors did not benefit from chemotherapy [HR, 1.06; 95% confidence interval (CI), 0.53–2.14; P = 0.86], whereas patients with non–luminal A subtypes did (HR, 0.50; 95% CI, 0.38-0.66; P < 0.001; Pinteraction = 0.048).

Conclusions: In a prospective–retrospective analysis of a randomized trial, patients with Luminal A breast cancers did not benefit from adjuvant cyclophosphamide-based chemotherapy. Clin Cancer Res; 23(4); 946–53. ©2016 AACR.
Who's Eligible Anyway? Risk Modeling for Clinical Trial Accrual
Authors: Mileham Kathryn F. , Kim Edward S.
Published: September 2016

Accrual continues to be a challenge for oncology clinical trials. Interventions to enhance accrual after study activation exist, including corrective action plans for NCI-sponsored trials. Clinical trials would benefit from a proactive approach rather than a reactive approach. Accrual strategy planning early in trial development is suggested. Clin Cancer Res; 22(22); 5397–9. ©2016 AACR.

See related article by Massett et al., p. 5408
Selumetinib Attenuates Skeletal Muscle Wasting in Murine Cachexia Model through ERK Inhibition and AKT Activation
Authors: Quan-Jun Yang , Yan Huo , Yong-Long Han , Li-Li Wan , Jie Li , Jin-Lu Huang , Jin Lu , Peng-Guo Chen , Run Gan , Cheng Guo
Published: September 2016

Cancer cachexia is a multifactorial syndrome affecting the skeletal muscle. Previous clinical trials showed that treatment with MEK inhibitor selumetinib resulted in skeletal muscle anabolism. However, it is conflicting that MAPK/ERK pathway controls the mass of the skeletal muscle. The current study investigated the therapeutic effect and mechanisms of selumetinib in amelioration of cancer cachexia. The classical cancer cachexia model was established via transplantation of CT26 colon adenocarcinoma cells into BALB/c mice. The effect of selumetinib on body weight, tumor growth, skeletal muscle, food intake, serum proinflammatory cytokines, E3 ligases, and MEK/ERK–related pathways was analyzed. Two independent experiments showed that 30 mg/kg/d selumetinib prevented the loss of body weight in murine cachexia mice. Muscle wasting was attenuated and the expression of E3 ligases, MuRF1 and Fbx32, was inhibited following selumetinib treatment of the gastrocnemius muscle. Furthermore, selumetinib efficiently reduced tumor burden without influencing the cancer cell proliferation, cumulative food intake, and serum cytokines. These results indicated that the role of selumetinib in attenuating muscle wasting was independent of cancer burden. Detailed analysis of the mechanism revealed AKT and mTOR were activated, while ERK, FoxO3a, and GSK3β were inhibited in the selumetinib -treated cachexia group. These indicated that selumetinib effectively prevented skeletal muscle wasting in cancer cachexia model through ERK inhibition and AKT activation in gastrocnemius muscle via cross-inhibition. The study not only elucidated the mechanism of MEK/ERK inhibition in skeletal muscle anabolism, but also validated selumetinib therapy as an effective intervention against cancer cachexia. Mol Cancer Ther; 16(2); 334–43. ©2016 AACR.
Novel Blood Biomarkers Are Associated with White Matter Lesions in Fragile X- Associated Tremor/Ataxia Syndrome
Authors: Loesch Danuta Z. , Annesley Sarah J. , Trost Nicholas , Bui Minh Q. , Lay Sui T. , Storey Elsdon , De Piazza Shawn W. , Sanislav Oana , Francione Lisa M. , Hammersley Eleanor M. , Tassone Flora , Francis David , Fisher Paul R.
Published: September 2016

Background: The need for accessible cellular biomarkers of neurodegeneration in carriers of the fragile X mental retardation 1 (FMR1) premutation (PM) alleles. Objective: To assess the mitochondrial status and respiration in blood lymphoblasts from PM carriers manifesting the fragile X-associated tremor/ataxia syndrome (FXTAS) and non-FXTAS carriers, and their relationship with the brain white matter lesions. Methods: Oxygen consumption rates (OCR) and ATP synthesis using a Seahorse XFe24 Extracellular Flux Analyser, and steady-state parameters of mitochondrial function were assessed in cultured lymphoblasts from 16 PM males (including 11 FXTAS patients) and 9 matched controls. The regional white matter hyperintensity (WMH) scores were obtained from MRI. Results: Mitochondrial respiratory activity was significantly elevated in lymphoblasts from PM carriers compared with controls, with a 2- to 3-fold increase in basal and maximum OCR attributable to complex I activity, and ATP synthesis, accompanied by unaltered mitochondrial mass and membrane potential. The changes, which were more advanced in FXTAS patients, were significantly associated with the WMH scores in the supratentorial regions. Conclusion: The dramatic increase in mitochondrial activity in lymphoblasts from PM carriers may represent either the early stages of disease (specific alterations in short-lived blood cells) or an activation of the lymphocytes under pathological situations. These changes may provide early, convenient blood biomarkers of clinical involvements.
Sensitivity of the GEPARD Patient Questionnaire to Identify Psoriatic Arthritis in Patients with Psoriasis in Daily Practice: The GEPARD-Life Study
Authors: Härle Peter , Letschert Katrin , Wittig Bianca , Mrowietz Ulrich
Published: September 2016

Early detection of psoriatic arthritis (PsA) remains a challenge in clinical practice. Tools such as the German Psoriasis Arthritis Diagnostic (GEPARD) questionnaire have been developed for this purpose. The aim of this study was to determine the performance of the GEPARD questionnaire in the detection of PsA in psoriasis patients following rheumatology evaluation in daily clinical practice in Germany. This was a multicenter study involving 59 dermatology units (university/general hospital/office based), and the GEPARD questionnaire was distributed to psoriasis patients. Patients who had a sum score of ≥4 positive answers were referred to a rheumatologist for evaluation of PsA. We recruited 1,512 patients, of whom approximately 50% were referred. One third of the referred patients were classified as having PsA after rheumatological assessment. Rates of PsA in university/general hospital settings were higher than those observed in a doctor's office-based setting (43.7 vs. 25.8%). The GEPARD questionnaire demonstrated easy screening of psoriasis patients for PsA.
FK506 Binding Protein 10 Is Overexpressed and Promotes Renal Cell Carcinoma
Authors: Ge Yukun , Xu Abai , Zhang Meng , Xiong Hu , Fang Lu , Zhang Xiaolong , Liu Chunxiao , Wu Song
Published: September 2016

Introduction: FK506 binding proteins (FKBPs) function as oncogenes or tumor suppressors by interacting with steroid hormone receptors, kinases, or other cellular factors in addition to intracellular ligands FK506 and rapamycin. In this study, we aimed at evaluating the expression and function of FKBPs in renal cell carcinoma (RCC). Materials and Methods: Thirty-four RCC specimens were analyzed by whole transcriptome sequencing. Small interfere RNA was employed to knockdown FKBP10 in 786-O and A-704 cells, and cell proliferation, cell cycle progression, invasion and migration were evaluated. Results: FKBP10 was different from other members of FKBPs with most significant upregulation in almost all RCC specimens, compared to normal mucosa. FKBP10 expression was high in additional 38 RCC specimens and RCC cell lines compared to paired non-tumor tissues and normal renal tubule cells. FKBP10 knockdown led to cell cycle arrest at G0/G1 phase, and reduced cell proliferation, invasion, and migration in 786-O and A-704 cells. In addition, heat shock protein 90 was significantly downregulated after FKBP10 knockdown. Conclusions: FKBP10 is overexpressed and promotes RCC and is a new promising biomarker and therapy target for RCC.
rAed a 4: A New 67-kDa Aedes aegypti Mosquito Salivary Allergen for the Diagnosis of Mosquito Allergy
Authors: Peng Zhikang , Caihe Li , Beckett Andrew N. , Guan Qingdong , James Anthony A. , Simons F. Estelle R.
Published: September 2016

Background: Accurate diagnosis of mosquito allergy has been hampered by the laborious task of obtaining mosquito salivary allergens. We have previously studied 3 recombinant (r) Aedes aegypti mosquito salivary allergens: rAed a 1, rAed a 2 and rAed a 3. Here, we report the expression, purification, identification and evaluation of rAed a 4, a 67-kDa α-glucosidase. Methods: rAed a 4 was expressed using a baculovirus/insect cell system, purified by a combination of anion- and cation-exchange chromatography, and identified by immunoblotting. A. aegypti saliva extract was prepared in our laboratory. An indirect enzyme-linked immunosorbent assay (ELISA) was developed to measure rAed a 4-specific immunoglobulin E (IgE) and IgG antibodies in sera from 13 individuals with a positive mosquito-bite test from a laboratory-reared mosquito. Sera from 18 individuals with a negative bite test served as controls. Results: Purified rAed a 4 bound to the IgE in mosquito-allergic sera, as detected by ELISA and immunoblotting. The binding of rAed a 4 to IgE could be inhibited in a dose-dependent manner by the addition of an A. aegypti extract. Mosquito-allergic individuals had significantly higher mean levels of rAed a 4-specific IgE and IgG than controls. Using the mean of the controls ± 2 SD as a cut-off level, 46% of the 13 allergic individuals had a positive IgE, while none of the controls was positive (p < 0.001). Conclusions: Aed a 4 is a major allergen in mosquito saliva. Its recombinant form has the hydrolase function and can be used for the diagnosis of mosquito allergy.
Lipoic Acid in the Prevention of Acute Kidney Injury
Authors: Zhang Jun , McCullough Peter A.
Published: September 2016

Hypoxia, reactive oxygen species (ROS) and oxidative stress contribute to contrast-induced acute kidney injury (CI-AKI) and ischemic reperfusion injury (IRI) in the kidney and heart. Imbalance between the increased formation of ROS by hypoxia in the cardiac and renal tissue and the low availability of endogenous antioxidants is a common cause of cellular and tissue damage. Therefore, a strategy to inhibit ROS generation or to scavenger free radicals becomes an important intervention to prevent CI-AKI and myocardial IRI. Evidence has shown that a naturally occurring cellular antioxidant lipoic acid (LA) (1,2-dithilane-3-pentanoic acid) acts as a free radical scavenger of ROS and reactive nitrogen oxide species for cardioprotection and renoprotection. The mechanisms whereby LA exerts its protective effects are not entirely understood, but may be related to the phosphatidylinositol 3-kinase/Akt/Nrf2 pathway and the PI3-kinase/Akt pathways. This review will provide the current information of LA as an exogenous antioxidant for cardioprotection and renoprotection, with emphasis on antioxidant functions of LA and multiple signaling pathways underlying protective effects of LA on CI-AKI as well as cardiac and renal IRI.